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Purpose: The purpose of this study was to investigate the associations between visual function and severity grading, corneal scatter, or higher-order aberrations (HOAs) in patients with Fuchs endothelial corneal dystrophy (FECD)., Methods: This observational case series study included 49 eyes of 27 patients with FECD and 10 eyes of 10 healthy individuals. We evaluated corrected distance visual acuity (CDVA) using Landolt-C and Early Treatment Diabetic Retinopathy Study charts and contrast sensitivity using the CSV-1000E chart and CSV-1000RN letter chart. We analyzed the associations between visual function and explanatory variables, including age, modified Krachmer grade, central corneal thickness (CCT), anterior segment optical coherence tomography (AS-OCT)-based grade, HOAs, intraocular straylight, and corneal densitometry. We additionally conducted receiver operating characteristic (ROC) analysis to identify the corneal densitometry thresholds for decreased visual function., Results: There were significant associations between visual function and the modified Krachmer grade, CCT, AS-OCT-based grade, HOAs, intraocular straylight, and corneal densitometry. A modified Krachmer grade ≥ 3 was identified as a threshold for decreased visual function. Multivariate analysis showed that corneal densitometry was significantly associated with all visual function parameters, and HOAs were significantly associated with CDVA but not with contrast sensitivity. ROC analysis revealed that corneal densitometry of the posterior layer at 0 to 2 mm ≥ 10 grayscale units (GSU), was identified as a threshold for decreased visual function., Conclusions: HOAs, forward and backward light scatter affected visual function, with backward light scatter being the most influential. In patients with FECD, modified Krachmer grade ≥ 3 and corneal densitometry ≥ 10 GSU were thresholds for visual disturbance.

Mitochondrial function is essential for the viability of aerobic eukaryotic cells, as mitochondria provide energy through the generation of adenosine triphosphate (ATP), regulate cellular metabolism, provide redox balancing, participate in immune signaling, and can initiate apoptosis. Mitochondria are dynamic organelles that participate in a cyclical and ongoing process of regeneration and autophagy (clearance), termed mitophagy specifically for mitochondrial (macro)autophagy. An imbalance in mitochondrial function toward mitochondrial dysfunction can be catastrophic for cells and has been characterized in several common ophthalmic diseases. In this article, we review mitochondrial homeostasis in detail, focusing on the balance of mitochondrial dynamics including the processes of fission and fusion, and provide a description of the mechanisms involved in mitophagy. Furthermore, this article reviews investigations of ocular diseases with impaired mitophagy, including Fuchs endothelial corneal dystrophy, primary open-angle glaucoma, diabetic retinopathy, and age-related macular degeneration, as well as several primary mitochondrial diseases with ocular phenotypes that display impaired mitophagy, including mitochondrial encephalopathy lactic acidosis stroke, Leber hereditary optic neuropathy, and chronic progressive external ophthalmoplegia. The results of various studies using cell culture, animal, and human tissue models are presented and reflect a growing awareness of mitophagy impairment as an important feature of ophthalmic disease pathology. As this review indicates, it is imperative that mitophagy be investigated as a targetable mechanism in developing therapies for ocular diseases characterized by oxidative stress and mitochondrial dysfunction.

Purpose: Fuchs' endothelial corneal dystrophy (FECD), a degenerative disease of the corneal endothelium that leads to vision loss, is a leading cause of corneal transplantation. The cause of this disease is still unknown, but the implication of oxidative stress is strongly suggested. In this study, we analyzed the impact of FECD on mitochondrial DNA (mtDNA) integrity and telomere length, both of which are affected by the oxidative status of the cell., Methods: We compared the levels of total mtDNA, mtDNA common deletion (4977 bp), and relative telomere length in the corneal endothelial cells of fresh Descemet's membrane-endothelium explants and cultured cells from healthy and late stage FECD subjects. Oxidant-antioxidant gene expression and sensitivity to ultraviolet A (UVA)- and H2O2-induced cell death were assessed in cultured cells., Results: Our results revealed increased mtDNA levels and telomere shortening in FECD explants. We also found that cell culture restores a normal phenotype in terms of mtDNA levels, telomere length, oxidant-antioxidant gene expression balance, and sensitivity to oxidative stress-induced cell death in the FECD cells compared with the healthy cells., Conclusions: Taken together, these results bring new evidence of the implication of oxidative stress in FECD. They also show that FECD does not evenly affect the integrity of corneal endothelial cells and that cell culture can rehabilitate the molecular phenotypes related to oxidative stress by selecting the more functional FECD cells.

Purpose: To determine directional changes in peripheral corneal thickness and corneal astigmatism over a range of severity of Fuchs' endothelial corneal dystrophy (FECD)., Methods: Eyes with FECD were categorized as mild, moderate, or advanced according to the area and confluence of guttae and the presence of clinical edema. Normal corneas were devoid of guttae. Peripheral thickness centered on the corneal apex, and radii of posterior curvature were measured with Scheimpflug imaging. Variables were compared between groups by using generalized estimating equation models., Results: Scheimpflug images were acquired in 101 normal corneas and 112 corneas with FECD. Normal corneas were 8.6 ± 4.8 μm thicker vertically than horizontally (P = 0.001); the steep posterior meridian was vertical in 91% of corneas. The difference between vertical and horizontal thicknesses decreased to 4.7 ± 7.3 μm in advanced FECD (P = 0.008); 46% had a steep vertical posterior meridian (P = 0.001). Vertical radius of curvature was flatter than normal in moderate (by 0.2 mm, P = 0.011) and advanced (by 0.4 mm, P < 0.001) FECD. Mean posterior corneal power was less negative in moderate (by 0.2 diopters [D], P = 0.009) and advanced (by 0.4 D, P < 0.001) FECD compared to normal., Conclusions: Posterior toricity is abnormal in advanced FECD because of relatively greater horizontal than vertical corneal thickening. Posterior corneal power decreases (i.e., is less negative) in moderate and advanced FECD, which can affect the choice of intraocular lens power during cataract surgery, and might explain the hyperopic shift after Descemet membrane endothelial keratoplasty.

Purpose: To determine whether people with age-related eye disease have lower cognitive scores than people with healthy vision., Methods: A hospital-based cross-sectional study was performed in which 420 people aged 65 and older from the ophthalmology clinics at Maisonneuve-Rosemont Hospital (Montreal, Canada) were recruited who had age-related macular degeneration (AMD), Fuch's corneal dystrophy, or glaucoma. Patients with AMD and Fuchs had to have visual acuity in the better eye of worse than 20/40 while patients with glaucoma had to have visual field in their worse eye of at least -4 dB. Controls, recruited from the same clinics, did not have significant vision loss. Cognitive status was measured using the Mini-Mental State Exam Blind Version (range, 0-22) which excludes eight items that rely on vision. Linear regression with bootstrapped standard errors was used to adjust for demographic and medical factors., Results: People with AMD, Fuch's corneal dystrophy, and glaucoma had lower cognitive scores, on average, than controls (P < 0.05). These relationships remained statistically significant after adjusting for factors such as age, sex, race, education, living alone, systemic comorbidities, and lens opacity., Conclusions: People with vision loss due to three different age-related eye diseases had lower cognitive scores. Reasons for this should be explored using longitudinal studies and a full battery of cognitive tests that do not rely on vision., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: We evaluated the in vivo functionality of a corneal endothelium tissue-engineered using corneal endothelial cells from human patients with Fuchs endothelial corneal dystrophy (FECD)., Methods: A total of 15 healthy cats underwent full-thickness corneal transplantation. All transplants were of xenogeneic human origin and all grafts but two were tissue-engineered. In seven animals the graft corneal endothelium was tissue-engineered using cultured corneal endothelial cells from humans with FECD (TE-FECD). Two control animals were grafted with an endothelium engineered using cultured endothelial cells from normal eye bank corneas (TE-normal). Two controls received a native full-thickness corneal transplant, and four other controls were grafted with the stromal carrier only (without endothelial cells). Outcome parameters included graft transparency (0, opaque to 4, clear), pachymetry, optical coherence tomography, endothelial cell morphometry, transmission electron microscopy (TEM), and immunostaining of function-related proteins., Results: Seven days after transplantation, 6 of 7 TE-FECD grafts, all TE-normal grafts, and all normal native grafts were clear (transparency score >3), while all carriers-only grafts were opaque (score <1). The mean pachymetry was 772 ± 102 μm for TE-FECD, 524 ± 11 μm for TE-normal, 555 ± 48 for normal native, and 1188 ± 223 μm for carriers only. TEM showed subendothelial loose fibrillar material deposition in all TE-FECD grafts. The TE endothelium expressed Na(+)-K(+)/ATPase and Na(+)/HCO3(-)., Conclusions: Restoration of transparency and corneal thickness demonstrated that the TE-FECD grafts were functional in vivo. This novel FECD seven-day living model suggests a potential role for tissue engineering leading to FECD cell rehabilitation.

Purpose: The purpose of this study is to examine whether patients with age-related eye diseases, like age-related macular degeneration (AMD), glaucoma, or Fuchs corneal dystrophy, are more likely to show signs of depression compared to a control group of older adults with good vision, and to determine whether reduced mobility mediates these relationships., Methods: We recruited 315 eligible patients (81 with AMD, 55 with Fuchs, 91 with glaucoma, and 88 controls) from the ophthalmology clinics of a Montreal hospital from September 2009 until December 2011. Depressive symptoms were assessed using the Geriatric Depression Scale Short Form (GDS-15). Life space was measured using the Life Space Assessment. Logistic regression was used to adjust for demographic, health, and social factors, and mediation was assessed using the methods of Baron and Kenny., Results: There were 78 people (25%) meeting the criteria for depression in the cohort. All three groups with eye disease were more likely to be depressed than the control group after adjusting for age, sex, ethnicity, education, cognitive score, limitations in activities of daily living, social support, and lens opacity (P < 0.05). Life space and limited activities due to a fear of falling appeared to mediate the relationship between eye disease and depression., Conclusions: Visually limiting eye disease is associated with depression in older adults. Further research on interventions to prevent depression in patients with eye disease is warranted and should consider strategies to alleviate mobility limitation. Greater attention from families, physicians, and society to the mental health needs and mobility challenges of patients with eye disease is needed.

Purpose: To examine the extent of mobility limitations in patients with age-related macular degeneration (AMD), glaucoma, or Fuchs' corneal dystrophy compared with that in a control group of older adults with good vision., Methods: Two hundred seventy-two patients (68 with AMD, 49 with Fuchs' dystrophy, 82 with glaucoma, and 73 controls) from the ophthalmology clinics of Maisonneuve-Rosemont Hospital (Montreal, Canada) participated in a cross-sectional study from September 2009 until February 2011. Control patients who had normal visual acuity and visual fields were recruited from the same clinics. Questionnaire (life space, falls, and driving) and performance-based (one-legged balance test, Timed Up and Go [TUG] test) mobility data were collected; visual acuity, contrast sensitivity, and visual field were measured; and the medical record was reviewed., Results: The three eye diseases were associated with different patterns of mobility limitations. Patients with glaucoma had the most types of mobility limitations, as they had reduced life-space scores, had worse TUG scores, were less likely to drive, and were more likely to have poor balance than the control group (P < 0.05). Compared with the controls, patients with AMD and Fuchs' corneal dystrophy had reduced life-space scores and were less likely to drive (P < 0.05)., Conclusions: The results suggest that eye diseases, especially glaucoma, restrain the mobility of older people in many different ways. It is important to further explore the impact of eye disease on mobility in this population, to develop interventions that could help affected older adults maintain their independence.

Purpose: To determine the effect of corneal transplantation for Fuchs' dystrophy and of recipient age on the large- and small-angle domains of the retinal point-spread function., Methods: Retinal stray light (large-angle domain) and the full-width-at-half-maximum intensity of the point-spread function (50% width, small-angle domain) were measured in 40 pseudophakic eyes after keratoplasty (Descemet stripping with endothelial keratoplasty [DSEK], 30 eyes; penetrating keratoplasty [PK], 10 eyes) for Fuchs' dystrophy and in 30 otherwise normal pseudophakic eyes. Correlations were assessed between the optical variables, high-contrast visual acuity (HCVA), and recipient age, and variables were compared between groups by using generalized estimating equation models., Results: The 50% width was higher in pseudophakic eyes after DSEK or PK compared with otherwise normal pseudophakic eyes (P < 0.001) but did not differ between DSEK and PK (P = 0.36). After DSEK, HCVA correlated with the 50% width (r = 0.48, P < 0.001, n = 25) and stray light (r = 0.44, P = 0.01, n = 30), whereas after PK, HCVA correlated with the 50% width (r = 0.77, P = 0.003, n = 10) but not with stray light (r = 0.01, P = 0.98, n = 8). Stray light correlated with recipient age after DSEK (r = 0.67, P < 0.001, n = 30), but not after PK (r = 0.35, P = 0.39, n = 8,), and not with age of otherwise normal pseudophakic eyes (r = 0.32, P = 0.18, n = 29)., Conclusions: The degradation of the small-angle domain of the point-spread function after DSEK suggests that aberrations contribute to decreased visual acuity after DSEK. The poorer optical properties of the eye with older recipient age after DSEK can be attributed to the retained host cornea.

Purpose: To develop a mathematical model that can predict refractive changes after Descemet stripping endothelial keratoplasty (DSEK)., Methods: A mathematical formula based on the Gullstrand eye model was generated to estimate the change in refractive power of the eye after DSEK. This model was applied to four DSEK cases retrospectively, to compare measured and predicted refractive changes after DSEK., Results: The refractive change after DSEK is determined by calculating the difference in the power of the eye before and after DSEK surgery. The power of the eye post-DSEK surgery can be calculated with modified Gullstrand eye model equations that incorporate the change in the posterior radius of curvature and change in the distance between the principal planes of the cornea and lens after DSEK. Analysis of this model suggests that the ratio of central to peripheral graft thickness (CP ratio) and central thickness can have significant effect on refractive change where smaller CP ratios and larger graft thicknesses result in larger hyperopic shifts. This model was applied to four patients, and the average predicted hyperopic shift in the overall power of the eye was calculated to be 0.83 D. This change reflected in a mean of 93% (range, 75%-110%) of patients' measured refractive shifts., Conclusions: This simplified DSEK mathematical model can be used as a first step for estimating the hyperopic shift after DSEK. Further studies are necessary to refine the validity of this model.

Purpose: Fuchs corneal dystrophy (FCD) is a progressive corneal disease marked by the development of guttae, focal excrescences of Descemet's membrane. Retroillumination photography is a useful technique for illuminating the presence of guttae and has been used to document progression of disease. This study was undertaken to quantitatively assess disease progression in a cohort of individuals with late-onset FCD linked to chromosome 13., Methods: Retroillumination photography was performed on 13 related individuals (26 eyes) with the FCD1 disease haplotype at a 30- to 34-month interval. Individual guttae were counted in each image and the distribution recorded. A polar coordinate system was used to delineate regional differences in development of guttae., Results: An increase of 29.1% was found in the total number of guttae over approximately 30 months (mean increase of 669 guttae/eye, P < 0.001) among 26 eyes. A rapid rate of progression begins at approximately age 50, representing an exponential increase (r(2) = 0.60) among individuals mildly affected for decades. Individuals with the disease haplotype but with two affected parents demonstrated an earlier disease onset. A significantly greater proportion of guttae were present in the inferotemporal quadrant of the cornea (P < 0.001), an effect that grew in significance over time., Conclusions: The study demonstrated quantitative progression of FCD with the use of retroillumination photography in an FCD1-linked pedigree. Comparison of severity versus age suggests a rapid increase in the number of guttae at approximately age 50. Individuals with the FCD1 disease haplotype and a second likely genetic lesion exhibit a markedly increased disease severity suggestive of genetic interaction between FCD loci.

Purpose: To investigate the effects of Fuchs' corneal dystrophy (FCD) on corneal biomechanical properties and the results of IOP readings in relation to changes in corneal hysteresis (CH) and central corneal thickness (CCT)., Methods: Corneal biomechanical properties, including CH, corneal resistance factor (CRF), and CCT, were measured with the ocular response analyzer (ORA) in 11 eyes of 11 patients with clinically confirmed FCD and 12 eyes of 12 healthy subjects. The ORA was also used to determine the values of intraocular pressure (IOP(g)) and corneal compensated IOP (IOP(cc)). Goldmann applanation tonometry (GAT) was also measured., Results: CH measured 10.3 +/- 1.6 mm Hg (range, 8.7-13.8) in normal eyes and 6.9 +/- 1.8 mm Hg (range, 4.6-11.7) in FCD eyes (P = 0.001). CRF in the normal and FCD eyes was 10.5 +/- 1.5 mm Hg (range, 8.5-13.3) and 8.1 +/- 1.9 (range, 4.5-11.2), respectively (P = 0.005). CCT was higher in FCD eyes (606 +/- 20 microm; range, 578-635) than in normal eyes (538.4 +/- 24.9 microm; range, 495-575; P = 0.0001). IOP(g) was 16.2 +/- 2.2 mm Hg (range, 13.5-18.7) in control eyes compared with 17.6 +/- 2.7 mm Hg (range, 12.8-18.6) in FCD eyes (P = 0.201). However, IOP(cc) in the FCD group (21.8 +/- 4.6 mm Hg; range, 12.8-29.0) was higher than in the control group (16.5 +/- 3.4 mm Hg; range, 11.9-23.9; P = 0.006). GAT in the normal and FCD eyes was 16.7 +/- 2.1 mm Hg (range, 12.8-18.6) and 16.9 +/- 2.3 mm Hg (range, 13.1-19.0), respectively (P = 0.205)., Conclusions: FCD led to a change of corneal biomechanical properties. CH and CRF were significantly lower in FCD eyes than in normal eyes. IOP(cc) was significantly higher in FCD eyes than in control eyes. These values may be useful in addition to CCT when assessing corneal rigidity. Thus, FCD may cause an underestimation error in IOP measurement.

Measurements of corneal thickness, endothelial cell size, endothelial permeability to fluorescein, and intraocular pressure were made in two groups of human subjects: 21 persons with cornea guttata (early Fuchs dystrophy without epithelial edema) and 17 persons age- and sex-matched but with normal corneas. Statistically significant differences were found between the two groups in all four measured variables. The two groups did not differ with respect to the variability in endothelial cell sizes. There were statistically significant positive correlations between endothelial permeability to fluorescein, endothelial cell size, and corneal thickness. The endothelial pump rate was calculated for each group, and the difference was not statistically significant. Our results suggest that the earliest defect in Fuchs' dystrophy is solely a breakdown in barrier function and thus increased permeability, resulting in a thicker cornea.