Fabry Disease Rat Model Develops Age- and Sex-Dependent Anterior Segment Ocular Abnormalities.

Purpose: Fabry disease is an X-linked lysosomal storage disorder that results in multi-systemic renal, cardiovascular, and neuropathological damage, including in the eyes. We evaluated anterior segment ocular abnormalities based on age, sex (male and female), and genotype (wild-type, knockout [KO] male, heterozygous [HET] female, and KO female) in a rat model of Fabry disease. Methods: The α-Gal A KO and WT rats were divided into young (6-24 weeks), adult (25-60 weeks), and aged (61+ weeks) groups. Intraocular pressure (IOP) was measured. Eyes were clinically scored for corneal and lens opacity as well as evaluated for corneal epithelial integrity and tear break-up time (TBUT). Anterior chamber depth (ACD) and central corneal thickness (CCT) using anterior segment-optical coherence tomography (AS-OCT). Results: The Fabry rats showed an age-dependent increase in IOP, predominantly in the male genotype. TBUT was decreased in both male and female groups with aging. Epithelial integrity was defective in KO males and HET females with age. However, it was highly compromised in KO females irrespective of age. Corneal and lens opacities were severely affected irrespective of sex or genotype in the aging Fabry rats. AS-OCT quantification of CCT and ACD also demonstrated age-dependent increases but were more pronounced in Fabry versus WT genotypes. Conclusions: Epithelial integrity, corneal, and lens opacities worsened in Fabry rats, whereas IOP and TBUT changes were age-dependent. Similarly, CCT and ACD were age-related but more pronounced in Fabry rats, providing newer insights into the anterior segment ocular abnormalities with age, sex, and genotype in a rat model of Fabry disease.

Depth-resolved Corneal Biomechanical Changes Measured Via Optical Coherence Elastography Following Corneal Crosslinking.

Purpose: To evaluate depth-resolved changes of corneal biomechanical properties in eyes with corneal ectasia after corneal crosslinking (CXL) using optical coherence elastography. Methods: In a prospective pilot series of eyes with corneal ectasia, a custom high-speed swept source optical coherence tomography system was used to image the cornea before and 3 months after CXL during a low-speed applanating deformation while monitoring applanation force. Cross-correlation was applied to track frame-by-frame two-dimensional optical coherence tomography speckle displacements, and the slope of force versus local axial displacement behavior during the deformation was used to produce a two-dimensional array of axial stiffness (k). These values were averaged for anterior (ka) and posterior (kp) stromal regions and expressed as a ratio (ka/kp) to assess depth-dependent differences in stiffness. CXL was performed according to the Dresden protocol with a system approved by the U.S. Food and Drug Administration. Results: Four eyes from four patients with keratoconus (n = 3) or post-LASIK ectasia (n = 1) underwent optical coherence elastography before and 3 months after CXL. The mean ka/kp was 1.03 ± 0.07 before CXL compared with 1.34 ± 0.17 after the CXL procedure. All four eyes demonstrated at least a 20% increase in the ka/kp. Conclusions: Preferential stiffening of the anterior stroma with the standard CXL protocol was demonstrated with optical coherence elastography in live human subjects. Translational Relevance: Although ex vivo studies have demonstrated anterior stiffening effects after CXL using various destructive and nondestructive methods, this report presents the first evidence of such changes in serial live human measurements.

Depth-Dependent Corneal Biomechanical Properties in Normal and Keratoconic Subjects by Optical Coherence Elastography.

Purpose: Compare depth-resolved biomechanical properties in normal and keratoconic corneas in live human subjects using optical coherence elastography (OCE). Methods: In a prospective series of normal and keratoconus (KC) eyes, a corneal perturbation was applied by a custom swept-source OCE system using a transparent flat lens coupled to force transducers. Cross-correlation was applied to track frame-by-frame OCT speckle displacement. Regional displacements for the anterior and posterior stroma were plotted in force versus displacement (k) graphs. A spatial biomechanical property ratio (ka/kp ) was defined by dividing the maximum total displacement by the maximum force for the anterior (ka ) and posterior cornea (kp) and was compared between normal and KC groups with the Mann-Whitney U test. Area under the receiver operating characteristics curve (AUROC) for differentiating normal and KC eyes was calculated for ka/kp , kmax, and thinnest point of corneal thickness (TPCT). Results: Thirty-six eyes were analyzed (21 eyes of 12 normal subjects and 15 KC eyes of 12 subjects). The ka/kp for the normal group was 1.135 ± 0.07 (mean ± standard deviation) and 1.02 ± 0.08 for the KC group (P < 0.001), indicating a relative deficit in anterior stromal stiffness in KC eyes. AUROC was 0.91 for ka /kp , 0.95 for kmax, and 1 for TPCT. Conclusions: Significant differences in depth-dependent corneal biomechanical properties were observed between normal and KC subjects. Translational Relevance: OCE was applied for the first time to human KC subjects and revealed alterations in the normal anterior-to-posterior stromal stiffness gradient, a novel and clinically accessible disease biomarker.

Analysis of planning strategies in primary eyes gaining a line or more of visual acuity after topography-guided laser in situ keratomileusis.

PURPOSE: To analyze planning strategies for eyes that gained 1 or more lines of corrected distance visual acuity (CDVA) after topography-guided custom treatment (TCAT). SETTING: Refractive Surgery Clinic, Cleveland Clinic, Ohio, USA. DESIGN: Retrospective case series. METHODS: Eyes having TCAT by the same surgeon between February 2016 and June 2017 were enrolled. The corneal shape was captured with the Wavelight Allegretto Topolyzer diagnostic device coupled with refraction, generating an ablation profile. The cylinder magnitude and axis of laser entry were decided by the surgeon based on the manifest and measured values, assisted by additional data from the Pentacam Scheimpflug tomographer and Ladarwave ocular wavefront aberrometer. RESULTS: The study comprised 256 eyes. At 3 months, uncorrected distance visual acuity was 20/20 or better in 95.7% and 20/15 or better in 81.4%; 25.6% gained 1 or more lines of CDVA. The measured and manifest axes differed by less than 15 degrees in 59%, between 15 degrees and 30 degrees in 18%, and by more than 30 degrees in 23%. When it differed by at least 5 degrees, the measured axis was treated in 79%, 75%, and 73% of eyes, respectively. In eyes with higher measured cylinder, 75% were treated between the manifest and measured values, with 7% at full measured value. When the manifest value was greater, 60% were treated at the total measured value and 40% in between. Whole-eye aberrometry showed a small increase in coma, spherical aberration and the total root mean square (all P < .001). CONCLUSIONS: The TCAT procedure achieved visual acuity better than the preoperative CDVA in more than 25.0% of eyes. Tomography and wavefront aberrometry assisted in the selection process to achieve optimum visual outcomes.

Noninvasive Assessment of Corneal Crosslinking With Phase-Decorrelation Optical Coherence Tomography.

Purpose: There is strong evidence that abnormalities in corneal biomechanical play a causal role in corneal ectasias, such as keratoconus. Additionally, corneal crosslinking (CXL) treatment, which halts progression of keratoconus, directly appeals to corneal biomechanics. However, existing methods of corneal biomechanical assessment have various drawbacks: dependence on IOP, long acquisition times, or limited resolution. Here, we present a method that may avoid these limitations by using optical coherence tomography (OCT) to detect the endogenous random motion within the cornea, which can be associated with stromal crosslinking. Methods: Phase-decorrelation OCT (PhD-OCT), based in the theory of dynamic light scattering, is a method to spatially resolve endogenous random motion by calculating the decorrelation rate, Γ, of the temporally evolving complex-valued OCT signal. PhD-OCT images of ex vivo porcine globes were recorded during CXL and control protocols. In addition, human patients were imaged with PhD-OCT using a clinical OCT system. Results: In both the porcine cornea and the human cornea, crosslinking results in a reduction of Γ (P < 0.0001), indicating more crosslinks. This effect was repeatable in ex vivo porcine corneas (change in average Γ = -41.55 ± 9.64%, n = 5) and not seen after sham treatments (change in average Γ = 2.83 ± 12.56%, n = 5). No dependence of PhD-OCT on IOP was found, and correctable effects were caused by variations in signal-to-noise ratio, hydration, and motion. Conclusions: PhD-OCT may be a useful and readily translatable tool for investigating biomechanical properties of the cornea and for enhancing the diagnosis and treatment of patients.

Live human assessment of depth-dependent corneal displacements with swept-source optical coherence elastography.

PURPOSE: To assess depth-dependent corneal displacements in live normal subjects using optical coherence elastography (OCE). METHODS: A corneal elastography method based on swept-source optical coherence tomography (OCT) was implemented in a clinical prototype. Low amplitude corneal deformation was produced during OCT imaging with a linear actuator-driven lens coupled to force transducers. A cross-correlation algorithm was applied to track frame-by-frame speckle displacement across horizontal meridian scans. Intra-measurement force and displacement data series were plotted against each other to produce local axial stiffness approximations, k, defined by the slope of a linear fit to the force/displacement data (ignoring non-axial contributions from corneal bending). Elastographic maps displaying local k values across the cornea were generated, and the ratio of mean axial stiffness approximations for adjacent anterior and posterior stromal regions, ka/kp, was calculated. Intraclass correlation coefficients (ICC) were used to estimate repeatability. RESULTS: Seventeen eyes (ten subjects) were included in this prospective first-in-humans translational study. The ICC was 0.84. Graphs of force vs. displacement demonstrated that, for simultaneously acquired measurements involving the same applied force, anterior stromal displacements were lower (suggesting stiffer behavior) than posterior stromal displacements. Mean ka was 0.016±0.004 g/mm and mean kp was 0.014±0.004 g/mm, giving a mean ka/kp ratio of 1.123±0.062. CONCLUSION: OCE is a clinically feasible, non-invasive corneal biomechanical characterization method capable of resolving depth-dependent differences in corneal deformation behavior. The anterior stroma demonstrated responses consistent with stiffer properties in compression than the posterior stroma, but to a degree that varied across normal eyes. The clinical capability to measure these differences has implications for assessing the biomechanical impact of corneal refractive surgeries and for ectasia risk screening applications.

Custom air puff-derived biomechanical variables in a refractive surgery screening setting: Study from 2 centers.

PURPOSE: To assess the ability of air puff-derived biomechanical variables to predict surgeon-perceived candidacy for laser in situ keratomileusis (LASIK). SETTING: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, and Emory Eye Institute, Emory University, Atlanta, Georgia, USA. DESIGN: Retrospective case series. METHODS: Data were collected from refractive surgery screening examinations by 2 surgeons at 2 centers. Disqualified cases (19 eyes and 28 eyes from each surgeon) were judged not to be candidates based on available data including standard variables from the Ocular Response Analyzer. Controls consisted of LASIK candidates (n = 26 and 23). Three custom biomechanical variables not available during screening were calculated and compared by group and surgeon. RESULTS: The hysteresis loop area was significantly different between disqualified cases and controls for both surgeons (Surgeon 1: controls, 121.50 ± 25.38 [SD], disqualified, 107.62 ± 18.50, P = .04; Surgeon 2: controls, 135.89 ± 22.47, disqualified, 106.11 ± 16.40, P < .001). The area under the curves of the receiver operating characteristics and the cutoff values were statistically significant for the concavity minimum and hysteresis loop area for Surgeon 1 and for all variables except concavity minimum for Surgeon 2. The hysteresis loop area had the highest odds ratio (Surgeon 1, 4.48, Surgeon 2, 20.00). Adjusted R2 in best-subsets regressions were 40.2% for Surgeon 1 and 62.9% for Surgeon 2. CONCLUSIONS: The hysteresis loop area was predictive of which patients were disqualified for LASIK at different sites. Certain measures of the corneal dynamic response to an air puff might serve as correlates to clinically perceived ectasia risk.

Comparison of Patient-Specific Computational Modeling Predictions and Clinical Outcomes of LASIK for Myopia.

Purpose: To assess the predictive accuracy of simulation-based LASIK outcomes. Methods: Preoperative and 3-month post-LASIK tomographic data from 20 eyes of 12 patients who underwent wavefront-optimized LASIK for myopia were obtained retrospectively. Patient-specific finite element models were created and case-specific treatment settings were simulated. Simulated keratometry (SimK) values and the mean tangential curvature of the central 3 mm (Kmean) were obtained from the anterior surfaces of the clinical tomographies, and computational models were compared. Correlations between Kmean prediction error and patient age, preoperative corneal hysteresis (CH), and corneal resistance factor (CRF) were assessed. Results: The mean difference for Kmean between simulated and actual post-LASIK cases was not statistically significant (-0.13 ± 0.36 diopters [D], P = 0.1). The mean difference between the surgically induced clinical change in Kmean and the model-predicted change was -0.11 ± 0.34 D (P = 0.2). Kmean prediction error was correlated to CH, CRF, and patient age (r = 0.63, 0.53, and 0.5, respectively, P < 0.02), and incorporation of CH values into predictions as a linear offset increased their accuracy. Simulated changes in Kmean accounted for 97% of the variance in actual spherical equivalent refractive change. Conclusions: Clinically feasible computational simulations predicted corneal curvature and manifest refraction outcomes with a level of accuracy in myopic LASIK cases that approached the limits of measurement error. Readily available preoperative biomechanical measures enhanced simulation accuracy. Patient-specific simulation may be a useful tool for clinical guidance in de novo LASIK cases.

Experimental investigation of needles, syringes and techniques for intravitreal injections.

BACKGROUND: To assess the techniques and materials used in intravitreal injections. DESIGN: Descriptive study realized at the Vision Institute of the Federal University of São Paulo, Brazil. SAMPLES: Different brands of needles and syringes, as well as enucleated porcine eyeballs. METHODS: The ultra-structures of commonly used needles were analysed by scanning electron microscope, and they were compared using different criteria, such as irregularities and debris from the lubrication process. The scleral incision was also assessed using needles of different brands and sizes. Accuracies in drug administration were studied by comparing the residual and delivered volume of needles and also by the analysis of reflux after intravitreal injections. MAIN OUTCOME MEASURES: Efficiency and quality of materials used in intravitreal injections. RESULTS: Ultra-structure analyses showed that all needles had different types of irregularities. Some photographs showed debris from the lubrication process, especially in BD needles. Scleral incision analysis showed a tendency of reducing the ocular damage with increasing gauge (P=0.024). The investigation of delivery accuracy showed that almost all needles underdosed the amount injected (P<0.05), and that the reflux could be minimized by tunnelled injections with thinner needles. CONCLUSION: Needles used in intravitreal injections possess many irregularities in their structures, which may cause different injection outcomes. Analyses of scleral incisions showed that the larger the needle gauge, the lesser the scleral damage and the risk of complications. Moreover, drug administration inaccuracies might be one of the causes for some unsuccessful attempts of treatment.