Epi-off CXL Research Articles

Epithelium-off versus epithelium-on corneal collagen cross-linking with accelerated UV − a protocol for treatment of keratoconus

Purpose Our purpose was to compare the efficacy of ‘epithelium-off’ and ‘epithelium-on’ cross-linking (CXL) in treatment of progressive keratoconus. Patients and methods This study included 48 eyes of 26 patients who met our inclusion criteria. The Epi-Off CXL group included 32 eyes of 17 patients, and the Epi-On CXL group included 16 eyes of nine patients. Preoperative assessments of uncorrected and best-corrected visual acuities, refractive errors, keratometry, and corneal tomography including pachymetry, were compared with the postoperative values. Results Preoperatively, there was a statistically nonsignificant difference between the two groups in all studied variables except for the pachymetry at thinnest location. In the Epi-Off group, there was a significant improvement of uncorrected visual acuity, best-corrected visual acuity, Kmax, and inferior–superior value at the 12-month visit. There was late significant worsening of the back elevation and spherical equivalent at the 12-month visit and also significant thinning of pachymetry at thinnest location associated with significant worsening of the average thickness increase. All other variables showed nonsignificant change (stabilization) at both postoperative visits. In the Epi-On group, there was significant thinning of pachymetry at thinnest location and stabilization of uncorrected corrected visual acuity, best-corrected visual acuity, K1, Kmax, (inferior–superior), Y-coordinate, and front elevation at both postoperative visits, and early stabilization with late worsening of all of other variables. Conclusion The Epi-Off CXL was found to be more superior to Epi-On CXL in terms of stabilization of progressive keratoconus but was inevitably associated with complications related to epithelial debridement.

Effect of a Matrix Therapy Agent on Corneal Epithelial Healing After Standard Collagen Cross-linking in Patients With Keratoconus: A Randomized Clinical Trial.

Corneal abrasions are frequent after standard (epithelium-off [epi-off]) corneal collagen cross-linking (CXL) in patients with progressive keratoconus. A new matrix therapy agent (ReGeneraTing Agent [RGTA]) has been developed to promote corneal wound healing. To assess the effect of the new type of matrix therapy agent on corneal wound healing after epi-off CXL in patients with keratoconus. This double-masked randomized clinical trial enrolled 40 patients with keratoconus undergoing epi-off CXL from July 18, 2014, to October 21, 2015, when the last follow-up was completed. The analysis of the intention-to-treat population was performed at the Department of Clinical Pharmacology in cooperation with the Center for Medical Physics and Biomedical Engineering and the Department of Ophthalmology and Optometry of the Medical University of Vienna. Patients were randomized to receive the matrix therapy agent or hyaluronic acid-containing eyedrops, 0.1%, every other day starting immediately after surgery. The size of the corneal defect was measured using ultrahigh-resolution optical coherence tomography (OCT) and slitlamp photography (SLP) with fluorescein staining. Corneal wound healing rate, defined as the size of the defect over time. Among the 40 patients undergoing epi-off CXL (31 men; 9 women; mean [SD] age, 31 [10] years), wound healing was significantly faster in the matrix therapy agent group compared with the hyaluronic acid group (4.4 vs 6.1 days; mean difference, 1.7 days; 95% CI, 0.25-3.15 days; P = .008). The defect size was smaller in the matrix therapy agent group than in the hyaluronic acid group as measured with OCT (12.4 vs 23.9 mm2; mean difference, 11.6 mm2; 95% CI, 0.8-23.5 mm2; P = .045) and SLP (11.9 vs 23.5 mm2; mean difference, 11. 6 mm2; 95% CI, 1.3-22.9 mm2; P = .03). A correlation between the defect size measured with OCT and SLP was found (r = 0.89; P < .001). No ocular or serious adverse events occurred. Use of a new matrix therapy agent appears to improve corneal wound healing after CXL in patients with keratoconus. Monitoring of corneal wound healing using ultrahigh-resolution OCT might be an attractive alternative to SLP because OCT provides an objective and 3-dimensional evaluation of the corneal defect. clinicaltrials.gov Identifier: NCT02119039.

Cross-Linking in Keratoconus: "Epi-off" or "Epi-on"?

Corneal cross-linking can halt the progression of keratoconus, but what is the best approach for treatment? There are a number of treatment options for keratoconus, but only corneal cross-linking (CXL) appears to halt the progression of the disease. To guarantee effective cross-linking, CXL treatment involves removal of the corneal epithelium prior to riboflavin application and ultraviolet light illumination - "epi-off" CXL. Several methods of "epi-on" (transepithelial) CXL have been proposed, such as keeping the corneal epithelium intact which should be less painful and help avoid other CXL-associated adverse events. The evidence so far is that epi-off CXL remains the most effective method of strengthening the cornea and slowing keratoconus progression - but transepithelial methods are gaining ground.

Évaluation de la douleur en postopératoire de cross-linking du collagène cornéen en comparant la procédure par iontophorèse à la technique épithélium-off rapide chez des patients atteints de kératocône évolutif

Cross-linking (CXL) increases corneal biomechanical strength in progressive keratoconus. Since riboflavin cannot penetrate intact corneal epithelium, removal of epithelium is necessary for the classic CXL procedure (epi-off), but can cause severe postoperative pain. To avoid this problem, a method preserving the epithelium (epi-on) is used. In this study, we aimed to evaluate and compare postoperative pain after epi-off CXL and epi-on CXL. We present a retrospective study assessing the level of pain postoperatively in 38 patients between the age of 12 and 53 years who underwent CXL procedures at the University Hospital of Clermont-Ferrand from July 2013 to May 2014. Epi-off consisted of manual corneal de-epithelialization and riboflavin instillation for 20minutes, followed by UVA exposure for 9minutes. The epi-on technique used an applicator on the eye, filled with riboflavin, and a generator delivered a continuous low-level current for 5minutes. The duration of light exposure was similar in both groups. Postoperative medications were the same for both techniques. Assessment of pain and analgesic intake were reported by the patient on paper questionnaires. Pain was evaluated from preoperatively up until the end of the month. Statistical analyses were performed in bilateral formulation to an alpha type I and error risk of 5%. Twenty-three epi-off patients and 15 epi-on patients. Twenty-nine men and 9 women (76.3%/23.7%). Mean age: 28 years. Reference base time was the return from the operating room. In the epi-off group, pain increased significantly until the morning of D2 and did not return to its intraoperative level until noon D2, 1.8±2.0 vs 2.5±2.5 (P=0.12). Pain remained stable until the morning of D4. From noon D4 until D30, it was significantly less than intraoperatively 1.8±2.0 vs 0.7±1.4 (P=0.01). In the epi-on group, pain was significantly higher than intraoperatively until noon of D1 2.5±2.2 vs 3.8±2.5 (P=0.01). From the evening of D1, it returned to its intraoperative level until the evening of D2 2.5±2.2 vs 2±1.7 (P=0.34). From the morning of D3 it was significantly less than intraoperatively 2.5±2.2 vs 0.8±0.9 (P=0.001). Considering all measurement times, there was no significant difference between the two groups (P=0.75), except from evening of D2 until evening of D3 in favor of iontophoresis: 1.9±2.3 vs 1.0±1.3 (P=0.038). Epi-on seems less painful in the short term (up to noon of D1 for epi-on vs morning of D2 for epi-off) and with a shorter duration than epi-off. This can be explained by the absence of corneal de-epithelialization. However, the reduction in pain is not significant at all postoperative times, and a risk of epithelial abrasion during placement and removal of the corneal applicator may exist. Iontophoresis maintains the corneal epithelium, decreases pain and improves patient comfort. A new study involving more patients and strict monitoring of medication intake would strengthen the validity of these results.

Transepithelial Versus Epithelium-off Corneal Cross-linking for the Treatment of Progressive Keratoconus: A Randomized Controlled Trial

To compare the clinical effects and safety of transepithelial corneal cross-linking (CXL) to epithelium-off (epi-off) CXL in progressive keratoconus. Randomized clinical trial (noninferiority). Patients received either transepithelial CXL with Ricrolin TE (n= 35) or epi-off CXL with isotonic riboflavin (n= 26) in 1 academic treatment center, using a simple unrestricted randomization procedure. The main outcome measure was clinical stabilization of keratoconus after 1 year, defined as a maximal keratometry (Kmax) increase <1 diopter (D). Average Kmax was stable at all visits in the transepithelial group, while after epi-off CXL a significant flattening of 1.2-1.5 D was demonstrated from the 3-month follow-up onwards. The trend over time in Kmax flattening was significantly different between the groups (P= .022). Eight eyes (23%) in the transepithelial group showed a Kmax increase of >1 D after 1 year (range 1.3-5.4 D) vs none in the epi-off group (P= .017). There was significant different trend in corrected distance visual acuity (CDVA), with a more favorable outcome in the transepithelial group (P= .023). In the transepithelial group, no complications occurred and in the epi-off group, 4 eyes (15%) developed complications owing to healing problems (sterile infiltrate, herpes keratitis, central haze, and stromal scar). This study showed that although transepithelial CXL was a safe procedure without epithelial healing problems, 23% of cases showed a continued keratoconus progression after 1 year. Therefore, at this time, we do not recommend replacing epi-off CXL by transepithelial CXL for treatment of progressive keratoconus.

Recovery of corneal sensitivity after collagen crosslinking with and without epithelial debridement in eyes with keratoconus

To evaluate the changes in corneal sensitivity after corneal collagen crosslinking (CXL) with the epithelium off (epi-off) and with the epithelium on (epi-on) in eyes with keratoconus. Prospective interventional case series. Eye Clinic, A. Fiorini Hospital, Terracina (Latina), Rome, Italy. On the basis of the corneal pachymetry at the area of topographic steepening, eyes treated with CXL were divided in 2 groups: those with a corneal thickness of 400 μm or more (epi-off) and those with a corneal thickness of less than 400 μm (epi-on). Corneal sensitivity was measured using a contact esthesiometer (Cochet-Bonnet) before treatment and 1 and 7 days and 1, 3, 6, 9, and 12 months after treatment. The study evaluated 50 CXL-treated eyes in 50 patients (25 epi-on and 25 epi-off) from January 7, 2012, to December 15, 2012. In the epi-off group, corneal sensitivity was statistically significantly reduced for up to 3 months after CXL and gradually returned to normal levels. In the epi-on group, corneal sensitivity was statistically significantly reduced for up to 7 days but was not statistically significantly different from preoperative values at other measurement times. At 7 days, the corneal sensitivity was statistically significantly lower in the epi-off eyes than in the epi-on eyes. Epi-off and epi-on CXL both caused hypoesthesia, but corneal sensitivity subsequently recovered completely. The corneal hypoesthesia was more pronounced in eyes in which the epi-off technique was used, and the recovery time was shorter for eyes treated using epi-on CXL. No author has a financial or proprietary interest in any material or method mentioned.

Corneal Cross-linking can halt the Progression of Keratoconus, but what is the Best Approach to Treatment?

ABSTRACT There are a number of treatment options for keratoconus, but only corneal collagen cross-linking (CXL) appears to halt the progression of the disease. To guarantee effective cross-linking, CXL treatment involves removal of the corneal epithelium prior to riboflavin application and ultraviolet light illumination to ensure that riboflavin reaches the collagen in the stroma—epithelial-on cross-linking (‘Epi-off’ CXL). Several methods of ‘Epi-on’ (transepithelial) CXL have been proposed, as keeping the corneal epithelium intact should be less painful and help avoid other CXL-associated adverse events. The evidence to date is that Epi-off CXL remains the most effective method of strengthening the cornea and slowing keratoconus progression—but transepithelial methods are gaining ground. How to cite this article Raiskup F, Hillen M. Corneal Crosslinking can halt the Progression of Keratoconus, but what is the Best Approach to Treatment? Int J Kerat Ect Cor Dis 2015; 4(2):47-51.

Comparison of transepithelial corneal collagen crosslinking with epithelium-off crosslinking in progressive keratoconus

To evaluate the safety and efficacy of transepithelial corneal collagen crosslinking (TE-CXL) as compared to epithelium-off crosslinking (epi-off CXL) in progressive keratoconus. Records of keratoconus patients treated with TE-CXL or epi-off CXL were reviewed retrospectively. Patients were included if they had at least 12months follow-up. Pre- and postoperative measurements of visual acuity, refractive errors, keratometry, corneal topography and pachymetry were assessed and compared. There was no statistically significant difference between two groups at baseline in terms of demographic, refractive and corneal parameters. Mean maximum cone apex curvature (apical K) increased from 51.62±5. Eighty-four diopters (D) to 53.70±5.49 D in the TE-CXL group (n=17), and decreased from 52.02±4.07 D to 51.22±3.51 in the epi-off CXL group (n=19) at the end of the follow-up period. The difference between two groups was statistically significant (P=0.0002). An increase of≥1D in apical K was observed in two of 19 eyes (11%) in the epi-off CXL group, and 11 of 17 eyes (65%) in TE-CXL group at the last follow-up visit, compared to baseline (P<0.0001). Fourteen patients in the epi-off CXL group exhibited corneal edema that resolved without haze with topical corticosteroid treatment by 4months. No postoperative corneal edema was observed in TE-CXL group. Although it is safe and well tolerated, TE-CXL does not effectively halt the progression of keratoconus. Epi-off CXL appears to be effective in stopping progression and even improves corneal parameters.

Transepithelial corneal collagen crosslinking for progressive keratoconus: 24-month clinical results

To assess the clinical results of transepithelial collagen crosslinking (CXL) in patients 26 years and younger with progressive keratoconus suitable for epithelium-off (epi-off) CXL. Department of Ophthalmology, Siena University Hospital, Siena, Italy. Prospective case series. The study included 26 eyes (26 patients) treated by transepithelial (epithelium-on) CXL. The mean age was 22 years (range 11 to 26 years) (10 younger than 18 years; 16 between 19 years and 26 years). Preoperative and postoperative examinations included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, simulated maximum keratometry (K), coma and spherical aberration, and corneal optical coherence tomography optical pachymetry. The solution for transepithelial CXL (Ricrolin TE) comprised riboflavin 0.1%, dextran 15.0%, trometamol (Tris), and ethylenediaminetetraacetic acid. Ultraviolet-A treatment was performed with the Caporossi Baiocchi Mazzotta X Linker Vega at 3 mW/cm(2). After relative improvement in the first 3 to 6 months, the UDVA and CDVA gradually returned to baseline preoperative values. After 12 months of stability, the simulated maximum K value worsened at 24 months. Coma aberration showed no statistically significant change. Spherical aberration increased at 24 months. Pachymetry showed a progressive, statistically significant decrease at 24 months. Fifty percent of pediatric patients were retreated with epi-off CXL due to significant deterioration of all parameters after 12 months of follow-up. Functional results after transepithelial CXL showed keratoconus instability, in particular in pediatric patients 18 years old and younger; there was also functional regression in patients between 19 years and 26 years old after 24 months of follow-up. mentioned.

Brillouin Microscopy of Collagen Crosslinking: Noncontact Depth-Dependent Analysis of Corneal Elastic Modulus

Corneal collagen crosslinking (CXL) is designed to halt the progression of keratoconus and corneal ectasia by inducing corneal stiffening. However, it currently is difficult to monitor and evaluate CXL outcome objectively due to the lack of suitable methods to characterize corneal mechanical properties. We validated noncontact Brillouin microscopy to quantify corneal mechanical properties before and after CXL. CXL was performed on fresh porcine eyes using various presoaking times and light doses, with or without epithelial debridement. From Brillouin maps of corneal elastic modulus, stiffness and average modulus of anterior, middle, and posterior stroma were analyzed. Corneal stiffening index (CSI) was introduced as a metric to compare the mechanical efficacy of a given CXL protocol with respect to the standard protocol (30-minute riboflavin presoak, 3 mW/cm² ultraviolet illumination for 30 minutes). Brillouin corneal stiffness increased significantly (P < 0.001) by epi-off and epi-on CXL. The increase of Brillouin modulus was depth-dependent, indicating that anterior stromal stiffening contributes the most to mechanical outcome. The increase of anterior Brillouin modulus was linearly proportional to the light dose (R² > 0.98). Compared to the standard epi-off procedure, a typical epi-on procedure resulted in a third of stiffness increase in porcine corneas (CSI = 33). Brillouin microscopy allowed imaging and quantifying CXL-induced mechanical changes without contact in a depth-dependent manner at high spatial resolution. This technique may be useful to evaluate the mechanical outcomes of CXL procedures, to compare different crosslinking agents, and for real-time monitoring of CXL in clinical and experimental settings.