Standard Corneal Cross-linking Research Articles

A Case Series of Infectious Keratitis After Corneal Cross-linking.

To present the 7-year experience of a tertiary eye hospital while exploring possible risk factors and incidence of infectious keratitis in patients undergoing standard corneal cross-linking (CXL). This retrospective cohort study included patients with progressive keratoconus undergoing standard CXL in the Farabi Eye Hospital and all other patients who had undergone CXL in other facilities and were diagnosed as having infectious keratitis in the 7-year period of the study. Among the total of 4,863 eyes that underwent CXL, 6 eyes developed infectious keratitis, yielding an incidence rate of 0.12%. Additionally, 13 eyes from 10 patients with a CXL history in other facilities who developed infectious keratitis were included. The mean age was 23.75 years, and 75% of patients were men and 25% were women. Gram-positive bacteria and Staphylococcus aureus were the most prevalent pathogens. Meibomian gland dysfunction, dry eye disease, or blepharitis were present in 12 patients. Medical treatment did not arrest the disease progress in 5 patients, which eventually required cases to undergo keratoplasty. This study supports the need for proper patient selection by using a comprehensive medical history. It also highlights the imperative role of rigorous patient education and follow-up, particularly in the first postoperative week. Finally, the study emphasizes aggressive early therapy for patients with suspicious findings. [J Refract Surg. 2023;39(8):564-572.].

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.

Topography-Guided Photorefractive Keratectomy After Intacs Corneal Implantation for Keratoconus and Ectasia

Purpose: To evaluate outcomes of topography-guided photorefractive keratectomy (TG-PRK) after Intacs (Addition Technology) implantation for eyes with keratoconus or ectasia. Methods: Three eyes of 3 patients with keratoconus or ectasia after laser in situ keratomileusis were treated with TG-PRK 6 months after simultaneous Intacs implantation and standard corneal cross-linking (CXL) was performed. Results: After Intacs implantation/CXL, uncorrected distance visual acuity improved four lines in 1 eye and did not change significantly in the other eyes. At 1 year of follow-up after TG-PRK, uncorrected distance visual acuity further improved more than two lines in all eyes. After Intacs implantation/CXL, corrected distance visual acuity did not change significantly in all eyes. One year after TG-PRK, corrected distance visual acuity improved more than two lines in all eyes. After both procedures, the inferior-superior value decreased and maximum keratometry flattened significantly in all eyes. The change in thinnest pachymetry was less than 32 µm. Conclusions: TG-PRK appears promising as a treatment modality to improve visual acuity and corneal topography in patients with keratoconus and ectasia with prior Intacs placement who may have previously required segment explantation after poor refractive outcomes. [ Journal of Refractive Surgery Case Reports. 2023;3(2):e10–e13.]

Three-year follow-up of accelerated versus standard corneal cross-linking in paediatric Keratoconus.

Standard corneal collagen cross-linking (S-CXL) is an effective treatment to arrest Keratoconus (KC) progression in children. Less is known on the long-term efficacy of accelerated CXL (A-CXL) in paediatric populations. A historical cohort analysis of paediatric patients (≤18 years) with KC who underwent S-CXL and A-CXL at two tertiary referral centres in Israel between 2010-2017. Preoperative and 3-year postoperative evaluation included changes in visual acuity (best spectacle corrected [BSCVA]) and uncorrected [UCVA]), refractive errors, and keratometric data. Ninety-three eyes of 93 patients were analysed (A-CXL: n = 39; S-CXL: n = 54). Baseline characteristics were similar between groups. Both groups showed a significant improvement in visual acuity compared to baseline (S-CXL: 0.810-0.602 LogMAR UCVA; A-CXL: 0.890-0.306 LogMAR UCVA, p < 0.05 for both). Improvement in BSCVA and UCVA following A-CXL was non-inferior to S-CXL (< ± 0.2 LogMAR). Kmax decreased by a mean of 0.98 ± 5.56 dioptres following S-CXL (p = 0.02) and by 1.48 ± 8.4 dioptres following A-CXL (p = 0.015). Thinnest pachymetry decreased following both treatments (S-CXL: by 26.8 ± 40.7 µm, p = 0.001, A-CXL: by 10.2 ± 13.4 µm, p = 0.028), the difference between groups was within the non-inferiority margin (< ± 10 µm). Paediatric patients followed for three years after A-CXL showed improved visual function, reduced corneal astigmatism and Kmax, and decreased thinnest corneal thickness. A-CXL was non-inferior to S-CXL at three years in terms of best-corrected and uncorrected visual acuity, thinnest pachymetry, and astigmatism. For Kmax, non-inferiority could not be concluded.

Efficacy and Safety of Standard Corneal Cross-Linking Procedures Performed With Short Versus Standard Riboflavin Induction: A Save Sight Keratoconus Registry Study.

The objective of this study was to compare the effectiveness and safety of short versus standard riboflavin induction times in cross-linking (CXL) for keratoconus. A retrospective comparative study was conducted with data from the Save Sight Keratoconus Registry. Inclusion criteria were epithelium-off technique, standard UVA CXL protocol (3 mW/cm 2 for 30 minutes), riboflavin induction for 15 minutes (short) or 30 minutes (standard), and 1 year of follow-up data after CXL. Outcome measures included changes in best-corrected visual acuity (BCVA), keratometry in the steepest meridian (K2), maximum keratometry (Kmax), thinnest pachymetry (TCT), and adverse events. Analysis was conducted using mixed-effects regression models adjusted for age, sex, visual acuity, keratometry, pachymetry, practice, and eye laterality. Two hundred eighty eyes (237 patients; mean, 27.3 ± 10.5 years old; 30% female) were included. The riboflavin induction time was short in 102 eyes (82 patients) and standard in 178 eyes (155 patients). The baseline characteristics (sex, mean age, BCVA, keratometry, and pachymetry [TCT]) were similar between the groups. At the 1-year follow-up visit, no statistically significant differences were observed in flattening in K2 and improvement in BCVA. Greater Kmax flattening [-1.5 diopters (D) vs. -0.5D, P = 0.031] and a greater proportion of >2% increase in TCT (23.5 vs. 11.3, P = 0.034) and haze (29 vs. 15, P = 0.005) were observed with short riboflavin induction. Short and standard riboflavin induction times achieved similar degrees of flattening in K2 and improvement in vision. Greater improvements in Kmax and TCT were seen with short riboflavin times; however, this group had higher rates of haze.

Bactericidal Efficacy of High Irradiance Ultraviolet A Photoactivation of Riboflavin Versus Standard Corneal Cross-Linking Protocol In Vitro.

The purpose of this study was to compare the efficacy of high ultraviolet A (UVA) irradiance photoactivation of riboflavin (vitamin B2) versus the standard corneal cross-linking protocol on bacterial viability. Methicillin-sensitive Staphylococcus aureus (MSSA) Newman strain and methicillin-resistant multidrug-resistant S. aureus (MDR-MRSA) USA300, CA409, CA127, GA656, and NY315 strains were exposed to a UVA energy dose of 5.4 to 6 J/cm 2 by 2 high irradiance regimens: A) 30 mW/cm 2 for 3 minutes and B) 10 mW/cm 2 for 10 minutes with B2 0.1%. Control groups included B2/UVA alone, CA409 exposed to standard B2 0.1% + UVA (3 mW/cm 2 for 30 minutes), and an untreated sample. Cell viability was assessed. Triplicate values were obtained. The Mann-Whitney test and Student t test were used for statistical analysis. There was no difference comparing the median bacterial load (log CFU/mL) of the untreated samples versus regimen A: Newman P = 0.7, CA409 P = 0.3, USA300 P = 0.5, CA127 P = 0.6, GA656 P = 0.1, and NY315 P = 0.2 ( P ≥ 0.1); and B: Newman P = 0.1, CA409 P = 0.3, USA300 P = 0.4, CA127 P = 0.6, GA656 P = 0.1, and NY315 P = 0.3 ( P ≥ 0.1). Standard regimen killed 100% of CA409. Photoactivation of B2 by high UVA irradiance does not seem to be effective for bacterial eradication in this study.

Estimation of corneal thickness ex vivo and in vivo at instillation of photosensitizer solutions in different modifications of UV corneal crosslinking

Objectives: to evaluate the effectiveness of photosensitizer solutions in the experiment in different modifications of standard UV corneal crosslinking. Materials and Methods. Experiments were performed on 32 enucleated porcine eyes ex vivo and 12 rabbits (24 eyes) in vivo, divided into 4 groups depending on instillations of the photosensitizer solutions: Dextralink, Ribolink, Hypolink and Riboflavin. Evaluation of corneal saturation was performed using two modifications of standard UV CXL: in the first case, instillation of the photosensitizer solution was performed during the entire crosslinking procedure (30 min - saturation and 30 min - ultraviolet irradiation); in the second case, instillations lasted only for the first 30 minutes, the precorneal riboflavin film was removed, and instillation of solution was not performed. Results and Discussion. Instillation of photosensitizer solutions within 60 minutes showed that Dextralink significantly reduced the thickness of the cornea by about 24 % ex vivo and 21 % in vivo, while Hypolink, on the contrary, caused its increase by 9 % ex vivo and 23 % in vivo, respectively. The use of Ribolink and Riboflavin did not change the linear parameters of the cornea during the entire follow-up period. The results of the 2nd series of studies showed that effects of solutions on the cornea during their instillation for 30 minutes were generally preserved during the entire observation period up to 60 minutes. In the group where Dextralink and Hypolink solutions were used, there was a slight tendency to normalization of the initial parameters of the cornea. Conclusion. Safe and effective implementation of UV crosslinking of the cornea is possible on the basis of a rational approach to the performing the stages of stroma saturation with photosensitizer solutions, depending on the initial state of the cornea: Dextralink is recommended for a thickness of more than 450 m, Ribolink - at 400-450 m, Hypolink - from 350 to 400 m. Halting of instillations on the saturated stroma during UV irradiation is advisable to be accompanied by intraoperative control of its thickness. When performing a standard crosslinking technique, where instillations of photosensitizer accompany the stage of UV irradiation of the cornea, it is necessary to take into account the presence of a precorneal film that can absorb some of the radiation energy. The peculiarity of this crosslinking technique can be considered as a potential way to protect intraocular tissues from excessive exposure to UV radiation.

Evaluation of the Physiological Corneal Intrastromal Riboflavin Concentration and the Corneal Elastic Modulus After Violet Light Irradiation.

PurposeKeraVio is a corneal crosslinking treatment modality that utilizes violet light (VL)-emitting glasses and topical epithelium-on riboflavin administration. We focus on the new KeraVio protocol without riboflavin. This study aims to quantify the physiological intrastromal concentrations of riboflavin in corneas without riboflavin decreases and evaluate the biomechanics of corneas after VL irradiation.MethodsTwelve human donor corneas were included in this study and randomly categorized into four groups. The corneas underwent four imbibition techniques (physiological riboflavin without drops, epithelial [epi]-on with 0.05% flavin adenine dinucleotide [FAD], epi-off with FAD, and 0.1% riboflavin epi-off). Corneas in the FAD epi-on, FAD epi-off, and riboflavin epi-off groups were instilled with the respective solution every 2 minutes for 30 minutes. An ex vivo experiment was conducted with 24 porcine corneas arranged into three treatment groups and one control group. Corneas in the KeraVio with FAD epi-on group were treated with VL irradiation at 0.31 mW/cm2 for 4.8 hours (5.4 J/cm2) and simultaneously received FAD drops every 30 minutes during the VL irradiation. Corneas in the group with KeraVio without FAD epi-on were only treated with VL irradiation (5.4 J/cm2).ResultsWe identified the original physiological riboflavin of human corneal stroma at a concentration of 0.31 ± 0.03 µg/g, but its value was approximately 39-fold smaller than that in the 0.1% riboflavin epi-off group. The group with KeraVio without FAD and the standard corneal crosslinking group showed a significant increase in biomechanical stability compared with the controls, whereas the elastic modulus in the treated groups was equivalent.ConclusionsWe preliminarily identified physiological riboflavin in human corneas without adding riboflavin drops. The VL exposure may strengthen the corneal biomechanics without requiring the use of additional riboflavin drops.Translational RelevanceWe preliminarily identified physiological riboflavin in the human cornea without adding riboflavin drops. VL irradiation without riboflavin drops may increase the corneal stiffness using physiological riboflavin.

Accelerated versus Standard Corneal Cross-linking for Progressive Keratoconus in Syria.

PurposeTo compare the outcomes of accelerated versus standard corneal cross-linking for the treatment of progressive keratoconus.Methods In this retrospective comparative study, 63 eyes of 40 patients with progressive keratoconus were divided into two groups; 27 eyes in group one were treated with an accelerated protocol (10 mW/cm, 9 min) and 36 eyes in group two were treated with the standard method (3 mW/cm, 30 min). Visual acuity, refraction, corneal topography, corneal tomography, and anterior and posterior corneal higher-order aberrations (HOAs) were assessed preoperatively and 18–30 months postoperatively.ResultsThe LogMAR uncorrected and corrected distance visual acuity values were improved in both groups postoperatively. However, the improvement was significantly higher in group one (P 0.05, all). The flattening in the anterior keratometry readings, flat K, steep K, and average K were significantly higher in group two (P 0.001, all). The maximum anterior keratometry (AKf) values significantly decreased in both groups, whereas the maximum posterior keratometry (AKb) values increased. The reduction in the minimum corneal thickness (ThKmin) was significantly greater (36.49um) in group two, compared to 10.85um in group one. There was a significant increase in the posterior average keratometry, and a significant decrease in the posterior astigmatism, along 3 mm meridian in S-CXL (P = 0.03, P = 0.008, respectively), while the corresponding values showed no statistical significance in group one (P 0.05). The anterior corneal trefoil was significantly reduced in group one (P = 0.002), whereas anterior total HOAs and coma were significantly improved in group two (P 0.0014, all). The posterior corneal spherical aberration decreased significantly in group one (P = 0.02), while group two revealed significant reduction in the posterior trefoil values (P = 0.011). The change in the anterior maximum keratometry was significantly and positively correlated to the preoperative maximum keratometry in group two (P = 0.53, P = 0.003).ConclusionAn accelerated cross-linking protocol using 10 mW/cm for 9 min showed more visual improvement and less pachymetric reduction when compared to the standard protocol, however, anterior corneal flattening, posterior corneal steepening, and the change in the posterior astigmatism were significantly higher in the standard protocol; while corneal HOAs were improved in both protocols.

Infective Keratitis Following Iontophoresis-assisted Corneal Crosslinking (I-CXL): A Case Report

Introduction: The standard corneal crosslinking (S- CXL) technique requires corneal epithelial removal, thus increasing the risk of postoperative complications. Newer technique like iontophoresis-assisted corneal crosslinking (I-CXL) with comparable efficacy as S-CXL but without the increased risk of complications associated with corneal epithelium removal is used. However, being a comparatively newer technique, the safety and efficacy of I-CXL have not been fully explored. Case Description: Here, we present a case of a 28-year-old woman who presented with infective keratitis in one eye after uneventful bilateral I-CXL for keratoconus. Two days after the procedure, the patient presented with decreased vision and pain in the right eye. Clinical examination revealed ciliary injection and central corneal rounded infiltrates measuring 3.0 mm × 3.0 mm with an overlying epithelial defect. Microbiological studies revealed negative results. Based on clinical examination, the patient was managed successfully with fortified topical antibiotics. Conclusion: To the best of our knowledge, we report the first documented case of unilateral infective keratitis following bilateral I-CXL. Ophthalmologists should monitor the possible complications post-I-CXL as it might not be as safe as we expect.

Comparison of Standard and Transepithelial Corneal Cross-Linking for the Treatment of Keratoconus: A Meta-analysis.

Purpose To compare the clinical results of standard corneal cross-linking (SCXL) with transepithelial corneal cross-linking (TECXL) in progressive keratoconus using a meta-analysis. Methods PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were searched up to June 2020 to identify relevant studies. The PRISMA guidelines were followed. Primary outcomes were change in uncorrected distance visual acuity and maximum keratometry (Kmax) after CXL. Secondary outcomes were change in corrected distance visual acuity, mean refractive spherical equivalent (MRSE), spherical and cylindrical error, endothelial cells density (ECD), and central corneal thickness (CCT). Results Sixteen studies with a total of 690 eyes (SCXL: 332 eyes; TECXL: 358 eyes) were included. At the last follow-up, SCXL provided a greater decrease in maximum keratometry (Kmax) than TECXL (weighted mean difference (WMD) −1.12; 95% confidence interval (CI) −1.96, −0.29). For the other outcomes, there were no statistically significant differences. Conclusions Except for a greater decrease in Kmax with SCXL group, both groups have a comparable effect on visual, pachymetric, and endothelial parameters at 24 months after surgery. Larger studies with a longer follow-up time are necessary to determine whether these techniques are comparable in the long term.

Accelerated and Standard Corneal Cross-Linking Protocols in Patients with Down Syndrome: A Non-inferiority Contralateral Randomized Trial.

IntroductionTo compare the results of an accelerated corneal cross-linking (CXL) protocol (9 mW/cm2, 10 min) with the standard CXL protocol (3 mW/cm2, 30 min) in patients with Down syndrome (DS) who have keratoconus (KC).MethodsTwenty-seven 10- to 20-year-old patients with DS who had bilateral progressive KC were enrolled in a contralateral randomized trial and completed 2 years of follow-up examinations. Fellow eyes were randomly allocated to the accelerated CXL group or the standard CXL group. The main outcome measure was change in maximum keratometry (Kmax) centered on the steepest point (zonal Kmax − 3 mm) with a non-inferiority margin of 1.0 diopter (D). Vision and refraction tests, ophthalmic examinations, and corneal tomography were performed at baseline and at 6, 12, and 24 months after CXL. Failure was defined as an increase of ≥ 1.0 D in zonal Kmax − 3 mm within a 12-month period.ResultsThe mean age (± standard deviation) of the patients was 15.71 ± 2.40 years. The within-group change in zonal Kmax − 3 mm was not significant after 2 years in either group, and within-group zonal Kmax − 3 mm remained stable. At 2 years after CXL, the mean change in the zonal Kmax − 3 mm was – 0.02 ± 0.81 D and – 0.31 ± 0.86 D in the accelerated CXL and standard CXL groups, respectively (P = 0.088). At 1 year of follow-up, three patients in the accelerated CXL group showed treatment failure (mean change in zonal Kmax − 3 mm + 2.12 ± 0.11 D); no patients in the standard CXL group showed treatment failure. At 2 years of follow-up, these three patients showed a decrease of – 0.43 ± 0.18 D in zonal Kmax − 3 mm from a baseline value of 55.11 ± 0.32 D. The 2-year trends of the inferior–superior asymmetry and vertical coma were statistically significantly different between the two groups, with the accelerated CXL protocol showing superiority in patients with higher baseline values.ConclusionIn young patients with Down syndrome, the accelerated CXL protocol was able to halt disease progression and may be an alternative for the standard CXL protocol. In advanced KC, the efficacy of the accelerated approach was delayed and appeared later in the follow-up. In asymmetric cornea, the accelerated CXL resulted in centralization of the corneal cone.Trial RegistrationIranian Registry of Clinical Trials, IRCT20100706004333N3Electronic supplementary materialThe online version of this article (10.1007/s40123-020-00303-4) contains supplementary material, which is available to authorized users.

Changes and quantitative characterization of hyper-viscoelastic biomechanical properties for young corneal stroma after standard corneal cross-linking treatment with different ultraviolet-A energies

Corneal collagen cross-linking (CXL) treatment can restore vision in patients suffering from keratoconus and corneal injury, by improving the mechanical properties of the cornea. The correlation between ultraviolet-A (UVA) irradiant energies of standard CXL (SCXL) and corneal visco-hyperelastic mechanical behavior remains unknown. In this study, SCXL with four different UVA irradiant energy doses (0–5.4 J/cm2) were administered as part of quantitative treatments of corneal stromal lenticules extracted from young myopic patients via small incision lenticule extraction (SMILE) corneal refractive surgery. Double-strip samples with symmetric geometries were cut simultaneously for SCXL treatment and non-treated control. First, 40 pairs of strips were loaded to failure to assess the mechanical parameters of the material. Then, another 40 pairs were tested using a special uniaxial tensile test including quasi-static loading–unloading, instantaneous loading, and stress relaxation, to determine the visco-hyperelastic mechanical behavior. Upon combining the collagen fibril crimping constitutive model with the quasi-linear viscoelastic model, it was observed that with increasing UVA energy dose, the corneal strength and hyperelastic stiffness were significantly enhanced, while the maximum stretch and viscosity of the cornea were significantly reduced. Considering the quantitative analysis of SCXL and the rehabilitation prediction of keratoconus treatment, the results clarify the biomechanical behavior of human corneal stroma in SCXL clinical surgery. Statement of SignificanceThis study quantitatively analyzes the improvement in the biomechanical properties of young central corneal stroma, due to SCXL treatment with different energies. Furthermore, the correlation between the hyper-viscoelastic mechanical parameters and UVA irradiant energy doses of SCXL are clarified. The contribution of this study fills the knowledge gap of the CXL on corneal biomechanics. It can not only clarify this mechanism better but also assist with guiding SCXL surgery for individualized patient corneas.

Changes and Quantitative Characterization of Hyper-Viscoelastic Biomechanical Properties for Young Corneal Stroma after Standard Corneal Cross-Linking Treatment with Different Ultraviolet-A Energies

Corneal collagen cross-linking (CXL) treatment can restore vision in patients suffering from keratoconus and corneal injury, by improving the mechanical properties of the cornea. The correlation between ultraviolet-A (UVA) irradiant energies of standard CXL (SCXL) and corneal visco-hyperelastic mechanical behavior remains unknown. In this study, SCXL with four different UVA irradiant energy doses (0-5.4 J/cm2) were administered as part of quantitative treatments of corneal stromal lenticules extracted from young myopic patients via small incision lenticule extraction (SMILE) corneal refractive surgery. Double-strip samples with symmetric geometries were cut simultaneously for SCXL treatment and non-treated control. First, 40 pairs of strips were loaded to failure to assess the mechanical parameters of the material. Then, another 40 pairs were tested using a special uniaxial tensile test including quasi-static loading-unloading, instantaneous loading, and stress relaxation, to determine the visco-hyperelastic mechanical behavior. Upon combining the collagen fibril crimping constitutive model with the quasi-linear viscoelastic model, it was observed that with increasing UVA energy dose, the corneal strength and hyperelastic stiffness were significantly enhanced, while the toughness and viscosity of the cornea were significantly reduced. Considering the quantitative analysis of SCXL and the rehabilitation prediction of keratoconus treatment, the results clarify the biomechanical behavior of human corneal stroma in SCXL clinical surgery.

Biomechanical efficacy of corneal cross-linking using hypoosmolar riboflavin solution.

The use of hypoosmolar riboflavin solution has been suggested for cross-linking thin corneas. The aim of this study was to compare the biomechanical efficacy of corneal cross-linking using hypoosmolar dextran-free riboflavin solution (HCXL) versus isoosmolar standard corneal cross-linking treatment (CXL). A total of 24 postmortem porcine eyes with debrided corneas were subdivided into three treatment groups: Controls, the isoosmolar group with isoosmolar 0.1% riboflavin-20% dextran solution and the hypoosmolar group with dextran-free, 0.1% riboflavin solution. The samples were irradiated with UVA light of 365 nm wavelength and an irradiance of 3 mW/cm² for 30 min (dose 5.4 J/cm²). For the biomechanical measurements, 400-µm-deep anterior corneal flaps were created using a lamellar rotating microkeratome. Uniaxial stress-strain measurements were performed. In the isoosmolar treatment group, stress and Young's modulus at 8% strain were significantly increased by 67.97%, respectively, 62.62% versus the controls. In the hypoosmolar treatment group, stress and Young's modulus at 8% strain were significantly increased by 81.21%, respectively, 51.40% versus the controls. There was no significant difference between the iso- and hypoosmolar groups in biomechanical efficacy. On histology, there was no edema in the anterior 200 µm of the corneas after stromal swelling by the hypoosmolar riboflavin solution. Corneal cross-linking using isoosmolar or hypoosmolar riboflavin solution induces a comparable biomechanical effect. This is explained by the localization of the maximum cross-linking effect in the anterior 200 µm of the cornea which are not affected by the swelling effect of hypoosmolar riboflavin solution.

Topographic Localization of the Demarcation Line after UV Corneal Crosslinking in Progressive Keratoconus

Purpose: To assess the topographic location of the demarcation line in in different areas of the cornea after standard corneal crosslinking. Patients and methods. 12 patients (15 eyes) with keratoconus of stages 1–2 of Amsler-Kruimerich classification were observed. UV cross-linking was performed in all patients according to the standard Dresden protocol with 0.1% aqueous solution of riboflavin. The patients underwent optical coherence tomography of the anterior segment of the eye on “DRI OCT Triton” (“Topcon”, Japan) in different areas of the cornea to assess the location of the demarcation line. Results. Demarcation line was revealed in 1 month after standard corneal cross-linking in most cases (87%). Biomicroscopy showed that DL limited the anterior and middle laers of the stroma from the posterior one. The stromal demarcation line depth according to OCT averaged 305.73 ± 41.08 μm (range of 282–345 μm) at the center, nasally — 215.16 ± 35.5 μm (range of 160–289 μm) and temporally 205,23 ± 32.81 μm (range of 190–276 μm). A significant difference in the depth of DL localization in the central zone of the cornea and a 6 mm zone (p < 0.001) was noted. Conclusion. The corneal stromal (обычно) demarcation line is one of the indicators of the depth of photochemical process of corneal cross-linking. Optimal timing of detection of DL following corneal collagen crosslinking is 2 weeks — 3 months. The depth of DL in the corneal studied areas is different; it is deeper in the central zone than in the peripheral ones.

Multipoint assessment of demarcation line depth after standard and accelerated cross-linking in central and inferior keratoconus

PurposeTo determine the changes in the depth of the demarcation line in the central to peripheral cornea following accelerated compared to standard corneal cross-linking (CXL). MethodsIn this prospective, non-randomized study, 60 eyes with progressive keratoconus underwent accelerated or standard CXL (30 in each group). Anterior segment optical coherence tomography (AS-OCT) was done one month later by two independent masked examiners to measure the depth of the demarcation line in the central cornea and on peripheral rings. ResultsThe inter-examiner agreement (intra-class correlation coefficient) was >0.75 for all measured points, and average measurements were used in the analysis. The depth of the visualized demarcation line in the center was 223.4 ± 67.4 μm and 354.9 ± 79.0 μm in the accelerated and standard groups, respectively (P < 0.001). The depth significantly decreased from the center to the 7 mm ring in both groups (all P < 0.05). This change was 7.7–26.1% and 2.2%–11.1% in the accelerated and standard groups, respectively. In the accelerated group, the demarcation line was deeper in the central cone sub-group compared to the inferior cone sub-group, but in the standard group, the demarcation line was deeper in the inferior cone sub-group (all P < 0.05). Cases with an inferior cone showed greater inter-group differences in all studied points. ConclusionsThe depth of the demarcation line with accelerated CXL is less than the standard protocol and decreases from the center towards the periphery. Demarcation lines are more homogenized with standard CXL. In cases with an inferior cone, demarcation line depth varies throughout the cornea.

Subclinical Inflammatory Response: Accelerated versus Standard Corneal Cross-Linking

ABSTRACTPurpose: To compare the subclinical inflammatory response (as measured by anterior chamber flare) induced after standard (3 mW/cm2, 30 min) and accelerated (18 mW/cm2, 5 min) corneal cross-linking (CXL).Methods: In this comparative, non-randomized study, patients with progressive keratoconus who underwent standard or accelerated CXL were studied. Laser flare photometery (FM-600; Kowa, Tokyo, Japan) was used to measure anterior chamber flare preoperatively and at 1 week, 1 month, 3 months, and 6 months after the procedure.Results: Sixty eyes of 60 patients were studied; 30 eyes in each group. Mean baseline flare values were 4.15 ± 1.19 and 4.57 ± 2.17 ph/ms in standard and accelerated groups, respectively (p = 0.228).and after surgery increased in all follow-up measurements in the both groups similarly (P > 0.05).Conclusion: Both standard and accelerated CXL results in induction of a subclinical inflammatory response that persists up to 6 month. The response was similar between the two groups.

Prospective Randomized Trial of Corneal Cross-linking Riboflavin Dosing Frequencies for Treatment of Keratoconus and Corneal Ectasia

To investigate whether the riboflavin dosing frequency affects corneal cross-linking efficacy or safety, given that isotonic riboflavin solution is viscous and each installation coats the corneal surface with a film that absorbs some of the incident ultraviolet A light. Prospective, randomized, single-center equivalence trial. Patients with progressive keratoconus or ectasia after refractive surgery (n= 510). One eye per patient was prospectively randomized to 2-minute or 5-minute riboflavin dosing intervals with standard corneal cross-linking (epithelial removal and 30-minute irradiation with 3 mW/cm2 ultraviolet A light). Block randomization resulted in comparable representation of keratoconus and ectasia after refractive surgery in the 2 treatment arms. Treatment equivalence was assessed using the 2 one-sided test. Fellow eyes (n= 207) were treated with 5-minute dosing and considered in the safety analysis. The primary hypothesis was equivalent change in the topography-derived maximum keratometry value from baseline to 6 months with 2-minute vs. 5-minute dosing. A ±0.75-diopter margin of equivalence for the treatment difference between dosing regimens was considered clinically relevant. Adverse events and changes from baseline to 6 months in corrected distance visual acuity (CDVA), uncorrected distance visual acuity, and minimum corneal thickness were assessed. The mean reduction in maximum keratometry from baseline was equivalent with 2-minute and 5-minute riboflavin dosing intervals at 6 months (0.97 and 0.76 diopters, respectively; 90% confidence interval for treatment difference,-0.23 to 0.66; per-protocol population). With both dosing intervals, the mean improvement in CDVA was 0.07 logarithm of the minimum angle of resolution or 3.5 letters at 6 months. Of the 635 study and fellow eyes examined at 6 months, 134 (21%) gained and 32 (5%) lost 2 or more lines of CDVA. Three eyes (0.4%) developed sterile infiltrates, 1 (0.1%) had delayed epithelial healing with dendrites, and 3 (0.4%) had recurrent epithelial defects. Three eyes (0.4%) were re-treated. The 2 riboflavin dosing regimens produced equivalent reduction in the maximum keratometry value, with a favorable safety profile.

Randomized Controlled Trial Comparing Transepithelial Corneal Cross-linking Using Iontophoresis with the Dresden Protocol in Progressive Keratoconus

To compare clinical outcomes of transepithelial corneal cross-linking using iontophoresis (T-ionto CL) and standard corneal cross-linking (standard CL) for the treatment of progressive keratoconus 12 months after the operation. Prospective randomized controlled clinical trial. Thirty-four eyes of 25 participants with progressive keratoconus were randomized into T-ionto CL (22 eyes) or standard CL (12 eyes). T-ionto CL was performed using an iontophoresis device with dextran-free 0.1% riboflavin-5-phosphate solution with enhancers and by irradiating the cornea with a 10 mW/cm2 ultraviolet A device for 9 minutes. Standard CL was performed according to the Dresden protocol. The primary outcome measure was stabilization of keratoconus after 12 months through analysis of maximum simulated keratometry readings (Kmax, diopters). Other outcome measures were corrected distance visual acuity (CDVA, logarithm of the minimum angle of resolution [logMAR]), manifest spherical equivalent refraction (D), central corneal thickness (CCT, micrometers) and endothelial cell density (ECD). Follow-up examinations were arranged at 3 and 7 days and 1, 3, 6, and 12 months. Twelve months after T-ionto CL and standard CL, Kmax on average flattened by-0.52±1.30 D (P=0.06) and-0.82±1.20 D (P= 0.04), respectively. The mean change in CDVA was-0.10±0.12 logMAR (P=0.003) and-0.03±0.06 logMAR (P= 0.10) after T-ionto CL and standard CL, respectively. The manifest spherical equivalent refraction changed on average by+0.71±1.44 D (P= 0.03) and+0.21±0.76 D (P= 0.38), respectively. The CCT and ECD measures did not change significantly in any group at 12 months. Significant differences in the outcome measures between treatments were found in the first week postoperatively. No complications occurred in the T-ionto CL group; 1 eye (8%) had sterile corneal infiltrates, which did not affect the final visual acuity, in the standard CL group. Significant visual and refractive improvements were found 12 months after T-ionto CL, though the average improvement in corneal topography readings was slightly lower than the Dresden protocol in the same period.