Corneal High-Order Aberrations and Backscatter in Fuchs' Endothelial Corneal Dystrophy

doi:10.1016/j.ophtha.2015.05.005

Ophthalmology

Volume 122, Issue 8, August 2015, Pages 1645-1652

Presented in part at: the annual meetings of the Association for Research in Vision and Ophthalmology, Orlando, Florida, May 6, 2014, and Denver, Colorado, May 3, 2015.

https://doi.org/10.1016/j.ophtha.2015.05.005 Get rights and content

Purpose

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).

Design

Cross-sectional study.

Participants

A total of 108 eyes (62 subjects) with a range of severity of FECD and 71 normal eyes (38 subjects).

Methods

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.

Main Outcome Measures

High-order aberrations, expressed as root mean square of wavefront errors, and backscatter of the anterior and posterior cornea.

Results

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; P < 0.001), and advanced (0.23±0.09 μm; P < 0.001) 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).

Conclusions

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.

Section snippets

Subjects and Clinical Grading

All subjects were examined by cornea specialists using slit-lamp biomicroscopy. Severity of FECD was graded clinically on the basis of the area and confluence of guttae, and the presence of edema, as described previously.15, 16 Corneas with 1 to 12 or ≥12 nonconfluent central guttae (grades 1 and 2) were considered to have mild FECD; corneas with confluent guttae of 1- to 2-mm and 2- to 5-mm diameter (grades 3 and 4) were considered to have moderate FECD, and corneas with >5-mm diameter of

Subjects

A total of 108 corneas from 62 subjects with FECD and 71 normal corneas from 38 subjects were examined; the median age was 66 years (range, 40–89 years) (Table 1). Subjects with FECD were older than controls (mean difference, 7.9 years; P = 0.002). Subjects with mild (P = 0.01) and moderate (P = 0.03) FECD were more often pseudophakic than controls.

Corneal High-Order Aberrations

Data from 1 eye with FECD were excluded from analysis because of acquisition errors. Anterior corneal total HOAs were increased in moderate (P =

Discussion

Anterior corneal HOAs were increased in moderate and advanced FECD compared with controls, before clinically visible corneal edema, and posterior corneal HOAs and corneal backscatter were increased even in mild FECD. Increased posterior corneal HOAs and anterior and posterior corneal backscatter were associated with lower ECD_e and thicker corneas in FECD. These data indicate that surface changes occur earlier than previously thought.

Increased anterior corneal HOAs in advanced FECD (with corneal

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The cornea, as a dynamic and responsive tissue, constantly interacts with mechanical forces in order to maintain its structural integrity, barrier function, transparency and refractive power. Cells within the cornea sense and respond to various mechanical forces that fundamentally regulate their morphology and fate in development, homeostasis and pathophysiology. Corneal cells also dynamically regulate their extracellular matrix (ECM) with ensuing cell-ECM crosstalk as the matrix serves as a dynamic signaling reservoir providing biophysical and biochemical cues to corneal cells. Here we provide an overview of mechanotransduction signaling pathways then delve into the recent advances in corneal mechanobiology, focusing on the interplay between mechanical forces and responses of the corneal epithelial, stromal, and endothelial cells. We also identify species-specific differences in corneal biomechanics and mechanotransduction to facilitate identification of optimal animal models to study corneal wound healing, disease, and novel therapeutic interventions. Finally, we identify key knowledge gaps and therapeutic opportunities in corneal mechanobiology that are pressing for the research community to address especially pertinent within the domains of limbal stem cell deficiency, keratoconus and Fuchs’ endothelial corneal dystrophy. By furthering our understanding corneal mechanobiology, we can contextualize discoveries regarding corneal diseases as well as innovative treatments for them.
Translation and validation of the Visual Function and Corneal Health Status (V-FUCHS) questionnaire into Spanish language
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Traducir y validar al castellano el cuestionario V-FUCHS en una población de pacientes que padecen distrofia endotelial de Fuchs (DEF).
El V-FUCHS consta de 15 preguntas, que valoran aspectos visuales de la calidad de vida en los pacientes con DEF, las cuales se pueden agrupar en 7 que valoran el factor «dificultad visual» y 8 que valoran el factor «deslumbramiento». Para la traducción y adaptación se siguieron las normas estandarizadas, destacando, una traducción, una retro-traducción y una aplicación en pacientes con DEF.
En una primera fase se llegó al consenso de la traducción al castellano del V-FUCHS. Posteriormente, se incluyeron 25 pacientes para realizar la fase pre-test con el objetivo de valorar la aplicabilidad y la viabilidad del test. La puntuación de las mismas obtuvo un valor mínimo de −0,88 y un valor máximo de + 2,44, según la escala probabilística de Rasch. El valor medio obtenido de las preguntas que conforman el factor dificultad visual fue de 0,61 (± 0,71) y la media del factor deslumbramiento (Glare) fue de 0,41 (± 0,51).
La validación del cuestionario V-FUCHS, tras su traducción y adaptación al castellano, demostró ser una herramienta útil para la valoración de la calidad visual de los pacientes con DEF. Los pacientes con un estado más avanzado de la enfermedad presentaron una mayor severidad en el resultado de la prueba. Asimismo, el factor deslumbramiento se correlaciona mejor con el aumento paquimétrico que con la agudeza visual del paciente.
To translate and validate the V-FUCHS questionnaire into Spanish in a population of patients with Fuchs endothelial dystrophy (DEF).
The V-FUCHS consists of 15 short, easily understandable questions that assess visual aspects of quality of life in patients with DEF, which can be gathered into a group of seven that assess the “Visual Difficulty” factor and another group of eight that assess the “Glare Factor”. For the translation and cultural adaptation, the standardized norms for this process were followed, among other phases, a translation, a back-translation and an application in patients with DEF.
In the first phase, consensus was reached on the Spanish translation of the V-FUCHS. Subsequently, 25 patients were included to carry out the pre-test phase with the aim of assessing the applicability and feasibility of the test. The score obtained a minimum value of −0.88 and a maximum value of +2.44, according to the Rasch probabilistic scale. The mean value obtained from the Visual Difficulty factor was 0.61 (±0.71), while the mean for the Glare factor was 0.41 (±0.51).
The validation of the V-FUCHS questionnaire, after its translation and adaptation into Spanish, proved to be a useful tool for assessing the visual quality of patients with DEF. Patients with a more advanced stage of the disease presented a greater severity in the test result. Likewise, the Glare factor (Glare) correlates better with the pachymetric increase than with the visual acuity of the patient.
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To evaluate the change in corneal high order aberrations (HOAs) and anterior chamber parameters following scleral fixation in aphakic patients using the Scheimpflug camera system.
This retrospective study included patients who were aphakic after phacoemulsification surgery and underwent scleral-fixed intraocular lens (SF-IOL) implantation with Z suture technique between 2010 and 2022. Preoperative and postoperative best corrected visual acuity (BCVA), anterior segment parameters and corneal aberrations were evaluated with a combined Scheimpflug-Placido disk corneal topography device (Sirius Costruzione Strumenti Oftalmici, Florence, Italy). The following values were recorded: Simulated keratometry (SimK), flat meridian (K1), steep meridian (K2), iridocorneal angle (ICA), temporal anterior chamber angle (T-ACA), nasal anterior chamber angle (N-ACA), horizontal anterior chamber diameter (HACD), anterior chamber volume (ACV), corneal volume (CV), total Root Mean Square (RMS), high order aberrations (HOAs), spherical aberration, coma, trefoil, quadrifoil, and secondary astigmatism.
The study included 31 eyes of 31 patients (mean age: 63.00 ± 19.41 years, 17 males/14 females). Postoperative BCVA was better than preoperative BCVA (p = 0.012). Postoperatively, there was a statistically significant increase in ACV and CV values and a statistically significant decrease in K2 (p = 0.009, p = 0.032, p = 0.015). Preoperative T-ACA and preoperative and postoperative ACV were negatively correlated with postoperative intraocular pressure (r=-0.427 p = 0.033, r=-0.406 p = 0.032 and r=-0.561 p = 0.001). There were statistically significant postoperative increases in corneal RMS, trefoil and HOAs for 3 mm pupil diameter (p = 0.0177, p = 0.001, p = 0.031) and in corneal RMS, trefoil and quadrifoil aberrations for 6 mm pupil diameter (p = 0.033, p = 0.001, p = 0.001).
In conclusion, SF-IOL implantation with Z-suture technique used for visual rehabilitation of aphakic patients may affect visual quality by increasing corneal HOAs while improving visual acuity.
Loss of Corneal Nerves and Corneal Haze in Patients with Fuchs’ Endothelial Corneal Dystrophy with the Transcription Factor 4 Gene Trinucleotide Repeat Expansion
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Seventy percent of Fuchs’ endothelial corneal dystrophy (FECD) cases are caused by an intronic trinucleotide repeat expansion in the transcription factor 4 gene (TCF4). The objective of this study was to characterize the corneal subbasal nerve plexus and corneal haze in patients with FECD with (RE+) and without the trinucleotide repeat expansion (RE−) and to assess the correlation of these parameters with disease severity.
Cross-sectional, single-center study.
Fifty-two eyes of 29 subjects with a modified Krachmer grade of FECD severity from 1 to 6 were included in the study. Fifteen of the 29 subjects carried an expanded TCF4 allele length of ≥ 40 cytosine-thymine-guanine repeats (RE+).
In vivo confocal microscopy assessments of corneal nerve fiber length (CNFL), corneal nerve branch density, corneal nerve fiber density (CNFD), and anterior corneal stromal backscatter (haze); Scheimpflug tomography densitometry measurements of haze in anterior, central, and posterior corneal layers.
Using confocal microscopy, we detected a negative correlation between FECD severity and both CNFL and CNFD in the eyes of RE+ subjects (Spearman ρ = −0.45, P = 0.029 and ρ = −0.62, P = 0.0015, respectively) but not in the eyes of RE− subjects. Additionally, CNFD negatively correlated with the repeat length of the expanded allele in the RE+ subjects (Spearman ρ = −0.42, P = 0.038). We found a positive correlation between anterior stromal backscatter and severity in both the RE+ and RE− groups (ρ = 0.60, P = 0.0023 and ρ = 0.44, P = 0.024, respectively). The anterior, central, and posterior Scheimpflug densitometry measurements also positively correlated with severity in both the RE+ and RE− groups (P = 5.5 × 10⁻⁵, 2.5 × 10⁻⁴, and 2.9 × 10⁻⁴, respectively, after adjusting for the expansion status in a pooled analysis. However, for patients with severe FECD (Krachmer grades 5 and 6), the posterior densitometry measurements were higher in the RE+ group than in the RE− group (P < 0.05).
Loss of corneal nerves in FECD supports the classification of the TCF4 trinucleotide repeat expansion disorder as a neurodegenerative disease. Haze in the anterior, central, and posterior cornea correlate with severity, irrespective of the genotype. Quantitative assessments of corneal nerves and corneal haze may be useful to gauge and monitor FECD disease severity in RE+ patients.
Visual Function in Pseudophakic Eyes with Fuchs’ Endothelial Corneal Dystrophy
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To assess vision in pseudophakic eyes with Fuchs’ endothelial corneal dystrophy (FECD) before the onset of clinically detectable corneal edema.
Cross-sectional study.
Sixty-one otherwise healthy pseudophakic eyes of 38 subjects with FECD (without clinically detectable edema) and 17 otherwise healthy pseudophakic eyes of 9 subjects with normal corneas. Subjects underwent clinical examination to determine the morphologic distribution of guttae (severity grading). Standardized best-corrected high-contract and low-contrast (photopic and mesopic) visual acuity (HCVA, LCVA) and straylight were measured. Scheimpflug tomography posterior elevation and pachymetry maps were interpreted for 3 tomographic features of subclinical edema: loss of regular isopachs, displacement of the thinnest point of the cornea, and presence of posterior surface depression.
In FECD without tomographic features of edema (ie, normal tomography patterns), HCVA, LCVA, and straylight did not differ from that of eyes with normal corneas (P ≥ .09); these eyes encompassed the full range of severity grading of guttae. In FECD with all 3 tomographic features of edema, the same parameters were worse compared with eyes with normal corneas (P ≤ .02). In FECD with 1 or 2 tomographic abnormalities, mesopic LCVA (P = .04) and straylight (P = .003) were worse compared with eyes with normal corneas.
Impairment of vision was associated with the presence of tomographic edema in eyes with FECD. When tomography patterns were normal in FECD (ie, guttae were present without tomographic edema), visual acuity and straylight were normal, and therefore corneal surgical intervention would not typically be indicated to improve vision.
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To develop a model to predict corneal improvement after Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial corneal dystrophy (FECD) from Scheimpflug tomography.
Cross-sectional study.
Forty-eight eyes (derivation group) and 45 eyes (validation group) with a range of severity of FECD undergoing DMEK.
Scheimpflug images were obtained before and after DMEK. Before DMEK, pachymetry map and posterior elevation map patterns were quantified by a special image analysis program measuring tomographic features of edema (loss of regular isopachs, displacement of the thinnest point of the cornea, posterior surface depression). Image-derived novel parameters were combined with instrument-derived parameters, and the relative influences of parameters associated with the change in central corneal thickness (CCT) after DMEK in the derivation group were determined by using a gradient boosting machine learning model. The parameters with highest relative influence were then fit in a linear regression model. The derived model was applied to the validation group. Correlations and agreement were assessed between predicted and observed changes in CCT.
Predictive power (R²) and mean difference between predicted and observed change in CCT.
The gradient boosting machine model identified 4 novel parameters of isopach circularity and eccentricity and 1 instrument-derived parameter (posterior surface radius); preoperative CCT was a poor predictor. In the derivation group, the model strongly predicted the change in CCT after DMEK (R² = 0.80; 95% confidence interval [CI], 0.71–0.89) and the mean difference between predicted and observed change was, by definition, 0 μm. When the same 5 parameters were fit to the validation group, the model performed very highly (R² = 0.89; 95% CI, 0.84–0.94). When the coefficient estimates from the derivation model were used to predict the change in CCT in the validation group, the predictive power was also high (R² = 0.78; 95% CI, 0.68–0.88), and the mean difference was 4 μm (predicted minus observed).
Scheimpflug tomography maps of corneas with FECD can predict the improvement in CCT after DMEK, independent of preoperative corneal thickness measurement. The model could be applied in clinical practice or for clinical research of FECD.

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: Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

: Supported by Research to Prevent Blindness, New York, New York (unrestricted grant to the Department of Ophthalmology and support (to S.V.P.) as Olga Keith Wiess Special Scholar); Dr. Werner Jackstaedt-Stiftung, Wuppertal, Germany (Research Fellowship to K.W.); Mayo Clinic Center for Translational Science Activities (grant no. UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health, Bethesda, MD); and Mayo Foundation, Rochester, Minnesota. The funding organizations had no role in the design or conduct of this research.

: Author Contributions:

: Conception and design: Wacker, McLaren, Amin, Baratz, Patel

: Data collection: Wacker, Amin, Patel

: Analysis and interpretation: Wacker, McLaren, Amin, Baratz, Patel

: Obtained funding: Not applicable

: Overall responsibility: Wacker, McLaren, Amin, Baratz, Patel

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Original articleCorneal High-Order Aberrations and Backscatter in Fuchs' Endothelial Corneal Dystrophy

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Subjects and Clinical Grading

Subjects

Corneal High-Order Aberrations

Discussion

Ophthalmology

Ophthalmology

Ophthalmology

J Cataract Refract Surg

Ophthalmology

J Cataract Refract Surg

Ophthalmology

Ophthalmology

Am J Ophthalmol

Am J Ophthalmol

Surv Ophthalmol

Ophthalmology

Biophys J

Cont Lens Anterior Eye

Ophthalmology

Ophthalmology

Fuchs' dystrophy

Cornea

Potential causes of incomplete visual rehabilitation at 6 months postoperative after Descemet membrane endothelial keratoplasty

Am J Ophthalmol

Original article
Corneal High-Order Aberrations and Backscatter in Fuchs' Endothelial Corneal Dystrophy