Epi-on CXL Research Articles

Hyperbaric Oxygenation Maintains Elevated Stromal Oxygen Availability During Corneal Collagen Crosslinking with and Without Epithelial Removal

Purpose Corneal collagen cross-linking (CXL) can halt corneal ectasia. Leaving corneal epithelium intact during treatment may reduce the incidence of complications. However, it is under debate whether this reduces efficacy and if oxygen supplementation may be necessary to optimize the cross-linking effect. This study aimed to investigate the impact of hyperbaric oxygenation (HBO) on intracorneal oxygen concentrations during epi-off and epi-on CXL. Methods CXL was performed using riboflavin and ultraviolet-A (UV-A) irradiance (3 mW/cm2 for 30 min) on porcine corneas under normobaric and hyperbaric conditions, with and without supplemented oxygen, with and without epithelium. Intracorneal oxygen concentrations were continuously monitored before and during irradiation. Biomechanical properties were assessed through tensile strength testing. Results HBO alone did not cause perceivable changes in stromal oxygen concentrations. Oxygen supplementation resulted in higher oxygen concentration in corneal stroma during CXL. HBO may cause a further increase in oxygen levels, although this was not statistically significant in this study. Notably, a tendency of oxygen levels to rise continuously during UV-irradiation was observed using HBO. Biomechanical properties showend no statistically significant differences between any groups. Conclusions In this ex-vivo model, HBO increased stromal oxygen levels during CXL, regardless of the presence of corneal epithelium. The dynamics in oxygen concentrations in corneal stromal tissue during CXL suggest that time is an important factor to consider in modifications of established protocols. Also, we hypothesize that stromal levels of riboflavin and UV-A irradiance may be more critical to the CXL effect when oxygen is supplemented and epithelium is not removed.

Randomized clinical trial comparing customized corneal crosslinking: epi-on in high oxygen and epi-off in room air for keratoconus.

To compare clinical outcomes of customized transepithelial (epi-on) corneal crosslinking (CXL) in high oxygen and customized CXL with epithelial removal (epi-off) in room air for keratoconus (KC). Umeå University Hospital, Umeå, Sweden. Prospective, randomized, single-masked, intraindividually comparing study. 32 participants with bilateral progressive KC were treated with bilateral customized topography-guided CXL, 30 mW/cm 2 ; 7.2 to 15 J/cm 2 and were randomized to epi-on in one eye (32 eyes) and epi-off in the fellow eye (32 eyes). Uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA), maximal keratometry (Kmax), subjective ocular discomfort, low-contrast visual acuities (LCVAs) at 10% and 2.5% contrast, ocular and anterior corneal wavefront aberrations, manifest refractive spherical equivalent, endothelial cell count (ECC), and adverse events were assessed through 24 months. Both treatments showed improvements at 24 months in UDVA; -0.16 ± 0.24 ( P < .001) and -0.13 ± 0.20 logMAR ( P = .006), respectively, CDVA; -0.10 ± 0.11 ( P < .001) and -0.10 ± 0.12 ( P = .001), Kmax; -1.74 ± 1.31 ( P < .001) and -1.72 ± 1.36 D ( P < .001). LCVA 10% improved for both protocols ( P < .001), but LCVA 2.5% improved for epi-on CXL only ( P = .001). ECC was unaltered, and no adverse events occurred. The epi-on eyes had significantly less discomfort symptoms during the whole first week posttreatment ( P < .05). High-oxygen customized epi-on CXL is a viable alternative to room air customized epi-off CXL, with faster improvements in CDVA and LCVA and less early ocular discomfort.

Assessment of the Predictive Ability of Theranostics for Corneal Cross-linking in Treating Keratoconus: A Randomized Clinical Trial

PurposeTo validate the ability of theranostic imaging biomarkers in assessing the propensity of corneal cross-linking (CXL) in flattening the maximum keratometry (Kmax) index. DesignProspective, randomized, multicenter, masked clinical trial (NCT05457647). ParticipantsFifty patients with progressive keratoconus. InterventionParticipants were stratified to undergo epithelium-off (epi-off; 25 eyes) and epithelium-on (epi-on; 25 eyes) CXL protocols using UV-A medical device incorporating theranostic software module. The device used controlled UV-A light both for performing CXL and for estimating the corneal riboflavin concentration (riboflavin score) and assessing treatment effect (theranostic score) in real time. A 0.22% riboflavin formulation was applied onto the cornea for 15 minutes and 20 minutes in epi-off and epi-on protocols respectively. All eyes underwent 9 minutes UV-A irradiance at 10 mW/cm2. Main Outcome MeasuresThe primary outcome measure was validation of the combined use of theranostic imaging biomarkers through measurement of their accuracy (proportion of correctly classified eyes) and precision (positive predictive value) to correctly classify eyes and positively predict a Kmax flattening at 1 year after CXL. Other outcome measures were the change of Kmax, endothelial cell density, uncorrected and corrected distance visual acuity, manifest spherical equivalent refraction, and central corneal thickness one year after CXL. ResultsAccuracy and precision of the combined use of theranostic imaging biomarkers in predicting eyes that had more than 0.1 diopter (D) Kmax flattening at 1 year were 91% and 95% respectively. The Kmax value significantly flattened by a median of -1.3 D (IQR: -2.11, -0.49 D; P < 0.001); both the uncorrected and corrected distance visual acuity improved by a median of -0.1 LogMAR (IQR: -0.3, 0.0 LogMAR; P < 0.001 and IQR: -0.2, 0.0 LogMAR; P < 0.001 respectively). There were no significant changes in endothelial cell density (P = 0.33) and central corneal thickness (P = 0.07) 1 year postoperatively. ConclusionsThe study demonstrated the efficacy of integrating theranostics in a UV-A medical device for the precise and predictive treatment of keratoconus with epi-off and epi-on CXL protocols. The concentration of riboflavin and its UV-A light mediated photo-activation in the cornea are the primary factors determining CXL treatment efficacy.

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

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. Private eye clinic, Brisbane, Australia. Retrospective, single-center, nonrandomized case series. 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. 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. 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.

Advances in the Treatment of Keratoconus: Epithelial-On (EPI-On) Corneal-Collagen Cross-Linking (CXL) and CXL-Plus Procedures.

Keratoconus (KC) incidence is on the increase. The advent of corneal-collagen cross-linking (CXL) has revolutionized the management of KC. This systematic review looks at the efficacy and complications of two novel treatments within CXL: Epithelial-On (Epi-On) and CXL-plus procedures. Two separate literature searches were carried out up until July 1, 2021. Articles only published in the last two years were included to ensure that only the most recent articles were reviewed. A total of 15 articles were selected for this review. There were varied results regarding the efficacy of Epi-On.No significant difference was found between Epi-On and standardEpithelial-Off (Epi-Off) CXL. However, it was found that Epi-On was inferior to standard CXL in terms of reducing KMAX. There was a higher risk of progression in patients treated with Epi-On CXL, with an increased rate of patients requiring re-treatment due to the advancement of their KC. While some studies report CXL-plus procedures demonstrate long-term efficacy and safety, a considerable number of studies advise caution, reporting a significant deterioration in corrected distance visual acuity (CDVA). Consequently, a question persists regarding the safest and most efficacious approach, given the lack of robust large randomized controlled trials (RCTs) in the current literature.

Thermographic analysis of the corneal surface in epi-on and epi-off corneal crosslinking for keratoconus.

To analyse the temperature of the corneal surface in keratoconus during corneal customized crosslinking (CXL) with a preserved epithelium (epi-on) under oxygen flow, and epi-off CXL in room air, and to assess the effect of pre-heating the oxygen. This masked, intra-individual comparing randomized study included 14 participants with bilateral progressive keratoconus treated with bilateral CXL: one eye with epi-on CXL under a flow of 2.5 L/min oxygen; the fellow eye with epi-off CXL in room air. In a second setting involving 12 healthy participants, room-tempered oxygen was flushed over one eye and oxygen pre-heated to 37°C over the fellow eye. The corneal surface temperature was assessed with infrared photography. A reduction in corneal surface temperature was seen from the pre-treatment application of topical riboflavin in the epi-off group (-1.1 ± 1.0°C, p < 0.001). The temperature increased during the first half of the CXL treatment in both groups (+0.7 ± 1.2°C, p = 0.041 for epi-on; +0.7 ± 0.9°C, p = 0.023 for epi-off CXL, respectively). In epi-on CXL an overall temperature increase was seen during the treatment (+0.8 ± 1.2°C, p = 0.016). In the second setting, pre-heating the oxygen rendered a surface temperature increase of +1.8 ± 0.2°C (p < 0.001). In epi-off CXL, the application of topical room-tempered riboflavin decreases the corneal surface temperature, likely due to increased evaporation. A slight temperature increase is seen during CXL with both epi-on and epi-off CXL, albeit far below the corneal safety limit. The corneal temperature can, however, be increased by applying pre-heated oxygen, a possible approach to modify or augment the treatment effect in CXL.

Study Of Macular Function and Morphology After Transepithelial Accelerated Corneal Collagen Cross-linking in Progressive Keratoconus

Objective The aim of this work is to evaluate the effect of transepithelial accelerated cross-linking (Epi-on CXL) on the macular function and morphology in progressive keratoconus. Patients and Methods The study included 25 patients with progressive keratoconus with age ranged between 18 and 32 years. Epi-On Accelerated CXL was done for all cases. Evaluation was performed 2 and 6 weeks postoperatively after transepithelial (Epi-on) accelerated CXL by Optical coherence tomography (OCT) and multifocal electroretinography (mf-ERG). Results The central foveal thickness (CFT) decreased from 165.1 ± 21.5 µm to 163.4 ± 24.2 µm 2 weeks postoperatively to 164.8 ± 23.9 µm 6 weeks postoperatively, with no statistically significant difference. The preoperative retinal response density (RRD) decreased in macular ring 1 (foveal area of 2.8 degrees) from 179.5 ± 52.1 nV/deg2 preoperatively to 134.7 ± 43.2 nV/deg2 and 146.7 ± 41.6 nV/deg2 in 2 and 6 weeks, respectively postoperatively with statistically significant difference (p = 0.012), while the other 4 rings showed statistically insignificant difference (p &gt;0.05) .On the other hand, implicit time latency (Pl) showed statistically insignificant difference between preoperative and postoperative values (p &gt;0.05) in all macular rings. Conclusion There is a minimal change in macular morphology after Epi-on accelerated CXL in progressive keratoconus, however, no significant change in macular function without any structural changes in progressive keratoconus 6 weeks postoperatively. A longer follow-up period studies are recommended to provide more information.

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.

Outcomes of Epi-On Collagen Cross-Linkage Procedure Assessed in Progressive Keratoconus Patients.

Keratoconus is a corneal ectasia that causes astigmatism and reduced vision. Conventional treatment to stop the progression of ectasia involves debridement of corneal epithelium, followed by ultraviolet light and riboflavin drops to reinforce the collagen covalent bonds, called collagen cross-linkage (CXL). Epi-on (epithelium-on) is a modified techniquewithout epithelial debridementand associated complications of pain, infection, and damage to the cornea. However, despite a good safety index and efficacy, Epi-on has not completely replaced the conventional Epi-off (epithelium-off) CXL. We aim to report our five-year experience and outcomes with Epi-on CXL Methods: In this five-year retrospective clinical audit, we included all patients who underwent Epi-on CXL from December 2014 to June 2020 at the Aga Khan University Hospital. Outcomes werebased on best-corrected visual acuity (BCVA) and topographic indicators such askeratometry-max (K-max), keratometry mean (K-mean), pachymetry apex (Pachapex), and pachymetry thinnest (Pachthin) performed during pre-CXL clinical visit within one month of the procedure and were compared with the most remotefollow up within three years post-CXL. A p-value of <0.05 was considered statistically significant. A total of 223 eyes of 134 patients had undergone CXL of which 32 eyes of 18 patients were included in the study based on the inclusion criteria. The mean age was 26.8 (+/- 6.137) years; nine were males and 16 were right eyes. Mean BCVA was 0.383 logMAR (logarithm of the minimum angle of resolution) units which improved to 0.292 units post CXL (p=0.02) and K-max decreased from 57.4 to 56.60 diopters (p=0.048), both outcomes were statistically significant. Pachapex decreased slightly from 471 to 460 micrometers (p=0.099), K-mean was almost stable from 48.8 to 48.7 diopters (p=0.9), and Pachthinalso decreased slightly from 455 to 445 micrometers (p=0.117), however, these outcomes were not statistically significant. Other studies reported similar improvements in K-max and visual acuity. Epi-on CXL is an effective treatment for halting the progression of keratoconus. Our results showed significant improvement in visual acuity and K-max readings indicating a halting of the progression of keratoconus in our patients. Long-term follow-up is required for all patients to assess detailed outcomes. Further studies comparing Epi-on CXL with other methods may be carried out.

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

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). Private eye clinic in Brisbane, Queensland, Australia. Retrospective single-center nonrandomized uncontrolled longitudinal cohort case series. 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. 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. 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.

Corneal Cross-Linking: Epi-On.

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.

Analysis of Tear Function Outcomes following Collagen Cross-Linking Treatment in Ectatic Corneas

Purpose To analyze tear function outcomes following collagen cross-linking (CXL) treatment in ectatic corneas. Methods Fifty-seven eyes of 34 patients were included, and patients with keratoconus who underwent epithelium-on (epi-on) or epithelium-off (epi-off) CXL were evaluated. The following tests were performed preoperatively and at 1, 3, 6, and 12 months postoperatively: best-corrected visual acuity (BCVA), maximum keratometry value (Kmax), ocular surface disease index (OSDI) questionnaire, slit-lamp examination, tear meniscus height, first noninvasive Keratograph breakup time (1st NIKBUT), average NIKBUT, and bulbar redness. Results BCVA improved in both epi-on and epi-off groups at most follow-up points, but was not significantly different between groups. At 12-month follow-up, Kmax in the epi-on and epi-off groups improved after CXL, but there was no significant difference between the groups. The OSDI in both groups decreased after operation compared with before surgery, and there was no significant difference between the two groups. Comparing the two groups, only the change in the tear meniscus height at 6 months postoperatively was statistically significant, and the pre- and postoperative values of the two groups were within the normal range (>0.20 mm). The change was small and had no clinical significance. There was no change in the 1st NIKBUT and average NIKBUT between the epi-on and epi-off groups. A change in bulbar redness was significantly better in the epi-off group than in the epi-on group at 3 months postoperatively. Comparing the effects at 1 year postoperatively, both groups had positive results in OSDI, NIKBUT, tear meniscus height, and bulbar redness. Conclusion Both epi-on and epi-off CXL can control the progression of keratoconus, although epi-off CXL is more effective. Both methods have a positive effect on dry eye, which can improve the condition of the tear film and reduce dry eye symptoms in patients with keratoconus.

Up-Dated the Critical Issues of Corneal Cross-Linking (Type-I and II): Safety Dose for Ultra-Thin Cornea, Demarcation Line Depth and the Role of Oxygen

Purpose: To update analytic formulas for the overall efficacy of corneal collagen crosslinking (CXL) including both type-I and oxygen-mediated type-II mechanisms, the role of oxygen and the initiator regeneration. Also, to derive the formulas for the minimum corneal thickness and demarcation line depth. Study Design: Modeling the kinetics of CXL in UV light and using riboflavin as the photosensitizer. Place and Duration of Study: New Taipei City, Taiwan, between June, 2021 and July, 2021. Methodology: Coupled kinetic equations are derived under the quasi-steady state condition for the 2-pathway mechanisms of CXL. For type-I CXL, the riboflavin (RF) triplet state [T] may interact directly with the stroma collagen substrate [A] to form radical (R) and regenerate initiator. For type-II process, [T] interacts with oxygen to form a singlet oxygen [1 O2 ]. Both reactive radical (R) and [1 O2 ], can relax to their ground state, or interact with the substrate [A]) for crosslinking. Based on a safety dose, formulas for the minimum corneal thickness and demarcation line depth (DLD) are derived. Results: Our updated theory/modeling showed that oxygen plays a limited and transient role in the process, in consistent with that of Kamave. In contrary, Kling et al believed that type-II is the predominant mechanism, which however conflicting with the epi-on CXL results. For both type-I and type-II, a transient state conversion (crosslink) efficacy in an increasing function of light intensity (or dose), whereas, its steady state efficacy is a deceasing function of light intensity. RF depletion in type-I is compensated by the RF regeneration term (RGE) which is a decreasing function of oxygen. For the case of perfect regeneration case (or when oxygen=0), RF is a constant due to the catalytic cycle. Unlike the conventional Dresden rule of 400 um thickness, thin cornea CXL is still safe as far as the dose is under a threshold dose (E*), based on our minimum thickness formula (Z*). Our formula for thin cornea is also clinically shown by Hafez et al for ultra thin (214 nm) CXL. Conclusion: For both type-I and type-II, a transient state conversion (crosslink) efficacy in an increasing function of light intensity (or dose), whereas, its steady state efficacy is a deceasing function of light intensity. CXL for ultra thin corneas are still safe, as far as it is under a threshold dose (E*), based on our minimum thickness formula, which has a similar tend as that of demarcation line depth. the type-II efficacy also provides the survival rate for the treatment of corneal keratitis.

Efficacy Analysis of Corneal Crosslinking (CXL): Comparing Epi-on and Epi-off Procedures

Purpose: To analyze the factors influencing the corneal crosslinking (CXL) efficacy and comparison of epi-on and epi-off procedures.&#x0D; Study Design: modeling the efficacy of epi-off and epi-on CXL.&#x0D; Place and Duration of Study: New Taipei City, Taiwan, between November, 2021 and December, 2021.&#x0D; Methodology: Solving the rate equations for the CXL efficacy which includes the roles of concentration of the photosensitizer, riboflavin (RF), RF depletion effects, dynamic of light intensity, and the non-uniform distribution of RF in the stroma, or the diffusion depth of RF. Both steady-state and transient state features are explored for the efficacy, crosslink depth (CD) and the effects of epithelium layer for the epi-on situation.&#x0D; Results: The steady-state efficacy is proportional to the square-root of [RF-concentration] /[light-intensity], The competing factors of reduced RF, F(z), and reduced light intensity in the stroma determine the relative efficacy of epi-on and epi-off. For example, for F(z)&lt;0.5, epi-on is more efficient than epi-off. In contrast, in the transient state (with efficacy &lt;0.6), the efficacy is proportional to the light dose, and therefore epi-on is always less efficient than epi-off. The crosslink depth (CD) has an inverse trend, such that higher light intensity and lower RF concentration lead to deeper CD. The analytic formulas are developed under simplified conditions, in which numerical simulation is required for non-uniform distribution, and when RF depletion are included. Various strategies for improved steady-state efficacy efficacy and crosslink depth for epi-on CXL are explored including the use of higher RF concentration and lower light intensity; enhancing the RF diffusion by an electrode device, or diffusion enhancing medicine. The analytic formulas are compared with measured data.&#x0D; Conclusion: For the steady-state epi-on is more efficient than epi-off, when the RF reduction factor is less than the light intensity gain factor. In contrast, in the transient state (with efficacy &lt;0.6), the efficacy is proportional to the light dose, and therefore epi-on is always less efficient than epi-off.

Preliminary Characterization of Predictive Factors of the Visual Change after Epi-On and Epi-Off Corneal Collagen Crosslinking Techniques.

Purpose To investigate the potential predictive factors of the visual change achieved with accelerated epi-on and epi-off corneal collagen crosslinking (CXL) in keratoconus. Methods This retrospective comparative study analyzed 67 eyes treated with an accelerated epithelium-on (epi-on group) and epithelium-off (epi-off group) CXL. The clinical outcomes were evaluated and compared during a 1-year follow-up. Likewise, the relationship of the change achieved with both CXL techniques in the corrected distance visual acuity (CDVA) with different preoperative data was investigated. Results The mean CDVA change at 3 months postoperatively was −0.04 ± 0.19 and −0.07 ± 0.25 in the epi-on and epi-off groups, respectively (p = 0.809). In the epi-on group, this change was significantly correlated with the preoperative apical (r = −0.375, p = 0.045) and central corneal thickness (r = −0.402, p = 0.031). In the epi-off group, the CDVA change was significantly correlated with not only the preoperative apical (r = 0.402, p = 0.028) and central corneal thickness (r = 0.367, p = 0.046) but also with some topometric and aberrometric indices (r ≤ −0.374, p ≤ 0.042). Furthermore, the change in CDVA in the epi-on group could be predicted from age, preoperative refractive astigmatism J45 component, anterior corneal asphericity, and posterior corneal high order aberration root mean square (p = 0.002, R2 = 0.503). In the epi-off group, the CDVA change could be predicted from the preoperative minimum corneal thickness and magnitude of the vertical anterior corneal primary coma component (p = 0.001, R2 = 0.446). Conclusions Clearly, different predictive factors of the visual change induced with the accelerated epi-on and epi-off CXL techniques are present, suggesting a different mechanism of action for stiffening the cornea and inducing changes in this structure.

Critical Analysis of Corneal Cross-linking (Part-I): Formulas for Efficacy, Safety Dose, Minimum Thickness, Demarcation Line Depth and the Role of Oxygen

Purpose: To update and derive formulas for the efficacy and kinetics of corneal collagen crosslinking (CXL) including both type-I and oxygen-mediated type-II mechanisms, the role of oxygen, the initiator regeneration, safety dose, minimum corneal thickness and demarcation line depth.&#x0D; Study Design: Modeling the kinetics of CXL in UV light and using riboflavin as the photosensitizer.&#x0D; Place and Duration of Study: Taipei, Taiwan, between June, 2021 and July, 2021.&#x0D; Methodology: Coupled kinetic equations are derived under the quasi-steady state condition for the 2-pathway mechanisms of CXL. For type-I CXL, the riboflavin (RF) triplet state [T] may interact directly with the stroma collagen substrate [A] to form radical (R) and regenerate initiator. For type-II process, [T] interacts with oxygen to form a singlet oxygen [1O2]. Both reactive radical (R) and [1O2], can interact with the substrate [A]) for crosslinking. Based on a safety dose and a threshold dose, formulas for the minimum corneal thickness and demarcation line depth (DLD) are derived.&#x0D; Results: Our updated theory/modeling showed that oxygen plays a limited and transient role in the process, in consistent with that of Kamave. In contrary, Kling et al believed that type-II is the predominant mechanism, which however conflicting with the epi-on CXL results. For both type-I and type-II, a transient state conversion (crosslink) efficacy in an increasing function of light intensity (or dose), whereas, its steady state efficacy is a deceasing function of light intensity. RF depletion in type-I is compensated by the RF regeneration term (RGE) which is a decreasing function of oxygen. For the case of perfect regeneration case (or when oxygen=0), RF is a constant due to the catalytic cycle. Unlike the conventional Dresden rule of 400 um thickness, thin cornea CXL is still safe as far as the dose is under a threshold dose (E*), based on our minimum thickness formula (Z*). Our formula for thin cornea is also clinically shown by Hafez et al for ultra thin (214 nm) CXL.&#x0D; Conclusion: For both type-I and type-II, the transient state conversion (crosslink) efficacy in an increasing function of light intensity (or dose), whereas, its steady state efficacy is a deceasing function of light intensity. CXL for ultra thin corneas are still safe, as far as it is under a threshold dose (E*), based on our minimum thickness (Z*) formula, which has a similar tend as that of demarcation line depth (Z').

Epithelium-on Corneal Collagen Cross-Linking with Hypotonic Riboflavin Solution in Progressive Keratoconus.

IntroductionEpithelium-off cross-linking (epi-off CXL) has long been established as the gold standard treatment for progressive keratoconus. Several protocols for epithelium-on (epi-on) CXL have been proposed to help reduce post-operative pain and facilitate visual recovery, but there is no epi-on treatment approach that is currently approved in the United States. The hydrophilic and macromolecular characteristics of conventional epi-off riboflavin formulations may create clinical challenges for absorption through an intact epithelium. This study investigates the clinical efficacy of a dextran-free hypotonic riboflavin ophthalmic solution (Photrexa, Glaukos, Burlington, MA, USA), approved for epi-off CXL, in a novel epi-on CXL protocol.MethodsTwenty-five eyes of 17 patients were treated in this prospective, single-arm study using a hypotonic riboflavin formulation without dextran and low irradiance UVA (3mW/cm2) for epi-on CXL. Visual acuity, as well as refractive and keratometry outcomes, were observed over 12 months.ResultsAt 12 months, Kmax was stable with no clinically or statistically significant change from a mean pre-op of 55.4D to 55.9D (p=0.13). Uncorrected and best corrected logMAR visual acuity significantly improved from 0.77 to 0.62 and from 0.17 to 0.12, respectively. There were no significant adverse safety events.ConclusionPatients who underwent epi-on CXL with dextran-free hypotonic riboflavin demonstrated improvements in uncorrected and best corrected visual acuity with stable keratometry at 12 months post-operatively. The efficacy is consistent with other epi-on studies to date but remains lower than standard epi-off CXL. New technologies, including supplemental oxygen and transepithelial riboflavin ophthalmic solutions, are currently under clinical evaluation and may offer a path forward for epi-on CXL in the USA.

Surgical Management of Keratoconus in a Young Adult with Cognitive and Behavioral Disability

Case Presentation: A 25-year-old man with cognitive impairment (CI) and behavioral issues presented for corneal collagen crosslinking (CXL) surgical management of progressive keratoconus. Results: The conventional CXL technique was modified to avoid complications due to potential postoperative behavioral issues. Conclusions: Significant post-operative pain and aggressive behaviour can occur following epi-on CXL. Aggressive behaviour can result in significant complications in relatively low-risk eye surgery. Preoperatively, it is appropriate to devise a multifaceted surgical, medical and behavioural treatment plan including psychotropic if needed in patients with history of cognitive impairment and aggressive behaviour.

Accelerated epithelium-on or accelerated epithelium-off corneal collagen cross-linking: Contralateral comparison study.

PURPOSE:The aim of the study is to compare the accelerated epithelial-on corneal collagen cross-linking (epi-on CXL) and accelerated epithelial-off corneal collagen cross-linking (epi-off CXL) in terms of clinical and confocal microscopy results.MATERIALS AND METHODS:Forty-two eyes of 21 patients with progressive keratoconus and simultaneously undergoing accelerated epi-on CXL in one eye and accelerated epi-off CXL in other eye were evaluated. Uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA) with spectacle in logMAR and topographic findings (mean keratometry [Kmean] and maximum keratometry [Kmax]) were recorded at 1, 3, 6, 12, 18, 24, and 30 months. Eyes were compared in terms of subjective pain scores after the procedures. Furthermore, anterior segment optical coherence tomography and confocal microscopy were performed at 1 month.RESULTS:Kmean and Kmax were less than baseline in both the groups; however, the reduction was significantly higher in epi-off CXL than epi-on CXL eyes at 18 and 30 months. The UCVA and BCVA increased approximately 1 Snellen line at the end of mean follow-up in epi-off CXL and in epi-on CXL. Stromal demarcation line for epi-off CXL is 276.4 ± 58.9 while 148.3 ± 24.8 for epi-on CXL (P = 0.001). Furthermore, subepithelial nerves were observed in any eye in epi-off CXL; however, subepithelial nerves were observed in 12 eyes (80%), in epi-on CXL (P = 0.01).CONCLUSION:Both techniques were able to stop progression; however, in contrast to expectations, the pain was felt more in epi-on CXL than epi-off CXL.

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

ABSTRACTPurpose: 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.