Oxygen-supplemented and topography-guided epithelium-on corneal crosslinking with pulsed irradiation for progressive keratoconus.

PURPOSE: To investigate the effects of customized topography-guided epithelium-on crosslinking (epi-on CXL) with oxygen supplementation on procedural efficacy and corrected distance visual acuity (CDVA) in patients with progressive keratoconus (KC) at 1 year. SETTING: Private eye clinic, Brisbane, Australia. DESIGN: Retrospective, single-center, nonrandomized case series. METHODS: Topography-guided epi-on CXL using the Mosaic system was performed on patients with progressive KC. Oxygen goggles; transepithelial riboflavin; and pulsed, high UV-A irradiance (1 second on, 1 second off; 30 mW/cm2) were applied to enhance oxygen kinetics and bioavailabilities of riboflavin and UV-A. Guided by baseline topography, a higher UV-A dose (15 J/cm2) was applied to the area of steepest anterior curvature with decreasing fluence (as low as 7.2 J/cm2) toward the outer 9 mm. Postoperative CDVA and maximum keratometry (Kmax) were evaluated. RESULTS: 102 eyes (80 patients) were followed for 11.5 ± 4.8 months. At the latest follow-up, mean CDVA (logMAR), mean K, and Kmax (diopters [D]) improved from 0.18 ± 0.28, 46.2 ± 3.8, and 53.0 ± 5.67 at baseline to 0.07 ± 0.18, 45.8 ± 3.7, and 51.9 ± 5.56, respectively (P < .001). 3 eyes (3%) lost more than 1 CDVA line, and another 3 eyes (3%) had increased Kmax greater than 2 D. 43 eyes were followed for at least 12 months (n = 43): mean CDVA, mean K, and Kmax improved from 0.19 ± 0.33 logMAR, 46.5 ± 3.5 D, and 53.6 ± 5.67 D to 0.07 ± 0.17 logMAR, 46.0 ± 3.5 D, and 52.33 ± 5.49 D, respectively (P ≤ .002). No complications were observed. CONCLUSIONS: Tailoring oxygen-supplemented epi-on CXL with differential UV-A energy distributions, guided by baseline topography, in patients with KC seems to be safe and effective. At 1 year, study reports sustained improved CDVA and corneal stabilization.

Transepithelial corneal crosslinking with oxygen enhancement and pulsed light for progressive ectasia: one-year results.

PURPOSE: To evaluate the efficacy and safety of transepithelial accelerated crosslinking (TE-ACXL) using pulsed light and supplemental oxygen. METHODS: Thirty eyes of 30 consecutive patients with progressive keratoconus or post-LASIK ectasia were enrolled in a prospective non-comparative study conducted at the Magrabi Eye Center (Jeddah, Saudi Arabia). All eyes underwent TE-ACXL with supplemental oxygen. Primary outcome measures were the mean change in corrected distance visual acuity (CDVA) (logMAR) and maximum keratometry (max K) from preoperatively to 12 months postoperatively. Secondary outcome measures included change in manifest refractive spherical equivalent (MRSE), refractive cylinder, keratometry, symmetry index (SI), center-surrounding index (CSI) and ectasia index (EI) of the anterior and posterior corneal surfaces, corneal and epithelial thickness at corneal vertex and thinnest location, corneal densitometry, corneal high order aberrations (HOA) and endothelial cell density (ECD). RESULTS: Mean age was 29.6 ± 8.2 years. At 1 year, the follow up rate was 93.3%. CDVA improved statistically significantly at 12 months (p = 0.027). Measures of corneal keratometry or pachymetry did not change significantly (p < 0.05). Postoperatively, a demarcation line was documented in 78.6% eyes at 1 month, and in 12 (42.9%) eyes at 12 months. The mean depth of the demarcation line was 341.9 ± 49.4 µm. Corneal densitometry increased significantly at 1- and 3-months (p < 0.05) and returned to normal levels at 6- and 12-months postoperatively. CONCLUSION: TE-ACXL with oxygen supplement is effective at halting the progression of corneal ectasia for at least 1 year and can be a refractive neutral procedure.

Antioxidant and Anti-Inflammatory Effects of Oral Supplementation with a Highly-Concentrated Docosahexaenoic Acid (DHA) Triglyceride in Patients with Keratoconus: A Randomized Controlled Preliminary Study.

A prospective, randomized, single-center preliminary study was performed in patients with keratoconus stages I-III (Amsler-Krumeich), who received a high rich docosahexaenoic acid (DHA) (1000 mg/day) supplement for 3 months versus untreated patients. One eye per patient was evaluated. Thirty-four patients were recruited (75% men, mean age 31 years), with 15 randomized to the control group and 19 to the DHA-treated group. Corneal topography variables and plasma biomarkers of oxidative stress and inflammatory status were evaluated. A panel of fatty acids in blood samples was also assessed. There were significant between-group differences in the astigmatism axis, asphericity coefficient, and intraocular pressure in favor of the DHA group. Additionally, between-group significant differences in total antioxidant capacity (TAC), malondialdehyde (MDA), free glutathione (GSH) and GSH/GSSG ratio, as well as reduced values of inflammatory markers, including interleukin (IL)-4, IL-6, and vascular endothelial growth factor (VEGF-A) were found. These preliminary findings support the usefulness of the antioxidant and anti-inflammatory effects of DHA supplementation for targeting underlying pathophysiological mechanisms of keratoconus. Prolonged duration of DHA supplementation may be needed to detect more noticeable clinical changes in corneal topography.

Vitamin D Supplementation Impacts Systemic Biomarkers of Collagen Degradation and Copper Metabolism in Patients With Keratoconus.

Purpose: To evaluate the impact of vitamin D (Vit D) supplementation on systemic biomarkers of collagen degradation, inflammation, oxidative stress, and copper metabolism in adolescent patients with keratoconus (KC). Methods: This was a prospective observational pilot study. Twenty patients (age range, 16-19 years) presenting KC and Vit D insufficiency (<30 ng/mL) were included. Vit D supplementation was prescribed by their general practitioner as per the standard of care. Patients were followed up for 12 months. At each visit, best spectacle-corrected visual acuity (BSCVA), maximal keratometry (Kmax), and thinnest corneal thickness (TCT) were evaluated. The primary outcome of the study was the proportion of patients with Kmax progression of less than 1 D throughout the 12-month follow-up time. Blood samples were collected at different time points to evaluate Vit D levels and systemic markers of collagen degradation, inflammation, oxidative stress, and copper metabolism by ELISA or RT-PCR. Results: Lower Vit D levels in the plasma were correlated with higher levels of systemic biomarkers of collagen degradation. Vit D supplementation increased the cell availability of copper. Moreover, stabilization of KC progression was found in 60% of patients (72% of eyes) after 12 months with Vit D supplementation. BSCVA, Kmax, and TCT rates remained stable during the observation period. Conclusions: Our findings support that Vit D administration could affect ocular and systemic biomarkers in KC and illuminate a possible mechanism that can be used to develop new treatment alternatives. Translational Relevance: Although KC therapy currently relies exclusively on surgical procedures, Vit D supplementation may offer a non-invasive and inexpensive alternative with minimal associated side effects.

Theranostic-guided corneal cross-linking: Preclinical evidence on a new treatment paradigm for keratoconus.

Theranostics is an emerging therapeutic paradigm of personalized medicine; the term refers to the simultaneous integration of therapy and diagnostics. In this work, theranostic-guided corneal cross-linking was performed on 10 human sclero-corneal tissues. The samples were soaked with 0.22% riboflavin formulation and underwent 9 minutes UV-A irradiance at 10 mW/cm2 using theranostic device, which provided both a measure of corneal riboflavin concentration and a theranostic score estimating treatment efficacy in real time. A three-element viscoelastic model was developed to fit the deformation response of the cornea to air-puff excitation of dynamic tonometry and to calculate the mean corneal stiffness parameter before and after treatment. Significant correlation was found between the theranostic score and the increase in mean corneal stiffness (R = 0.80; P < .001). Accuracy and precision of the theranostic score in predicting the induced corneal tissue stiffening were both 90%. The riboflavin concentration prior to starting the UV-A photo-therapy phase was the most important variable to allow corneal cross-linking to be effective. Theranostic UV-A light mediated imaging and therapy enables the operator to adopt a precise approach for achieving highly predictable biomechanical strengthening on individual corneas.

Corneal Cross-Linking: Epi-On.

ABSTRACT: When treating corneal ectasias, successful corneal cross-linking (CXL) requires three factors: riboflavin saturation of the corneal stroma, ultraviolet (UV) light, and oxygen. Riboflavin is too large to pass through epithelial tight junctions, so traditionally epithelial debridement is performed before riboflavin is applied making this approach an epithelium-off (epi-off) technique. However, this can result in pain as the epithelium regrows, corneal haze, and an increased infection risk postoperatively, which needs careful management with pharmacotherapy. Epithelium-on (epi-on) CXL should reduce the extent of these issues. Riboflavin can be passed through the epithelium into the stroma either by iontophoresis or with penetration enhancers, however this alone results in suboptimal cross-linking effects, as the epithelium not only absorbs around 20% of incoming UV energy, it also acts as a barrier to oxygen diffusion into the stroma. While it is simple to adjust the UV fluence delivered to the stroma to compensate for the energy lost in the epithelium, compensating for the lack of stromal oxygen is less simple. Several approaches (including oxygen goggles) have been taken to achieve this. However, adding iontophoresis and supplemental oxygen through goggles in the operating theater adds complexities that could be engineered out. Accordingly, the technique has advanced in the laboratory to a point where penetration enhancers, optimized UV irradiation profiles, and atmospheric oxygen can now provide epi-on CXL with the same corneal strengthening efficacy as epi-off CXL, suggesting simple, effective epi-on CXL could soon be in clinical use.

Ruthenium-induced corneal collagen crosslinking under visible light.

Corneal collagen crosslinking (CXL) is a commonly used minimally invasive surgical technique to prevent the progression of corneal ectasias, such as keratoconus. Unfortunately, riboflavin/UV-A light-based CXL procedures have not been successfully applied to all patients, and result in frequent complications, such as corneal haze and endothelial damage. We propose a new method for corneal crosslinking by using a Ruthenium (Ru) based water-soluble photoinitiator and visible light (430 nm). Tris(bipyridine)ruthenium(II) ([Ru(bpy)3]2+) and sodium persulfate (SPS) mixture covalently crosslinks free tyrosine, histidine, and lysine groups under visible light (400-450 nm), which prevents UV-A light-induced cytotoxicity in an efficient and time saving collagen crosslinking procedure. In this study, we investigated the effects of the Ru/visible blue light procedure on the viability and toxicity of human corneal epithelium, limbal, and stromal cells. Then bovine corneas crosslinked with ruthenium mixture and visible light were characterized, and their biomechanical properties were compared with the customized riboflavin/UV-A crosslinking approach in the clinics. Crosslinked corneas with a ruthenium-based CXL approach showed significantly higher young's modulus compared to riboflavin/UV-A light-based method applied to corneas. In addition, crosslinked corneas with both methods were characterized to evaluate the hydrodynamic behavior, optical transparency, and enzymatic resistance. In all biomechanical, biochemical, and optical tests used here, corneas that were crosslinked with ruthenium-based approach demonstrated better results than that of corneas crosslinked with riboflavin/ UV-A. This study is promising to be translated into a non-surgical therapy for all ectatic corneal pathologies as a result of mild conditions introduced here with visible light exposure and a nontoxic ruthenium-based photoinitiator to the cornea. STATEMENT OF SIGNIFICANCE: Keratoconus, one of the most frequent corneal diseases, could be treated with riboflavin and ultraviolet light-based photo-crosslinking application to the cornea of the patients. Unfortunately, this method has irreversible side effects and cannot be applied to all keratoconus patients. In this study, we exploited the photoactivation behavior of an organoruthenium compound to achieve corneal crosslinking. Ruthenium-based organic complex under visible light demonstrated significantly better biocompatibility and superior biomechanical results than riboflavin and ultraviolet light application. This study promises to translate into a new fast, efficient non-surgical therapy option for all ectatic corneal pathologies.

Oxygen-supplemented transepithelial-accelerated corneal crosslinking with pulsed irradiation for progressive keratoconus: 1 year outcomes.

PURPOSE: To investigate the effects of combining oxygen supplementation with enhanced UV-A light and increased riboflavin permeability in improving the efficacy of epithelium-on crosslinking (epi-on CXL). SETTING: Private eye clinic in Brisbane, Queensland, Australia. DESIGN: Retrospective single-center nonrandomized uncontrolled longitudinal cohort case series. METHODS: Transepithelial CXL was performed on keratoconic eyes. Applications of an oxygen goggle and pulsed UV-A irradiation (1 second on, 1 second off) were used to enhance oxygen kinetics during epi-on CXL. Additional procedural modifications included the use of benzalkonium chloride and high UV-A irradiance level (30 mW/cm 2 ) to improve the stromal bioavailability of riboflavin and UV-A. The main efficacy outcomes were the changes in mean corrected distance visual acuity (CDVA) and safety over 12 months. Additional refractive and keratometry (K) outcomes were also observed. RESULTS: 53 eyes (38 patients) were included in this study. 12 months postoperatively, mean CDVA improved from a mean of 0.18 ± 0.2 at baseline to 0.07 ± 0.1 logMAR ( P < .0001). No statistically significant change was observed in maximum K (Kmax) and mean K, which were respectively 51.7 ± 5.8 diopters (D) and 46.4 ± 3.85 D at baseline and 51.2 ± 5.7 D ( P = .152) and 46.0 ± 3.84 D ( P = .06) 12 months postoperatively. Only 3 eyes experienced an increase of more than 2 D in Kmax; however, none of these eyes experienced a CDVA loss. There were no reported infections, corneal scarring, or other severe adverse effects. CONCLUSIONS: Performing supplemental oxygen epi-on CXL with accelerated, pulsed UV-A irradiation in conjunction with riboflavin permeability enhancers resulted in improved CDVA ( P < .0001) and stable keratometry up to 12 months postoperatively with a good safety profile.

Comparison of topical omega-3 fatty acids with topical sodium hyaluronate after corneal crosslinking : Short term results.

PURPOSE: To evaluate the effect of topical omega 3 on ocular surface following corneal crosslinking (CXL) in keratoconus and compare with topical sodium hyaluronate. MATERIAL METHODS: 50 patients who underwent CXL were divided into two groups. In addition to topical steroids and antibiotics, Group A was prescribed topical omega 3; Group B was prescribed 0.3% sodium hyaluronate. Postoperatively, epithelial defect was measured everyday and at the first month corneal staining, Schirmer test was performed, tear break up time (TBUT), tear meniscus height (TMH) were measured. RESULTS: Preoperative keratometric values were similar between groups; there was no difference in terms of corneal staining, tear film stability; epithelial closure time (p: 0.052), and postoperative pain scores between groups. At 1st month, TBUT and TMH were significantly better in Group A than Group B(p: 0.001, p: 0.047). CONCLUSION: Topical omega 3 increases tear film stability more prominent than sodium hyaluronate following crosslinking.

Comparison of Continuous versus Pulsed Mode in Accelerated Corneal Collagen Cross-linking for Keratoconus.

PURPOSE: To compare efficacy and safety between the two modes of energy delivery-pulsed and continuous, in accelerated corneal collagen cross-linking (KXL) to stop the keratoconus advancement through topographical, visual, and refractive endpoints. METHODS: It was a prospective, comparative, randomized, interventional trial. Patients with bilateral progressive keratoconus were subjected to pulsed mode KXL (P-KXL) in the right and continuous mode KXL (C-KXL) treatment in the left eye. In both methods, additional supplemental oxygen was delivered to corneal surface using a nasal cannula connected to an oxygen supply. Uncorrected distance visual acuity (UDVA) and corrected distance visual acuity, posttreatment manifest spherical equivalent and astigmatism, and corneal topography were studied. The deformation amplitude index (DAI) was measured by Corvis-ST. Postoperative follow-up was done. RESULTS: One hundred eyes of 50 patients underwent P-KXL in the right eye and C-KXL in the left eye. The average follow-up was 12.1 ± 1.2 months. At 1 year posttreatment, the UDVA had a mean change of 0.11 ± 0.14 logMAR in P-KXL and 0.18 ± 0.14 logMAR in C-KXL groups. The line of demarcation was observed at 251.13 ± 18.28 µ and 245.28 ± 28.26 µ deep, respectively, in P-KXL- and C-KXL-treated eyes at 6 months' follow-up. The DAI as measured by Corvis-ST showed a significant decrease from pretreatment values of 1.12 ± 0.13 mm to 0.84 ± 0.14 mm (P < 0.01) in P-KXL eyes and from 1.04 ± 0.14 mm to 0.85 ± 0.15 mm (P = 0.03) in C-KXL eyes. Both the groups did not show any statistically significant endothelial cell loss posttreatment. CONCLUSION: C-KXL can give similar functional outcomes as P-KXL with the help of supplemental oxygen delivery with the added advantage of a shortened procedure time in comparison to pulsed mode.

Arginine Supplementation Promotes Extracellular Matrix and Metabolic Changes in Keratoconus.

Keratoconus (KC) is a common corneal ectatic disease that affects 1:500-1:2000 people worldwide and is associated with a progressive thinning of the corneal stroma that may lead to severe astigmatism and visual deficits. Riboflavin-mediated collagen crosslinking currently remains the only approved treatment to halt progressive corneal thinning associated with KC by improving the biomechanical properties of the stroma. Treatments designed to increase collagen deposition by resident corneal stromal keratocytes remain elusive. In this study, we evaluated the effects of arginine supplementation on steady-state levels of arginine and arginine-related metabolites (e.g., ornithine, proline, hydroxyproline, spermidine, and putrescine) and collagen protein expression by primary human corneal fibroblasts isolated from KC and non-KC (healthy) corneas and cultured in an established 3D in vitro model. We identified lower cytoplasmic arginine and spermidine levels in KC-derived constructs compared to healthy controls, which corresponded with overall higher gene expression of arginase. Arginine supplementation led to a robust increase in cytoplasmic arginine, ornithine, and spermidine levels in controls only and a significant increase in collagen type I secretion in KC-derived constructs. Further studies evaluating safety and efficacy of arginine supplementation are required to elucidate the potential therapeutic applications of modulating collagen deposition in the context of KC.

Singlet oxygen formation during accelerated and hyperaccelerated corneal cross-linking: in vitro study.

BACKGROUND: To evaluate the singlet oxygen (1O2) production of oxygen assisted %0.1 riboflavin and ultraviolet-A (UVA) crosslinking therapy (with and without oxygen assistance), in combination with standard, accelerated and hyper-accelerated procedures via an important quantitive marker of 1O2 which is the photo-oxidation of 1,3 diphenylisobenzofuran (DPBF). METHODS: %0.1 riboflavin-containing wells were irradiated with UVA light (365-nm wavelength) with or without 2-4-6-8 L/min oxygen flow assistance. Measurements of decrease in absorbance of DPBF were made in 30 mW (hyper-accelerated), 9 mW (accelerated), and 3 mW UV-A (standard) applications, and with additional 2-4-6-8 L/min oxygen flow in 30 mW and 2 L/min oxygen flow in 9 mW. A total of 8 different UV-A irradiance with and without oxygen supplementation groups were formed. RESULTS: 2 L/min oxygen assisted accelerated UV-A irradiance group has shown a greater decrease in DPBF absorbance compared to Dresden protocol. (p = 0.014) Also, Dresden protocol has shown a greater decrease in DPBF compared to all groups except accelerated crosslinking with 2 L/min oxygen. (p < 0.001) Oxygen assisted hyper-accelerated crosslinking groups were showed greater reduction in DPBF absorbance compared to standard crosslinking without oxygen groups. (p < 0.001). CONCLUSION: Oxygen supplementation may increase the singlet oxygen generation to the similar levels of Dresden Protocol's in accelerated group. Also, more singlet oxygen generation with oxygen supplementation compared to standard UV-A application might be considered to be promising in terms of shortening the crosslinking therapy.

The efficiency and safety of oxygen-supplemented accelerated transepithelial corneal cross-linking.

PURPOSE: To investigate the impact of oxygen delivery on the clinical outcomes of accelerated transepithelial corneal cross-linking (A-TE CXL). METHODS: Fifty-seven eyes of 44 progressive keratoconus (KCN) patients were randomly separated into two age-sex-matched groups. Twenty-nine eyes of 23 KCN patients that underwent oxygen-supplemented A-TE CXL formed the study group and 28 eyes of 21 patients treated with the same procedure but under room air conditions formed the control group. All patients were examined preoperatively, one, six and twelve months after the procedure. The logMAR spectacle-corrected distance visual acuity (CDVA), maximum keratometry (Kmax), mean keratometry, apical posterior keratometry, cylindrical power, minimum central corneal thickness, keratoconus vertex front and back, ocular aberrations, endothelial cell density (ECD), demarcation line depth (DLD) and proportion measures were recorded for statistical analysis. RESULTS: The preoperative, 1st, 6th and 12th months mean Kmax values of the study group were 55.14 ± 3.99D, 54.85 ± 3.82D, 54.37 ± 3.84D and 54.40 ± 3.86, respectively, and 54.47 ± 3.17D, 54.52 ± 2.97D, 54.25 ± 2.95D and 54.20 ± 2.97 in the control group. The mean Kmax value was decreased significantly more in the oxygen-supplemented group after 12 months compared to the control group (p = 0.019). The mean DLD was also significantly deeper in the study group (320 ± 17 µm) compared to the control group (269 ± 19 µm). There was no significant difference between the two groups in terms of ECD alterations at any of the time intervals (p > 0.05). CONCLUSION: Keratoconus progression was significantly halted in both groups 12 months after the treatment. In addition, oxygen supplementation during A-TE CXL further significantly increased clinical outcomes compared to room air conditions without any significant change in ECD measures.

Comparison of Visual, Tomographic, and Biomechanical Outcomes of 360 Degrees Intracorneal Ring Implantation With and Without Corneal Crosslinking for Progressive Keratoconus: A 5-Year Follow-up.

PURPOSE: To evaluate the long-term (5 years) results of 360 degrees intracorneal ring (ICR) implantation with and without corneal crosslinking (CXL) in patients with progressive keratoconus (KCN). METHOD: This historical cohort study was performed on 35 eyes with progressive KCN, which was randomly divided into 2 groups. Fourteen patients were implanted only with ICR, and 21 patients with KCN were treated with ICR plus CXL simultaneously. Uncorrected distance visual acuity (UCDVA), corrected distance visual acuity (CDVA), and refractive components were collected from patients' medical records. The biomechanical properties of patients were measured using the Corvis ST (Oculus, Inc, Weltzar, Germany). Corneal topography and aberrometry parameters were also recorded from the Pentacam HR device (Oculus). RESULTS: Both UCVA and CDVA increased in both groups after ICR implantation; however, this improvement was more significant in the ICR plus CXL group (P = 0.002 and P = 0.001, respectively). The mean improvement of CDVA in patients with ICR implantation with and without CXL was 0.56 ± 0.67 and 0.33 ± 0.61, respectively. A comparison of the long-term postoperative Tomographic and Biomechanical Index between 2 groups showed a better result in the ICR plus CXL group (P = 0.012). Topographic findings of the anterior corneal surface (flat-K, steep-K, mean-K, and astigmatism) after surgery were significantly better than before surgery in both groups (P < 0.05). CONCLUSIONS: Although ICR implantation alone might halt the KCN progression with acceptable visual, topographic, and biomechanical outcomes, the combination of ICR and CXL has an adjuvant and synergistic effect, especially in long-term follow-up.

Transepithelial Corneal Cross-linking With Supplemental Oxygen in Keratoconus: 1-Year Clinical Results.

PURPOSE: To evaluate the efficacy and safety of transepithelial corneal cross-linking (CXL) with supplemental oxygen. METHODS: This was a prospective, non-comparative, pilot cohort study conducted at the National Reference Center for Keratoconus (Toulouse, France) on patients with progressive keratoconus. Transepithelial, pulsed, accelerated CXL was performed in an oxygen-rich atmosphere. Oxygen goggles were applied to the eyes to maintain a high level of oxygen during treatment. The main efficacy outcome was the mean change from baseline in maximum keratometry (Kmax) and the secondary outcomes were the mean changes in flat keratometry (K1), steep keratometry (K2), mean keratometry (Km), corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), and demarcation line depth. The safety outcomes were the incidence of adverse events, the mean change in pachymetry, and endothelial cell count. RESULTS: Thirty-four eyes of 34 patients were included. At 12 months postoperatively, the Kmax decreased by 1.56 ± 1.71 diopters (D) (P < .0001) and CDVA improved by 0.093 ± 0.193 logMAR (P < .02). The K2 and Km decreased by 0.51 ± 1.03 D (P < .02) and 0.40 ± 0.78 D (P < .01), respectively. There was no change in K1 and UDVA. The most frequent adverse event was corneal haze (64.78%). There were neither cases of infectious keratitis or loss of more than two lines in CDVA nor changes in pachymetry or endothelial cell count. CONCLUSIONS: Transepithelial CXL performed in an oxygen-rich atmosphere results in improved Kmax and CDVA with good safety. These promising findings suggest that this procedure could be safe and capable of halting the progression of keratoconus. [J Refract Surg. 2021;37(1):42-48.].

Systemic supplemental oxygen therapy during accelerated corneal crosslinking for progressive keratoconus: randomized clinical trial.

PURPOSE: To investigate the potential additive effect of systemic supplemental oxygen administered during accelerated corneal crosslinking (CXL) for progressive keratoconus (KC). SETTING: Academic center. DESIGN: Randomized clinical trial. METHODS: Eyes with progressive KC randomized to 3 different CXL protocols were included. The first group (OA-CXL) included 19 eyes that underwent an accelerated CXL protocol (9 mW/cm2 for 10 minutes) while receiving systemic oxygen at a rate of 5 L/min for 10 minutes. The second group consisted of 14 eyes undergoing the same accelerated CXL protocol without supplemental oxygen therapy (A-CXL). The third group (C-CXL) comprised 14 eyes undergoing conventional CXL according to the Dresden protocol. All subjects were followed up for at least 6 months. Visual acuity, keratometry and corneal biomechanical parameters including corneal hysteresis and corneal resistance factor (CRF) were measured preoperatively and 6 months postoperatively. RESULTS: Reduction in maximum keratometry (Kmax) was significantly greater in the OA-CXL group (P = .01). At baseline, the mean Kmax was 54.31 ± 3.64 diopters (D) in the OA-CXL group, 54.66 ± 4.99 D in the A-CXL group, and 56.03 ± 5.28 D in the C-CXL group (P = .58), which reached 53.58 ± 3.24 D, 54.59 ± 4.65 D, and 55.87 ± 4.73 D at 6 months in the 3 study groups, respectively (P = .115). The mean CRF increased significantly only in the OA-CXL group from a baseline value of 6.32 ± 2.12 mm Hg to 7.38 ± 1.88 mm Hg at 6 months (P = .009). CONCLUSIONS: This study suggests superior efficacy of an accelerated CXL protocol coupled with systemic oxygen supplementation when compared with the accelerated CXL protocol and the conventional protocol in eyes with progressive KC. In addition to greater reduction in Kmax as the primary outcome, improvement in corneal biomechanics was also observed at 6 months.

Customized corneal crosslinking for treatment of progressive keratoconus: Clinical and OCT outcomes using a transepithelial approach with supplemental oxygen.

PURPOSE: To evaluate the outcomes of customized corneal crosslinking (CXL) for treatment of progressive keratoconus (KC) using a transepithelial approach with supplemental oxygen. SETTING: Siena Crosslinking Center, Siena, Italy. DESIGN: Prospective interventional case series. METHODS: Twenty-seven eyes of 24 patients (mean age 29.3 ± 7.3 years) with progressive KC underwent customized corneal CXL using a transepithelial approach with supplemental oxygen. Ultraviolet (UV)-A irradiation of 365 nm wavelength was delivered in an accelerated (30 mW/cm) pulsed-light UV light exposure in a 2-zone elliptical pattern. A total dose of 10 J/cm was delivered at the KC apex, surrounded by a broadbeam spot of 7.2 J/cm. After 0.25% riboflavin corneal soaking, the UV-A irradiation was initiated in the presence of additional oxygen (≥90% concentration) delivered through special goggles connected to an oxygen delivery system (flow-rate 2.5 liters per minute). Key outcome measures included corrected distance visual acuity (CDVA), keratometry (AK, K1, K2, and K-average), corneal higher-order aberrations, topographic and manifest cylinder, corneal optical coherence tomography (OCT) demarcation line, and endothelial cell count. RESULTS: Of the 27 eyes studied, a significant improvement of CDVA was recorded at 6-month follow-up visits, from baseline 0.19 ± 0.06 logarithm of the minimum angle of resolution (logMAR) to 0.11 ± 0.04 logMAR (P < .05). Significant flattening of steep keratometry (K2) was reported with mean change of -1.9 diopters (D) (P < .05), and coma values improved from 0.47 ± 0.28 µm to 0.28 ± 0.16 µm (P < .05). OCT revealed 2 demarcation lines at mean depths of 218.23 ± 43.32 µm and 325.71 ± 39.70 µm. CONCLUSIONS: In this series, customized CXL using a transepithelial approach with intraoperative supplemental oxygen resulted in clinically meaningful improvements in corneal curvature and CDVA without significant adverse events.

Accelerated corneal collagen cross-linking in clinical management of infectious keratitis.

OBJECTIVE: To evaluate the clinical efficacy of corneal collagen cross-linking (CXL) in the treatment of infectious corneal diseases. METHODS: This study retrospectively analyzed the clinical efficacy of CXL in 65 eyes with infectious keratitis in Jinan Second People's Hospital from December 2016 to June 2018. During 6 months of follow-up after CXL treatment, the results of confocal microscopy and anterior segment optical coherence tomography, as well as visual acuity and corneal biomechanical parameters, were recorded in detail. RESULTS: In general, the overall cure rate was 93.85%; no corneal endothelial dysfunction was encountered in any patients. After 6 months of follow-up, the visual acuity of cured patients was significantly enhanced, while corneal thickness was significantly reduced. Hyphae growth of patients with fungal keratitis was completely inhibited at 1 month postoperatively. Furthermore, corneal biomechanical parameters (i.e., central corneal thickness, deformation amplitude, and pachymetry intraocular pressure) were significantly improved after surgery, compared with baseline measurements. CONCLUSION: Accelerated CXL may be an effective adjuvant treatment for infectious keratitis.

Optimization of Oxygen Dynamics, UV-A Delivery, and Drug Formulation for Accelerated Epi-On Corneal Crosslinking.

Purpose: Corneal collagen crosslinking (CXL) through an intact epithelium (epi-on) at high irradiance could potentially improve patient comfort, visual recovery, and clinical workflow compared to conventional epi-off CXL. However, intact epithelium limits stromal delivery of the oxygen, photosensitizer, and ultraviolet-A (UV-A) radiation needed to drive CXL. This ex vivo study evaluated three different epi-on CXL protocols compared to positive and negative controls, specifically focusing on the impact of supplemental oxygen. Endpoints included stromal oxygen levels, stiffness of crosslinked tissue, and acute flattening of whole eyes.Materials & Methods: Ex vivo porcine eyes were held in a custom environmental chamber. Intrastromal oxygen levels were continuously measured before, during, and after UV illumination by a fiberoptic probe inserted into a laser-cut flap. Accelerated, high irradiance, epi-on CXL protocols using riboflavin formulated with benzalkonium chloride (BAC) were studied, with and without supplemental oxygen. These were compared to an alternate, low irradiance, epi-on protocol using riboflavin formulated with sodium iodide. Both negative (no CXL) and positive (epi-off modified Dresden protocol) controls were performed. Post-CXL elastic modulus was measured using extensiometry and anterior tangential curvature was measured using a Scheimpflug tomographer.Results: Protocols including supplemental oxygen resulted in an approximately 5-fold increase in stromal oxygen levels prior to CXL. During epi-on, high-irradiance UV-A delivery under hyperoxic conditions, an aerobic state was maintained. Conversely, under normoxic conditions, stromal oxygen rapidly depleted to 0-5% for all other protocols. The combination of supplemental oxygen, BAC formulation, and high-irradiance UV-A resulted in the largest biomechanical changes and most pronounced flattening effects of the three epi-on protocols.Conclusions: Ex vivo analysis of stromal oxygen levels, corneal stiffness, and acute anterior curvature change indicates that simultaneous optimization of the oxygen environment, riboflavin formulation, and UV-A protocol can significantly increase the effects of corneal collagen crosslinking.

Superior outcome of corneal collagen cross-linking using riboflavin with methylcellulose than riboflavin with dextran as the main supplement.

PURPOSE: To compare the effect of corneal collagen cross-linking (CXL) on progressive keratoconus using 0.1% riboflavin with either dextran or methylcellulose as the main supplement. METHODS: In a comparative case series, CXL was performed in 40 patients (40 eyes) using a riboflavin solution containing either dextran (dextran-riboflavin; n = 20) or methylcellulose (methylcellulose-riboflavin; n = 20). Changes in central corneal thickness (CCT), Scheimpflug tomography, maximal keratometry reading (Kmax ), visual acuity (VA) and endothelial cell density (ECD) were recorded. Stromal changes one month after surgery were analysed using optical coherence tomography (OCT) and in vivo confocal microscopy (IVCM). RESULTS: The CCT was significantly higher in the methylcellulose-riboflavin group during the CXL procedure. The IVCM demarcation line depth was 274 ± 80 (SD) µm in the dextran-riboflavin group and 442 ± 80 µm in the methylcellulose-riboflavin group (p < 0.001). Complete absence of keratocytes in the pre-endothelial stroma was found in none of the corneas treated with dextran-riboflavin and in 42% of the corneas treated with methylcellulose-riboflavin. Visibility of the OCT demarcation line was significantly lower in the methylcellulose-riboflavin group. Kmax and corrected distance visual acuity were improved in the methylcellulose-riboflavin group and stable in the dextran-riboflavin group after 2 years. Endothelial cell density (ECD) was stable in both groups. CONCLUSION: We found deeper structural changes in the methylcellulose-riboflavin group than in the dextran-riboflavin group. This may be explained by different riboflavin solution properties and raises safety concerns. The study also indicates improved effect using methylcellulose-riboflavin than dextran-riboflavin, possibly explained by deeper stromal CXL effect.