Epithelium-on CXL Research Articles

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.

A randomized clinical trial assessing theranostic-guided corneal cross-linking for treating keratoconus: the ARGO protocol

The Assessment of theranostic guided riboflavin/UV-A corneal cross-linking for treatment of keratoconus (ARGO; registration number NCT05457647) clinical trial tests the hypothesis that theranostic-guided riboflavin/UV-A corneal cross-linking (CXL) can provide predictable clinical efficacy for halting keratoconus progression, regardless of treatment protocol, i.e., either with or without epithelial removal. Theranostics is an emerging therapeutic paradigm of personalized and precision medicine that enables real-time monitoring of image-guided therapy. In this trial, the theranostic software module of a novel UV-A medical device will be validated in order to confirm its accuracy in estimating corneal cross-linking efficacy in real time. During CXL procedure, the theranostic UV-A medical device will provide the operator with an imaging biomarker, i.e., the theranostic score, which is calculated by non-invasive measurement of corneal riboflavin concentration and its UV-A light mediated photo-degradation. ARGO is a randomized multicenter clinical trial in patients aged between 18 and 40 years with progressive keratoconus aiming to validate the theranostic score by assessing the change of the maximum keratometry point value at 1-year postoperatively. A total of 50 participants will be stratified with allocation ratio 1:1 using a computer-generated stratification plan with blocks in two treatment protocols, such as epithelium-off or epithelium-on CXL. Following treatment, participants will be monitored for 12 months. Assessment of safety and performance of theranostic-guided corneal cross-linking treatment modality will be determined objectively by corneal tomography, corneal endothelial microscopy, visual acuity testing and slit-lamp eye examination.

Oxygen in Corneal Collagen Crosslinking to Treat Keratoconus: A Systematic Review and Meta-Analysis.

Keratoconus is a disorder that results in visual loss from increased corneal high-order aberrations and irregular astigmatism and reduces quality of life. The primary treatment for progressive keratoconus is crosslinking (CXL). Recently, it has been suggested that oxygen enhances the type II photodynamic reaction of CXL that is oxygen dependent. Our study investigated the effect of increased oxygen availability in epithelium-on CXL on visual acuity and corneal curvature. We searched PubMed, EMBASE, Medline, Web of Science, and Scopus databases on November 3, 2021. We included studies that reported increased oxygen availability during CXL in patients with keratoconus published within the last 10 years. A meta-analysis on the primary outcomes, maximum keratometry, and corrected distance visual acuity, was conducted. The search yielded 108 publications which were screened and assessed for eligibility. Six studies were included in the systematic review and 5 studies were included in our meta-analysis of the outcomes of increased oxygen availability in accelerated CXL. The meta-analysis on data after 6 months of follow-up found a significant decrease in mean maximum keratometry of 1.2 diopter (95% confidence interval: 0.2-2.3; P =0.02) and an improvement in mean corrected distance visual acuity by 0.08 logMAR (95% confidence interval, 0.02-0.13; P =0.01). There were no serious adverse events reported. Increasing oxygen during epithelium-on CXL improved visual acuity and produced corneal flattening without any serious adverse events in patients with keratoconus. The demarcation line depth was significantly higher with oxygen compared to the control group. Further data are required with a control group and long-term follow-up across a range of CXL protocols for implementation into standard clinical practice.

Evaluation of tear parameters and meibomian gland morphology in keratoconus patients after epithelial-on corneal cross-linking.

To evaluate the variations in tear parameters and meibomian gland morphology after epithelial-on (epi-on) corneal collagen cross-linking (CXL) in keratoconus (KC) patients. This prospective observational study included 38 KC eyes that underwent epithelium-on CXL. Thirty-three eyes of 33 stable KC patients with no prior CXL treatment formed the KC group and 35 eyes of 35 healthy volunteers were recruited as the control group. All participants were evaluated by Schirmer I test, first and average noninvasive tear break-up time (NITBUT), ocular surface disease index (OSDI) questionnaire, and meibography scores. The CXL patients were evaluated preoperatively and at the 1st, 3rd, and 6th months, and participants without any intervention (KC and control groups) were evaluated initially, at 1st, 3rd, and 6th months. The KC patients had significantly lower average NITBUT, higher OSDI scores, and impaired meibomian gland morphology than healthy individuals (NITBUT(seconds): KC, 12.8(2.4-17.6), healthy group (HG), 17.1(6.8-17.6); p = 0.012, OSDI: KC, 27.5(0.0-87.5), HG, 7.5(0.0-55.0); p < 0.001, p < 0.001, respectively). A significant difference was found in Schirmer values of the CXL group at 0-1st months, first NITBUT values at 1-6 months, and average NITBUT values at 1-3 and 1-6 months (p = 0.003, p = 0.001, p = 0.003, p = 0.001, respectively). All meibography parameters remained unchanged after CXL over a 6-month follow-up compared to initial measurements. Even though the KC patients had lower NITBUT, higher OSDI scores, and increased meibomian gland disfunction, the CXL treatment did not significantly affect tear quantity, dry eye symptoms, and meibomian gland morphology.

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.

Pachymetric Assessment After EpiSmart® Epithelium-on Cross-Linking for Keratoconus and Post-Surgical Ectasia

PurposeTo assess the change in corneal pachymetry after a novel epithelium-on (EpiSmart®) corneal crosslinking procedure (CXL).MethodsEyes treated as part of the open-label, non-controlled arm of the study “Collagen Crosslinking with Ultraviolet-A in Asymmetric Corneas” (NCT01097447) were examined at baseline, 3-, 6- and 12-months post-CXL. Thinnest pachymetry readings based on Pentacam (OCULUS GmbH, Wetzlar, Germany) were recorded.ResultsA total of 101 eyes met the study inclusion criteria. Thinnest pachymetric readings at baseline averaged 451 ± 50 microns. The mean (± SD) minimum thickness was 450 ± 46 microns at 3 months, 452 ± 47 microns at 6 months, and 451 ± 48 microns at 12 months post-CXL. The changes from baseline (mean ± SE) at 3, 6, and 12 months post-CXL were −1.2 ± 1.5 microns, 0.5 ± 1.6 microns, and 0.4 ± 1.6 microns, respectively. Student’s t-tests showed no statistically significant change in pachymetry from baseline for any exam period.ConclusionThis study demonstrated that, after EpiSmart® epithelium-on CXL, there was no substantial corneal thinning observable on Scheimpflug tomography out to 12 months.

Case for Epithelium-Off Corneal Cross-linking.

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

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.

Current clinical approach to pediatric keratoconus patients

Introduction Due to structural differences between pediatric and adult corneas, keratoconus (KC) is considered more aggressive in pediatrics than in adults. It is controversial whether therapeutic intervention in pediatric KC should differ from adult KC. Areas covered We investigate if there is a substantial difference between pediatric and adult KC regarding disease severity and progression rate, factors important for treatment timing and prognosis. Then, feasibility of current treatment modalities is discussed based on current evidence. Expert opinion Despite several conflicting reports, pediatric KC is more severe at initial diagnosis with faster progression. Therefore, pediatric patients should be followed closely for evidence of progression. This can be tracked in a variety of ways, including with the Belin ABCD progression system. Controlling ocular allergy and eye rubbing is the first step in treatment. The epithelium-off Dresden protocol remains the gold standard CXL approach to stop progression in pediatric KC, whereas epithelium-off accelerated CXL might be an alternative. In pediatric patients, both penetrating and lamellar keratoplasty can be challenging; however, lamellar keratoplasty seems to offer the advantage of lower graft rejection rate. Epithelium-on CXL, intracorneal ring segment implantation, excimer laser ablation and CXL protocols are not recommended in pediatric KC. Nevertheless, there remains a need for evidence-based clinical practical guidelines in pediatric KC.

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.

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.

Comparison of Visual and Tomographic Outcomes of Epithelium-On and Epithelium-Off Accelerated Corneal Crosslinking: A Longitudinal Study

To compare the visual and tomographic outcomes of epithelium-on and epithelium-off corneal collagen crosslinking (CXL) in an accelerated protocol in eyes with progressive keratoconus. Sixty-one patients with progressive keratoconus (female patients, n = 30; male patients, n = 31) aged 17 and 48 years (mean age: 25.8 ± 6.2 yrs) were included in this study. Patients underwent either epithelium-off (n = 27) or epithelium-on (n = 34) CXL using an accelerated protocol. Patients with at least 12 months of follow-up were included in the study. Visual and tomographic data from 3, 6, and 12 months after surgery were analyzed. There were no differences between the visual and tomographic characteristics of the epithelium-on and epithelium-off groups at baseline (P > 0.05). No significant changes in uncorrected and best spectacles-corrected visual acuity were found at any stage during the first 12 months within either group or between the groups (all P > 0.05). There were no changes in thickness and keratometric parameters at any stage during the first 12 months within either group, or between groups (P > 0.05) except for a transient significant thinning of the central cornea in all groups in the first 3 months which recovered by 6 months. There was no significant difference between groups regarding the number of eyes with progression in the 12 months after treatment (P > 0.05). Epithelium-on and epithelium-off CXL in an accelerated protocol provide comparable visual and tomographic outcomes after 1 year in eyes with progressive keratoconus.

COMPARATIVE STUDY BETWEEN EPITHELIUM ON AND EPITHELIUM OFF COLLAGEN CROSS LINKING WITH RIBOFLAVIN AND UVR IN TREATMENT OF EARLY KERATOCONUS

Objective: To compare the safety and efficacy epithelium on versus epithelium off collagen crosslinking with riboflavin and UVR in treatment of early keratoconus. Patients and Methods: Thepresent study was a prospective, randomized study. 40 eyes from 25 patients with a mean age of 24years (range: 15–35 years) were included. There were 15 males and 10 females, and all of themunderwent corneal CXL using riboflavin and ultraviolet-A light at the Tipa Eye Hospital, Assuit.Results: Among the included samples, 20 eyes underwent epithelium-on corneal collagen CXL, and20 eyes underwent epithelium-off corneal CXL. The incidence of postoperative pain was lowered byabout 20% in the trans-epithelial group as compared with the epithelial-off group in the first postoperative week. In addition, the incidence of postoperative corneal haze was lowered by about 50% inthe transepithelial group as compared with the epithelial-off group in the first postoperative week. Itwas also noticed that the CXL was formed in the upper-third of the corneal stroma, 20-30 μmbeneath bowman membrane in the transepithelial CXL technique, while in the classic debridementtechnique; it was formed much deeper in the stoma. In group I, after 3 and 6 months, there was anon-statistically significant corneal thinning. In group II, none statistically significant corneal thinningwas detected after 3 months, but after 6 months there was some regression in the form of cornealthinning by nearly 5-10 μm in 20% of cases. Conclusion: Both epithelium-off CXL and the epitheliumon CXL were effective in stabilizing the progression of keratoconus at least for 6 months; however,the epithelium-off CXL appeared to be much more effective in improving the refractive best-correctedvisual acuity and topographic outcomes in keratoconic eyes compared with the epithelium-on CXL.

Pentacam topographic changes after Epithelium-off collagen cross-linking versus Epithelium-on collagen cross-linking in patients with keratoconus

Keratoconus is a bilateral non-inflammatory disease .One of its characteristics is reduction of biomechanical strength of cornea and stromal thinning , which gradually decreases corneal thickness and induces irregular astigmatism , myopia , corneal scaring, andreduction of visual acuity.(1)For early stages of keratoconus , one would use spectacles and contact lenses though the progression of the disease can lead to irregular astigmatism or corneal scaring, leaving no other option but corneal transplantation in about 20% of patients.(2)Corneal transplantation is an expensive procedure with many complications such as high astigmatism and graft rejection; hence, seeking for a way to halt this progressive disease seems to be of crucial importance.(3) For more than a decade, corneal cross-linking (CXL) has been considered as the only method for improvingcorneal biomechanical power.(4)Corneal collagen cross-linking (CXL) is a low-invasive treatment aimed to improve biomechanical stability in eyes with keratectasia.(5) The “standard CXL protocol” described by Wollensak and colleagues includes removal of the corneal epithelium in a diameter of 9 mm , followed by saturation of the corneal stroma using 0.1% isotonic riboflavin solution in 20% dextran.(6)This procedure is proved to be effective in increasing corneal stiffness , stabilization of keratoconus , and in some cases in improving the refractive and topographic features.Even so, the epithelial removal may lead to serious complications that include infection(7),stromal haze (8), and corneal melting (9)in addition to severe pain and decrease in vision occurring during the first days after the treatment.To avoid such complications, Boxer Wachler et al. suggested a modification of the technique by keeping the epithelium intact (epithelium-on or transepithelial CXL) (10).In this study, we sought to compare keratoconus indices before and after crosslinking either epi-off or epi-on CXL by Pentacam criteria.

Corneal crosslinking without epithelial removal

To evaluate the effect of riboflavin-ultraviolet (UV)-A corneal crosslinking (CXL) without epithelial removal on ectatic corneal disease. Woolfson Eye Institute, Atlanta, Georgia, USA. Prospective observational study. Patients were treated with a new riboflavin formulation without epithelial removal, then exposed to UV light (365nm) at 4mW/cm2 with on-off cycling for 30minutes. Uncorrected (UDVA) and corrected (CDVA) distance visual acuities, maximum corneal curvature (maximum keratometry [Kmax]), total higher-order aberrations (HOAs), and coma were measured at 3, 6, 12, and 24months postoperatively. Progression was defined as an increase of more than 1 diopter (D) in Kmax and loss of more than 1 line of CDVA. Five hundred twelve eyes of 308 patients with keratoconus or forme fruste keratoconus and 80 eyes of 55 patients with ectasia after laser insitu keratomileusis (LASIK) were treated with the new riboflavin formulation without epithelial removal; 229 patients received bilateral treatments, 95 of which were simultaneous. The mean UDVA and CDVA improved by 1 to 1.5 Snellen lines at 1 and 2years postoperatively (P<.0001). Mean Kmax decreased by 0.48 D at 2years postoperatively (P=.0002). Mean total HOAs and coma decreased by 36% (P<.0001) and 37% (P=.0002), respectively, at 2years postoperatively. Kmax decreased more than 1 D in three times as many eyes as it increased more than 1 D (P<.0001). No eyes progressed, and there was no loss of effect between 1 and 2years postoperatively. No vision-threatening events were observed. Pain typically resolved within 24hours, and visual acuity returned to preoperative levels in 1 to 2days. Epithelium-on CXL using this new protocol halted the progression of keratoconus and ectasia after LASIK. It was safer and provided more rapid visual recovery than CXL with epithelial removal, allowing routine bilateral, simultaneous treatment.

Efficacy of iontophoresis-assisted epithelium-on corneal cross-linking for keratoconus.

Corneal cross-linking (CXL) is a noninvasive therapeutic procedure for keratoconus that is aimed at improving corneal biomechanical properties by induction of covalent cross-links between stromal proteins. It is accomplished by ultraviolet A (UVA) radiation of the cornea, which is first saturated with photosensitizing riboflavin. It has been shown that standard epithelium-off CXL (S-CXL) is efficacious, and it has been recommended as the standard of care procedure for keratoconus. However, epithelial removal leads to pain, transient vision loss, and a higher risk of corneal infection. To avoid these disadvantages, transepithelial CXL was developed. Recently, iontophoresis has been adopted to increase riboflavin penetration through the epithelium. Several clinical observations have demonstrated the safety and efficacy of iontophoresis-assisted epithelium-on CXL (I-CXL) for keratoconus. This review aimed to provide a comprehensive summary of the published studies regarding I-CXL and a comparison between I-CXL and S-CXL. All articles used in this review were mainly retrieved from the PubMed database. Original articles and reviews were selected if they were related to the I-CXL technique or related to the comparison between I-CXL and S-CXL.

Comparison of epithelium-off and transepithelial corneal collagen cross-linking for the treatment of keratoconus

Objective The aim of the study was to assess the safety and efficacy of epithelium-off corneal cross-linking versus epithelium-on cross-linking in the treatment of keratoconus. Patients and methods This study was performed on 42 eyes of 22 patients who were divided into two groups. The first group was the epithelium-off cross-linking (CXL) group that included 23 eyes of 12 patients, whereas the second group was the epithelium-on cross-linking group (the TECXL group) that included 19 eyes of 10 patients. Results On comparing the effect of epi-off and epi-on we found that epithelium-on CXL is superior to epithelium-off CXL regarding pain, complications, early patient convalescence as we found significant difference between epi-on and epi-off groups in postoperative complications. In epithelium-on CXL regarding eight (42%) eyes had pain, 0 eye had delayed reepithelization, one (5.26%) eye had stromal haze, and six (31.57%) eyes had treatment failure. However, epithelium-off CXL is superior to epithelium-on CXL regarding the efficacy in visual stabilization and improvement as we found a significant improvement in anterior elevation and Kmax with P = 0.04 and 0.02, respectively. Epithelium-off CXL had significant reduction in Kmax with P = 0.03, anterior elevation had significant reduction with P = 0.04 epithelium-on CXL having nonsignificant change in Kmax and anterior elevation. Conclusion Actually, in this study, it was found that TECXL was the procedure of choice for patient comfortability, safety, and convalescence. However, the results of the study confirmed that epithelium-off CXL was the procedure of choice for the patient benefit and guaranteed visual stabilization and additional visual improvement convalescence.

An investigation into corneal enzymatic resistance following epithelium-off and epithelium-on corneal cross-linking protocols

The aim of this study was to investigate corneal enzymatic resistance following epithelium off and on riboflavin/UVA cross-linking (CXL). One hundred and fourteen porcine eyes were divided into four non-irradiated control groups and seven CXL groups. The latter comprised; (i) epithelium-off, 0.1% iso-osmolar riboflavin, 9 mW UVA irradiation for 10 min, (ii) disrupted epithelium, 0.1% hypo-osmolar riboflavin, 9 mW UVA for 10 min, (iii) epithelium-on, 0.25% hypo-osmolar riboflavin with 0.01% benzylalkonium chloride (BACS), 9 mW UVA for 10 min, (iv) epithelium-on, 5 min iontophoresis at 0.1 mA for 5 min with 0.1% riboflavin solution, 9 mW UVA for 10 min or (v) 12.5 min, (vi) epithelium-on, prolonged iontophoresis protocol of 25 min with 1.0 mA for 5 min and 0.5 mA for 5 min with 0.25% riboflavin with 0.01% BACS, 9 mW UVA for 10 min or (vii) 12.5 min. Enzymatic resistance was assessed by daily measurement of a corneal button placed in pepsin solution and measurement of corneal button dry weight after 11 days of digestion. This study revealed that the enzymatic resistance was greater in CXL corneas than non-irradiated corneas (p < 0.0001). Epithelium-off CXL showed the greatest enzymatic resistance (p < 0.0001). The prolonged iontophoresis protocol was found to be superior to all other trans-epithelial protocols (p < 0.0001). A 25% increase in UVA radiance significantly increased corneal enzymatic resistance (p < 0.0001). In conclusion, although epithelium-on CXL appears to be inferior to epithelium-off CXL in terms of enzymatic resistance to pepsin digestion, the outcome of epithelium-on CXL may be significantly improved through the use of higher concentrations of riboflavin solution, a longer duration of iontophoresis and an increase in UVA radiance.

Epithelium-on corneal collagen crosslinking for management of advanced keratoconus

To report the 1-year visual and keratometric results of epithelium-on corneal collagen crosslinking (CXL) for advanced keratoconus (median maximum keratometry [K]≥58.0 diopters [D]). School of Ophthalmology and Optometry and Eye Hospital of Wenzhou Medical College, Wenzhou, China. Prospective case series. Patients with bilateral progressive keratoconus had tetracaine-enhanced epithelium-on CXL. The worse eye had CXL, and the fellow eye was not treated. Results were reported 1, 3, 6, and 12months postoperatively. The outcomes were compared with those in the fellow untreated eyes. Twenty-one eyes of 21 patients with a median age of 20.4years (interquartile range [IQR], 9.5years) were treated. A significant improvement in postoperative uncorrected distance visual acuity was observed at 12months (P=.002). Postoperative corrected distance visual acuity improved at 6months and 12months (P≤.009) compared with baseline values. The maximum K decreased by 1.63 D from the median preoperative maximum K of 62.7 D (IQR, 12.9 D) at 12months (P<.001). The reduction in maximum K was higher after CXL than in untreated eyes at the end of 12months (P=.001). Correlation analysis between the preoperative maximum K values and the change over 6 to 12months between different studies showed a significant correlation (r=-0.764, P<.001; Spearman correlation). Epithelium-on CXL was an effective treatment for patients with advanced keratoconus. A higher preoperative maximum K value correlated with greater corneal flattening after CXL. None of the authors has a financial or proprietary interest in any material or method mentioned.

Epithelium-on corneal cross-linking treatment of progressive keratoconus: a prospective, consecutive study.

PurposeTo evaluate the outcome of collagen cross-linking (CXL) without corneal epithelial debridement in patients treated for progressive keratoconus for whom the standard epithelium-off treatment cannot be applied, as their central corneal thickness (CCT) is less than 400 μm.Patients and methodsThis was a prospective, uncontrolled, interventional study involving 32 eyes of 30 patients with progressive keratoconus and CCT of less than 400 μm. All patients received CXL treatment with application of riboflavin and exposure to ultraviolet light A for 30 minutes without corneal epithelial debridement. Patients were followed up to 12 months postoperatively. The main outcomes were changes in maximum-K reading, manifest refractive spherical equivalent, CCT, and best-corrected visual acuity (logarithm of minimum angle of resolution). Patients were also asked to report any pain or discomfort during the procedure.ResultsAt the end of the 12-month follow-up, CCT showed no significant change: from 392±5.17 μm preoperatively to 390±4.45 μm (P=0.102). Maximum-K reading decreased significantly, from 49.19±2.30 D preoperatively to 46.96±6.03 D postoperatively (P<0.05). The mean manifest spherical equivalent showed no significant change: from 4.04±1.51 D preoperatively to 4.17±1.63 D postoperatively (P=0.110). Mean best-corrected visual acuity showed no significant change: from 0.29±0.12 preoperatively to 0.31±0.11 postoperatively (P=0.110).ConclusionEpithelium-on CXL exhibits potential as a method for treating patients with progressive keratoconus and CCT of less than 400 μm, in which the standard epithelium-off CXL cannot be applied. Over 12 months of follow-up, the epithelium-on CXL was safe and effective, with results comparable to that achieved with the epithelium-off technique in thicker corneas, and reduced rates of operative and postoperative discomfort.