Dystrophy Eyes Research Articles

Oxygen exposure in inherited diseases of the retina

AbstractPurposePatients with inherited retinal diseases (IRDs) share altered retinal metabolic function. The aim of our study was to investigate the relationship between retinal metabolic alterations (retinal vessel Oximetry, RO) and structural findings (central retinal thickness and retinal nerve fibre layer thickness, RNFL) in IRDs.MethodsA total of 181 eyes of 92 subjects were examined: 121 eyes of 62 patients with IRDs were compared to 60 eyes of 30 healthy age‐matched controls. The retinal vessel oximetry was performed with the oxygen saturation measurement tool of the Retinal Vessel Analyser (RVA; IMEDOS Systems UG, Jena, Germany). The oxygen saturation in all four major peripapillary retinal arterioles (A‐SO2; %) and venules (V‐SO2; %) were measured and their difference (A‐V SO2; %) was calculated. In addition, we calculated the mean central retinal oxygen exposure (cO2‐E; %/µm) and the mean peripapillary oxygen exposure (pO2‐E; %/µm) per micron of central retinal thickness and nerve fibre layer thickness.ResultsRod‐cone dystrophy patients had the highest V‐SO2 and A‐SO2, the lowest A‐V SO2, the narrower D‐A and D‐V and the thickest RNFL, when compared to controls (p≤0.040), but also to patients with other IRDs. Furthermore, in rod‐cone dystrophies, the cO2‐E and the pO2‐E were higher in comparison to controls and to patients with other IRDs (p≤0.005). Cone‐rod dystrophy patients had the lowest cO2‐E compared to controls and patients with other IRDs (p≤0.035). Evaluated in central zones, the cO2‐E was significantly different when comparing CRD‐ against RCD patients in all zones (p<0.001), whereas against controls and patients with inherited macular dystrophy only in zones 1 and 2 (p≤0.018). The oxygen exposure was also the highest in the RCD, for both the nasal and the temporal peripapillary area among evaluated groups (p ≤ 0.025)ConclusionsClearly demonstrated through the O2‐E comparisons, rod‐cone dystrophy eyes seem to be more exposed to oxygen, the later presumably leading to more pronounced oxidative damage‐related remodeling.

Retinal Oxygenation in Inherited Diseases of the Retina.

(1) Background: The aim of our study was to investigate the relationship between retinal metabolic alterations (retinal vessel oximetry, RO) and structural findings (retinal vessel diameter, central retinal thickness and retinal nerve fiber layer thickness, RNFL) in patients with inherited retinal diseases (IRDs). (2) Methods: A total of 181 eyes of 92 subjects were examined: 121 eyes of 62 patients with IRDs were compared to 60 eyes of 30 healthy age-matched controls. The retinal vessel oximetry was performed with the oxygen saturation measurement tool of the Retinal Vessel Analyser (RVA; IMEDOS Systems UG, Jena, Germany). The oxygen saturation in all four major peripapillary retinal arterioles (A-SO2; %) and venules (V-SO2; %) were measured and their difference (A-V SO2; %) was calculated. Additionally, retinal vessel diameters of the corresponding arterioles (D-A; µm) and venules (D-V; µm) were determined. The peripapillary central retinal thickness and the RNFL thickness were measured using spectral domain optical coherence tomography (SD-OCT) (Carl Zeiss Meditec, Dublin, CA, USA). Moreover, we calculated the mean central retinal oxygen exposure (cO2-E; %/µm) and the mean peripapillary oxygen exposure (pO2-E; %/µm) per micron of central retinal thickness and nerve fiber layer thickness by dividing the mean central retinal thickness (CRT) and the RNFL thickness with the mean A-V SO2. (3) Results: Rod-cone dystrophy patients had the highest V-SO2 and A-SO2, the lowest A-V SO2, the narrowest D-A and D-V and the thickest RNFL, when compared not only to controls (p ≤ 0.040), but also to patients with other IRDs. Furthermore, in rod-cone dystrophies the cO2-E and the pO2-E were higher in comparison to controls and to patients with other IRDs (p ≤ 0.005). Cone-rod dystrophy patients had the lowest cO2-E compared to controls and patients with other IRDs (p ≤ 0.035). Evaluated in central zones, the cO2-E was significantly different when comparing cone-rod dystrophy (CRD) against rod-cone dystrophy (RCD) patients in all zones (p < 0.001), whereas compared with controls and patients with inherited macular dystrophy this was observed only in zones 1 and 2 (p ≤ 0.018). The oxygen exposure was also the highest in the RCD group for both the nasal and the temporal peripapillary area, among all the evaluated groups (p ≤ 0.025). (4) Conclusions: The presented metabolic-structural approach enhances our understanding of inherited photoreceptor degenerations. Clearly demonstrated through the O2-E comparisons, the central and the peripapillary retina in rod-cone dystrophy eyes consume less oxygen than the control-eyes and eyes with other IRDs. Rod-cone dystrophy eyes seem to be proportionally more exposed to oxygen, the later presumably leading to more pronounced oxidative damage-related remodeling.

Diurnal Variation in Corneal Edema in Fuchs Endothelial Corneal Dystrophy

The extent of diurnal variation in corneal edema in Fuchs dystrophy is unknown. We measured corneal thickness and posterior profile over the course of the day using Scheimpflug imaging. Prospective cohort study. Participants with clinically advanced Fuchs dystrophy eyes undergoing endothelial keratoplasty and participants with healthy corneas were assessed around noon the day before surgery and late afternoon, in presumed steady state. After controlled overnight patching to standardize eyelid closure, participants were assessed immediately upon eye opening in hospital the morning of surgery. Directly upon awakening, patients had mean corneal thickness of 663μm (interquartile range [IQR], 625-707) in Fuchs dystrophy (n= 44) and controls (n= 11) had thickness of 557μm (IQR, 527-601). In control corneas, there were no systematic changes with time. In Fuchs dystrophy eyes, corneal thickness decreased after awakening. Ninety-five percent of patients can be expected to have a decrease in corneal thickness over the first 4 hours after awakening between 31μm and 58μm (95% prediction interval). Posterior Q decreased on average by 0.15 (95% confidence interval [CI], 0.07-0.23) and posterior radius of curvature decreased by 0.20mm (95% CI, 0.14-0.27) over the first 4 hours, indicating that edema resolution steepened the central posterior cornea. Beyond 4 hours after awakening, corneas no longer changed considerably in Fuchs dystrophy. Impaired hydration control in clinically advanced Fuchs dystrophy makes measurements of key corneal parameters unreliable directly after eye opening. Beyond the first hours after eye opening, corneal thickness measurements are unlikely to vary more in Fuchs dystrophy eyes than in normal eyes.

Evaluation of endothelial/Descemet membrane complex of eye bank donor corneas using enhanced depth imaging optical coherence tomography.

Objective: We present a novel method for screening eye bank donor corneas using high definition optical coherence tomography (HD-OCT). This technology allows for the quantification of endothelial/Descemet membrane (En/DM) complex thickness ex vivo.Design: Prospective interventional study.Participants: Fifty-two corneal grafts from 27 donors were included in this study. Twenty additional control eyes and 11 eyes with Fuchs’ endothelial corneal dystrophy were also evaluated for comparison.Methods: A custom built, high speed HD-OCT device (Envisu R2210, Bioptigen, Buffalo Grove, IL, USA) was used to obtain images, and custom-made graph-based segmentation software was used to automatically deconstruct corneal images into micro-layers. HD-OCT imaging was used to scan through the sealed sterile case of donor corneas stored in McCarey-Kaufman medium to image their En/DM complex through the center of the cornea.Results: This technology allowed for quantification of En/DM complex thickness in all donor corneas through the sealed sterile container used to transport graft tissue. Mean En/DM complex thickness of donor corneas was 17±4 μm. The difference between donor cornea En/DM thickness and that of control subjects (16±2 μm) was not statistically significant (p=0.3), suggesting that the transport container and media do not affect measurements. There was a significant difference between En/DM thickness of Fuchs’ endothelial corneal dystrophy eyes (25±5 μm) and both donor corneas (p<0.0001) and control subjects (p<0.0001).Conclusions: We have described a new technique to measure En/DM complex thickness in eye bank donor corneas stored in a sealed sterile case. This may represent a novel adjunctive approach to screen corneal grafts for early endothelial disease.

Avoiding Hyperopic Surprises After Descemet Membrane Endothelial Keratoplasty in Fuchs Dystrophy Eyes by Assessing Corneal Shape

It is unclear which patients unexpectedly have a hyperopic refractive outcome after combined Descemet membrane endothelial keratoplasty and cataract surgery (triple DMEK). We assessed how corneal shape predicts hyperopia after triple DMEK. Retrospective cohort study. Patients with Fuchs endothelial corneal dystrophy (FECD) with Scheimpflug examinations before uncomplicated triple DMEK at a tertiary referral center were included. The arithmetic error was calculated (stable postoperative refraction minus predicted refraction). Using multinomial logistic regression, risk ratios of >+0.5 diopter (D) hyperopic and > 0.5 D myopic arithmetic errors were calculated. In 112 eyes, the median predicted refraction was-0.43 D (interquartile range [IQR],-0.47 to-0.17) with an achieved refraction of-0.63 to 0.56 (IQR). The arithmetic error was 0.34 D (IQR,-0.22 to 0.81). A hyperopic arithmetic error was present in 46% of eyes. FECD eyes with an oblate posterior cornea (Q value >0) had a 3.0 times higher risk of hyperopic shift after triple DMEK (95% confidence interval [CI], 1.3-7.0; P= .011), compared to spherical or prolate corneas (Q value ≤ 0). In eyes with posterior Q > 0, the mean prediction error was+0.50 D higher than in eyes with negative Q values (95% CI, 0.19-0.82; P= .002), independent of corneal thickness. Hyperopic surprises after triple DMEK particularly occur in corneas that are flatter centrally than the periphery because of edematous changes (oblate posterior profile). Eyes with a positive Q value on Scheimpflug imaging should be considered for additional power at the intraocular lens level.

Corneal Abnormalities Early in the Course of Fuchs' Endothelial Dystrophy

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 (P < 0.001). Abnormal subepithelial cells were visible in 9%, 19%, and 30% of corneas with mild, moderate, and advanced Fuchs' dystrophy, respectively. Only corneas with advanced Fuchs' dystrophy were thicker than normal (P < 0.001). 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.

Optical Quality of the Cornea After Descemet Membrane Endothelial Keratoplasty

To evaluate corneal higher-order aberrations (HOAs) and backscattered light before and after Descemet membrane endothelial keratoplasty (DMEK) and their correlation with visual outcome. Retrospective study. In a total of 118 consecutive eyes of 118 patients who underwent uneventful DMEK for Fuchs endothelial dystrophy at a tertiary referral center, best spectacle-corrected visual acuity (BSCVA), corneal HOAs, and backscattered light were evaluated preoperatively and at 6 months postoperatively. Outcome data were compared to an age-matched control group with uncomplicated eyes (n = 27). Compared to the control group, Fuchs endothelial dystrophy eyes, before as well as 6 months after DMEK, showed higher values of anterior and posterior HOAs and backscattered light (P < .033). Postoperative anterior HOAs and backscattered light (0-2 mm) were associated with lower 6-month BSCVA (positively related with logMAR BSCVA) (P ≤ .020). Anterior corneal HOAs did not change from preoperative to 6 months after DMEK (P = .649), while total posterior HOAs (RMS third to sixth Zernike order) and haze decreased (P < .001). Anterior and posterior corneal HOAs, as well as backscattered light from the cornea, were elevated in eyes suffering from Fuchs endothelial dystrophy and remained higher throughout 6 months after DMEK. If present, anterior surface irregularities and anterior corneal haze may be the most important limiting factors in visual rehabilitation after DMEK.

Use of Ultra-High-Resolution Optical Coherence Tomography to Detect In Vivo Characteristics of Descemet's Membrane in Fuchs' Dystrophy

To demonstrate the capability of ultra-high-resolution (UHR) anterior segment optical coherence tomography (OCT) to image Descemet's membrane (DM) and measure its thickness in vivo. (2) To evaluate the use of DM characteristics and thickness in the diagnosis of Fuchs' dystrophy. Case-control study. Twenty eyes of 12 Fuchs' dystrophy patients, 20 eyes of 13 young normal, and 20 eyes of 15 elderly normal subjects. Subjects were imaged using novel, custom-built UHR-OCT. Images were used to describe the characteristics of DM. Custom-made software was used to measure DM thickness and central corneal thickness (CCT). Specimens of DM obtained from Fuchs' dystrophy patients who underwent endothelial keratoplasty (EK) were histopathologically examined. Regression analyses were used to assess the correlation of DM thickness measured by UHR-OCT in vivo and by light microscopy and to determine the intergroup correlations between age, CCT, and DM thickness. We assessed DM characteristics and thickness, CCT, and age. Using UHR-OCT, the DM seemed in normal young subjects as a single, opaque, smooth line and in normal elderly subjects as a band of 2 smooth opaque lines with a translucent space in between. In Fuchs' dystrophy, DM appeared as a thickened band of 2 opaque lines; the anterior line was smooth whereas the posterior line had a wavy and irregular appearance with areas of localized thickenings. The DM thickness measured in vivo by UHR-OCT correlated significantly with that measured by light microscopy in 5 Fuchs' dystrophy eyes that underwent EK. The average central thicknesses of DM in normal young, in normal elderly and in Fuchs' dystrophy eyes were 10+/-3, 16+/-2, and 34+/-11 microm, respectively (P<0.001). There was a significant correlation between age and DM thickness only in normal groups. In Fuchs' dystrophy patients, there was a significant correlation between CCT and DM thickness that was not significant for normal groups. Ultra-high-resolution OCT is an innovative technique for the in vivo imaging of DM. Determining DM characteristics and thickness by UHR-OCT could be a new approach for the diagnosis of Fuchs' dystrophy.

S156C Mutation in Tissue Inhibitor of Metalloproteinases-3 Induces Increased Angiogenesis

Tissue Inhibitor of metalloproteinases-3 (TIMP-3) is a potent matrix-bound angiogenesis inhibitor. Mutations in TIMP-3 cause Sorsby Fundus Dystrophy, a dominant inherited, early onset macular degenerative disease, with choroidal neovascularization causing a loss of vision in the majority of patients. Here we report that expression of S156C TIMP-3 mutation in endothelial cells results in an abnormal localization of the protein, increased glycosylation, decreased matrix metalloproteinase inhibitory activity, and increased vascular endothelial growth factor (VEGF) binding with a consequent increase in VEGF-dependent migration and tube formation. These enhanced signaling events appear to be mediated as a consequence of a post-transcriptionally regulated increase in the expression of membrane-associated VEGFR-2 in endothelial cells of Timp-3(156/156) mutant mice as well as in human Sorsby fundus dystrophy eyes. Understanding the mechanism(s) by which mutant TIMP-3 can induce abnormal neovascularization provides important insight into the pathophysiology of a number of diseases with increased angiogenesis.

A Pilot Study of Fourier-Domain Optical Coherence Tomography of Retinal Dystrophy Patients

To characterize the macular anatomy of retinal dystrophy eyes using high-speed, high-resolution, Fourier-domain optical coherence tomography (FD-OCT). Case-control study. Retinal dystrophy patients and normal age- and gender-matched controls underwent FD-OCT imaging using the RTVue (Optovue Inc., Fremont, California, USA). Vertical and horizontal 8-mm scans of 1024 lines/cross-section were obtained. Based on boundaries manually drawn on computer displays of OCT cross-sections, the thicknesses of the retina, inner retinal layer (IRL), and outer retinal layer (ORL) were averaged over both 5-mm (macular) and 1.5-mm (foveal) regions centered at the fovea. The IRL was the sum of nerve fiber layer (NFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) thicknesses. Total retinal thickness (RT) was measured between the internal limiting membrane (ILM) and the retinal pigment epithelium. ORL thickness was calculated by subtracting IRL thickness from RT. Fourteen patients (three retinitis pigmentosa, two cone-rod degeneration, two Stargardt disease, and seven normal controls) underwent FD-OCT imaging. Mean foveal RT was 271.3 +/- 23.3 microm for controls and 158.4 +/- 47.1 microm for retinal dystrophy patients (P < .001). Mean macular RT was 292.8 +/- 8.1 microm for controls and 199.1 +/- 32.6 microm for retinal dystrophy patients (P < .001). Mean macular ORL was 182.9 +/- 4.7 microm for controls and 101.3 +/- 18.7 microm for retinal dystrophy patients (P < .001); mean macular IRL was 109.9 +/- 6.4 microm for controls and 97.9 +/- 20.7 microm for retinal dystrophy patients (P = .06). Eyes with retinal dystrophy had a small (11%) decrease in macular IRL and severe (45%) decrease in macular ORL compared to normal controls.