Salzmann's Nodular Degeneration in Refractive Surgery: The Earlier Hit Hypothesis of EBM Injury-Related Fibrosis of the Subepithelial Space and Deeper Corneal Extension.

PURPOSE: To review the atypical development of Salzmann's nodular degeneration (SND) after two cases of laser in situ keratomileusis (LASIK) and one case of photorefractive keratomileusis (PRK), and to highlight the pathophysiology of SND and its treatment. METHODS: Three cases of SND (two following LASIK performed with microkeratomes and one following PRK) were reviewed and Pubmed.gov and internet searches were performed. RESULTS: SND is myofibroblast-generated fibrosis in the subepithelial space between the epithelium and Bowman's layer that develops years or decades after traumatic, surgical, infectious, or inflammatory injuries to the cornea in which the epithelial basement membrane is damaged in one or more locations and does not fully regenerate. It is hypothesized based on these cases, and the previous immunohistochemistry of other investigators, that myofibroblast precursors, such as fibrocytes or corneal fibroblasts, that enter the subepithelial space are driven to develop into myofibroblasts, which slowly proliferate and extend the fibrosis, by transforming growth factor-beta from epithelium and tears that passes through the defective epithelial basement membrane. These myofibroblasts and the disordered collagens, and other extracellular matrix components they produce, make up the subepithelial opacity characteristic of SND. Nodules are larger accumulations of myofibroblasts and disordered extracellular matrix. If the injury is associated with damage to the underlying Bowman's layer and stroma, as in LASIK flap generation, then the myofibroblasts and fibrosis can extend into Bowman's layer and the underlying anterior stroma. CONCLUSIONS: SND fibrosis often extends into Bowman's layer and the anterior stroma if there are associated Bowman's defects, such as incisions or lacerations. In the latter cases, SND frequently cannot be removed by simple scrape and peel, as typically performed for most common SND cases, but can be trimmed to remove the offending tissue. This condition is more accurately termed Salzmann's subepithelial fibrosis. [J Refract Surg. 2024;40(5):e279-e290.].

Subclinical Keratoconus Detection and Characterization Using Motion-Tracking Brillouin Microscopy.

PURPOSE: To characterize focal biomechanical alterations in subclinical keratoconus (SKC) using motion-tracking (MT) Brillouin microscopy and evaluate the ability of MT Brillouin metrics to differentiate eyes with SKC from normal control eyes. DESIGN: Prospective cross-sectional study. PARTICIPANTS: Thirty eyes from 30 patients were evaluated, including 15 eyes from 15 bilaterally normal patients and 15 eyes with SKC from 15 patients. METHODS: All patients underwent Scheimpflug tomography and MT Brillouin microscopy using a custom-built device. Mean and minimum MT Brillouin values within the anterior plateau region and anterior 150 µm were generated. Scheimpflug metrics evaluated included inferior-superior (IS) value, maximum keratometry (Kmax), thinnest corneal thickness, asymmetry indices, Belin/Ambrosio display total deviation, and Ambrosio relational thickness. Receiver operating characteristic (ROC) curves were generated for all Scheimpflug and MT Brillouin metrics evaluated to determine the area under the ROC curve (AUC), sensitivity, and specificity for each variable. MAIN OUTCOME MEASURES: Discriminative performance based on AUC, sensitivity, and specificity. RESULTS: No significant differences were found between groups for age, sex, manifest refraction spherical equivalent, corrected distance visual acuity, Kmax, or KISA% index. Among Scheimpflug metrics, significant differences were found between groups for thinnest corneal thickness (556 µm vs. 522 µm; P < 0.001), IS value (0.29 diopter [D] vs. 1.05 D; P < 0.001), index of vertical asymmetry (IVA; 0.10 vs. 0.19; P < 0.001), and keratoconus index (1.01 vs. 1.05; P < 0.001), and no significant differences were found for any other Scheimpflug metric. Among MT Brillouin metrics, clear differences were found between control eyes and eyes with SKC for mean plateau (5.71 GHz vs. 5.68 GHz; P < 0.0001), minimum plateau (5.69 GHz vs. 5.65 GHz; P < 0.0001), mean anterior 150 µm (5.72 GHz vs. 5.68 GHz; P < 0.0001), and minimum anterior 150 µm (5.70 GHz vs. 5.66 GHz; P < 0.001). All MT Brillouin plateau and anterior 150 µm mean and minimum metrics fully differentiated groups (AUC, 1.0 for each), whereas the best performing Scheimpflug metrics were keratoconus index (AUC, 0.91), IS value (AUC, 0.89), and IVA (AUC, 0.88). CONCLUSIONS: Motion-tracking Brillouin microscopy metrics effectively characterize focal corneal biomechanical alterations in eyes with SKC and clearly differentiated these eyes from control eyes, including eyes that were not differentiated accurately using Scheimpflug metrics. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Motion-Tracking Brillouin Microscopy Evaluation of Normal, Keratoconic, and Post-Laser Vision Correction Corneas.

PURPOSE: To characterize focal biomechanical differences between normal, keratoconic, and post-laser vision correction (LVC) corneas using motion-tracking Brillouin microscopy. DESIGN: Prospective cross-sectional study. METHODS: Thirty eyes from 30 patients (10 normal controls [Controls], 10 post-LVC, and 10 stage I or II keratoconus [KC]) had Scheimpflug and motion-tracking Brillouin microscopy imaging using a custom-built device. Mean, maximum (max) and minimum (min) Brillouin shift, spatial standard deviation, and max-min values were compared. Min values were correlated with local Brillouin values at multiple Scheimpflug imaging locations. RESULTS: Mean (P < .0003), min (P < .00001), spatial standard deviation (P < .01), and max-min (P < .001) were significantly different between the groups. In post hoc pairwise comparisons, the best differentiators for group comparisons were mean (P = .0004) and min (P = .000002) for Controls vs KC, min (P = .0022) and max-min (P = .002) for Controls vs LVC, and mean (P = .0037) and min (P = .0043) for LVC vs KC. Min (area under the receiver operating characteristic = 1.0) and mean (area under the receiver operating characteristic =  0.96) performed well in differentiating Control and KC eyes. Min values correlated best with Brillouin shift values at the thinnest corneal point (r2 = 0.871, P = .001) and maximum keratometry value identified in the tangential curvature map (r2 = 0.840, P = .002). CONCLUSIONS: Motion-tracking Brillouin microscopy effectively characterized focal corneal biomechanical alterations in LVC and KC and clearly differentiated these groups from Controls. Primary motion-tracking Brillouin metrics performed well in differentiating groups as compared with basic Scheimpflug metrics, in contrast to previous Brillouin studies, and identified focal changes after LVC where prior Brillouin studies did not.

Phase-Decorrelation Optical Coherence Tomography Measurement of Cold-Induced Nuclear Cataract.

Purpose: The purpose of this work is to determine the sensitivity of phase-decorrelation optical coherence tomography (OCT) to protein aggregation associated with cataracts in the ocular lens, as compared to OCT signal intensity. Methods: Six fresh porcine globes were held at 4°C until cold cataracts developed. As the globes were re-warmed to ambient temperature, reversing the cold cataract, each lens was imaged repeatedly using a conventional OCT system. Throughout each experiment, the internal temperature of the globe was recorded using a needle-mounted thermocouple. OCT scans were acquired, their temporal fluctuations were analyzed, and the rates of decorrelation were spatially mapped. Both decorrelation and intensity were evaluated as a function of recorded temperature. Results: Both signal decorrelation and intensity were found to change with lens temperature, a surrogate of protein aggregation. However, the relationship between signal intensity and temperature was not consistent across different samples. In contrast, the relationship between decorrelation and temperature was found to be consistent across samples. Conclusions: In this study, signal decorrelation was shown to be a more repeatable metric for quantification of crystallin protein aggregation in the ocular lens than OCT intensity-based metrics. Thus, OCT signal decorrelation measurements could enable more detailed and sensitive study of methods to prevent cataract formation. Translational Relevance: This dynamic light scattering-based approach to early cataract assessment can be implemented on existing clinical OCT systems without hardware additions, so it could quickly become part of a clinical study workflow or an indication for use for a pharmaceutical cataract intervention.

Optimized Artificial Intelligence for Enhanced Ectasia Detection Using Scheimpflug-Based Corneal Tomography and Biomechanical Data.

PURPOSE: To optimize artificial intelligence (AI) algorithms to integrate Scheimpflug-based corneal tomography and biomechanics to enhance ectasia detection. DESIGN: Multicenter cross-sectional case-control retrospective study. METHODS: A total of 3886 unoperated eyes from 3412 patients had Pentacam and Corvis ST (Oculus Optikgeräte GmbH) examinations. The database included 1 eye randomly selected from 1680 normal patients (N) and from 1181 "bilateral" keratoconus (KC) patients, along with 551 normal topography eyes from patients with very asymmetric ectasia (VAE-NT), and their 474 unoperated ectatic (VAE-E) eyes. The current TBIv1 (tomographic-biomechanical index) was tested, and an optimized AI algorithm was developed for augmenting accuracy. RESULTS: The area under the receiver operating characteristic curve (AUC) of the TBIv1 for discriminating clinical ectasia (KC and VAE-E) was 0.999 (98.5% sensitivity; 98.6% specificity [cutoff: 0.5]), and for VAE-NT, 0.899 (76% sensitivity; 89.1% specificity [cutoff: 0.29]). A novel random forest algorithm (TBIv2), developed with 18 features in 156 trees using 10-fold cross-validation, had a significantly higher AUC (0.945; DeLong, P < .0001) for detecting VAE-NT (84.4% sensitivity and 90.1% specificity; cutoff: 0.43; DeLong, P < .0001) and a similar AUC for clinical ectasia (0.999; DeLong, P = .818; 98.7% sensitivity; 99.2% specificity [cutoff: 0.8]). Considering all cases, the TBIv2 had a higher AUC (0.985) than TBIv1 (0.974; DeLong, P < .0001). CONCLUSIONS: AI optimization to integrate Scheimpflug-based corneal tomography and biomechanical assessments augments accuracy for ectasia detection, characterizing ectasia susceptibility in the diverse VAE-NT group. Some patients with VAE may have true unilateral ectasia. Machine learning considering additional data, including epithelial thickness or other parameters from multimodal refractive imaging, will continuously enhance accuracy. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Case for Epithelium-Off Corneal Cross-linking.

ABSTRACT: The question of whether the epithelium should be removed in corneal cross-linking (CXL) in the treatment of keratoconus and other corneal ectatic disorders remains controversial. The motivation for epithelium-on CXL methods, which are not yet FDA approved and vary greatly in methodology, is to reduce the risk of vision-threatening complications related to debridement. However, as discussed in this counterpoint piece, most high-level evidence suggests that removal of the epithelium facilitates greater crosslinking effectiveness as measured by primary clinical outcome metrics such as topographic flattening and stabilization of disease. Furthermore, quality evidence is still lacking for a significant reduction in rates of infectious keratitis or loss of vision that can be attributed to debridement-related complications. In the absence of comparative effectiveness trials or long-term follow-up studies that show otherwise, the FDA-approved epi-off protocol is still the standard-bearer for safe and effective stabilization of corneal ectatic disease.

Determining the Utility of Epithelial Thickness Mapping in Refractive Surgery Evaluations.

PURPOSE: To determine the impact of corneal epithelial thickness maps on screening for refractive surgery candidacy in a single refractive surgical practice. DESIGN: Comparison of screening methods. METHODS: A total of 100 consecutive patients who presented for refractive surgery screening were evaluated. For each patient, screening based on Scheimpflug tomography, clinical data, and patient history was performed and a decision on eligibility for laser in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), and small incision lenticule extraction (SMILE)was independently made by 2 masked examiners. Examiners were then shown patients' epithelial thickness maps derived from optical coherence tomography (OCT). The percentage of screenings that changed after evaluating the epithelial thickness maps, with regard to candidacy for surgery, and ranking of surgical procedures from most to least favorable was determined. RESULTS: Candidacy for corneal refractive surgery changed in 16% of patients after evaluation of the epithelial thickness maps, with 10% of patients screened in and 6% screened out. Surgery of choice changed for 16% of patients, and the ranking of surgical procedures from most to least favorable changed for 25% of patients. A total of 11% of patients gained eligibility for LASIK, whereas 8% lost eligibility for LASIK. No significant difference was found between the evaluations of the 2 examiners. CONCLUSIONS: Epithelial thickness mapping derived from optical coherence tomography imaging of the cornea altered candidacy for corneal refractive surgery, as well as choice of surgery, in a substantial percentage of patients in our practice, and was thus a valuable tool for screening evaluations. Overall, the use of epithelial thickness maps resulted in screening in a slightly larger percentage of patients for corneal refractive surgery.

Biomechanics of Ophthalmic Crosslinking.

Crosslinking involves the formation of bonds between polymer chains, such as proteins. In biological tissues, these bonds tend to stiffen the tissue, making it more resistant to mechanical degradation and deformation. In ophthalmology, the crosslinking phenomenon is being increasingly harnessed and explored as a treatment strategy for treating corneal ectasias, keratitis, degenerative myopia, and glaucoma. This review surveys the multitude of exogenous crosslinking strategies reported in the literature, both "light" (involving light energy) and "dark" (involving non-photic chemical processes), and explores their mechanisms, cytotoxicity, and stage of translational development. The spectrum of ophthalmic applications described in the literature is then discussed, with particular attention to proposed therapeutic mechanisms in the cornea and sclera. The mechanical effects of crosslinking are then discussed in the context of their proposed site and scale of action. Biomechanical characterization of the crosslinking effect is needed to more thoroughly address knowledge gaps in this area, and a review of reported methods for biomechanical characterization is presented with an attempt to assess the sensitivity of each method to crosslinking-mediated changes using data from the experimental and clinical literature. Biomechanical measurement methods differ in spatial resolution, mechanical sensitivity, suitability for detecting crosslinking subtypes, and translational readiness and are central to the effort to understand the mechanistic link between crosslinking methods and clinical outcomes of candidate therapies. Data on differences in the biomechanical effect of different crosslinking protocols and their correspondence to clinical outcomes are reviewed, and strategies for leveraging measurement advances predicting clinical outcomes of crosslinking procedures are discussed. Advancing the understanding of ophthalmic crosslinking, its biomechanical underpinnings, and its applications supports the development of next-generation crosslinking procedures that optimize therapeutic effect while reducing complications.

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.