Corneal Cross-linking Research Articles

Management of keratoconus: an updated review.

Keratoconus is the most common corneal ectatic disorder. It is characterized by progressive corneal thinning with resultant irregular astigmatism and myopia. Its prevalence has been estimated at 1:375 to 1:2,000 people globally, with a considerably higher rate in the younger populations. Over the past two decades, there was a paradigm shift in the management of keratoconus. The treatment has expanded significantly from conservative management (e.g., spectacles and contact lenses wear) and penetrating keratoplasty to many other therapeutic and refractive modalities, including corneal cross-linking (with various protocols/techniques), combined CXL-keratorefractive surgeries, intracorneal ring segments, anterior lamellar keratoplasty, and more recently, Bowman's layer transplantation, stromal keratophakia, and stromal regeneration. Several recent large genome-wide association studies (GWAS) have identified important genetic mutations relevant to keratoconus, facilitating the development of potential gene therapy targeting keratoconus and halting the disease progression. In addition, attempts have been made to leverage the power of artificial intelligence-assisted algorithms in enabling earlier detection and progression prediction in keratoconus. In this review, we provide a comprehensive overview of the current and emerging treatment of keratoconus and propose a treatment algorithm for systematically guiding the management of this common clinical entity.

Safety and Efficacy of Corneal Cross-Linking in Patients Affected by Keratoconus: Long-Term Results.

The present study evaluated the effectiveness and safety of corneal collagen cross-linking (CXL). A total of 886 eyes with progressive keratoconus were enrolled in a retrospective cohort study in a tertiary care university hospital. CXL was performed using a standard epithelium-off Dresden protocol. Visual outcomes, maximum keratometry (Kmax), demarcation line measurements, and complications were recorded. Visual outcomes and keratometric data were analyzed in a subgroup comprising 610 eyes. Uncorrected distance visual acuity (UDVA) improved from 0.49 ± 0.38 LogMAR to 0.47 ± 0.39 LogMAR (p = 0.03, n = 610) three years after the procedure, while corrected distance visual acuity (CDVA) improved from 0.15 ± 0.14 LogMAR to 0.14 ± 0.15 LogMAR (p = 0.007, n = 610). A significant reduction of Kmax from 56.28 ± 6.10 to 54.98 ± 6.19 (p < 0.001, n = 610) was observed three years after CXL. In five eyes (0.82%, 5/610) keratoconus progression continued after CXL. Three eyes were retreated successfully with documented refractive and topographic stability after five years. In the 35 eyes that completed 10 years of follow-up, mean visual acuity and topographic parameters remained stable. In conclusion, CXL is a safe and effective treatment for avoiding keratoconus progression. Long-term data are encouraging, supporting a high safety profile for this procedure.

Dexpanthenol/sodium hyaluronate eye drops for corneal epithelial healing following corneal cross-linking in patients with keratoconus.

To evaluate the effect of dexpanthenol 2%/sodium hyaluronate 0.15% eye drops on corneal epithelial healing and corneal microstructural changes following corneal cross-linking (CXL) in patients with keratoconus. The study included 42 eyes of 21 patients with keratoconus who underwent CXL on both eyes. One eye of each patient was instilled dexpanthenol 2%/sodium hyaluronate 0.15% eye drops (DP/SH group) and the fellow eye was instilled unpreserved sodium hyaluronate 0.15% eye drops (SH group). The epithelial healing process was assessed every day until complete reepithelialization was achieved. The in vivo confocal microscopy (IVCM) findings were also recorded. The mean epithelial defect size 48.6 ± 6.7 mm2 for the DP/SH group and 48.2 ± 5.3 mm2 for the SH group. Complete reepithelialization was seen after 2.24 ± 0.44days (range 2-4days) in the DP/SH group and 3.43 ± 0.60days (3 to 5days) in the SH group. Posterior keratocyte density and endothelial cell density were similar in both groups. The mean subbasal nerve plexus density was significantly higher in the DP/SH group (postoperative 1month: 1.13 ± 1.51, 3months: 3.53 ± 2.55, 6months: 7.07 ± 1.42) compared to the SH group (postoperative 1month: 0.87 ± 1.43, 3months: 2.89 ± 2.62, 6months 6.33 ± 1.29). The DP/SH group revealed faster subbasal nerve regeneration and less edema compared to the SH group. Dexpanthenol 2%/sodium hyaluronate 0.15% eye drops were effective and safe for corneal epithelial healing, and promoted faster corneal reepithelialization, nerve regeneration, and keratocyte repopulation with reduced corneal edema compared to sodium hyaluronate eye drops.

Diagnosis and management of keratoconus in the paediatric age group: a review of current evidence.

The diagnosis and management of keratoconus in the paediatric age group presents additional challenges to those encountered in adults. The most significant of these, encountered in some young patients, are delayed presentation of unilateral disease, more advanced disease at diagnosis, difficulty in obtaining reliable corneal imaging, faster rates of disease progression and challenges in contact lens management. The stabilisation effect of corneal cross-linking (CXL), more extensively studied in adults with randomised trials and long-term follow-up, has been much less rigorously examined in children and adolescents. The high heterogeneity of published studies in younger patients, particularly in the choice of tomography parameters designated as primary outcome measures and the definitions of progression, indicates that improved standardisation for future studies on CXL will be necessary. There is no evidence that corneal transplant outcomes in young patients are poorer than those in adults. This review provides a current perspective on the optimal diagnosis and treatment of keratoconus in children and adolescents.

Donor Endothelial Cell Density Not Changed Immediately After Ex Vivo Corneal Cross-Linking

Purpose: The aim of this study was to evaluate the effect of corneal cross-linking on central endothelial cell density (ECD) by comparing masked measurements before and immediately after preparation of cross-linked (CXL) and non–cross-linked (non-CXL) donor corneas. Methods: Thirty donor corneas were randomized 1:1 to either CXL or non-CXL using a modified Dresden protocol. Specular microscopic images of the central corneal endothelium were obtained within 36 hours of recovery and within 3 hours of preparation completion. Images were sent to a central cornea image analysis reading center for ECD determination in a masked, dual-graded manner. Results: Before and after preparation, the mean ECD was 2567 ± 305 cells/mm2 and 2525± 339 cells/mm2 for the CXL group (n =15) and 2652 ± 365 cells/mm2 and 2572 ± 513 cells/mm2 for the non-CXL group (n =15), respectively. The mean difference in ECD before and after preparation was not statistically significant for the CXL and non-CXL groups (P = 0.36; P = 0.31, respectively). In addition, an independent sample t test showed no statistically significant difference in the ECD change between the CXL and non-CXL groups (P = 0.67). Conclusions: Our specular microscopic findings show that ex vivo cross-linking of donor corneas does not seem to produce acute decrease of central endothelial cell density. These findings are encouraging and assist in warranting a clinical trial examining its value in reducing refractive errors and improving postoperative visual outcomes in eyes with keratoconus that undergo keratoplasty.

The Biomechanical E-Staging: In Vivo Biomechanics in Keratoconus.

Belin's ABCD keratoconus classification system allows keratoconus staging based on the criteria of anterior (A) and posterior (B) corneal curvature, thinnest corneal thickness (C), and best spectacle-corrected visual acuity (D). These parameters also provide a progression assessment, but do not take corneal biomechanics into account. The analysis of corneal biomechanics by the Corvis ST (Oculus, Wetzlar, Germany) allows for separation of healthy and keratoconus corneas, based on the Corvis Biomechanical Index (CBI) and the Tomographic Biomechanical Index (TBI). As Corvis ST measurements are highly reliable and are independent of keratoconus severity, a biomechanical parameter was developed for keratoconus corneas based on the linear term of the CBI. This provides biomechanical keratoconus staging. The Corvis Biomechanical Factor (CBiF) is the basis for the introduction of the biomechanical E-staging, which augments the ABCD classification to the ABCDE classification, thus including the cornerstone of corneal biomechanics. This article highlights strengths and limitations of the ABCDE classification. "Unilateral keratoconus" supposedly turns out to be mostly a snapshot of a highly asymmetric keratectasia. Regular astigmatism is sometimes an important differential diagnosis to keratectasia and may be difficult to differentiate from it. Furthermore, the use of the biomechanical E-staging in daily practice for progression assessment of keratoconus and after its treatment by corneal cross-linking or implantation of intracorneal ring segments will be demonstrated and discussed.

Brillouin Spectroscopy in Ophthalmology.

Information about corneal biomechanics is crucial for achieving satisfactory outcomes after surgical corneal interventions, e.g., for astigmatic keratotomies, but also to identify corneas that are at risk for postoperative complications such as corneal ectasia. Hitherto, approaches to characterize corneal biomechanics in an in vivo setting have yielded only minor success, demonstrating the unmet medical need for a diagnostic technique to measure ocular biomechanics. This review shall explain the mechanism of Brillouin spectroscopy and summarize the current scientific knowledge for ocular tissue. PubMed research of relevant experimental and clinical publications, as well as reporting of own experience using Brillouin spectroscopy. Brillouin spectroscopy can measure different biomechanical moduli with a high spatial resolution. Currently, available devices are able to detect focal corneal weakening, e.g., in keratoconus, as well as stiffening after corneal cross-linking. Also, the mechanical properties of the crystalline can be measured. Corneal anisotropy and hydration, together with the dependence on the angle of the incident laser beam in Brillouin spectroscopy, are challenges in the precise interpretation of measured data. A clear advantage in the detection of subclinical keratoconus compared to corneal tomography, however, has not been shown yet. Brillouin spectroscopy is a technique to characterize biomechanical properties of ocular tissue in vivo. Published results confirm ex vivo data of ocular biomechanics; however, further improvements in the acquisition and interpretation of measured data are required until this technique can be used in a clinically viable setting.

Predicting corneal cross-linking treatment efficacy with real-time assessment of corneal riboflavin concentration.

To assess predictability of tissue biomechanical stiffening induced by UV-A light-mediated real-time assessment of riboflavin concentration during corneal crosslinking (CXL) of human donor tissues. Studio Italiano di Oftalmologia, Rome, Italy. Laboratory study. 20 sclerocorneal tissues were randomly stratified to undergo CXL with either the epithelium intact (n = 12) or removed (n = 8). Samples underwent corneal soaking with 0.22% riboflavin formulation (RitSight) with dosing time of t = 10 minutes and t = 20 minutes in epithelium-off and epithelium-on protocols, respectively. All tissues underwent 9-minute UV-A irradiance at 10 mW/cm 2 using theranostic device (C4V CHROMO4VIS). The device used controlled UV-A light irradiation to induce both imaging and treatment of the cornea, providing a real-time measure of corneal riboflavin concentration and treatment efficacy (ie, theranostic score) during surgery. Tissue biomechanics were assessed with an air-puff device (Corvis), which was performed before and after treatment. A 3-element viscoelastic model was developed to fit the corneal deformation response to air-puff excitation and to calculate the mean corneal stiffness parameter (k c ). Significant corneal tissue stiffening ( P < .05) was induced by the theranostic UV-A device in either CXL treatment protocol. Significant correlation was found between the theranostic score and the increase in k c ( R = 0.75; P = .003). The score showed high accuracy (94%) and precision (94%) to predict correctly samples that had improved tissue biomechanical strengthening. Real-time assessment of corneal riboflavin concentration provided a predictive and precise approach for significant improvement of tissue strength on individual corneas, regardless of CXL treatment protocol.

Acoustic Micro-Tapping Optical Coherence Elastography to Quantify Corneal Collagen Cross-Linking

To evaluate changes in the anisotropic elastic properties of exvivo human cornea treated with ultraviolet cross-linking (CXL) using noncontact acoustic micro-tapping optical coherence elastography (AμT-OCE). Acoustic micro-tapping OCE was performed on normal and CXL human donor cornea in an exvivo laboratory study. Normal human donor cornea (n=22) divided into 4 subgroups. All samples were stored in optisol. Elastic properties (in-plane Young's, E, and out-of-plane, G, shear modulus) of normal and ultraviolet CXL-treated human corneas were quantified using noncontact AμT-OCE. A nearly incompressible transverse isotropic model was used to reconstruct moduli from AμT-OCE data. Independently, cornea elastic moduli were also measured with destructive mechanical tests (tensile extensometry and shear rheometry). Corneal elastic moduli (in-plane Young's modulus, E, in-plane, μ, and out-of-plane, G, shear moduli) can be evaluated in both normal and CXL treated tissues, as well as monitored during the CXL procedure using noncontact AμT-OCE. Cross-linking induced a significant increase in both in-plane and out-of-plane elastic moduli in human cornea. The statistical mean in the paired study (presurgery and postsurgery, n=7) of the in-plane Young's modulus, , increased from 19 MPa to 43 MPa, while the out-of-plane shear modulus, G, increased from 188 kPa to 673 kPa. Mechanical tests in a separate subgroup support CXL-induced cornea moduli changes and generally agree with noncontact AμT-OCE measurements. The human cornea is a highly anisotropic material where in-plane mechanical properties are very different from those out-of-plane. Noncontact AμT-OCE can measure changes in the anisotropic elastic properties in human cornea as a result of ultraviolet CXL.

CUSTOMIZED CORNEAL CROSSLINKING WITH EXCIMER LASER ASSISTED EPITHELIUM REMOVAL FOR PROGRESSIVE KERATOCONUS - ONE YEAR RESULTS.

To evaluate the one year visual and tomographic results of customized cross-linking using excimer laser assisted epithelium removal and topography-guided irradiation in the treatment of progressive keratoconus. Coimbra Ophthalmology Unit. Private practice. Coimbra, Portugal. Prospective non-randomized clinical trial. Eyes with documented progressive keratoconus were enrolled. Following de-epithelization with PTK, customized UV irradiation was performed, designed as 3 concentric circular areas centered on the thinnest point (Mosaic System, Avedro, USA). Energy exposure was 5.4J/cm2 in the outer circle and then increased centripetally to 7.2 J/cm2 and 10 J/cm2 . Corrected distance visual acuity (CDVA), refractive outcomes, and Scheimpflug tomographies (Allegro Oculyzer (WaveLight, Germany) were assessed at baseline, and 6 and 12 months postoperatively. This prospective study enrolled 37 eyes of 32 patients. Mean diameter for treated areas was 6.17 ± 0.80, 4.45 ± 0.47, and 2.58 ± 0.14 mm for the outer, medium, and inner circle, respectively. At the 1 year follow-up, mean CDVA improved significantly from 0.38 ± 0.19 to 0.20 ± 0.16 logMAR (p<0.01), with 34 of the 37 eyes (91.89%) retaining or improving CDVA. Mean pre-operative minimum pachimetry decreased from 449.26 ± 41.62 μm to 443.26 ± 41.06 μm (p=0.02). The maximal curvature (Kmax) decreased significantly from 58.50 ± 7.84 D to 57.05 ± 7.27 D (p<0.01). After 1 year, 34 eyes (91.89%) showed no signs of progression. One year after surgery, patients showed a significant improvement in visual acuity while achieving stabilization of disease progression.

Случаи отсутствия лечебного эффекта кросслинкинга при лечении кератоконуса

Purpose. Study of changes in morphometric parameters of cornea in keratoconus before and after corneal collagen crosslinking (CXL). Material and methods. 35 patients (35 eyes) with progressive keratoconus stages 1–3. The indexes of photokeratoscopy were studied in depth (topographer Pentacam (Oculus, Germany). CXL was performed according to the Dresden protocol. A corneal lenticule was used in 6 eyes. The analysis of the studied parameters was carried out initially and after 12 months. Results. By the end of the observation, in all patients, the average values of maximum keratometry (Kmax) decreased statistically significantly from 54.5 to 53.1 diopters, which indicated positive trend. Most indices of keratoconus according to topographer data (ISV, IVA, KI, CKI, IHA, Rmin), as well as the central corneal thickness, on average, significantly decreased. But in 5 patients (all men, mean age 25 years), the Kmax exceeded initial values (from 61.7 to 64.5 diopters), which indicated further progression of keratoconus. The initial values of Kmax in 3 out of 5 of these patients exceeded 57 diopters, which is risk of further progression of keratoconus. Conclusion. With a follow-up period of one year, it was found that CXL in 5 patients (14 %) with keratoconus stages 2-3 turned out to be ineffective. Keywords: keratoconus, photokeratoscopy, corneal collagen crosslinking

Short-Term Effect of Conventional Versus Accelerated Corneal Cross-Linking Protocol on Corneal Geography and Stability.

Purpose: To determine the 6-month effect of conventional (CXL30) and accelerated cross-linking with a UVA intensity of 9 mW/cm2 (CXL10) on corneal stability and to investigate whether there was a difference in ABCD grading system parameters regarding the two different procedures. Methods: Twenty-eight eyes of 28 patients with a documented keratoconus (KN) progression were included. Patients were selected to undergo either epi off CXL30 or CXL10. At the baseline and the follow-up visits after one (V1), three (V2), and six months (V3), the patients underwent complete ophthalmic examination and corneal tomography. Results: In the CXL30 group, all the parameters from the ABCD grading system significantly changed from baseline to V3; parameter A decreased (p = 0.048), B and C increased (p = 0.010, p < 0.001), and D decreased (p < 0.001). In the CXL10 group, there were no changes in parameters A (p = 0.247) and B (p = 0.933), though parameter C increased (p = 0.001) and D decreased (p < 0.001). After an initial decline after one month, visual acuity (VA) recovered on V2 and V3 (p < 0.001), and median maximal keratometry (Kmax) decreased in both groups (p = 0.001, p = 0.035). In the CXL30 group, there were significant changes in other parameters; average pachymetric progression index (p < 0.001), Ambrósio relational thickness maximum (ARTmax) (p = 0.008), front and back mean keratometry (p < 0.001), pachymetry apex (PA) (p < 0.001), and front elevation (p = 0.042). However, in the CXL10 group, there were significant changes only in ARTmax (p = 0.019) and PA (p < 0.001). Conclusion: Both epi-off CXL protocols showed similar short-term efficacy in improving VA and Kmax, halting the progression of KN, and both similarly changed tomographic parameters. However, the conventional protocol modified the cornea more significantly.

Clinical Results of Accelerated Iontophoresis-Assisted Epithelium-on Corneal Cross-linking for Progressive Keratoconus in Children.

To evaluate the clinical characteristics of pediatric patients with progression of keratoconus after accelerated iontophoresis-assisted epithelium-on corneal cross-linking (I-ON CXL) and to assess the efficacy and safety of re-treatment using accelerated epithelium-off CXL (epi-OFF CXL). Sixteen eyes of 16 patients (mean age: 14.6 ± 2.5 years) with keratoconus underwent I-ON CXL. The main outcome measures were uncorrected distance visual acuity, corrected distance visual acuity, maximum keratometry index (Kmax), minimum corneal thickness, elevation front and elevation back measured at the thinnest point, total higher order aberrations root main square (HOA RMS), coma RMS, and spherical aberration. An increment of Kmax greater than 1.00 diopter (D) and a decrease of greater than 20 µm in pachymetry were considered to determine the progression of keratoconus. Patients with progression of keratoconus after I-ON CXL were re-treated using an epi-OFF CXL protocol. Two years after I-ON CXL, 12 patients showed progression of keratoconus, whereas 4 patients were stable. There was significant worsening of Kmax (P = .04) and steepest keratometric reading (P = .01). Furthermore, a significant correlation was documented between progression of keratoconus and age (P = .02). These patients were re-treated using an epi-OFF protocol and after 2 years all patients were stable, and a statistically significant reduction of the mean Kmax (P = .007), HOA RMS (P = .05), and coma RMS (P = 05) was observed. I-ON CXL was ineffective in the treatment of pediatric keratoconus in younger children, whereas it had an efficacy of 2 years in older children. Re-treatment using epi-OFF CXL proved effective to halt progression of keratoconus after I-ON CXL failure. [J Pediatr Ophthalmol Strabismus. 2024;61(1):44-50.].

Efficacy of customized corneal crosslinking versus standard corneal crosslinking in patients with progressive keratoconus (C-CROSS study): study protocol for a randomized controlled trial

BackgroundKeratoconus is a degenerative disorder of the cornea leading to a protrusion and thinning with loss of visual acuity. The only treatment to halt the progression is corneal crosslinking (CXL), which uses riboflavin and UV-A light to stiffen the cornea. Recent ultra-structural examinations show that the disease is regional and does not affect the entire cornea. Treating only the affected zone with CXL could be as good as the standard CXL, that treats the entire cornea.MethodsWe set up a multicentre non-inferiority randomized controlled clinical trial comparing standard CXL (sCXL) and customized CXL (cCXL). Patients between 16 and 45 years old with progressive keratoconus were included. Progression is based on one or more of the following changes within 12 months: 1 dioptre (D) increase in keratometry (Kmax, K1, K2); or 10% decrease of corneal thickness; or 1 D increase in myopia or refractive astigmatism, requiring corneal crosslinking.DiscussionThe goal of this study is to evaluate whether the effectiveness of cCXL is non-inferior to sCXL in terms of flattening of the cornea and halting keratoconus progression. Treating only the affected zone could be beneficial for minimalizing the risk of damaging surrounding tissues and faster wound healing. Recent non-randomized studies suggest that a customized crosslinking protocol based on the tomography of the patient’s cornea may stop the progression of keratoconus and result in flattening of the cornea.Trial registrationThis study was prospectively registered at ClinicalTrials.gov on August 31st, 2020, the identifier of the study is NCT04532788.

Comparison of topographic outcomes between HPMC based and vitamin E TPGS based riboflavin solutions after corneal cross-linking.

To compare the visual and topographic results between patients who underwent epithelium-off cross-linking using riboflavin solutions compounds hydroxypropyl methylcellulose (HPMC) 1.1% and D-alpha-tocopheryl polyethylene-glycol 1000 succinate (VE-TPGS). In this study, 37 eyes treated with HPMC and 29 eyes treated with VE-TPGS were evaluated retrospectively. Spherical equivalent (SE), refractive cylinder, corrected distance visual acuity tests (CDVA), corneal topography indices (flat and steep meridians' keratometry (K1 and K2)), maximum keratometry (K max), central, thinnest, and apical corneal thicknesses, the front and back keratoconus vertex index (KVf, KVb), and the surface asymmetry index of the front and back surface (SIf, SIb), and endothelial cell density were compared at baseline and postoperative follow-up visits (1, 3, 6, and 12months). At the end of the 12th-month, K1, K2, and Kmax were decreased in both groups. In comparison to baseline, there was a decline in the HPMC group in the 3rd- month Kmax change, an increase was observed in the VE-TPGS group. In the 12th-month KVb change, an increase was observed in the HPMC group compared to the baseline, while a decrease was observed in the VE-TPGS group. The other parameters did not show a statistically significant difference between the groups (p > 0.05). At the end of 12 months, both riboflavins were effective in stopping the progression of keratoconus and were safe for endothelium. Although both riboflavins provide a decrease in keratometry values, it can be said that VE-TPGS is superior to HPMC in correcting the ectasia on the posterior corneal surface.

How Modifications of Corneal Cross-Linking Protocols Influence Corneal Resistance to Enzymatic Digestion and Treatment Depth.

The purpose of this study was to determine the effects of the Photoactivated Chromophore for Keratitis Corneal Cross-Linking (PACK-CXL) protocol modifications on corneal resistance to enzymatic digestion and treatment depth. Eight hundred one ex vivo porcine eyes were randomly divided into groups of 12 to 86 corneas, treated with various epi-off PACK-CXL modifications, including acceleration (30 > 2 minutes, 5.4J/cm2), increased fluence (5.4 > 32.4J/cm2), deuterium oxide (D2O) supplementation, different carrier types (dextran versus hydroxypropyl methylcellulose [HPMC]), increased riboflavin concentration (0.1 > 0.4%), and riboflavin replenishment during irradiation (yes/no). Control group eyes did not receive PACK-CXL. A pepsin digestion assay was used to determine corneal resistance to enzymatic digestion. A phalloidin fluorescent imaging assay was used to determine the PACK-CXL treatment effect depth. Differences between groups were evaluated using a linear model and a derivative method, respectively. PACK-CXL significantly increased corneal resistance to enzymatic digestion compared to no treatment (P < 0.03). When compared to a 10 minute, 5.4J/cm2 PACK-CXL protocol, fluences of 16.2J/cm2 and higher increased corneal resistance to enzymatic digestion by 1.5- to 2-fold (P < 0.001). Other protocol modifications did not significantly change corneal resistance. A 16.2J/cm2 fluence also increased collagen compaction in the anterior stroma, whereas omitting riboflavin replenishment during irradiation increased PACK-CXL treatment depth. Increasing fluence will likely optimize PACK-CXL treatment effectiveness. Treatment acceleration reduces treatment duration without compromising effectiveness. The generated data help to optimize clinical PACK-CXL settings and direct future research efforts.

Outcome indicators for cross linking in pediatric keratoconus.

To evaluate the predictive factors for successful corneal collagen cross-linking (CXL) in pediatric patients with Keratoconus (KC). This retrospective study was conducted using a prospectively built database. Patients (18 years old or younger) underwent CXL for KC between 2007 and 2017, with a 1-year follow-up period or longer. The outcomes included changes in Kmax (delta [Δ] Kmax = Kmaxlast - Kmaxpre) and LogMAR visual acuity (ΔLogMAR = LogMARlast - LogMARpre).The effects of CXL type (accelerated or non-accelerated), demographics (age, sex, background of ocular allergy, ethnicity), preoperative LogMAR visual acuity, maximal corneal power (Kmax), pachymetry (CCTpre), refractive cylinder, and follow-up (FU) time on the outcomes were analyzed. One hundred thirty-one eyes of 110 children were included (mean age, 16 ± 2 years; range, 10-18 years). Kmax and LogMAR improved from baseline to last visit: from 53.81 D ± 6.39 D to 52.31 D ± 6.06 D (p < 0.001) and from 0.27 ± 0.23 LogMAR units to 0.23 ± 0.19 LogMAR units (p = 0.005), respectively. A negative ΔKmax (meaning corneal flattening) was associated with a long FU, low CCTpre, high Kmaxpre, high LogMARpre, and non-accelerated CXL on univariate analysis. High Kmaxpre and non-accelerated CXL were associated with negative ΔKmax in the multivariate analysis.A negative ΔLogMAR (meaning vision improvement) was associated with a high LogMARpre in univariate analysis. CXL is an effective treatment option in pediatric patients with KC. Our results showed that the non-accelerated treatment was more effective than the accelerated treatment. Corneas with advanced disease had a greater effect on CXL.

Corneal Collagen Cross-Linking for Late Onset Progressive Keratoconus in Iridocorneal Endothelial Syndrome.

The aim of this study was to report the first case of successful use of corneal collagen cross-linking (CXL) to halt the progression of keratoconus in a patient with concurrent iridocorneal endothelial (ICE) syndrome. A 30-year-old White man was referred to our subspecialty corneal clinic for further investigation of right corectopia. The patient was asymptomatic and was otherwise fit. Slit-lamp examination revealed a right oval-shaped pupil decentered superiorly, a transillumination defect at the 5-o'clock position, minimal gutta-like changes in the corneal endothelium, and few inferior peripheral anterior synechiae. Dilated fundoscopy was normal in both eyes, with healthy optic discs, maculae, and peripheral retinae. Specular microscopy and slit-lamp findings suggested ICE syndrome. Subsequent investigation with corneal tomography showed progressive signs of inferior corneal ectasia with steepening, and thinning in the right eye, consistent with keratoconus. The left eye was unremarkable. Epithelium-off accelerated corneal CXL was performed in the affected eye. Early post-CXL follow-up (1 week) was unremarkable, and further follow-ups were arranged at 3, 6, 12, and 24 months, respectively. In subsequent reviews, the patient's vision and corneal tomography findings were stable. We describe the first case of corneal CXL for progressive keratoconus with ICE syndrome. co-existing keratoconus and ICE syndrome can occur, and corneal cross-linking was used successfully in this case to halt keratoconus progression. However, further studies will need to establish the impact of epithelium-off corneal cross-linking, especially in more severely affected eyes.

Effect of Corneal Collagen Cross-Linking on Subsequent Corneal Fungal Infection in Rats.

The purpose of this study was to determine whether corneal collagen cross-linking (CXL) alters fungal susceptibility and increases the severity of keratitis through macrophage activation in rats. Four weeks following CXL pretreatment, the corneal epithelium of adult rats was removed and inoculated with Candida albicans (C. albicans; CXL+inoculation group). The non-CXL-pretreated corneas were also inoculated with C. albicans (inoculation group). Clinical scoring and histopathological examination were performed to determine the severity of fungal keratitis. Immunofluorescence and confocal microscopy imaging were applied to determine the effects of CXL treatment on corneal local macrophage content. Real-time polymerase chain reaction (RT-PCR) and Western blots were used to evaluate mRNA and protein expression. Flow cytometry assays were performed to detect M1- and M2-type macrophages. CXL pretreatment (CXL+inoculation) resulted in higher infection success rate and more severe fungal keratitis than inoculation alone (inoculation group). On days 1, 3, and 7 following fungal infection, the increase in macrophage infiltration and IL-1β, MMP-9, and VEGFA expression was greater in the CXL+inoculation group than in the inoculation group. Number of M1- and M2-type macrophages, M1 to M2 ratio, M1-type macrophage genes, inducible nitric oxide synthase (iNOS), and tumor necrosis factor (TNFα) expression were higher in the CXL+inoculation group compared with the inoculation group. Our data demonstrate that CXL may increase the colonization of macrophages and activate more M1-type macrophages to increase fungal susceptibility and severity of keratitis. This study may aid long-term risk assessment and treatment of the complications of CXL.

Analysis of Biomechanical Response After Corneal Crosslinking with Different Fluence Levels in Porcine Corneas

Purpose To evaluate corneal stiffening of porcine corneas induced by corneal crosslinking (CXL) with constant irradiance as a function of total fluence. Methods Ninety corneas from freshly enucleated porcine eyes were divided into five groups of 18 eyes. Groups 1–4 underwent epi-off CXL using a dextran-based riboflavin solution and an irradiance of 18 mW/cm2, group 5 served as the control group. Groups 1 to 4 were treated with a total fluence of 20, 15, 10.8, and 5.4 J/cm2, respectively. Thereafter, biomechanical measurements were performed on 5 mm wide and 6 mm long strips using an uniaxial material tester. Pachymetry measurements were performed on each cornea. Results At 10% strain, the stress was 76, 56, 52, and 31% higher in groups 1–4, respectively compared to the control group. The Young’s modulus was 2.85 MPa for group 1, 2.53 MPa for group 2, 2.46 MPa for group 3, 2.12 MPa for group 4, and 1.62 MPa for the control group. The difference between groups 1 to 4 and the control group 5 were statistically significant (p = <0.001; p = <0.001; p = <0.001; p = 0.021). In addition, group 1 showed significantly more stiffening than group 4 (p = <0.001), no other significant differences were found. Pachymetry measurements revealed no statistically significant differences among the five groups. Conclusion Additional mechanical stiffening can be achieved by increasing the fluence of the CXL. There was no threshold detected up to 20 J/cm2. A higher fluence could compensate the weaker effect of accelerated or epi-on CXL procedures.