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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.

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.

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.

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.

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.

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.

Fuchs Endothelial Corneal Dystrophy (FECD) is a late onset, autosomal dominant eye disease that can lead to loss of vision. Expansion of a CTG trinucleotide repeat in the third intron of the transcription factor 4 (TCF4) gene is highly associated with FECD. However, only about 75% of FECD patients in the northern European population possess an expansion of this repeat. The remaining FECD cases appear to be associated with variants in other genes. To better understand the pathophysiology of this disease, we compared gene expression profiles of corneal endothelium from FECD patients with an expanded trinucleotide repeat (RE+) to those that do not have a repeat expansion (RE-). Comparative analysis of these two cohorts showed widespread RNA mis-splicing in RE+, but not in RE- samples. Quantitatively, we identified 39 genes in which expression was significantly different between RE+ and RE- samples. Examination of the mutation profiles in the RE- samples did not find any mutations in genes previously associated with FECD, but did reveal one sample with a rare variant of laminin subunit gamma 1 (LAMC1) and three samples with rare variants in the gene coding for the mitochondrial protein peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1).

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 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.

The single nucleotide variant (SNV), rs613872, in the transcription factor 4 (TCF4) gene was previously found to be strongly associated (P = 6 × 10(-26)) with Fuchs' endothelial corneal dystrophy (FECD). Subsequently, an intronic expansion of the repeating trinucleotides, TGC, was found to be even more predictive of disease. We performed comprehensive sequencing of the TCF4 gene region in order to identify the best marker for FECD within TCF4 and to identify other novel variants that may be associated with FECD.Leukocyte DNA was isolated from 68 subjects with FECD and 16 unaffected individuals. A custom capture panel was used to isolate the region surrounding the two previously validated markers of FECD. Sequencing of the TCF4 coding region, introns and flanking sequence, spanning 465 kb was performed at1000× average coverage using the Illumina HiSequation 2000.TGC expansion (50 repeats) was present in 46 (68%) FECD-affected subjects and one (6%) normal subject. A total of 1866 variants, including 1540 SNVs, were identified. Only two previously reported SNVs resided in the TCF4 coding region, neither of which segregated with disease. No variant, including TGC expansion, correlated perfectly with disease status. Trinucleotide repeat expansion was a better predictor of disease than any other variant.Complete sequencing of the TCF4 genomic region revealed no single causative variant for FECD. The intronic trinucleotide repeat expansion within TCF4 continues to be more strongly associated with FECD than any other genetic variant.

PURPOSE: To estimate the cumulative probability of Nd:YAG laser posterior capsulotomy after cataract extraction in a geographically defined population. METHODS: Rochester Epidemiology Project databases were used to identify retrospectively all Nd:YAG laser posterior capsulotomies performed on Olmsted County, Minnesota, residents who had previously undergone cataract extraction between 1988 and 1996, inclusive. Demographic data and potential risk factors for laser, including age, sex, surgical technique, year of surgery, and intraocular lens material, were obtained by chart review or by retrieval from computer databases. The cumulative probability of Nd:YAG laser posterior capsulotomy was calculated by Kaplan-Meier estimates, and risk factors were analyzed using the Cox proportional hazards model. RESULTS: A total of 925 Nd:YAG laser posterior capsulotomies were identified after 3541 cataract extractions in 2718 patients. The cumulative probability of Nd:YAG laser posterior capsulotomy after cataract surgery was 6% (95% confidence interval = 5% to 7%) at 1 year, increasing to 38% (35% to 40%) at 9 years. Young age at the time of surgery (P = .02), polymethylmethacrylate intraocular lens material (P < .001), earlier year of surgery (P < .001), and extracapsular extraction (in comparison with phacoemulsification, P < .001) were found to increase significantly the risk of subsequent Nd:YAG laser posterior capsulotomy. Woman tended to have a greater probability of Nd:YAG laser posterior capsulotomy (P = .17), but this difference was not statistically significant. CONCLUSIONS: Nd:YAG laser posterior capsulotomy was common after cataract surgery but infrequent during the first postoperative year. Prolonged follow-up is necessary in investigations of the effects of new cataract surgery technologies on the probability of capsulotomy.

PURPOSE: To describe the clinical appearance of factitious (or self-inflicted) lesions on periocular skin and face. METHODS: All patients with factitious cutaneous disease who were examined at Mayo Clinic, Rochester, Minnesota, between 1985 and 1997 were identified. For patients with lesions on the face and periocular skin, the demographic features, clinical descriptive characteristics of their lesions, associated psychopathology, and treatments were ascertained. RESULTS: Of 38 patients with factitious dermatitis, 18 (47%) had facial lesions. Of these 18 patients, 15 (83%) were female. The mean age (± SD) of the patients with facial lesions was 35.2 ± 15.7 years (range, 9 to 66 years). Eight patients (44%) had neurotic excoriations, nine (50%) had dermatitis artefacta, and one (6%) had trichotillomania. The working diagnoses of five patients cared for initially in the Department of Ophthalmology were corneal epithelial and facial desquamation associated with severe pain of unknown cause, medial cicatricial ectropion of probable vasculitic cause, basal cell carcinoma of the nasojugal fold, recurrent preseptal cellulitis resistant to medical treatment, and madarosis of the upper eyelids of unknown cause. CONCLUSION: Cutaneous factitious disease may masquerade as numerous clinical entities and should be included in the differential diagnosis of lesions of the periocular skin.

Objective To estimate the incidence of rhegmatogenous retinal detachment (RD) in a geographically defined population and to compare the probability of RD in residents after cataract extraction with the probability of RD in residents who did not have cataract extraction. Design Rochester Epidemiology Project databases were used to perform a retrospective population-based incidence study of RD diagnosed between 1976 and 1995 with cohort analyses of the influence of risk factors on the occurrence of RD. Participants The population of Olmsted County, Minnesota, participated. Main outcome measure Incidence rates of RD adjusted to the age and gender distribution of the 1990 U.S. white population were measured. Results Three hundred eleven incident cases of rhegmatogenous RD were identified. The mean annual age- and gender-adjusted incidence rate of rhegmatogenous RD was 17.9 per 100,000 persons (95% confidence interval [CI], 15.9–19.9). For idiopathic rhegmatogenous RD alone, the mean annual age- and gender-adjusted incidence rate was 12.6 (95% CI, 10.9–14.3) per 100,000 persons. Ten years after phacoemulsification and extracapsular cataract extraction, the estimated cumulative probability of RD was 5.5 (95% CI, 3.4–7.6) times as high as would have been expected in a similar group of county residents not undergoing cataract surgery. Conclusions Cataract surgery is associated with a significantly elevated long-term cumulative probability of retinal detachment.

Purpose To investigate the effects of phacoemulsification in glaucomatous eyes with functioning Baerveldt tube shunts. Setting Department of Ophthalmology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. Methods This retrospective analysis followed 9 eyes of 8 patients with functioning Baerveldt tube shunts who had clear corneal phacoemulsification. Intraocular pressure (IOP), number of glaucoma medications, corneal thickness, visual acuity, and additional glaucoma surgery were measured. Results The mean follow-up was 21 months ± 3 (SD) (range 17 to 25 months). The mean change in IOP and the number of glaucoma medications used did not significantly change at 1 month (P>.19), 1 year (P>.17), or the last follow-up (P>.17). At the last examination, 2 eyes had IOP increases of 2 to 4 mm Hg, 3 eyes had no change, and 4 eyes had decreases of 4 to 7 mm Hg. Intraocular pressure increased in 1 eye at 8 months and required a tube shunt revision. No eye developed corneal decompensation. Visual acuity improved in 8 eyes; the mean improvement was 4 ± 3 Snellen lines. Conclusion In most cases, phacoemulsification in glaucomatous eyes with a functioning Baerveldt tube shunt improved vision and maintained control of IOP.

Corneas with advanced Fuchs' endothelial dystrophy that require endothelial keratoplasty manifest anterior corneal structural and cellular abnormalities that have been associated with visual deficits before and after endothelial keratoplasty. In this study, we determined the onset of these abnormalities in the course of the disease.Cross-sectional study.Sixty-three eyes (39 subjects) with a range of severity of Fuchs' dystrophy and 25 eyes (13 subjects) with normal corneas.All corneas were examined using slit-lamp biomicroscopy, ultrasonic pachymetry, and confocal microscopy. The clinical grade of Fuchs' dystrophy was assessed according to the presence and extent of guttae and clinically evident edema and was categorized as mild (grades 1 and 2), moderate (grades 3 and 4), or advanced (grades 5 and 6). Normal corneas were devoid of any central guttae (grade 0). Corneal backscatter (haze) was measured from the confocal image light intensity profile. Stromal cell density and number and the presence of abnormal subepithelial cells were determined from confocal images. Comparisons between groups were made by using generalized estimating equation models.Anterior corneal backscatter, stromal cell density and number, presence of subepithelial cells, and central corneal thickness.Anterior corneal backscatter was 18% to 67% higher in eyes with moderate and advanced Fuchs' dystrophy compared with normal eyes (P ≤ 0.003); a similar trend was noted in mild Fuchs' dystrophy eyes compared with normal eyes (P = 0.08). Stromal cell density and the absolute number of stromal cells in the anterior 10% of the stroma were approximately 20% and 27% lower, respectively, in Fuchs' dystrophy (regardless of severity) compared with normal (P0.001). Abnormal subepithelial cells were visible in 9%, 19%, and 30% of corneas with mild, moderate, and advanced Fuchs' dystrophy, respectively. Only corneas with advanced Fuchs' dystrophy were thicker than normal (P0.001).Anterior corneal cellular and structural abnormalities begin early in the course of Fuchs' dystrophy, before the onset of clinically evident edema. The chronicity of these changes can explain their incomplete resolution after endothelial keratoplasty, and understanding the onset of these may help to determine the optimal time to intervene to achieve best outcomes.

Fuchs endothelial corneal dystrophy (FECD) is a common, familial disease of the corneal endothelium and is the leading indication for corneal transplantation. Variation in the transcription factor 4 (TCF4) gene has been identified as a major contributor to the disease. We tested for an association between an intronic TGC trinucleotide repeat in TCF4 and FECD by determining repeat length in 66 affected participants with severe FECD and 63 participants with normal corneas in a 3-stage discovery/replication/validation study. PCR primers flanking the TGC repeat were used to amplify leukocyte-derived genomic DNA. Repeat length was determined by direct sequencing, short tandem repeat (STR) assay and Southern blotting. Genomic Southern blots were used to evaluate samples for which only a single allele was identified by STR analysis. Compiling data for 3 arms of the study, a TGC repeat length >50 was present in 79% of FECD cases and in 3% of normal controls cases (p50 TGC repeats, 13 (20%) had 50 repeats, 60 (95%) had 50 TGC repeats identifying FECD in this patient cohort was 79% and 96%, respectively Expanded TGC repeat was more specific for FECD cases than the previously identified, highly associated, single nucleotide polymorphism, rs613872 (specificity = 79%). The TGC trinucleotide repeat expansion in TCF4 is strongly associated with FECD, and a repeat length >50 is highly specific for the disease This association suggests that trinucleotide expansion may play a pathogenic role in the majority of FECD cases and is a predictor of disease risk.

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.Cross-sectional study.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.Corneas with Fuchs' dystrophy were graded by 2 corneal specialists based on the confluence and area of guttae and the presence or absence of edema. Central corneal thickness (CCT) and peripheral corneal thickness at 4 mm from the center (PCT4) were measured by using scanning-slit pachymetry. The value of CPTR4 was the quotient of CCT and PCT4.Interobserver agreement for clinical grade and CPTR4.Interobserver agreement for clinical grading of Fuchs' dystrophy was moderate (κ = 0.32; 95% confidence interval, 0.19-0.45). In normal corneas, CCT was not correlated with age (r = -0.10; P = 0.28; n = 267), PCT4 decreased with age (r = -0.33; P0.001; n = 254), and CPTR4 increased with age (r = 0.59; P0.001; n = 254). Central corneal thickness was higher in Fuchs' dystrophy (652 ± 61 μm; n = 118) than in normal corneas (559 ± 31 μm; n = 267; P0.001). Also, PCT4 was higher in Fuchs' dystrophy (650 ± 51 μm; n = 107) than in normal corneas (643 ± 43 μm; n = 254; P0.001 after adjusting thickness for age). Furthermore, CPTR4 was higher in advanced Fuchs' dystrophy (1.03 ± 0.07; n = 65) than in mild and moderate Fuchs' dystrophy (0.95 ± 0.07; n = 42; age-adjusted P0.001), which in turn was higher than in normal corneas (0.87 ± 0.05; n = 254; age-adjusted P0.001). Finally, CPTR4 was highly correlated with clinical grade of Fuchs' dystrophy (r = 0.77; P0.001; n = 361), was repeatable (median coefficient of variation, 1.3%), and provided excellent discrimination between Fuchs' dystrophy and normal corneas (area under the receiver operator characteristic curve, 0.93).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.

To quantify corneal light scatter and its relationship to vision after Descemet stripping with endothelial keratoplasty (DSEK).Eyes with Fuchs corneal dystrophy were examined before and 1, 3, 6, 12, and 24 months after DSEK. Outcome measures were high- and low-contrast visual acuity, contrast sensitivity, and forward light scatter. Corneal reflectivity (backscatter), expressed in scatter units (SU), was quantified using in vivo confocal microscopy.Comparing 49 study eyes with 35 normal eyes, the mean (SD) corneal subepithelial layer was more reflective than normal before (2325 [613] vs 1208 [287] SU, P.001) and through 24 months after DSEK (1760 [432] SU, P.001). Interface reflectivity remained higher than in normal stroma through 24 months (1228 [287] vs 827 [188] SU, P.001). At 1 year, forward light scatter correlated with subepithelial reflectivity (r=0.28, P=.01) but not interface reflectivity. Recipient age was correlated with improvement in subepithelial reflectivity at 12 months (r=–0.41, P=.01, 34 eyes) and 24 months (r=–0.36, P=.02, 26 eyes) after DSEK, and the improvement of subepithelial haze in eyes of participants aged 62 years or younger was correlated with improvement in forward light scatter at 12 months (r=0.52, P=.008) and 24 months (r=0.62, P=.004).In Fuchs corneal dystrophy, the corneal subepithelial region is a more important source of forward light scatter than the DSEK interface. Subepithelial haze improves more in younger patients and is associated with improvement in forward light scatter.Visual function after DSEK is affected by residual haze in the anterior host cornea more so than the surgical interface. Haze, which likely is experienced as glare disability, improves after surgical intervention but improves more in younger patients.

Purpose To determine the change in anterior corneal high-order aberrations (HOAs) after Descemet's stripping endothelial keratoplasty (DSEK) for Fuchs' dystrophy, and to compare the HOAs with those of age-matched controls. Design Prospective cohort and cross-sectional study. Participants and Controls Forty-eight eyes with Fuchs' dystrophy were examined before and after DSEK, and were compared with 52 eyes of age-matched controls with normal corneas. Methods Corneas of patients with Fuchs' dystrophy were examined prospectively before and at intervals through 2 years after DSEK. Wavefront errors from the anterior corneal surface were derived from corneal topograms and were expressed as Zernike polynomials through the sixth order. Best-corrected visual acuity (BCVA) was measured by the electronic Early Treatment of Diabetic Retinopathy Study protocol, and subepithelial haze was measured from the brightness of confocal images. Total HOAs were compared before and after DSEK, and with those of age-matched controls, by using generalized estimating equation models. Relationships between HOAs, BCVA, subepithelial haze, and recipient age were determined. Main Outcome Measures Anterior corneal HOAs, BCVA, and subepithelial haze (backscattered light). Results In Fuchs' dystrophy before DSEK, total HOAs (4 mm optical zone) from the anterior corneal surface (0.29±0.13 μm) were higher than those of controls (0.17±0.08 μm; P P = 0.99), and remained higher than in controls ( P r = 0.59; P r = 0.41; P = 0.01; n=25), and with recipient age ( r = 0.59; P Conclusions Anterior corneal HOAs are higher in Fuchs' dystrophy than in controls, and remain higher through 2 years after DSEK. The aberrated anterior surface might be related to anterior corneal ultrastructural changes and haze formation in Fuchs' dystrophy, and should not be ignored as a source of decreased visual acuity after DSEK. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.

To determine whole-eye high-order aberrations (HOAs) in pseudophakic eyes after Descemet stripping endothelial keratoplasty (DSEK) for Fuchs dystrophy, and to establish relationships between graft thickness, HOAs, and visual acuity.Cross-sectional study.Whole-eye HOAs were measured in pseudophakic eyes at intervals through 24 months after DSEK, and in otherwise healthy pseudophakic control eyes implanted with the same type of spherical intraocular lens. Wavefront errors were assessed by a Hartmann-Shack aberrometer over a 4-mm-diameter optical zone. In DSEK eyes, central graft thickness and stromal graft folds were measured using confocal microscopy in vivo, and best-corrected visual acuity (BCVA) was determined by the electronic Early Treatment of Diabetic Retinopathy Study method.Total HOAs at 24 months after DSEK (0.28 ± 0.11 μm, mean ± SD, n = 17) were higher than those in pseudophakic controls (0.16 ± 0.07 μm, n = 25, P.001); specifically, trefoil and quadrafoil were higher after DSEK. At 24 months, total HOAs (r = 0.69, P.001) and graft folds (r = 0.41, P = .02) were correlated with central graft thickness, and BCVA was correlated with total HOAs (r = 0.39, P = .01) but not with graft thickness (r = -0.24, P = .20, n = 27).Whole-eye HOAs are higher after DSEK compared to untreated corneas. Thicker grafts are associated with increased HOAs and more graft folds, suggesting that the donor lenticule contributes, in part, to the wavefront errors. Although BCVA is weakly related to total HOAs after DSEK, it is not related to graft thickness.

To determine relationships between vision, forward scatter, and total corneal and graft thicknesses after Descemet stripping endothelial keratoplasty (DSEK).Prospective, cohort study.Forty-four eyes with Fuchs endothelial dystrophy were examined before and at 1, 3, 6, and 12 months after DSEK; all eyes were pseudophakic after surgery. Central total corneal and graft thicknesses were measured using confocal microscopy. Best-corrected high-contrast visual acuity (BCVA) was measured using the electronic Early Treatment Diabetic Retinopathy Study protocol, and forward light scatter was measured using a straylight meter.Total corneal thickness was 610 ± 50 μm (mean ± standard deviation) before DSEK, increased to 680 ± 74 μm by 1 month after DSEK (P.001), and stabilized at 660 ± 68 μm by 3 months after DSEK (P = .03 vs 1 month). Graft thickness was 170 ± 57 μm at 1 month, decreased to 157 ± 49 μm by 3 months (P = .004), and then remained stable through 12 months (156 ± 51 μm; P = .99 vs 3 months). BCVA was 0.44 ± 0.21 logarithm of the minimal angle of resolution (logMAR) units (Snellen equivalent, 20/55) before DSEK, improved to 0.26 ± 0.20 logMAR units (Snellen equivalent, 20/36) by 3 months (P.001), and improved to 0.16 ± 0.16 logMAR units (Snellen equivalent, 20/29) at 12 months (P.001 vs 3 months). BCVA and forward light scatter did not correlate with corneal or graft thickness after DSEK.Stromal edema resolves by 3 months after DSEK for Fuchs dystrophy, whereas visual acuity continues to improve through 12 months. Thicker corneas and grafts are not associated with worse visual acuity or increased forward scatter.

Activation of the alternative pathway of complement is implicated in common neurodegenerative diseases including age-related macular degeneration (AMD). We explored the impact of common variation in genes encoding proteins of the alternative pathway on complement activation in human blood and in AMD. Genetic variation across the genes encoding complement factor H (CFH), factor B (CFB) and component 3 (C3) was determined. The influence of common haplotypes defining transcriptional and translational units on complement activation in blood was determined in a quantitative genomic association study. Individual haplotypes in CFH and CFB were associated with distinct and novel effects on plasma levels of precursors, regulators and activation products of the alternative pathway of complement in human blood. Further, genetic variation in CFH thought to influence cell surface regulation of complement did not alter plasma complement levels in human blood. Plasma markers of chronic activation (split-products Ba and C3d) and an activating enzyme (factor D) were elevated in AMD subjects. Most of the elevation in AMD was accounted for by the genetic variation controlling complement activation in human blood. Activation of the alternative pathway of complement in blood is under genetic control and increases with age. The genetic variation associated with increased activation of complement in human blood also increased the risk of AMD. Our data are consistent with a disease model in which genetic variation in the complement system increases the risk of AMD by a combination of systemic complement activation and abnormal regulation of complement activation in local tissues.

To report a case of delayed bilateral Descemet's detachment with spontaneous resolution in one eye following successful treatment of the fellow eye.Case report.A 78-year-old male who underwent uncomplicated bilateral cataract extraction with phacoemulsification developed delayed bilateral Descemet's membrane detachments. One eye was successfully treated with pneumatic descemetopexy. After appropriate positioning for the surgical eye, the fellow eye simultaneously and spontaneously resolved.Spontaneous resolution of delayed Descemet's membrane detachments can occur. We suggest a mechanism for spontaneous resolution that may have implications for nonsurgical treatment.

OBJECTIVE To establish an association between corneal light scatter and vision after Descemet stripping with endothelial keratoplasty (DSEK). METHODS Twenty eyes of patients with Fuchs endothelial dystrophy were examined before and at 1, 3, and 6 months after DSEK in a prospective study. Main outcome measures were high-contrast best-corrected visual acuity, intraocular forward light scatter, and corneal backscatter. RESULTS One eye was excluded because of endothelial graft failure within 1 month. Best-corrected visual acuity improved at 3 months after DSEK (mean [standard deviation], 0.31 [0.20] logarithm of the minimum angle of resolution [logMAR]; Snellen equivalent, 20/41) relative to before DSEK (0.46 [0.26] logMAR; Snellen equivalent, 20/58; P = .03). Posterior corneal backscatter decreased 1 month after DSEK (P < .001), but backscatter from the anterior, middle, and posterior cornea did not return to normal by 6 months (P < or = .02). At 6 months, best-corrected visual acuity correlated with recipient age (r = 0.84, P < .001) and with intraocular forward light scatter (r = 0.67, P < .001); forward light scatter also correlated with recipient age (r = 0.67, P < .001). CONCLUSIONS Six months after DSEK, corneal light scatter remained greater in eyes with Fuchs endothelial dystrophy than in normal eyes and correlated with recipient age and visual acuity. Recipient age might be the best preoperative predictor of vision after DSEK.

To evaluate high-order aberrations (HOA) induced by the anterior corneal surface after deep lamellar endothelial keratoplasty (DLEK) and penetrating keratoplasty (PK).Prospective, randomized clinical trial.Twenty-eight eyes of 25 patients with corneal edema resulting from Fuchs dystrophy underwent DLEK with a 9- to 10-mm incision (n = 13) or PK with double-running sutures (n = 15) at the Cornea Service, Mayo Clinic Department of Ophthalmology, Rochester, Minnesota. The main outcome measures were HOA from the anterior corneal surface calculated from corneal topography and decomposed into Zernike polynomials to the sixth order, high- and low-contrast visual acuity (VA), and contrast sensitivity. Variables after surgery were compared with those before surgery and between treatments by using generalized estimating equation models with Bonferroni adjustment.Total HOA through 24 months (0.48 +/- 0.15 microm) after DLEK was similar to total aberration before surgery (0.44 +/- 0.23 microm; P = .10). After PK, total HOA remained elevated through 24 months (1.68 +/- 0.58 microm) compared with that before surgery (0.49 +/- 0.27 microm; P.005) and compared with that after DLEK (P.006). At 24 months after PK, corneas with sutures removed had greater total HOAs than corneas with sutures intact (1.90 +/- 0.52 microm vs 1.18 +/- 0.33 microm; P = .001). High- and low-contrast VA and contrast sensitivity at 24 months after PK did not correlate with any HOA.HOAs from the anterior corneal surface were higher after PK compared with after DLEK but did not correlate with visual function after PK.

To compare vision, intraocular forward light scatter and corneal backscatter between deep lamellar endothelial keratoplasty (DLEK) and penetrating keratoplasty (PK) for endothelial dysfunction.A randomized clinical trial.Thirteen eyes (12 patients) were randomized to DLEK with a 9 mm scleral incision, and 15 eyes (14 patients) were randomized to PK. The primary outcome was high-contrast best spectacle-corrected visual acuity (BSCVA) at 12 months after surgery; intraocular forward light scatter and corneal backscatter were measured at one, three, six, and 12 months after surgery.BSCVA at 12 months was 0.34 +/- 0.16 logMAR (logarithm of the minimum angle of resolution) for DLEK and 0.25 +/- 0.21 logMAR for PK (P = .23; minimum detectable difference at 12 months was 0.23 logMAR). The change in postoperative forward light scatter after DLEK correlated with the change in BSCVA (r = -0.66; P.001; n = 11). Corneal backscatter was higher after DLEK than after PK at three and six months in the anterior third (Por = .005), at one through 12 months in the middle third (P.001), and at one through six months in the posterior third (Por = .02) of the cornea. Backscatter after DLEK did not return to normal through 12 months (P.001).BSCVA was similar at one year after DLEK and PK. Improvement in BSCVA after DLEK correlated with decreasing forward light scatter. Increased backscatter after DLEK originated not only from the posterior cornea (interface) but also from the host cornea, which might limit visual outcomes after posterior lamellar keratoplasty.

To evaluate the toxicity of 1 mg of intraocular rituximab and to present a small case-series of patients treated with intravitreal rituximab. Rituximab (1 mg/0.1 ml) was injected in the vitreous of one eye of three Dutch-belted rabbits. Two animals were injected with balanced salt solution as controls. At 1 month the rabbits were killed and the eyes examined by light microscopy. Three patients (five eyes) with intraocular lymphoma were also treated with a 1 mg injection of rituximab. The treated rabbit eyes and the control eyes showed no light microscopic evidence of ocular toxicity at 1 month following injection. The five human eyes of three patients have shown no evidence of intraocular toxicity with a median follow-up time of 3.6 months (range 2.0–6.4 months). One patient received a total of four injections in the right eye and three injections in the left eye. Intravitreal rituximab at a dose of 1 mg does not appear to cause toxicity in rabbit eyes and in the five eyes of three patients.

PURPOSE The purpose of this study was to evaluate the association between the intronic expansion of a trinucleotide repeat (TNR) in the TCF4 gene and Fuchs' endothelial corneal dystrophy (FECD) in a Japanese population. METHODS Forty-seven Japanese FECD patients and 96 age-matched controls were recruited. FECD patients and controls were examined by slit-lamp and noncontact specular microscopy. The repeat length was determined by direct sequencing and short tandem repeat assay of PCR-amplified DNA and Southern blotting of unamplified DNA. RESULTS A TNR expansion, defined as >50 CTG repeats in the TCF4 gene was identified in 12 of 47 FECD cases (26%) and 0 of 96 controls (0%; P < 0.001). Sensitivity and specificity in this study were 26% and 100%, respectively. The clinical characteristics of FECD patients with TNR expansion were not distinct from those without TNR expansion. CONCLUSIONS These findings show for the first time in a Japanese population the association of the TNR expansion in TCF4 with FECD. In contrast to Caucasian cohorts in whom the TNR expansion is present in most patients with FECD, a CTG expansion is present in a minority of Japanese subjects, indicating other genetic variants as common causes of phenotypically identical disease in this population.

To estimate the long-term cumulative risk of retinal detachment (RD) after cataract extraction (CE).Retrospective cohort study and nested case-control study.All residents of Olmsted County, Minnesota who had CE from 1980 through 2004 (10 256 CEs in 7137 residents) and were diagnosed subsequently with RD in the same period. Two controls chosen from the primary cataract surgery cohort were matched to each RD case by age, gender, and duration of follow-up.Cases were identified through the Rochester Epidemiology Project databases. Records were reviewed to confirm case status and ascertain risk factor information. The observed probability of RD after CE was estimated using the Kaplan-Meier method. A cumulative probability ratio of RD after CE was determined by comparing the observed probability of RD and the expected probability of RD in residents without CE. Logistic regression models assessed differences between cases and controls.Probability of and risk factors associated with RD after CE.Eighty-two cases of RD were identified. The cumulative probability of RD increased in a nearly linear manner over the 25-year study period. At 1, 5, 10, 15, and 20 years after extracapsular CE (ECCE) and phacoemulsification, cumulative probabilities of RD were 0.27%, 0.71%, 1.23%, 1.58%, and 1.79%, respectively. There was no significant difference in the probability of RD after ECCE when compared with phacoemulsification (P = 0.13). The cumulative probability ratio of RD at 20 years after ECCE and phacoemulsification remained 4.0-fold (95% confidence interval, 2.6-5.4) higher than would be expected in a similar group of residents not undergoing CE (P0.001). Male gender, younger age, myopia, increased axial length, and posterior capsular tear were associated significantly with RD (P0.01).The cumulative risk of RD after ECCE and phacoemulsification is increased for up to 20 years after surgery.

Purpose. To compare the histopathology of three PMMA collar button type keratoprosthesis (KPro)/corneal specimens, explanted due to various complications, with that from one KPro/corneal specimen taken postmortem from an otherwise “healthy” enucleated eye. Methods. Patient 1 (chemical injury) had no problems for 3 years after KPro placement; the entire eye was obtained postmortem. Patient 2 (repeated graft failures, nonautoimmune disease) developed an “unlaserable” retroprosthesis membrane 4 months after KPro placement. A new KPro was placed. Patient 3 [ocular cicatricial pemphigoid (OCP)] developed tissue melt at the KPro–cornea interface 7 months after KPro placement, and the KPro was replaced. Patient 4 (OCP) developed progressive corneal melt around the KPro 3.5 years after placement resulting in replacement. All KPro/cornea specimens were processed and sectioned for histology with the KPro in place. Results. All patients exhibited growth of corneal or conjunctival derived epithelium under the KPro front plate. In patients 1 and 2, no epithelial downgrowth was noted and the keratocyte density appeared normal with few inflammatory cells present. Dense fibrous tissue was present behind the KPro in patient 2. Patients 3 and 4 showed massive inflammatory cell infiltration and tissue necrosis with “melt” adjacent to the stem resulting in epithelial downgrowth. Conclusions. Corneal inflammation and degradation after KPro placement correlate well with the preoperative diagnostic category. Patients with immune-related corneal surface disease can exhibit marked inflammatory responses leading to necrosis, stromal melting, and the formation of an epithelial fistula. In contrast, patients without autoimmune corneal disease demonstrate a remarkably noninflamed cornea with intact keratocytes and without epithelial ingrowth, commensurate with their clinical appearance.

Purpose To report two cases of spontaneous, late-onset haptic disinsertion from a three-piece posterior chamber intraocular lens (IOL). Design Interventional case reports. Methods Two eyes of two patients had uncomplicated phacoemulsification and presented 16 and 20 years after surgery with spontaneous, nontraumatic haptic disinsertion from a three-piece IOL. Results In one case, the disinserted haptic dislocated into the anterior chamber while the IOL optic-single haptic complex remained centered and supported within the capsular bag. Cystoid macular edema was present, but resolved after removal of the disinserted haptic. In the second case, the disinserted haptic remained within the capsular bag while the IOL optic dislocated into the anterior chamber. Removal of the IOL and exchange with a sulcus-fixated single piece IOL was required. Conclusions Nontraumatic haptic disinsertion from a three-piece IOL is a rare long-term complication after phacoemulsification.

Objective: To analyze population-based trends in cataract extraction. Design: Rochester Epidemiology Project databases, which capture virtually all health care services provided to residents of Olmsted County, Minnesota, were used to perform retrospective cohort analyses of rates of primary cataract extractions performed between 1980 and 1994. Participants: The population of Olmsted County, Minnesota. Main Outcome Measures: Incidence rates adjusted to the age and sex distribution of the 1990 US white population were analyzed using Poisson regression. Results: The 4257 procedures performed on 3176 patients of all ages represented overall annual age-adjusted rates of 404 procedures per 100 000 females and 320 per 100 000 males. Annual age- and sex-adjusted rates for both sexes combined rose from 133 procedures per 100 000 in 1980 to a peak of 507 per 100 000 in 1992. The rates fell to 470 per 100 000 in 1994. Manual review of a random sample of records estimated case overascertainment at 0.9%. Conclusions: With the exception of 1988 and 1989, rates of cataract surgery in this geographically circumscribed population increased every year between 1980 and 1992. Data from 1993-1994 indicate that rates may have plateaued and possibly declined slightly. If sustained, these patterns could have major implications for future utilization of ophthalmologic resources.

Objective: To evaluate the corneal endothelial morphometric measures of the contralateral, clinically uninvolved eye of patients with the iridocorneal endothelial (ICE) syndrome. Design: A retrospective review of the specular microscopic photographs of the contralateral corneal endothelium of all patients with ICE syndrome seen at Mayo Clinic, Rochester, Minn. Setting: Ophthalmology department, Mayo Clinic. Participants: Twenty-eight patients with unilateral ICE syndrome who had bilateral endothelial photographs (ICE group) and 28 normal, age-matched control subjects (control group). Main Outcome Measures: Percentage of hexagonal cells, coefficient of variation of cell area, and endothelial cell density. Methods: For each patient and control, 100 endothelial cells were digitized from projected endothelial photomicrographs of the central corneas in the uninvolved eyes. Results: A statistically significant decrease was noted in the mean percentage of hexagonal cells (ICE, 62%; control, 69%; P =.002), and an increase was noted in the mean coefficient of variation of cell area (ICE, 0.28; control, 0.25; P =.02) in the patients with ICE syndrome compared with normal, age-matched controls. The mean endothelial cell density did not differ significantly between the 2 groups (ICE, 2588; control, 2759; P =.10). Conclusion: Our data suggest that the clinically uninvolved, contralateral eyes in patients with ICE syndrome have subclinical endothelial abnormalities as evidenced by a relatively low percentage of hexagonal cells and a relatively high coefficient of variation of cell area.

Objectives To provide an estimate of the incidence of herpes simplex virus (HSV) eye disease in a community-based cohort, and to investigate the effect of prophylactic oral antiviral therapy on HSV recurrences and outcomes. Methods All Olmsted County, Minnesota, residents diagnosed with ocular HSV from 1976 through 2007 were retrospectively reviewed. The frequency of recurrences and adverse outcomes, such as vision loss or need for surgery, were compared between untreated patients and those treated prophylactically with oral antiviral medication. Results Three hundred ninety-four patients with ocular HSV were identified, yielding an annual incidence of 11.8 per 100 000 people (95% confidence interval [CI], 10.6-13.0). No trends in incidence or adverse outcomes were identified during the 32-year period. Oral antiviral therapy was prescribed in 175 patients. Patients were 9.4 times more likely (95% CI, 5.0-17.9) to have a recurrence of epithelial keratitis, 8.4 times more likely (95% CI, 5.2-13.7) to have a recurrence of stromal keratitis, and 34.5 times more likely (95% CI, 10.8-111.1) to have a recurrence of blepharitis or conjunctivitis if not being treated prophylactically at the time of the recurrence. Twenty patients experienced adverse outcomes, and 17 (85%) were not being treated with oral antiviral medications immediately preceding the adverse event. Conclusions Oral antiviral prophylaxis was associated with a decreased risk of recurrence of epithelial keratitis, stromal keratitis, conjunctivitis, and blepharitis due to HSV. Patients with adverse outcomes due to ocular HSV were usually not being treated with oral antiviral prophylaxis.

PURPOSE. To develop an assay for determining the number of copies of the genes encoding complement factor H related 3 (CFHR3) and 1 (CFHR1) and determine the contribution of copy number variation (CNV) at CFHR3 and CFHR1 to the development of age-related macular degeneration (AMD). METHODS. A multiplex ligation-dependent probe amplification (MLPA) assay was developed to quantify the number of copies of CFHR3 and CFHRI in humans. Subjects with (n = 252) and without (n = 249) AMD were genotyped using the assay, and the impact on AMD risk was evaluated. RESULTS. The MLPA assay provided a consistent estimate of the number of copies of CFHR3 and CFHRI in 500 of the 501 samples. Four different combinations of CNVs were observed with frequencies as follows: both CFHR3 and CFHRI deletion (14%), CFHR3-only deletion (0.4%), CFHR1-only deletion (1.1%), and CFHRI duplication (0.1%). Deletion of both copies of CFHR3 and CFHR1 decreased the odds of having AMD eightfold (95% CI 2-36) and always occurred on a protective haplotype, never on the risk haplotype tagged by the Y402H risk allele in CFH. The protection conferred by deletion of CFHR3 and CPHR1 could not be distinguished from the absence of the risk haplotype. CONCLUSIONS. Both deletions and duplications of genes in the regulation of complement activation locus segregated in Caucasians. Deletion of CFHR3 and CFHR1 protected against the development of AMD at least in part because the deletion tagged a protective haplotype and did not occur on the risk haplotype.

Purpose To evaluate the outcomes of simple mechanical debridement for the management of anterior basement membrane dystrophy (ABMD) in a cohort of patients treated primarily for visual symptoms. Design Retrospective, observational case series. Methods setting: Single center. study population: Seventy-four eyes of 55 patients treated with mechanical epithelial debridement over a 15-year period. observation procedures: We recorded symptoms, pre- and postoperative best-corrected visual acuity (BCVA), surgical technique, complications, and evidence of disease recurrence. main outcome measures: Mean best-corrected logMAR acuity and refractive errors, compared by using paired t tests or Wilcoxon signed-rank tests. Interval to recurrence of ABMD was determined by using Kaplan-Meier estimates. Results Mean patient age was 74 years, and 80% were female. Visual difficulty was reported by the patient before the procedure in 61 eyes (82%), and erosion symptoms alone were noted before the procedure in the remaining 13 eyes. Mean BCVA improved from 20/44 before surgery to 20/30 (P = .0001) at the early follow-up visit and 20/33 (P = .0001) at the last follow-up (mean = 33 months). The mean refractive spherical equivalent changed –0.6 diopters (range, –4.75 to +2.0 diopters). No infections or persistent epithelial defects occurred. The most common postoperative complication was subepithelial haze, occurring in 19 eyes (26%). The five-year cumulative probability of recurrence of ABMD was 44.7%. Conclusions Our results with this simple technique are comparable to outcomes reported with other procedures used to treat ABMD. We recommend manual debridement as an effective option for ABMD affecting visual acuity.