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.

Results of intrastromal corneal ring segment implanted alone or combined with same-day corneal crosslinking and their correlation with preoperative corneal biomechanical strain from finite element analysis.

PURPOSE: To compare the results of intrastromal corneal ring segment (ICRS) alone or combined with same-day corneal crosslinking (CXL) and investigate the relationship of preoperative corneal biomechanics data on the outcomes. SETTING: Department of Ophthalmology of Federal University of Parana. DESIGN: Prospective nonrandomized interventional comparative study. METHODS: Forty-nine eyes of 44 keratoconus patients underwent ICRS only (n = 27, Group 1) or same day ICRS+CXL (n = 22, Group 2) and were followed up for at least 24 months. Visual acuity and preoperative and postoperative tomographic variables were compared between groups. Tomographic data were obtained with a dual Scheimpflug analyzer, and eye-specific finite-element models were used to derive 3 variables related to preoperative biomechanical strain (maximum principal strain [MPS]): mean MPS (mMPS), highest local MPS (hMPS), and position of the hMPS (hMPSx and hMPSy). The relationship between preoperative strain data and the change (∆, difference between postoperative and preoperative data) in tomographic parameters was also investigated. RESULTS: Steepest (K2) and maximum keratometry (Kmax), inferior-superior (I-S) index, coma, and cone location magnitude index (CLMI) significantly improved in both groups. Corrected distance visual acuity was significantly better after ICRS alone (P = .03), whereas corneal asymmetry measured through the I-S index was better after CXL+ICRS (P = .04). In Group 1, hMPSy significantly correlated with K2, tomographical cylinder, mean keratometry, and ∆spherical aberration, whereas mMPS significantly correlated with ∆eccentricity. In Group 2, hMPS significantly correlated with K2, Kmax, I-S index, and ∆coma, and hMPSy significantly correlated with I-S index and ∆coma. The mMPS significantly correlated with ∆CLMI. CONCLUSIONS: ICRS alone seems to be the most suitable option to improve visual acuity, whereas combined ICRS+CXL provided better corneal regularizing results. Preoperative peak strain (hMPS) was predictive of the extent of regularization and flattening after ICRS+CXL.

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.

Differences in Simulated Refractive Outcomes of Photorefractive Keratectomy (PRK) and Laser In-Situ Keratomileusis (LASIK) for Myopia in Same-Eye Virtual Trials.

The use of computational mechanics for assessing the structural and optical consequences of corneal refractive procedures is increasing. In practice, surgeons who elect to perform PRK rather than LASIK must often reduce the programmed refractive treatment magnitude to avoid overcorrection of myopia. Building on a recent clinical validation study of finite element analysis (FEA)-based predictions of LASIK outcomes, this study compares predicted responses in the validated LASIK cases to theoretical PRK treatments for the same refractive error. Simulations in 20 eyes demonstrated that PRK resulted in a mean overcorrection of 0.17 ± 0.10 D relative to LASIK and that the magnitude of overcorrection increased as a function of attempted correction. This difference in correction closely matched (within 0.06 ± 0.03 D) observed differences in PRK and LASIK from a historical nomogram incorporating thousands of cases. The surgically induced corneal strain was higher in LASIK than PRK and resulted in more forward displacement of the central stroma and, consequently, less relative flattening in LASIK. This FE model provides structural confirmation of a mechanism of action for the difference in refractive outcomes of these two keratorefractive techniques, and the results were in agreement with empirical clinical data.

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.

Contralateral Eye Comparison of SMILE and Flap-Based Corneal Refractive Surgery: Computational Analysis of Biomechanical Impact.

PURPOSE: Computational analyses were performed to quantify and directly compare the biomechanical impact of flapless and flap-based procedures in a series of patients undergoing small incision lenticule extraction (SMILE) in one eye and flap-based femtosecond lenticule extraction in the other. METHODS: Tomographic data from 10 eyes of 5 patients undergoing femtosecond laser refractive lenticule extraction for myopic astigmatism with or without a stromal flap (femtosecond lenticule extraction in one eye, SMILE in the contralateral eye) were used to generate computational models. Inverse finite element analyses were performed at physiologic intraocular pressure followed by forward analyses at elevated intraocular pressure to assess corneal displacement and stress under differential loading. Case-specific treatment settings were incorporated. Preoperative material constants were obtained through inverse finite element analyses, and the surgically induced change in fiber stiffness within each flap was determined by minimization of the error between the simulated and actual 6-month topographic outcomes. RESULTS: Flap-based procedures produced a 49% (range: 2% to 87%) greater mean reduction in effective stromal collagen fiber stiffness within the flap region than contralateral SMILE cases. Lower stresses and deformations were observed within the residual stromal bed in SMILE cases than in flap-based cases. Stromal bed displacements and stresses were more affected by a loading increase in flap-based eyes than flapless eyes. CONCLUSIONS: Intrastromal flapless procedures had less impact on anterior stromal collagen mechanics and resulted in lower stromal bed displacements and stresses than flap-based procedures in contralateral eyes. However, biomechanical impact varied widely between individuals and this reinforces the need for individualized assessment of ectasia risk. [J Refract Surg. 2017;33(7):444-453].

Computational Biomechanical Analysis of Asymmetric Ectasia Risk in Unilateral Post-LASIK Ectasia.

PURPOSE: To develop a computational approach to corneal biomechanical risk analysis in refractive surgery and to investigate its utility in an enigmatic case of unilateral ectasia after bilateral LASIK. METHODS: Preoperative corneal elevation datasets from both eyes of a patient who developed unilateral post-LASIK ectasia were used to construct geometrically patient-specific, microstructurally motivated finite element models. Models were assessed before and after implementation of case-specific treatment parameters for interocular differences in corneal geometry and strain behavior under physiological loading conditions. RESULTS: Standard clinical predictors of post-LASIK ectasia risk were similar for the affected and contralateral eyes, and no risk factor asymmetry was identified in tomographic screening that included posterior corneal elevation analysis. However, differences in the magnitude and distribution of strain and stress were observed that are consistent with greater predisposition to biomechanical instability in the affected eye. Load testing with simulated intraocular pressure increases provoked opposite trends in curvature change in the preoperative models representing affected and unaffected eyes, with steepening in the ectatic eye and flattening in the clinically stable eye. CONCLUSIONS: Patient-specific computational analyses revealed differences in intrinsic biomechanical behaviors that may predispose a cornea to instability after refractive surgery. Strain and stress analyses elucidated differential risk not ascertained with current refractive surgery screening paradigms. This pilot study illustrates a risk analysis approach that implicitly considers the entire corneal three-dimensional geometry and can be performed a priori in a screening setting. [J Refract Surg. 2016;32(12):811-820.].

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.

A Large-Scale Computational Analysis of Corneal Structural Response and Ectasia Risk in Myopic Laser Refractive Surgery.

PURPOSE: To investigate biomechanical strain as a structural susceptibility metric for corneal ectasia in a large-scale computational trial. METHODS: A finite element modeling study was performed using retrospective Scheimpflug tomography data from 40 eyes of 40 patients. LASIK and PRK were simulated with varied myopic ablation profiles and flap thickness parameters across eyes from LASIK candidates, patients disqualified for LASIK, subjects with atypical topography, and keratoconus subjects in 280 simulations. Finite element analysis output was then interrogated to extract several risk and outcome variables. We tested the hypothesis that strain is greater in known at-risk eyes than in normal eyes, evaluated the ability of a candidate strain variable to differentiate eyes that were empirically disqualified as LASIK candidates, and compared the performance of common risk variables as predictors of this novel susceptibility marker across multiple virtual subjects and surgeries. RESULTS: A candidate susceptibility metric that expressed mean strains across the anterior residual stromal bed was significantly higher in eyes with confirmed ectatic predisposition in preoperative and all postoperative cases (P≤.003). The strain metric was effective at differentiating normal and at-risk eyes (area under receiver operating characteristic curve ≥ 0.83, P≤.002), was highly correlated to thickness-based risk metrics (as high as R(2) = 95%, P<.001 for the percent of stromal tissue altered (PSTA)), and predicted large portions of the variance in predicted refractive response to surgery (R(2) = 57%, P<.001). CONCLUSIONS: This study represents the first large-scale 3-dimensional structural analysis of ectasia risk and provides a novel biomechanical construct for expressing structural risk in refractive surgery. Mechanical strain is an effective marker of known ectasia risk and correlates to predicted refractive error after myopic photoablative surgery.

Corneal Deformation Response and Ocular Geometry: A Noninvasive Diagnostic Strategy in Marfan Syndrome.

PURPOSE: To evaluate corneal air-puff deformation responses and ocular geometry as predictors of Marfan syndrome. DESIGN: Prospective observational clinical study. METHODS: Sixteen investigator-derived, 4 standard Ocular Response Analyzer (ORA), and geometric variables from corneal tomography and optical biometry using Oculus Pentacam and IOL Master were assessed for discriminative value in Marfan syndrome, measuring right eyes of 24 control and 13 Marfan syndrome subjects. Area under the receiver operating characteristic (AUROC) curve was assessed in univariate and multivariate analyses. RESULTS: Six investigator-derived ORA variables successfully discriminated Marfan syndrome. The best lone disease predictor was Concavity Min (Marfan syndrome 47.5 ± 20, control 69 ± 14, P = .003; AUROC = 0.80). Corneal hysteresis (CH) and corneal resistance factor (CRF) were decreased (Marfan syndrome CH 9.45 ± 1.62, control CH 11.24 ± 1.21, P = .01; Marfan syndrome CRF 9.77 ± 1.65, control CRF 11.03 ± 1.72, P = .01) and corneas were flatter in Marfan syndrome (Marfan syndrome Kmean 41.25 ± 2.09 diopter, control Kmean 42.70 ± 1.81 diopter, P = .046). No significant differences were observed in central corneal thickness, axial eye length, or intraocular pressure. A multivariate regression model incorporating corneal curvature and hysteresis loop area (HLA) provided the best predictive value for Marfan syndrome (AUROC = 0.85). CONCLUSIONS: This study describes novel biodynamic features of corneal deformation responses in Marfan syndrome, including increased deformation, decreased bending resistance, and decreased energy dissipation capacity. A predictive model incorporating HLA and corneal curvature shows greatest potential for noninvasive clinical diagnosis of Marfan syndrome.

Toric topographically customized transepithelial, pulsed, very high-fluence, higher energy and higher riboflavin concentration collagen cross-linking in keratoconus.

PURPOSE: To report a novel application of toric topographically customized transepithelial collagen cross-linking (CXL) aiming to achieve refractive astigmatic changes in a keratoconic cornea. METHODS: Specially formulated riboflavin transepithelial administration and delivery of high-fluence UVA in a topographically customized pattern was applied in an eye with progressive keratoconus. Visual acuity, cornea clarity, keratometry, topography, and pachymetry with a multitude of modalities, as well as endothelial cell counts were evaluated for >6 months. RESULTS: Uncorrected distance visual acuity changed from preoperative 20/40 to 20/25 at 6 months. A mean astigmatic reduction of 0.8 D, and significant cornea surface normalization was achieved 6 months postoperatively. There was some mild change in the epithelial distribution, with the treated area having a slight normalization in the average epithelial thickness. CONCLUSIONS: We introduce herein the novel application of a topographically customizable transepithelial CXL in progressive keratoconus in order to achieve an astigmatic refractive effect and ectasia stabilization. This novel technique offers a nonablative and nonincisional approach to treat irregular astigmatism in ectatic cornea with rapid visual rehabilitation.

Patterned corneal collagen crosslinking for astigmatism: computational modeling study.

PURPOSE: To test the hypothesis that spatially selective corneal stromal stiffening can alter corneal astigmatism and assess the effects of treatment orientation, pattern, and material model complexity in computational models using patient-specific geometries. SETTING: Cornea and Refractive Surgery Service, Academic Eye Institute, Cleveland, Ohio, USA. DESIGN: Computational modeling study. METHODS: Three-dimensional corneal geometries from 10 patients with corneal astigmatism were exported from a clinical tomography system (Pentacam). Corneoscleral finite element models of each eye were generated. Four candidate treatment patterns were simulated, and the effects of treatment orientation and magnitude of stiffening on anterior curvature and aberrations were studied. The effect of material model complexity on simulated outcomes was also assessed. RESULTS: Pretreatment anterior corneal astigmatism ranged from 1.22 to 3.92 diopters (D) in a series that included regular and irregular astigmatic patterns. All simulated treatment patterns oriented on the flat axis resulted in mean reductions in corneal astigmatism and depended on the pattern geometry. The linear bow-tie pattern produced a greater mean reduction in astigmatism (1.08 D ± 0.13 [SD]; range 0.74 to 1.23 D) than other patterns tested under an assumed 2-times increase in corneal stiffness, and it had a nonlinear relationship to the degree of stiffening. The mean astigmatic effect did not change significantly with a fiber- or depth-dependent model, but it did affect the coupling ratio. CONCLUSIONS: In silico simulations based on patient-specific geometries suggest that clinically significant reductions in astigmatism are possible with patterned collagen crosslinking. Effect magnitude was dependent on patient-specific geometry, effective stiffening pattern, and treatment orientation. FINANCIAL DISCLOSURES: Proprietary or commercial disclosures are listed after the references.