Article

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

Authors:
  • Near East University School of Medicine
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Objectif Évaluer l’efficacité et l’innocuité du cross-linking du collagène cornéen transépithélial (TE-CXL) par rapport au cross-linking conventionnel (épi-off CXL) dans le traitement du kératocône évolutif. Patients et méthodes Les patients atteints de kératocône traités par TE-CXL ou épi-off CXL ont été revus rétrospectivement. Les patients ont été inclus s’ils avaient au moins 12 mois de suivi. Les mesures pré- et postopératoires de l’acuité visuelle, des erreurs de réfraction, de la kératométrie, de la topographie cornéenne et de la pachymétrie ont été évaluées et comparées. Résultats Il n’y avait pas de différence statistiquement significative entre les paramètres préopératoires des deux groupes concernant les donnés démographiques, les données réfractives et topographiques cornéennes. La valeur moyenne de la courbure maximale du sommet du cône (apical K) a augmenté de 51,62 ± 5,84 dioptres (D) à 53,70 ± 5,49 D dans le groupe de TE-CXL (n = 17) et diminué de 52,02 ± 4,07 D à 51,22 ± 3,51 D dans le groupe d’épi-off CXL (n = 19) à la fin de la période de suivi. La différence entre les deux groupes était statistiquement significative (p = 0,0002). Une augmentation supérieure à 1 dioptrie d’apical K a été observée dans 11 % (2/19) du groupe d’épi-off CXL et 65 % (11/17) du groupe de TE-CXL, lors de la dernière visite de suivi, par rapport aux mesures préopératoires (p < 0,0001). Quatorze patients dans le groupe d’épi-off CXL ont présenté un œdème cornéen toujours résolutif avant 4 mois avec une corticothérapie topique. Il n’a pas été observé d’œdème cornéen postopératoire dans le groupe de TE-CXL. Conclusions Malgré une sécurité et une tolérance démontrées, le TE-CXL ne semble pas arrêter efficacement la progression du kératocône. Le cross-linking conventionnel est plus efficace dans la stabilisation du kératocône en améliorant même ses paramètres topographiques cornéens.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... In contrast, some studies have found that the patients treated with epi-on CXL had a greater KC progression than those treated with epi-off CXL [42]. Kocak et al. [43] reported a stabilization of the corneal ectasia in 89% of the eyes treated with epi-off CXL, whereas only in 35% of the eyes treated with epi-on CXL. Cerman et al. [44] found that 97% of the epi-off eyes achieved stabilization, whereas 80% of the epi-on eyes achieved stabilization in a comparative study, although these authors associated greater ectasia progression in the epi-on eyes to the presence of more cases of advanced and progressive KC disease in such group. ...
... e mean preoperative and postoperative K max (D) values in the epi-on group in different comparative studies were 52.41 ± 5.39 and 50.5 ± 5.37 D, [40] 49.27 ± 4.1 and 48.13 ± 5.4 D, [41] 48.75 ± 6.82 and 50.57 ± 6.82 D, [43] 60.12 ± 6.17 and 60.0 ± 6.31 D, [44] and 54.7 ± 4.0 and 53.7 ± 3.7 D, [45] respectively. Caruso et al. [46] observed a reduction in the mean K max value of −1.10 ± 1.22 D at the end of the followup after epi-on CXL. ...
... In our study, the mean preoperative and postoperative K max values in the epi-on group were 60.31 ± 6.47 and 59.88 ± 7.19 D, respectively. With respect to the mean values of CCT (microns) in the epi-on group in different comparative studies, the preoperative and postoperative values of 451 ± 39.51 and 448.4 ± 37.32 μm, [40] 490.2 ± 22.3 and 488.0 ± 19.3 μm, [41] 470 ± 38 and 446 ± 59 μm, [43] and 484 ± 37 and 491 ± 27 μm [45] have been reported, respectively. Cerman et al. [44] analyzed Besides these investigations, other CXL protocols have been evaluated that are based on the epi-on concept, such as the CXLO protocol that uses a new sodium iodide riboflavin formulation that theoretically allows a greater level of penetration [47][48][49][50][51]. ese investigations have shown that the use of the CXLO protocol can halt the progression of ectasia and result in better visual acuity without the risk associated to epi-off CXL [47][48][49][50][51]. ...
Article
Full-text available
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, R 2 = 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, R 2 = 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.
... [18][19][20][21][22][23][24] Some transepithelial (epithelium-on) CXL (TECXL) studies have demonstrated efficacy, whereas others have reported poor results with high rates of continued keratoconic progression. [23][24][25][26][27][28][29][30][31] The purpose of this study was to undertake a metaanalysis comparing SCXL to TECXL using a predefined protocol following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines 32 to determine which procedure provides superior clinical outcomes. ...
... Of the 8 trials, 5 were RCTs 25,26,36-38 and 3 were nonrandomized comparative trials. 28,29,31 ...
... We divided trials into 2 groups of TECXL protocols, those using chemical enhancers to improve riboflavin transepithelial penetration 25,28,29,[36][37][38] and those using current commercially available iontophoretic protocols. 26,31 Only in terms of mean K did we find a statistical difference between these 2 sub-analysis groups. ...
Article
Purpose: To systematically compare standard epithelium-off corneal collagen cross-linking (SCXL) and transepithelial corneal collagen cross-linking (TECXL) for treating keratoconus. Methods: PubMed, EMBASE, the Cochrane Library, the US trial registry (ClinicalTrials.gov), VIP Database, Wanfang Databse, and China National Knowledge Infrastructure searches up to February 2017 were conducted. Primary outcomes were changes at 1 year in uncorrected distance visual acuity, maximum keratometry (Kmax), and mean keratometry (mean K). Secondary outcomes were changes at 1 year in corrected distance visual acuity, mean refractive spherical equivalent, central corneal thickness, endothelial cell density, and the occurrence of adverse events. Results: Eight studies with a total of 455 eyes were included. For primary outcomes, SCXL showed a greater reduction in mean K [standardized mean difference (SMD) 0.28; 95% confidence interval (CI), 0.03-0.53; P = 0.03] compared with TECXL. Subgroup analysis indicated that SCXL had a comparable effect on reducing mean K with TECXL protocols using chemical enhancers (SMD 0.05; 95% CI, -0.36 to 0.45; P = 0.82) but a greater reduction in mean K compared with TECXL with current iontophoretic protocols (SMD 0.43; 95% CI, 0.10-0.75; P = 0.01). For the other outcomes, there were no statistically significant differences. Conclusions: With the exception of less reduction in mean K with current iontophoretic protocols, analysis of the limited number of comparative studies available seems to demonstrate that SCXL and TECXL have a comparable effect on visual, refractive, pachymetric, and endothelial parameters at 1 year after surgery. Further follow-up is required to determine whether these techniques are comparable in the long-term.
... Encouraging as well as unsuccessful results in visual acuity and keratometry (K) readings have been reported with transepithelial CXL. [8][9][10][11][12][13][14][15][16][17][18][19][20] The underlying mechanism and its effects on topographic indices are not completely understood, and there have been no adequate comparisons of the 2 modalities. To our ...
... Our literature review of transepithelial CXL found 13 clinical studies. [8][9][10][11][12][13][14][15][16][17][18][19][20] The only comparative study in adults comparing the topography indices of a transepithelial CXL group with those of an epithelium-off CXL group 13 reported an increase of 1.00 D or more in the apical K value in 65% of patients 12 months after transepithelial CXL; however, the report is not in English. Magli et al. 16 compared transepithelial CXL with epithelium-off CXL in a pediatric population; the 2 treatments showed similar effectiveness. ...
... In 5 studies including a total of 141 eyes, topographic parameters worsened. 9,10,[12][13][14] In the remaining 8 studies involving 223 eyes, the topographic parameters improved or stabilized. 8,11,[15][16][17][18][19][20] In 5 studies including a total of 244 eyes, the follow-up was 12 months, 8,15,[17][18][19] and in 3 studies including a total of 86 patients it was 18 months. ...
Article
To compare the efficacy of epithelium-off corneal collagen crosslinking (CXL) with transepithelial CXL in patients with progressive keratoconus. Department of Ophthalmology, Marmara University School of Medicine, Istanbul, Turkey. Retrospective cohort study. Eyes that had transepithelial CXL were compared with eyes treated with epithelium-off CXL. All patients with a follow-up of 18 months were evaluated for uncorrected (UDVA) and corrected (CDVA) distance visual acuities, corneal topography, aberrometry, and pachymetry (Pentacam). The mean patient age was 22.8 years ± 4.7 (SD) (range 18 to 31 years) in the transepithelial group (30 eyes) and 23.7 ± 3.9 years (range 18 to 30 years) in the epithelium-off group (30 eyes). The mean UDVA and CDVA significantly improved in both groups (P < .001). There was no significant difference in the CDVA gain between the 2 groups. In the epithelium-off group, significant improvements occurred in spherical error (P = .002), spherical equivalent (P = .004), maximum keratometry (K), flat K (P = .036), and steep K (P < .001). The reductions in flat K, steep K, and maximum K were greater in the epithelium-off group (P = .004 for flat K; P < .001 for steep K and maximum K). In the transepithelial group, significant improvements occurred in the cylindrical error (P = .009) and in the index of surface variance and index of surface asymmetry (both P < .001). Although transepithelial CXL seemed to have reduced effectiveness in inducing improvement in topographic indices, its effect on visual acuity is likely to be similar to that of epithelium-off CXL. No author has a financial or proprietary interest in any material or method mentioned. Copyright © 2015 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.
... Among possible changes in corneal architecture with transepithelial CXL is corneal epithelial remodeling, which can differ from traditional epithelium-off (epi-off) CXL. [20][21][22][23][24] Also, some studies [20][21][22][23] report that CXL does not penetrate as deeply into the stroma if it is performed epi-on, and therefore, corneal astigmatism, curvature, and the response to ablation might differ as well. More corneal flattening is seen in conventional epi-off CXL than in transepithelial CXL. ...
... Among possible changes in corneal architecture with transepithelial CXL is corneal epithelial remodeling, which can differ from traditional epithelium-off (epi-off) CXL. [20][21][22][23][24] Also, some studies [20][21][22][23] report that CXL does not penetrate as deeply into the stroma if it is performed epi-on, and therefore, corneal astigmatism, curvature, and the response to ablation might differ as well. More corneal flattening is seen in conventional epi-off CXL than in transepithelial CXL. ...
... More corneal flattening is seen in conventional epi-off CXL than in transepithelial CXL. [20][21][22][23][24] Therefore, this might produce variability in K readings, as seen in our study. [20][21][22][23][24] Based on our literature search, there does not appear to be a head-to-head trial of our modified epi-on CXL technique versus traditional epi-off CXL followed by topography-guided PRK to evaluate possible, and likely subtle topographic, changes secondary to the CXL technique. ...
Article
Full-text available
Purpose of Review This paper evaluated topography-guided excimer ablations and recent US experience of this technology. Personal clinical experience, initial approval of the technique, and its application to a potential extended spectrum of clinical conditions was reviewed. Recent Findings Topography-guided ablation can precisely treat corneas with variable topographic indices and attempt to neutralize irregularities by combining myopic and hyperopic ablation profiles. The T-CAT Phase III study demonstrated the safety and efficacy of this technique, which earned FDA approval in 2013. Current literature has reinforced its efficacy and explored off-label investigations, such as its use to improve visual results in abnormal corneas (e.g., keratoconus, post-LASIK ectasia). Summary Topography-guided ablation provides increased quality of vision without necessitating excess tissue removal in otherwise normal, keratoconic, ectatic, or post-corneal transplant eyes. In the future, we will likely see a combination of treatment strategies, enabling ophthalmologists to treat the entire refractive surface and refine these already remarkable results.
... Characteristics of all the 24 eligible studies are shown in Tables 1 and 2. Among these studies, only one study (4%) [22] was with respect to comparison of the three CXLs,13 studies (54%) [18,[23][24][25][26][27][28][29][30][31][32][33][34] were comparing between AC and SC, 10 studies (42%) [16][17][35][36][37][38][39][40][41][42] were on TC versus SC, and as for study design, 11 studies (46%) [16,[26][27][28][32][33]35,[39][40][41][42] were RCT, 8 studies (33%) [22][23][24][29][30]34,[37][38] were PCS and 5 studies (21%) [17][18]25,31,36] were RCS. The sample size varied widely among the studies, the largest sample size enrolled 153 patients (153 eyes) [27] , the smallest one just enrolled 13 patients (13 eyes) [35] , and the sample sizes of most were 30-70 eyes. ...
... Characteristics of all the 24 eligible studies are shown in Tables 1 and 2. Among these studies, only one study (4%) [22] was with respect to comparison of the three CXLs,13 studies (54%) [18,[23][24][25][26][27][28][29][30][31][32][33][34] were comparing between AC and SC, 10 studies (42%) [16][17][35][36][37][38][39][40][41][42] were on TC versus SC, and as for study design, 11 studies (46%) [16,[26][27][28][32][33]35,[39][40][41][42] were RCT, 8 studies (33%) [22][23][24][29][30]34,[37][38] were PCS and 5 studies (21%) [17][18]25,31,36] were RCS. The sample size varied widely among the studies, the largest sample size enrolled 153 patients (153 eyes) [27] , the smallest one just enrolled 13 patients (13 eyes) [35] , and the sample sizes of most were 30-70 eyes. ...
... Three studies (13%) [17,24,37] took juveniles (less than 18 years old) as their objects, the others (87%) were all adult patients. All eligible studies included both genders, and 18 studies [ [17,22,25,[28][29][30]33,[40][41][42] , the others were Mongolian (4 studies, 17%) [18,23,31,43] , Middle Eastern Ethnicity (4 studies, 17%) [16,26,27,32] , Turks (5 studies, 21%) [24,[35][36][37][38] and Indian (1 study, 4%) [39] . ...
Article
Full-text available
Aim: To compare the effectiveness and safety between modified cross-linking (MC) and standard cross-linking (SC) in mild or moderate progressive keratoconus. Methods: Eligible studies were retrieved from four electronic databases, including CENTRAL, Clinical Trials gov, PupMed and OVID MEDLINE. We set post-surgical maximum K value (Kmax) as the primary outcome. In addition, uncorrected and corrected distant visual acuity (UDVA and UDVA), spherical equivalent (SE), endothelial cell density (ECD), central cornea thickness (CCT) and depth of demarcation line (DDL) were Meta-analyzed as secondary outcomes. Mean differences for these outcomes were pooled through either a random-effect model or fixed-effect model according to data heterogeneity. Results: Twenty-four comparative studies either on accelerated cross-linking (AC) compared with SC or on trans-epithelial cross-linking (TC) compared with SC were included and pooled for analysis. The results indicated that MC was significantly inferior to SC at delaying Kmax deterioration [AC vs SC 0.49 (95% CI: 0.04-0.94, I(2)=75%, P=0.03); TC vs SC 1.15 (95% CI: 0.54-1.75, I(2)=50%, P=0.0002)]. SE decreased significantly for SC when compared to AC [0.62 (95% CI: 0.38-0.86, I(2)=22%, P<0.00001)]. DDL of SC was more significantly deeper than that of TC [-133.49 (95% CI: -145.94 to -121.04, I(2)=33%, P<0.00001)]. Other outcomes demonstrated comparable results between MC and SC. Conclusion: SC is more favorable at halting the progression of keratoconus, but visual acuity improvement showed comparable results between MCs and SC.
... [8] Literature review on comparison of transepithelial and epithelium-off CXL revealed controversial results in different age groups and populations. [6,[12][13][14][15][16][17] Magli et al. compared transepithelial and epithelium-off CXL in paediatric population with similar efficacy. [6,13] Buzzonetti and Petrocelli reported visual improvement at 18 months with no improvement in topographic indices. ...
... [15] Kocak et al. compared transepithelial and epithelium-off CXL at 12 months follow-up with no statistically significant change in UDVA and CDVA with progression in 11 out of 17 eyes in transepithelial CXL and deterioration in topographic indices in adult population. [16] Rossi et al. and Filippello et al. on the other hand reported clinical stability and similar refractive outcomes in both transepithelial and epithelium-off CXL at 12 months. [5,17] In our study, CDVA and UDVA improved significantly with no statistical significant difference between transepithelial and epithelium-off CXL group at 12 months which were comparable to the previous similar trials results of Çerman et al. [15,18] The mean reduction in corneal thickness in our study was 30 µ in epithelium-off CXL group and 4 µ in transepithelial group at 18 months postoperatively measured by dual Scheimpflug corneal topography in accordance with similar study. ...
... We achieved a 2.0D topographic flattening of maximum keratometry in epithelium-off CXL at 12 months which was comparable to 1.5D of Soeters et al. [18] and better than 0.27D flattening described by Kocak et al. in epithelium-off CXL at 1 year. [16] The flattening of keratometry achieved can be explained by a steeper preoperative K max values, 53.4D and 58D, respectively, against 48.97D, which are known to flatten more after CXL. [18] The average K max flattening achieved with epithelium-off CXL is statistically higher in our study, which suggests that transepithelial CXL is effective yet not comparable to epithelium-off CXL in reducing topographic keratometric indices, also indicated in the previous clinical trials. ...
Article
Full-text available
PURPOSE The purpose of this study is to compare the safety and efficacy of transepithelial corneal crosslinking (CXL) with epithelium-off crosslinking (epithelium-off CXL) in the treatment of progressive keratoconus in adult Pakistani population. MATERIALS AND METHODS Sixty-four eyes of 64 consecutive patients of progressive keratoconus were included in this quasi-experimental study. Thirty-two eyes received transepithelial CXL with Peschke TE (0.25% riboflavin (Vitamin B2), 1.2% hydroxypropyl methylcellulose (HPMC), 0.01% benzalkonium chloride) and 32 eyes received epithelium-off CXL with Peschke M (0.1% riboflavin (Vitamin B2) 0.1%, HPMC 1.1%.) The cornea was then exposed to ultraviolet A light at an irradiance of 3 mW/cm² for 30 min. The primary outcome measure, clinical stabilization of keratoconus was defined as an increase of no more than 1D in Kmax at 1 year. Other parameters evaluated at baseline and 3, 6, 12, and 18 months postoperatively were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), spherical equivalent (SE), astigmatism (Ast), simulated keratometry, steep keratmetry (steep K), and corneal thickness at thinnest point (pachy thin). RESULTS Both epithelium-off CXL and transepithelial CXL groups showed a significant reduction in Kmax, steep K, simulated K, corneal pachymetry at all test points (P < 0.05) with significantly greater reductions achieved in epithelium-off CXL group at 18 months follow-up. The mean UDVA, CDVA, SE, Ast significantly improved in both groups (P < 0.05). The mean postoperative UDVA and CDVA between the groups were not significant at 12 months (P = 0.650, 0.018, respectively). Clinical stabilization was achieved in 94% of eyes in epithelium-off CXL and 75% of eyes in transepithelial CXL. In epithelium-off CXL, three eyes exhibited stromal haze resolved by corticosteroid treatment. No complication was documented in transepithelial CXL group. CONCLUSION Transepithelial CXL is not recommended to be replaced completely by standard epithelium-off CXL due to continued ectatic progression in 25% of cases. However, thin corneas, unfit for standard epithelium-off CXL, can benefit from transepithelial CXL.
... The two groups were matched for demographic and other clinical parameters. The mean age was 26.52 ± 3.77 (range 18-34) for the standard CLX group and 28.32 ± 4.91 (range [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] for the I-CLX group. At baseline, before the intervention, the demographic data and the clinical parameters were statistically analyzed and no significant difference was found between the two groups (P[0.05) ( Table 1). ...
... Transepithelial CXL might be a solution for avoiding such complications and might also offer faster recovery times. The fact that it can stop the progression of keratoconus has been the subject of controversy and debate: some studies indicate a certain degree of efficiency, but lower than the efficiency of the standard CXL procedure [26,27], whereas other studies show a stabilization or improvement in various topographic parameters [18,[28][29][30]. On the other hand, there are also studies that have shown a lack of efficiency for this technique [31][32][33]. ...
Article
IntroductionThe purpose of this study was to evaluate the efficacy and safety of iontophoretic collagen cross-linking (I-CXL) compared to epithelium-off standard collagen cross-linking (CXL) in treating the early stages of progressive keratoconus. Methods This retrospective cohort study at Oftaprof Clinic, Iasi, Romania included 40 eyes of 40 patients with progressive keratoconus stage I according to the Amsler classification who underwent I-CXL and the results were compared with a matched group of 40 eyes from 40 patients who received standard CXL. The follow-up period was 24 months. Uncorrected (UCVA) and corrected (CDVA) distance visual acuities, corneal topography, and pachymetry were evaluated in all patients. ResultsThe mean patient age was 26.52 ± 3.77 years for the standard CXL group and 28.32 ± 4.91 for the I-CXL group. The mean UCVA and CDVA improved significantly in both groups. At 12 months, the improvement of UCVA was greater in the I-CXL group (P < 0.05). There was a statistically significant different trend in CDVA between groups with a more favorable outcome for the standard CXL group (P < 0.01). The manifest cylinder decreased by a mean of 0.962 ± 0.114 D in the epithelium-off CXL group and by 0.831 ± 0.082 D in the I-CXL group (P < 0.001). At 24 months, the Kmax values improved by 1.2 ± 0.199 D in the standard group and by 0.908 ± 0.177 D in the I-CXL group (P < 0.001). Conclusion All parameters either improved or remained unchanged after the iontophoretic collagen cross-linking intervention. I-CXL was found to be as effective as the standard technique.
... Kocak et al., [33] Retrospective study 12-months followup period Epithelium-off technique was effective in declining keratoconus progression. Choi et al.,[42] Quantitative study Corneal thickness improved by 107% post CXL administration in ex vivo models. ...
... Raiskup et al.,[32] suggested that the concentration of alcohol content in blood whether low or high obtain a similar level of riboflavin absorption through the epithelium of cornea. On the other hand, Kocak et al.,[33] compared the effectiveness of both the procedures and proposed that epithelium-off technique was effective in halting the progression of keratoconus; while transepithelial technique was ineffective in stopping keratoconus progression. ...
Article
Full-text available
Background The progression of keratoconus is stabilized with the help of corneal collagen cross-linking (CXL) supported through photosynthesized riboflavin. Objective This study aims to compare the effectiveness of the transepithelial procedure and epithelium off procedure of corneal collagen crosslinking among keratoconus patients in Jordan. Methods The study recruited 80 patients suffering from progressive keratoconus, from a tertiary care setting in Jordan. These participants were randomly divided into two groups; group 1 with 40 participants subjected to transepithelial (Corneal collagen cross-linking) CXL; and 40 participants in group 2 received conventional epithelium off CXL. Results Improvement was observed in the mean contact lens, which corrected distance visual acuity (CDVA) from logMAR 0.332 ± 0.09 (group 1), 0.35 ± 0.09 (group 2) to 0.241 ± 0.07 (group 1), 0.21 ± 0.07 (group 2), respectively at the end of follow-up (12 months). The mean pachymetry improved from 429.81 ± 18.96 μm (group 1), 430.08 ± 17.05 μm (group 2) to 436.5 ± 15.49 μm (group 1), 436.44 ± 12.53 μm (group 2), respectively, after twelve months. Additionally, the mean Sim K astigmatism declined from 7.0 ± 2.0 (group 1), 6.73 ± 1.98 (group 2) to 5.97 ± 1.88 (group 1), 5.53 ± 0.08 (group 2) respectively at twelve months post-treatment. Majority of the patients in group 2 experienced more pain as compared to group 1 participants. Conclusion The effectiveness of a cross-linking procedure related to keratometry readings and corneal thickness showed that conventional (epithelium off) CXL method is more effective than transepithelial CXL.
... 10,[17][18][19][20] The high rate of Keraring explantation in the present study (6.4%) could be attributed to eye rubbing associated with VKC in these eyes. 6,7,9,12,13,[21][22][23] In addition, a high rate of KC progression was noted (6.4%), which could be attributed to the incomplete effectiveness of the accelerated epithelium-on CXL. 24,25 As mentioned before, all investigated visual acuity parameters improved postoperatively. ...
... 21 Many authors have stressed that VKC must be treated aggressively in pediatric KC patients before cross-linking can be initiated. 7,9,12,13,22,23,28,29 Their statements are supported by the results in our study as four eyes (6.4%) had VKC and eventually required segment migration or extrusion. Yet, Shetty et al. had a higher complication rate as they record three eyes (10%) with KC progression resulting from VKC within a 2-year follow-up period after accelerated epithelium-off CXL. ...
Article
Full-text available
Purpose: To analyze the visual and refractive outcomes of combined accelerated cross-linking with femtosecond laser intracorneal ring segment implantation for the treatment of pediatric keratoconus. Materials and Methods: This retrospective multicenter non-comparative clinical study included 63 eyes of 37 patients (age, 9–17 years) who underwent between August and September 2016 combined cross-linking with intracorneal ring segment implantation for keratoconus. Preoperative and postoperative (6, 12, and 18 months) uncorrected (UDVA) and corrected (CDVA) distance visual acuities, subjective refractions, keratometry (K), and pachymetry measurements were compared. Results: The postoperative spherical equivalent refraction was within ± 1 D, ± 2 D, and ± 3 D in 19 (30.2%), 27 (42.9%), and 37 (58.8%) eyes, respectively. Only 27 eyes achieved the attempted preoperative spherical equivalent refraction. The mean spherical equivalent refraction significantly improved from −6.01 ± 2.97 to −3.13 ± 2.78 D postoperatively (P < 0.0001). The mean K average reading significantly decreased from 48.75 ± 4.25 to 46.65 ± 3.89 D postoperatively (P < 0.0001). The mean postoperative myopic, astigmatic, and spherical equivalent corrections were −2.17 ± 2.19, −1.52 ± 2.03, and −2.93 ± 2.35 D, respectively. The mean UDVA and CDVA showed significant improvements (0.89 ± 0.33 to 0.40 ± 0.28, P < 0.0001; 0.35 ± 0.31 to 0.25 ± 0.24, P = 0.004; respectively) at 18 months postoperatively. Keratoconus progression, segment migration, and segment extrusion were seen in 4 (6.4%), 1 (1.6%), and 3 (4.7%) eyes, respectively, probably contributing to the lower mean postoperative CDVA. Conclusion: Cross-linking plus is only partially effective for pediatric keratoconus. Despite some improvements in vision and keratometry measures, it resulted in complications such as keratoconus progression, segment extrusion, and segment migration which affected the vision in some patients. These findings suggest an assessment of standard epithelium-off collagen cross-linking as a sole procedure to treat pediatric keratoconus in future studies.
... After screening titles and abstracts, 1541 studies were excluded. Eleven articles [13][14][15][16][17][18][19][24][25][26][27] were initially considered potentially relevant; however, 4 of these were excluded because 3 articles were non-RCT trials and one was a short-term follow-up ( Figure 1, and Supplement 2, available at http:// jcrsjournal.org). Finally, the remaining seven RCTs involving 505 eyes were included in this metaanalysis. ...
... Three non-RCTs involving 136 eyes were individually analyzed. [24][25][26] Data were obtained on maximum K, CCT, BSCVA, UDVA, and cylindrical refraction. As shown in the statistical results in Figure 10, there was a significant reduction in maximum K in epi-off CXL at 1 year after surgery compared with transepithelial CXL (WMD, 1.54; 95% CI, 0.39 to 2.68; P = .008). ...
Article
This review compared the clinical results of transepithelial corneal crosslinking (CXL) to epithelium-off (epi-off) CXL in progressive corneal ectasia using a metaanalysis. The Cochrane databases and Medline were searched for randomized controlled trials (RCTs). Seven RCTs involving 505 eyes that met the eligibility criteria were identified. The epi-off CXL group showed significantly better outcomes in postoperative changes in maximum keratometry (K) during 1-year observation periods. Transepithelial CXL resulted in significantly greater post-treatment central corneal thickness and best spectacle-corrected visual acuity (BSCVA). The presence of a postoperative demarcation line was significantly more frequent after epi-off CXL than that after transepithelial CXL. No statistically significant difference was found between other parameters. Although patients in the transepithelial CXL group demonstrated a greater improvement in BSCVA compared with patients in the epi-off CXL group at the 1 year follow-up, transepithelial CXL had less impact on halting progressive corneal ectasia in terms of maximum K than epi-off CXL.
... 19,30,31 Although these experimental techniques show encouraging results in vitro, further investigation is required before they can be routinely applied in clinical practice. [32][33][34] In our study, we used a novel riboflavin solution containing 0.25% riboflavin and 0.01% benzalkonium chloride, similar to a composition we published previously that demonstrated an increase in biomechanical stiffness similar to that obtained in epithelium-off CXL in experimental conditions. 19 Also, unpublished data from in vitro experiments from our group show that this specific composition can achieve satisfactory absorption in the corneal tissue. ...
... Koppen et al. reported reduced efficacy of benzalkonium chloride-assisted transepithelial CXL compared to standard CXL in stabilizing progressive keratoconus in a cohort of 38 patients (53 eyes). 40 The same conclusion was reported by Kocak et al., 33 whereas Caporossi et al. found keratoconus instability after transepithelial CXL, in particular in pediatric patients 18 years old and younger, with functional regression in patients between 19 and 26 years old after 24 months of follow-up. 32 Recently, Soeters et al. documented in a randomized controlled trial that transepithelial CXL is less effective than standard epithelium-off CXL, showing a high failure rate (23%) in a cohort of 35 patients with progressive keratoconus. ...
Article
Full-text available
Purpose: To assess the efficacy of a modified high concentration riboflavin solution containing benzalkonium chloride 0.01% for transepithelial corneal cross-linking (CXL). Methods: In this prospective, interventional multicenter cohort study, 26 eyes of 26 patients with documented progressive keratoconus who underwent transepithelial CXL were included. Follow-up at 6 and 12 months postoperatively included slit-lamp examination, uncorrected and corrected distance visual acuity (logMAR), maximum keratometry (Kmax), and corneal pachymetry (corneal thinnest point) as determined by Scheimpflug imaging. Statistical analysis was performed using repeated measures analysis of variance and the Friedman test for parametric and non-parametric data, respectively. P values less than .05 were considered significant. Results: Kmax did not change significantly at postoperative months 6 and 12. Changes in corneal thinnest point did not change postoperatively over 12 months. Uncorrected and corrected distance visual acuity did not change postoperatively. Progression (defined by an increase in Kmax greater than 1.00 diopter occurred in 46% of eyes at 12 months. Corneal epithelial defects were observed in 46% of the patients and marked punctate corneal epitheliopathy/loose epithelium in 23% of the patients in the immediate postoperative period. No corneal infection, sterile infiltrates, or haze were observed. Conclusions: Transepithelial CXL with an enhanced riboflavin solution did not effectively halt progression of keratoconus. Significant epithelium damage was evident in the immediate postoperative period. [J Refract Surg. 2016;32(6):372-377.].
... Similarly, preparations without dextran but with sodiumKissner et al., 2010, Raiskup et al., 2012). Clinical studies with such formulations have demonstrated equivocal results with some suggesting similar efficacy to epithelium-off CXL (epi-off-CXL) (Filippello et al., 2012, Magli et al., 2013), and others showing less pronounced effects (Buzzonetti and Petrocelli, 2012, Kocak et al., 2014, Koppen et al., 2012, Leccisotti and Islam, 2010). As riboflavin is negatively charged at physiological pH and soluble in water, iontophoresis as a means of enhancing trans-epithelial absorption has also been postulated. ...
... Published clinical studies using enhanced riboflavin solutions with epithelial penetration enhancers are limited and have produced equivocal results. Some have reported similar efficacy to epi-off-CXL (Filippello et al., 2012, Magli et al., 2013), while others have demonstrated less pronounced effects with high rates of treatment failure (Buzzonetti and Petrocelli, 2012, Kocak et al., 2014, Koppen et al., 2012, Leccisotti and Islam, 2010). There are currently only three published randomized, controlled trials comparing epi-off and epi-on-CXL. ...
Article
Full-text available
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.
... These procedures attempt to reduce toxicity to the endothelium. The major objection to leaving the epithelium intact is that it may substantially reduce the effectiveness of the procedure [49][50][51]. The success of the corneal swelling procedure is difficult to evaluate because of heterogeneity in protocols [34,52]. ...
Article
Full-text available
Purpose To investigate, after 24 h, the safety of genipin or ultraviolet A (UVA)-riboflavin crosslinking of keratocytes and endothelial cells. Methods Fifteen New Zealand white rabbits were selected and divided into a PBS group (five rabbits), a 0.2% genipin crosslinking (GP-CXL) group (five rabbits), and a UVA-riboflavin crosslinking (UVA-CXL) group (five rabbits). In the GP-CXL and PBS groups, 0.2% genipin or PBS was applied to the corneal surface of the right eyes. In the UVA-CXL group, a clinical crosslinking procedure was used. Before and after surgery, the operated eyes of each group were characterized with confocal microscopy, and the corneal buttons were excised for endothelium staining and electron microscopy. Results The corneal endothelial cell density of the GP-CXL, UVA-CLX, and PBS groups changed. There was a statistically significant difference in thickness and changes in corneal endothelial cell density between the UVA-CXL group and the PBS group (p<0.05), and between the UVA-CXL group and the GP-CXL group (p<0.05), but no statistically significant difference between the GP-CXL group and the PBS group. Confocal microscopy, transmission electron microscopy, and hematoxylin and eosin staining showed that there was keratocyte apoptosis in the anterior and middle stroma and endothelial cell damage in the UVA-CXL group. In the GP-CXL group, only active keratocytes were found and minimal endothelial cell damage. Conclusions Treatment of rabbit corneas with 0.2% genipin showed minimal toxicity toward keratocytes and endothelial cells. Genipin is safer than UVA-CXL for crosslinking of thin corneas.
... Ex vivo evaluation of in situ (through a stromal pocket) CXL in porcine corneas (which do not have Bowman membrane) indicates that the biomechanical strengthening is reduced by approximately 50%, in comparison with standard protocol CXL. 30 There is thus inconclusive evidence in the peer-reviewed literature on the aspect of efficacy of some epithelium-on CXL variations. 3,8,26,31,32 The in situ riboflavin application naturally overcomes the first of the 2 obstacles, related to riboflavin penetration through the intact epithelium and in acting as a "blocking" agent against UV-A propagation. This is because the epithelium and Bowman layer, that the UV-A light has to transcend, are not soaked in riboflavin. ...
Article
Purpose To evaluate biomechanical changes induced by in-situ corneal cross-linking (CXL) with stromal pocket-delivered enhanced-concentration riboflavin and high-fluence, high-energy, UV-A irradiation. Methods Eight human donor corneas were subjected to intrastromal lamellar corneal tissue removal of anterior 140 μm, 80-μm thick× 5-mm diameter central stromal button, extracted through a 3.5-mm width tunnel, surfacing in the superior cornea periphery. Enhanced concentration riboflavin solution (0.25%) was instilled in the pocket. In the study group-A (CXL), superficial high-fluence UV-A irradiation was applied, while in the control group-B (no CXL), none. To comparatively assess changes in corneal rigidity the corneal specimens were subjected to transverse biaxial resistance measurements by application of unidirectional tangential shear force. Biomechanical differences were evaluated via stress and Young’s shear modulus. Results Stress at the 10% strain was 305±24 kPa in the study group-A, versus 157±11 kPa in the control group-B (relative difference Δ=107%, p=0.021). Stress at the 20% strain was 1,284±34 kPa in the study group-A, versus 874±29 kPa in the control group-B (Δ=47%, p=0.043). Average shear modulus in the study group-A at the 10% strain was 6.98±1.12 MPa, versus 4.04±0.85 MPa in the control group-B (Δ=73%, p=0.036). Average shear modulus in the study group-A at the 20% strain was 11.46±0.75 MPa, versus 8.80±0.72 MPa in the group-B (Δ=30%, p=0.047). Conclusions Adjunct CXL in this ex-vivo simulation refractive lens extraction procedure appears to provide significant increase in corneal rigidity, up to +107%. These findings also support our previous reported work on LASIK combined with CXL.
... There is still no consensus on how long the stroma should be imbibed with the solution (riboflavin 0.1% and dextran T 500 20%) in order to ensure a sufficient intrastromal concentration of vitamin B2. While some groups have studied the depth of riboflavin penetration [6,7], others have deliberated on the importance of removal of corneal epithelium during CXL [8,9]. Use of imaging modalities like the optical coherence tomography (OCT), Brillouin microscopy, and second harmonic imaging has allowed better understanding of changes occurring in the cornea and thereby helps in predicting treatment outcomes [10][11][12][13]. ...
Article
Full-text available
Purpose: To compare the penetration of riboflavin using a microscope-integrated real time spectral domain optical coherence tomography (ZEISS OPMI LUMERA 700 and ZEISS RESCAN 700) in keratoconus patients undergoing accelerated collagen crosslinking (ACXL) between epithelium on (epi-on) and epithelium off (epi-off). Methods: Intraoperative images were obtained during each of the procedures. Seven keratoconus patients underwent epi-on ACXL and four underwent epi-off ACXL. A software tool was developed using Microsoft.NET and Open Computer Vision (OpenCV) libraries for image analysis. Pre- and postprocedure images were analyzed for changes in the corneal hyperreflectance pattern as a measure of the depth of riboflavin penetration. Results: The mean corneal hyperreflectance in the epi-on group was 12.97 ± 1.49 gray scale units (GSU) before instillation of riboflavin and 14.46 ± 2.09 GSU after AXCL (P = 0.019) while in the epi-off group it was 11.43 ± 2.68 GSU and 16.98 ± 8.49 GSU, respectively (P = 0.002). The average depth of the band of hyperreflectance in the epi-on group was 149.39 ± 15.63 microns and in the epi-off group it was 191.04 ± 32.18 microns. Conclusion: This novel in vivo, real time imaging study demonstrates riboflavin penetration during epi-on and epi-off ACXL.
... [43][44][45][46] Consequently, its efficacy has been limited. [47][48][49] The long-term efficacy and safety of the epi-off approach have been widely demonstrated. [50][51] However, patient discomfort, slow recovery, and risk of complications have also been reported. ...
... Despite these chemical enhancers, results in clinical studies with transepithelial riboflavin preparations have been equivocal: Some studies report similar efficacy to epithelium-off CXL, 14,15 but most report inferior results. [10][11][12][16][17][18] Iontophoresis, in which an electrical gradient is used to drive negatively charged riboflavin molecules across the intact epithelium, may further enhance riboflavin penetration in transepithelial CXL. Laboratory studies of iontophoresis have been encouraging, demonstrating enhanced transepithelial riboflavin penetration and improvement of corneal biomechanics. ...
Article
Full-text available
Purpose: To measure corneal riboflavin penetration using different transepithelial iontophoresis protocols. Methods: Freshly enucleated rabbit eyes were divided into nine treatment groups of 4 eyes. One group, in which 0.1% wt/vol riboflavin was applied for 30 minutes without iontophoresis after corneal epithelial debridement, acted as a control. The remaining groups were treated with an intact epithelium using different riboflavin formulations and varying iontophoresis current, soak, and rinse times. After riboflavin application, eyes were snap frozen in liquid nitrogen. Corneal cross sections 35 μm thick were then imaged immediately by two-photon fluorescence microscopy, using image processing software to quantify stromal riboflavin concentration at different corneal depths. Results: In the epithelium-on iontophoresis treatment groups, greater stromal riboflavin penetration was achieved with higher-concentration riboflavin solutions, greater iontophoresis dosage, and longer solution contact times. A protocol utilizing 0.25% wt/vol riboflavin with benzalkonium chloride (BAC) 0.01% and two cycles of applied current and subsequent soaking (1 mA 5 minutes, soak 5 minutes; 0.5 mA 5 minutes, soak 5 minutes) achieved similar stromal riboflavin penetration to epithelium-off controls. The best-performing non-BAC-containing protocol produced stromal riboflavin penetration approximately 60% that of epithelium-off controls. Riboflavin solutions containing saline resulted in minimal stromal penetration. Riboflavin loading within the epithelium was equivalent to or higher than that in the subjacent stroma, despite rinsing the ocular surface with balanced salt solution. Conclusions: Modified iontophoresis protocols can significantly improve transepithelial riboflavin penetration in experimental corneal collagen cross-linking.
... [11][12][13][14][15][16] The method was also heavily marketed from the beginning. Unfortunately, the clinical results obtained with transepithelial CXL remained disappointing: the success rate in the so-called 'epi-on' technique dropped from 97 % (Dresden epi-off) to less than 80 %. [17][18][19] Another major modification in recent years was the attempt to shorten treatment time. There was consensus in the community that the overall fluence of 5.4 J/cm 2 should be maintained, but with the emergence of new and more powerful LED technologies, this same fluence could be delivered much faster, in 10, 5 and even 3 minutes. ...
Article
Full-text available
Ever since cross-linking (CXL) technology was introduced into clinical ophthalmology in 1999, the technique has established itself as a standard of care in the treatment of corneal ectasia. The original protocol, referred to as the ‘Dresden protocol’, consisted of 30 minutes of iso-osmolaric riboflavin instillation on a de-epithelialised cornea, followed by irradiation at 365 nm and 3 mW/cm 2 for 30 minutes. These settings correspond to a fluence of 5.4 J/cm2. A large variety of modifications of this original protocol have emerged in the past years: some of these modifications are backed up by a solid body of research evidence, both clinically and experimentally, whereas other modifications are based on little to no scientific evidence. Navigating through this ‘sea of new protocols’ is becoming increasingly difficult for the treating ophthalmologist. The two most important modifications are transepithelial (epi-on) CXL and accelerated CXL. Most interestingly, they seem to share a final common pathway, which determines efficacy: oxygen dependency.
... One mode adds enhancers to riboflavin solution with the purpose of promoting riboflavin saturation in the corneal stroma, but its therapeutic efficacy is controversial. Some researches showed that it was less effective than S-CXL (1,(6)(7)(8)(9)(10). Other studies indicated that its outcome was similar to S-CXL (11)(12)(13). ...
Article
Background: To compare the safety and efficacy of iontophoresis-assisted epithelial-on corneal crosslinking (I-CXL) using 0.1% riboflavin-distilled water solution with standard epithelium-off corneal crosslinking (S-CXL) for progressive keratoconus. Methods: In a retrospective analysis, progressive keratoconus patients treated with I-CXL (17 eyes of 17 patients) or S-CXL (13 eyes of 13 patients) were included. All patients were followed up at least 12 months. All patients underwent detailed ophthalmologic examinations involving pre- and postoperative visual acuity, topographic parameters and pachymetry. Intra- and postoperative complications were recorded. Results: No statistically significant differences were observed between the two groups at baseline with respect to visual acuity, age and thinnest corneal thickness (TCT). The postoperative decreases of K1 and Kmean in the S-CXL group represented statistically significantly better results than in the I-CXL group (t=2.093 and 2.123, P=0.046 and 0.043, respectively). Alterations of other parameters showed no significant differences between the two groups. There were no failure cases in the two groups. Conclusions: I-CXL using 0.1% riboflavin-distilled water solution provided effective treatment for progressive keratoconus at 12-month follow-up. However, the decreases of K1 and Kmean caused by I-CXL were less than those by S-CXL. Although treatment time, postoperative patient pain and risk of infection in I-CXL are all less than those in S-CXL, I-CXL is unable to completely replace S-CXL for progressive keratoconus temporarily.
... We selected one study because it included more measurements than the other [20]. erefore, 16 studies qualified for the meta-analysis ( Figure 1) [15,16,[20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Rossi et al. [31] evaluated the outcomes of conventional Drusen protocol compared with two different protocols of TECXL. ...
Article
Full-text available
Purpose: To compare the clinical results of standard corneal cross-linking (SCXL) with transepithelial corneal cross-linking (TECXL) in progressive keratoconus using a meta-analysis. Methods: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were searched up to June 2020 to identify relevant studies. The PRISMA guidelines were followed. Primary outcomes were change in uncorrected distance visual acuity and maximum keratometry (Kmax) after CXL. Secondary outcomes were change in corrected distance visual acuity, mean refractive spherical equivalent (MRSE), spherical and cylindrical error, endothelial cells density (ECD), and central corneal thickness (CCT). Results: Sixteen studies with a total of 690 eyes (SCXL: 332 eyes; TECXL: 358 eyes) were included. At the last follow-up, SCXL provided a greater decrease in maximum keratometry (Kmax) than TECXL (weighted mean difference (WMD) -1.12; 95% confidence interval (CI) -1.96, -0.29). For the other outcomes, there were no statistically significant differences. Conclusions: Except for a greater decrease in Kmax with SCXL group, both groups have a comparable effect on visual, pachymetric, and endothelial parameters at 24 months after surgery. Larger studies with a longer follow-up time are necessary to determine whether these techniques are comparable in the long term.
... By comparing postoperative topographic outcomes of the two groups at 6 months, we found that Kmax in group I had an increase in the mean reduction by 2.31 D and group II had an increase in the mean reduction by 0.8 D. Soeters et al., in his study to compare the clinical effects and safety of transepithelial CXL to epi-off CXL in progressive keratoconus noticed that average K max was stable at all visits in the transepithelial group, while after epioff CXL a significant flattening was demonstrated from the 3-month follow-up onwards and the trend over time in K max flattening was significantly different between the groups [10]. In in the epi-off CXL group at the end of 12 months with significant difference between two groups [11]. At the 6-month postoperative pachymetry (thinnest location) in group I, a non significant corneal thinning was recorded, which means that there was no progression of keratoconus. ...
... Epithelium-off corneal collagen crosslinking procedures performed by removal of corneal epithelium are more effective in stopping the progression of keratoconus than the epithelium-on procedures. 10 However, epithelial healing takes a certain time, and this period is painful for the patient. Although the release of inflammatory cytokines and damage to the corneal nerves due to ultraviolet-A exposure cause pain, epithelial debridement also increases this post-operative pain and causes foreign body sensation, burning, and tearing until the reepithelialization occurs. ...
Article
Full-text available
SIGNIFICANCE: After epithelium-off crosslinking (CXL), epithelial closure time and post-operative pain are an important issue in terms of possible complications and patient comfort. We report a prospective randomized study about the use of autologous serum eye drops after CXL. PURPOSE: This study aims to evaluate the effect of autologous serum eye drops on epithelial healing and post-operative pain after CXL. METHODS: Sixty patients diagnosed as having progressive keratoconus and treated with accelerated CXL (9 mW/cm for 10 minutes) randomly received 20% autologous serum eye drops (autologous serum group, n = 30) or artificial tears (control group, n = 30). Patients were evaluated every day after the surgery, and the day of epithelial closure was recorded. All patients were asked to report the maximum pain level using the Wong-Baker FACES Pain Rating Scale at the end of each day until the epithelial closure was completed. The change in topographic parameters and haze were recorded at 6 months. RESULTS: The mean epithelial closure time was significantly lower in the autologous serum group than in the control group (2.37 ± 0.49 and 2.67 ± 0.47 days, respectively; P = .02). There was a statistically significant difference between the pain scores in the first and second days of surgery between the two groups (first-day autologous serum autologous serum group: 2.80 ± 0.66 and control group: 3.50 ± 0.82, P = .01; second-day autologous serum group: 1.73 ± 0.69 and control group: 2.20 ± 0.76, P = .02). Pre-operative and post-operative topographic parameters and haze at 6 months were similar between the two groups (P > .05 for all). CONCLUSIONS: Use of autologous serum eye drops after CXL accelerates epithelial healing and reduces post-operative pain. Shortening the duration of epithelial closure would be beneficial in reducing possible complications and increasing patient comfort.
... The transepithelial CXL or "Epi-on" CXL was introduced recently as a mean of improving comfort for the patient and safety of the procedure by minimizing infections when the epithelium barrier was left in place [26,27]. Although this method seemed promising there have been mixed results regarding its efficacy and ability to deliver significant amount of Riboflavin in the corneal stroma [28,29] resulting in some cases in progression of Keratokonus [30,31]. In order to facilitate better results various ways of improving the epithelium penetration of Riboflavin have been proposed. ...
Article
Full-text available
Background The introduction of corneal cross-linking (CXL) with ultraviolet-A (UVA) and Riboflavin photosensitizer (Vit B2) from Seiler et al., revolutionized the treatment of Keratoconus and other corneal ectatic diseases. Today, the commonly known epithelium off Dresden protocol is in clinical use for the last 15 years with great success and regarded by many as the golden standard. Methods With several studies demonstrating its simplicity, efficacy and safety this revolutionary method, paved the way for new therapies and strategies in the treatment of corneal ectatic diseases and changed our understanding in corneal biomechanics. Recent scientific and technological advances enabled the creation of various modifications of the initial CXL protocol and the formation of new ones. Conclusion This work highlights the recent advances of CXL, such as the role of oxygen, higher fluence and shorter irradiation times as well as the various clinical applications and updates of this method.
... In some cases, CXL can be done with an intact epithelium (epithelial-on or transepithelial CXL), but efficacy has been shown to be reduced compared to epithelial-off procedures. [4][5][6] Unfortunately, CXL cannot be performed when the cornea is thinner than 400 µm following epithelial debridement. Therefore, the use of contact lenses was proposed as a method to augment stromal thickness before performing CXL in eyes with a stromal thickness between 350 and 400 µm. ...
Article
Full-text available
Aims: This study aimed to evaluate the safety and effectiveness of double contact lens-assisted corneal cross-linking (CXL) in keratoconus patients with very thin corneas. Settings and Design: This is a prospective, interventional, nonrandomized, and noncontrolled case series. Subjects and Methods: Twenty eyes of 15 patients with the corneal thinnest point (CTP)
... Mean CCT decreased at third month of CXL, but then increased gradually and reached to baseline level finally [13]. In this study, the pachymetry at thinnest point on corneal topography decreased significantly from baseline at 1-year follow-up time. ...
... With both techniques, the K-max values remained stable, thus halting further KC progression and taking into account that the patients with more advanced KC were treated with epioff CXL, which is similar to what was noted by Stojanovic et al. 26 and Cifariello et al. 11 Most of the studies to date have reported a decrease or stabilization of the K-max with both techniques. 10,19,25 However, Kocak et al. 30 obtained an improvement in the K-max after epi-off CXL and a worsening after TE-CXL. ...
Article
Full-text available
Purpose To compare the efficacy of epithelium-off corneal collagen crosslinking (CXL) with transepithelial CXL in patients with progressive keratoconus with a follow-up of 3 years, taking into account the patients’ age and the location of the corneal ectasia. Methods In this prospective study participated 64 eyes with progressive keratoconus were included in this long-term study, of which 31 eyes were treated by epithelium-off CXL and 33 by transepithelial CXL. All of the patients with a follow-up of 36 months were evaluated for visual variables (corrected distance visual acuity (CDVA), corneal aberrations, and corneal densitometry), structure variables (astigmatism, keratometry, corneal asphericity, maximum posterior elevation, corneal thickness, and corneal volume), and keratoconus index variables. Results After corneal CXL, CDVA improved significantly in both central and paracentral keratoconus, with greater improvement in the centrals (p = 0.001), asphericity at 6 mm improved in central keratoconus (p = 0.047). In the epi-off group, there was a significant improvement in coma-like (p = 0.038), higher-order aberrations (p = 0.036), asphericity at 8 mm (p = 0.049), asphericity at 10 mm (p = 0.049), and index of surface variance (p = 0.049). Conclusion Although both techniques halted and stabilized the progression of keratoconus, epithelium-off CXL was more effective. In addition, after the corneal CXL, there was a greater degree of regularization of the corneal surface and, therefore, a greater improvement in the CDVA with central keratoconus than with paracentral keratoconus.
... These six variables showed stabilization at the 6-month visit but significant worsening at the 12-month visit, which means stabilization effect has short duration at the first 6 months postoperatively. The published data about the efficacy of Epi-On CXL are generally disappointing, although there is general acceptance that it is a safe procedure [11,13,14,42,43]. ...
Article
Full-text available
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 Pre-operatively, there was a statistically non-significant 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 non-significant 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. Keywords: cross-linking, Epi-Off cross-linking, Epi-On cross-linking, keratoconus
... Moreover, many authors proved in their studies that epithelium-off CXL was more effective that transepithelial CXL. Kocaka [19] reported that epithelium-off CXL was more effective than epithelium-on CXL in halting KC progression and improving the refractive status in the eye. Furthermore, Soeters et al. [20] concluded that transepithelial CXL was a safe procedure; however, KC progression was recorded in 23% of cases so that they recommended continuing using epithelium-off CXL and not to shift to epitheliumon CXL. ...
Article
Full-text available
Purpose To analyze the results of three-year outcomes of combined epithelium-on cross-linking with femtosecond laser ICRS (cross-linking PLUS) for keratoconus management. Design A retrospective multicenter clinical study. Methods 43 eyes of 38 patients were subjected to preoperative and postoperative UCVA, BCVA, refraction, Pentacam pachymetry, and keratometry examinations at 3-, 6-, 12-, 24-, and 36-month follow-up period. Results The preoperative and postoperative mean UCVA was 1.30 ± 0.48 (logMAR ± SD) and 0.82 ± 0.22 respectively. The preoperative and postoperative mean BCVA was 0.90 ± 0.40 and 0.60 ± 0.30, respectively. The preoperative and postoperative mean K average was 50.63 ± 0.87 (D ± SD) and 45.56 ± 0.98, respectively. The preoperative and postoperative mean pachymetry was 471 ± 92.36 (μm ± SD) and 423 ± 39.58, respectively. The preoperative and postoperative mean astigmatism was 7.55 ± 1.75 and 3.39 ± 1.26, respectively. One eye showed ICRS edge exposure while 6 eyes showed progression of keratoconus. Conclusion CXL PLUS was proved to be a successful procedure to halt progression (mainly by CXL) and to correct the refractive status of the keratoconic eye (mainly by ICRS). CXL PLUS performed a synergistic action correcting and maintaining the correction of both myopic and astigmatic components of keratoconus.
... For example, transepithelial crosslinking may be less effective in halting the progression of keratoconus when compared to the traditional epithelium-off technique. 37 Similarly, the intrastromal application of riboflavin using a femtosecond laser-created pocket leads to a 50% reduction in biomechanical stiffening when compared to de-epithelialization and instillation of riboflavin drops. 35 Further, the crosslinking reaction appears to be non-linear, with possible collagen damage with longer UVA exposures. ...
Article
Objective: To examine the clinical relevance and pathophysiology of Boston keratoprosthesis (B-KPro)-related corneal keratolysis (cornea melt) and to describe a novel method of preventing corneal melt using ex vivo crosslinked cornea tissue carrier. Methods: A review of B-KPro literature was performed to highlight cases of corneal melt. Studies examining the effect of corneal collagen cross-linking (CXL) on the biomechanical properties of corneal tissue are summarized. The use of crosslinked corneal tissue as a carrier to the B-KPro is illustrated with a case. Results: Corneal melting after B-KPro is a relatively rare event, occurring in 3% of eyes during the first 3 years of postoperative follow-up. The risk of post-KPro corneal melting is heightened in eyes with chronic ocular surface inflammation such as eyes with Stevens-Johnson syndrome and mucous membrane pemphigoid. This chronic inflammation results in high tear levels of matrix metalloproteinases, the enzymes responsible for collagenolysis and corneal melt. Crosslinked corneal tissue has been shown to have stiffer biomechanical properties and to be more resistant to degradation by collagenolytic enzymes. We have previously optimized the technique for ex vivo corneal CXL and are currently studying its impact on the prevention of corneal melting after B-KPro surgery in high-risk eyes. Crosslinked carrier tissue was used in a 52-year-old man with familial aniridia and severe post-KPro corneal melt. The patient maintained his visual acuity and showed no evidence of corneal thinning or melt in the first postoperative year. Conclusion: Collagen crosslinking was previously shown to halt the enzymatic degradation of corneal buttons ex vivo. This study demonstrates the safety and potential benefit of using crosslinked corneal grafts as carriers for the B-KPro, especially in eyes at higher risk of postoperative melt.
Article
Introduction: 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. Materials and methods: 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%. Results: 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). Discussion: 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. Conclusion: 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.
Article
Members of the ASCRS Cornea Clinical Committee performed a review of the current literature on the corneal crosslinking (CXL) procedure for treating corneal ectasia. The members explored the data on the techniques currently in use and under investigation, including their advantages, safety profiles, risks, and cost analyses, compared with data on corneal transplantation. They concluded that CXL limits the progression of keratoconus, thus reducing the need for transplantation. They also found that compared with permitting the disease to progress naturally, CXL techniques carry significant and long-term cost and safety benefits, primarily by reducing the need for corneal transplantation. Studies of various CXL techniques (eg, epithelium-on treatment, changes in ultraviolet light parameters, riboflavin composition) continue with the ultimate goal of improving the procedure's safety and efficacy.
Article
Traditionally, the mainstay of treatment for advanced keratoconus (KC) has been either penetrating or deep anterior lamellar keratoplasty (PK or DALK, respectively). The success of both operations, however, has been somewhat tempered by potential difficulties and complications, both intraoperatively and postoperatively. These include suture and wound-healing problems, progression of disease in the recipient rim, allograft reaction, and persistent irregular astigmatism. Taken together, these have been the inspiration for an ongoing search for less troublesome therapeutic alternatives. These include ultraviolet crosslinking and intracorneal ring segments, both of which were originally constrained in their indication exclusively to eyes with mild to moderate disease. More recently, Bowman layer transplantation has been introduced for reversing corneal ectasia in eyes with advanced KC, re-enabling comfortable contact lens wear and permitting PK and DALK to be postponed or avoided entirely. We offer a summary of the current and emerging treatment options for advanced KC, aiming to provide the corneal specialist useful information in selecting the optimal therapy for individual patients. Copyright © 2015 Elsevier Inc. All rights reserved.
Article
To report the results 15 months after transepithelial corneal cross-linking by iontophoresis of riboflavin performed in pediatric patients affected by keratoconus. Fourteen eyes of 14 pediatric patients [mean age 13 ± 2.4 (SD) years; range, 10-18 years] were treated. Riboflavin solution was administered by iontophoresis for 5 minutes, and then UVA irradiation (10 mW/cm) was performed for 9 minutes. The corrected distance visual acuity measured as decimal number, spherical equivalent, refractive astigmatism, simulated K, corneal coma, spherical aberration, and high-order aberrations for 5.0-mm pupil and the thinnest point were measured preoperatively and 3, 6, 12, and 15 months postoperatively. The endothelial cell density was evaluated. The paired Student t test was used to compare data during the follow-up. Fifteen months after the procedure, the corrected distance visual acuity improved from 0.7 ± 1.7 to 0.8 ± 1.8 (P = 0.005). Spherical equivalent and refractive astigmatism as well as topographic and aberrometric data did not show significant changes. Also, the mean thinnest point and the endothelial cell density remained unchanged. The optical coherence tomography showed a nonhomogeneous but deep hyperreflective band with a fading effect extending through the anterior 180 μm of the cornea. No side effects were recorded. Transepithelial collagen cross-linking by iontophoresis, unlike other transepithelial techniques, seems to halt pediatric keratoconus progression over 15 months. However, we did not record significant improvement in higher-order aberrations and topographic indices.
Article
Collagen corneal cross-linking (CXL) is an invasive pharmacological treatment strategy used for corneal ectatic disorders and is currently the only treatment capable of halting the progression of the disease. In the past 20 years, the conservative management of progressive corneal ectasia has changed, thanks to this procedure that produces strengthening of the corneal tissue through the photochemical reaction generated by the combined action of riboflavin and ultraviolet A radiation. Many modified protocols have been implemented to halt the progression of the disease and to delay or prevent visual loss and surgical procedures such as corneal transplantation. Because of the variety of different protocols that are currently used, the results that are being reported are very variable, and could generate some confusion in relation to the true efficacy of the procedure. The aim of this review was to provide an overview of the aforementioned protocols that are designed to maintain the efficacy of CXL in halting the progression of the disease but avoiding the major limitations of the procedure.
Article
In den letzten Jahren hat sich die Hornhautvernetzung (Corneal Crosslinking/CXL) zur Behandlung von ektatischen Hornhauterkrankungen in der Hornhautchirurgie etabliert. Die Effektivität dieses Eingriffs konnte in zahlreichen Studien belegt werden. Rezent wurden unterschiedliche Behandlungsprotokolle vorgestellt, welche die Sicherheit durch eine transepitheliale Behandlung verbessern sollen. Ebenso wurden beschleunigte Verfahren vorgestellt, um die Behandlungsdauer signifikant zu reduzieren. In dieser Übersichtsarbeit werden transepitheliale Behandlungsprotokolle sowie beschleunigte Behandlungsprotokolle beschrieben und der Stand der Evidenz beurteilt. Abstract In the recent years corneal crosslinking has been established as a routine treatment for progressive ectatic corneal diseases. The effectiveness and safety of this intervention has been proven in several trials. Recently, several new treatment protocols have been introduced with the intention to reduce treatment time or the necessity to remove the epithelium. This overview describes some of this new treatment protocols and tries to assess the research evidence in this field.
Article
Full-text available
To measure depth-specific riboflavin concentrations in corneal stroma using two-photon fluorescence microscopy and compare commercially available transepithelial corneal collagen cross-linking (CXL) protocols. Transepithelial CXL riboflavin preparations-MedioCross TE, Ribocross TE, Paracel plus VibeX Xtra, and iontophoresis with Ricrolin+-were applied to the corneal surface of fresh postmortem rabbit eyes in accordance with manufacturers' recommendations for clinical use. Riboflavin 0.1% (VibeX Rapid) was applied after corneal epithelial debridement as a positive control. After riboflavin application, eyes were snap frozen in liquid nitrogen. Corneal cross sections 35-μm thick were cut on a cryostat, mounted on a slide, and imaged by two-photon fluorescence microscopy. Mean (SD) concentrations were calculated from five globes tested for each protocol. Peak riboflavin concentration of 0.09% (±0.01) was observed within the most superficial stroma (stromal depth 0-10 μm) in positive controls (epithelium-off). At the same depth, peak stromal riboflavin concentrations for MedioCross TE, Ricrolin+, Paracel/Xtra, and Ribocross TE were 0.054% (±0.01), 0.031% (0.003), 0.021% (±0.001), and 0.015% (±0.004), respectively. At a depth of 300 μm (within the demarcation zone commonly seen after corneal cross-linking), the stromal concentration in epithelium-off positive controls was 0.075% (±0.006), while at the same depth MedioCross TE and Ricrolin+ achieved 0.018% (±0.006) and 0.016% (0.002), respectively. None of the remaining transepithelial protocols achieved concentrations above 0.005% at this same 300-μm depth. Overall, MedioCross TE was the best-performing transepithelial formulation. Corneal epithelium is a significant barrier to riboflavin absorption into the stroma. Existing commercial transepithelial CXL protocols achieve relatively low riboflavin concentrations in the anterior corneal stroma when compared to gold standard epithelium-off absorption. Reduced stromal riboflavin concentration may compromise the efficacy of riboflavin/ultraviolet corneal CXL.
Article
Background: Keratoconus is the most common corneal dystrophy. It can cause loss of uncorrected and best-corrected visual acuity through ectasia (thinning) of the central or paracentral cornea, irregular corneal scarring, or corneal perforation. Disease onset usually occurs in the second to fourth decade of life, periods of peak educational attainment or career development. The condition is lifelong and sight-threatening. Corneal collagen crosslinking (CXL) using ultraviolet A (UVA) light applied to the cornea is the only treatment that has been shown to slow progression of disease. The original, more widely known technique involves application of UVA light to de-epithelialized cornea, to which a photosensitizer (riboflavin) is added topically throughout the irradiation process. Transepithelial CXL is a recently advocated alternative to the standard CXL procedure, in that the epithelium is kept intact during CXL. Retention of the epithelium offers the putative advantages of faster healing, less patient discomfort, faster visual rehabilitation, and less risk of corneal haze. Objectives: To assess the short- and long-term effectiveness and safety of transepithelial CXL compared with epithelium-off CXL for progressive keratoconus. Search methods: To identify potentially eligible studies, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature database (LILACS); ClinicalTrials.gov; and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not impose any date or language restrictions. We last searched the electronic databases on 15 January 2020. Selection criteria: We included randomized controlled trials (RCTs) in which transepithelial CXL had been compared with epithelium-off CXL in participants with progressive keratoconus. Data collection and analysis: We used standard Cochrane methodology. Main results: We included 13 studies with 723 eyes of 578 participants enrolled; 13 to 119 participants were enrolled per study. Seven studies were conducted in Europe, three in the Middle East, and one each in India, Russia, and Turkey. Seven studies were parallel-group RCTs, one study was an RCT with a paired-eyes design, and five studies were RCTs in which both eyes of some or all participants were assigned to the same intervention. Eleven studies compared transepithelial CXL with epithelium-off CXL in participants with progressive keratoconus. There was no evidence of an important difference between intervention groups in maximum keratometry (denoted 'maximum K' or 'Kmax'; also known as steepest keratometry measurement) at 12 months or later (mean difference (MD) 0.99 diopters (D), 95% CI -0.11 to 2.09; 5 studies; 177 eyes; I2 = 41%; very low certainty evidence). Few studies described other outcomes of interest. The evidence is very uncertain that epithelium-off CXL may have a small (data from two studies were not pooled due to considerable heterogeneity (I2 = 92%)) or no effect on stabilization of progressive keratoconus compared with transepithelial CXL; comparison of the estimated proportions of eyes with decreases or increases of 2 or more diopters in maximum K at 12 months from one study with 61 eyes was RR 0.32 (95% CI 0.09 to 1.12) and RR (non-event) 0.86 (95% CI 0.74 to 1.00), respectively (very low certainty). We did not estimate an overall effect on corrected-distance visual acuity (CDVA) because substantial heterogeneity was detected (I2 = 70%). No study evaluated CDVA gain or loss of 10 or more letters on a logarithm of the minimum angle of resolution (logMAR) chart. Transepithelial CXL may result in little to no difference in CDVA at 12 months or beyond. Four studies reported that either no adverse events or no serious adverse events had been observed. Another study noted no change in endothelial cell count after either procedure. Moderate certainty evidence from 4 studies (221 eyes) found that epithelium-off CXL resulted in a slight increase in corneal haze or scarring when compared to transepithelial CXL (RR (non-event) 1.07, 95% CI 1.01 to 1.14). Three studies, one of which had three arms, compared outcomes among participants assigned to transepithelial CXL using iontophoresis versus those assigned to epithelium-off CXL. No conclusive evidence was found for either keratometry or visual acuity outcomes at 12 months or later after surgery. Low certainty evidence suggests that transepithelial CXL using iontophoresis results in no difference in logMAR CDVA (MD 0.00 letter, 95% CI -0.04 to 0.04; 2 studies; 51 eyes). Only one study examined gain or loss of 10 or more logMAR letters. In terms of adverse events, one case of subepithelial infiltrate was reported after transepithelial CXL with iontophoresis, whereas two cases of faint corneal scars and four cases of permanent haze were observed after epithelium-off CXL. Vogt's striae were found in one eye after each intervention. The certainty of the evidence was low or very low for the outcomes in this comparison due to imprecision of estimates for all outcomes and risk of bias in the studies from which data have been reported. Authors' conclusions: Because of lack of precision, frequent indeterminate risk of bias due to inadequate reporting, and inconsistency in outcomes measured and reported among studies in this systematic review, it remains unknown whether transepithelial CXL, or any other approach, may confer an advantage over epithelium-off CXL for patients with progressive keratoconus with respect to further progression of keratoconus, visual acuity outcomes, and patient-reported outcomes (PROs). Arrest of the progression of keratoconus should be the primary outcome of interest in future trials of CXL, particularly when comparing the effectiveness of different approaches to CXL. Furthermore, methods of assessing and defining progressive keratoconus should be standardized. Trials with longer follow-up are required in order to assure that outcomes are measured after corneal wound-healing and stabilization of keratoconus. In addition, perioperative, intraoperative, and postoperative care should be standardized to permit meaningful comparisons of CXL methods. Methods to increase penetration of riboflavin through intact epithelium as well as delivery of increased dose of UVA may be needed to improve outcomes. PROs should be measured and reported. The visual significance of adverse outcomes, such as corneal haze, should be assessed and correlated with other outcomes, including PROs.
Chapter
This chapter reviews the published literature on epithelium-on (trans-epithelial) Riboflavin and Ultraviolet A (UVA) 370 nanometre (nm) light corneal collagen cross-linking (TE-CXL). Importance has been placed on seminal publications, systemic reviews, meta-analyses and randomized controlled clinical trials. Where such evidence was not available, cohort studies, case controlled studies and case series with follow-up greater than 12 months were examined.
Chapter
The aim of this chapter is to review the published literature on corneal collagen cross-linking (CXL). Emphasis has been placed on seminal publications, systemic reviews, meta-analyses and randomized controlled trials. Where such evidence does not exist, large series cohort studies, case-controlled studies and case series with follow-up greater than 12 months were included. Riboflavin/Ultraviolet A (UVA) corneal collagen cross-linking (CXL) is the first therapeutic intervention capable of arresting the progression of ectatic disorders of the cornea. In addition, the majority of investigators report significant improvements in visual, keratometric and topographic measurements 12 months after surgery. Its precise mode of action at a molecular level has not been fully determined. Follow-up is limited to 5–10 years but suggests sustained stability and enhancement in corneal shape with time. Virtually all published long-term data and comparative studies are with epithelium-off techniques. Epithelium-on CXL investigations suggest some efficacy but less than with the epithelium-off treatments and long-term data are not available. Accelerated techniques with higher UVA fluencies and shorter treatments times are the subject of current investigation, with some studies suggesting reduced efficacy compared to the standard 3 milli-watt per square centimetre (mW/cm2) for 30 min irradiation procedure. Research into other CXL methodologies is being undertaken.
Article
Full-text available
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.
Article
Full-text available
Objectives: To evaluate the efficacy of riboflavin/ultraviolet A epithelium-off (epi-off) and epithelium-on (epi-on) corneal collagen cross-linking (CXL) in progressive pediatric keratoconus. Methods: Thirty-six eyes of 27 patients aged 18 years or younger (12-18 years) diagnosed with progressive keratoconus and treated with epi-off (n=18 eyes) or epi-on (n=18 eyes) CXL were included in this study. All patients were followed up for 24 months postoperatively. Results: At 24-month follow-up, the mean corrected distance visual acuity (CDVA) improved from 0.24±0.17 to 0.17±0.11 logMAR in the epi-off group (P=0.032). In the epi-on group, CDVA improved from 0.33±0.23 to 0.26±0.20 logMAR (P=0.012), but the improvement was not significantly different between groups (P>0.05). In the epi-off group, all mean K values improved: K1 (Δ=-0.63 D, P=0.024), K2 (Δ=-0.73 D, P=0.008), and Kmax (Δ=-1.4 D, P=0.035), whereas in the epi-on group, Kmax and K2 did not change significantly and K1 (Δ=0.68 D, P=0.029) significantly worsened. Postoperative mild corneal haze occurred in 5 eyes (28%) in the epi-off group. No postoperative complications were observed in the epi-on group. In 94.4% of the epi-off group, keratoconus regressed (44.4%) or stabilized (50.0%), whereas in the epi-on group, only 66.6% regressed (33.3%) or stabilized (33.3%), and the difference was significant (P=0.038). Conclusions: The efficacy of the epi-on procedure in terms of its ability to halt keratoconus progression appears to be 0.70 of the efficacy of epi-off CXL.
Article
Purpose: To evaluate a sequential treatment algorithm for visual and keratometric improvement in keratoconus patients after corneal crosslinking (CXL) followed by topography-guided photorefractive keratectomy (PRK). Setting: Ophthalmic Consultants of Long Island, Garden City, New York, USA. Design: Retrospective case series. Methods: This study reviewed patients with keratoconus who had CXL followed by custom topography-guided PRK between April 2016 and December 2016. The following data were collected at baseline, the time of CXL, and 3 months and 6 months after PRK: uncorrected (UDVA) and corrected (CDVA) distance visual acuities, keratometric astigmatism, spherical equivalent, maximum and mean keratometry readings, and corneal thickness at the cone apex. Demographic data, age at time of CXL and PRK, and time elapsed between CXL and PRK were analyzed for significance and a correlation with visual and astigmatic outcomes. Results: The study comprised 56 patients (62 eyes), 34 who had both topographic and refractive treatment and 28 patients who had treatment of topographic irregularities only. The mean age was 38.08 years ± 13.07 (SD) at CXL and 40.33 ± 13.44 years at topography-guided PRK. Six months after PRK, there was a significant improvement in UDVA and CDVA in the refractive group (20/60 and 20/30, respectively) versus the nonrefractive group (20/100 and 20/40, respectively). Ninety-three percent of eyes that had refractive treatment had 20/40 or better CDVA. There were no significant adverse events in any case. Conclusions: The data support the use of refractive treatment in addition to topographic treatment for visual improvement in patients with keratoconus having CXL and PRK.
Article
Full-text available
Purpose of Review To review the current protocols for corneal cross-linking for the treatment of keratoconus, including a comparison of epithelial off (Epi-off) and epithelial on (Epi-on) treatments. Recent Findings After over 15 years of investigation, corneal cross-linking was approved in the USA in 2016. While Epi-off cross-linking is safe and effective, it is also associated with some drawbacks. Therefore, Epi-on is being investigated as a safer alternative. This paper reviews traditional Epi-off cross-linking and the latest Epi-on protocols. Summary While Epi-on protocols are being evaluated and have shown potential for success, most studies have shown Epi-off to be more effective. However, the well-known risks associated with Epi-off treatment may be significantly mitigated with Epi-on treatment. Therefore, if Epi-on proves to be as effective as Epi-off, and gains approval, it may become the preferred procedure.
Chapter
Full-text available
Corneal cross linking (CXL) has significant supporting evidence suggesting that it stabilizes keratoconus (KC) and increases corneal rigidity. Randomized clinical trials demonstrating this in a statistically significant manner would still be welcomed however. Stabilizing KC rarely leads to significant improvement in the visual acuity or visual quality however. For this reason, CXL has been combined with other procedures that have a refractive effect or a shape-changing effect on the corneal topography. This chapter examines the different methods of CXL application where visual acuity and quality are also considered. Starting with transepithelial or epithelium-on (Epi-On) CXL techniques that lead to a much faster visual rehabilitation and a safer technique in terms of loss of lines of corrected distance visual acuity (CDVA) than the traditional methods going through all the various refractive options including excimer laser (PTK and topography-guided PRK), intrastromal corneal ring segments (ISCR), and thermal procedures, we have attempted to cover the range of CXL procedures that are more than or different to the original Dresden (epithelium-off; Epi-Off) CXL technique. Additionally, photorefractive intrastromal CXL (PiXL) is discussed, as are intraocular approaches and nonsurgical approaches such as orthokeratology in combination with CXL. Patients have become more demanding, and our medical colleagues have become more innovative in finding solutions that can provide both stability to the cornea and improvement in the visual functioning. We are grateful to an outstanding faculty that has contributed to this chapter. The indications for CXL are expanding with time, and most of them are addressed in this book. This chapter is devoted to refractive indications of CXL, namely keratoconus (KC), pellucid marginal degeneration (PMD), and post-LASIK ectasia. Corneal infections are one of the medical indications of CXL, and will be dealt with in Chap. 9.
Article
Full-text available
The prevalence of corneal ectasias such as keratoconus has been widely documented. Keratoconus may lead to detrimental changes in visual acuity, which can often be corrected in the early stages but requires more invasive treatment as the condition progresses. Corneal cross-linking has become a treatment method of choice in early keratoconic patients and is used to stabilise the condition and prevent further progression of the disease. The principle behind this procedure is the creation of additional bonds within the corneal structure in order to enhance its mechanical properties and thereafter halt the progression of the condition. There are disagreements within the literature as to how these procedures can be performed, and there are various alternative methods. It can be concluded that corneal cross-linking is an effective treatment method for keratoconus and has been shown to produce various beneficial effects in terms of ocular structure and function.
Article
Purpose: To review the published literature on corneal collagen crosslinking (CXL). Methods: Importance has been placed on seminal publications, systemic reviews, meta-analyses, and randomized controlled clinical trials. Where such evidence was not available, cohort studies, case-controlled studies, and case series with follow-up greater than 12 months were examined. Results: Corneal collagen crosslinking with riboflavin and ultraviolet A (UVA) 370 nm radiation appears to be capable of arresting the progression of ectatic corneal disorders, with most studies reporting significant improvements in visual, keratometric, and topographic measurements. Its mode of action at the molecular level is undetermined. Follow-up is limited to 5-10 years but suggests sustained stability and enhancement in corneal shape with time. Nearly all published long-term data and comparative studies are with epithelium-off techniques. Epithelium-on investigations suggest some efficacy but less than with epithelium-off treatments and long-term data are unavailable. Accelerated techniques with higher UVA fluencies and shorter treatments times, delivering the same UVA energy dosage, are the subject of recent investigation, with some laboratory and clinical studies suggesting reduced efficacy compared to the standard 3 mW/cm2 for 30 minutes irradiation procedure. Combined methodologies of CXL with techniques such as photorefractive keratectomy and intrastromal rings show promise but long-term follow-up is indicated. Sight-threatening complications of CXL are rare. Conclusions: Studies of epithelium-off CXL with irradiation at 3 mW/cm2 for 30 minutes support its efficacy. Refinement in techniques may allow for safer and more rapid procedures with less patient discomfort but require further investigation.
Chapter
Corneal crosslinking (CXL) is performed in an outpatient setting. Thirty minutes in advance, a systemic analgosedation can be administered. Some surgeons use Pilocarpin 2% eye drops in order to reduce potential thermal and photochemical effects of UVA-radiation on the retina and the lens.
Article
Full-text available
Purpose: To evaluate the effectiveness of transepithelial cornea impregnation with riboflavin 0.1% by iontophoresis for collagen cross-linking. Material and methods: Transepithelial collagen cross-linking by iontophoresis of riboflavin was performed in a series of 22 eyes of 19 patients with progressive keratoconus I-II of Amsler classification. The riboflavin solution was administered by iontophoresis for 10 min in total, after which standard surface UVA irradiation (370 nm, 3 mW/cm(2) ) was performed at a 5-cm distance for 30 min. Results: The riboflavin/UVA treatment resulted in a decrease in the average keratometry level from 46.47 ± 1.03 to 44.12 ± 1.12 D 1 year after the procedure. Corneal astigmatism decreased from 3.44 ± 0.48 to 2.95 ± 0.23 D. Uncorrected distance visual acuity improved from 0.61 ± 0.44 up to 0.48 ± 0.41 (LogMAR). Preoperative and postoperative endothelial cell density remained unchanged at 2765 ± 21.15 cells/mm(2) . Conclusion: Transepithelial collagen cross-linking by iontophoresis might become an effective method for riboflavin impregnation of the corneal stroma reducing the duration of the procedure and being more comfortable for the patients. Further long-term studies are necessary to complete the evaluation of the efficacy and risk spectrum of the modified cross-linking technique.
Article
Full-text available
Background The purpose of this paper was to report the results of transepithelial corneal collagen cross-linking (CXL) with modified riboflavin and ultraviolet A irradiation in patients affected by keratoconus, each with thinnest pachymetry values of less than 400 μm (with epithelium) and not treatable using standard de-epithelialization techniques. Methods Sixteen patients affected by progressive keratoconus with thinnest pachymetry values ranging from 331 μm to 389 μm underwent transepithelial CXL in one eye using a riboflavin 0.1% solution in 15% Dextran T500 containing ethylenediamine tetra-acetic acid 0.01% and trometamol to enhance epithelial penetration. The patients underwent complete ophthalmological examination, including endothelial cell density measurements and computerized videokeratography, before CXL and at one day, one week, and one, 6, and 12 months thereafter. Results Epithelial healing was complete in all patients after one day of use of a soft bandage contact lens. No side effects or damage to the limbal region was observed during the follow-up period. All patients showed slightly improved uncorrected and spectacle-corrected visual acuity; keratometric astigmatism showed reductions (up to 5.3 D) and apical ectasia power decreased (Kmax values reduced up to 4.3 D). Endothelial cell density was unchanged. Conclusion Application of transepithelial CXL using riboflavin with substances added to enhance epithelial permeability was safe, seemed to be moderately effective in keratoconic eyes with ultrathin corneas, and applications of the procedure could be extended to patients with advanced keratoconus.
Article
Full-text available
The aim of this study was to investigate the possibility of induction of cross-links in corneal tissue in order to increase the stiffness as a basis for a future conservative treatment of keratectasia. Collagenous biomaterials can be stabilized by chemical and physical agents. The epithelium of enucleated porcine eyes was removed. Eight test groups, 10 eyes each, were treated with UV-light (lambda=254 nm), 0.5% riboflavin, 0.5% riboflavin and UV-light (365 nm) blue light (436 nm) and sunlight, and the chemical agents-glutaraldehyde (1% and 0.1%, 10 min) and Karnovsky's solution (0.1%, 10 min). Strips of 5 mm in width and 9 mm in length were cut from each cornea and the stress-strain behaviour of the strips was measured to assess the cross-linking process. For comparison, ten untreated corneas were measured by the same method. Compared to untreated corneas treatment with riboflavin and UV-irradiation as well as weak glutaraldehyde or Karnovsky's solutions resulted in an increased stiffness of the cornea. The biomechanical behaviour of the cornea can be altered by glutaraldehyde, Karnovsky's solution, and with riboflavin and UV-irradiation which offers the potential of a conservative treatment of keratoconus. To optimize this effect further investigation is necessary regarding the dose-response and in-vivo application.
Article
Full-text available
To evaluate the clinical effects of transepithelial corneal cross-linking (CXL) on keratoconic eyes pre-treated with substances enhancing epithelial permeability. Prospective, consecutive, single-masked, paired-eye study on 51 patients. The eye with more severe keratoconus was treated; the fellow eye served as the control. Gentamicin, benzalkonium chloride, and ethylenediaminetetraacetic acid were instilled for 3 hours, then oxybuprocaine for 30 minutes. Riboflavin 0.1% in 20% dextran T500 and oxybuprocaine were instilled for 30 minutes. Finally, ultraviolet A irradiation to the central 7.5 mm of the cornea was applied for 30 minutes, while riboflavin was instilled every 5 minutes. Mean corrected distance visual acuity improved by 0.036 logMAR after CXL and worsened by 0.039 logMAR in the control eyes (P<.05). Safety index was 1.05 after CXL and 0.96 in the control group. Mean spherical equivalent refraction decreased by 0.35 D (less myopic) after CXL and increased by 0.83 diopters (D) in the control eyes (P<.05). Mean apex curvature on tangential videokeratography increased by 0.51 D after CXL and by 1.61 D in the control eyes (P=.16). Mean average simulated keratometry decreased by 0.10 D after CXL and increased by 0.88 D in the control eyes (P<.05). Mean index of surface variance increased (worsened) by 0.9 after CXL and 5.3 in the control eyes (P<.05). Mean endothelial cell density was unchanged. A limited but favorable effect of transepithelial CXL was noted on keratoconic eyes, without complications. The effect appears to be less pronounced than described in the literature after CXL with de-epithelialization.
Article
Full-text available
To increase the stability of the cornea by artificial cross-linking (radiation or chemical agents) and to investigate a future therapy for keratoconus. The epithelium of enucleated porcine eyes was removed. Ten eyes in each of eight test groups were treated with UV light (lambda = 254 nm), 0.5% riboflavin and UV light (365 nm), blue light (436 nm) and sunlight, and the chemical agents glutaraldehyde (1% and 0.1%, 10 min) and Karnovsky's solution (0.1%, 10 min). Strips of 5 mm in width and 9 mm in length were cut from each cornea and the stress-strain behaviour of the strips was measured. For comparison, eight groups of ten untreated corneas each were measured by the same method. Compared to untreated corneas riboflavin and UV irradiation as well as glutaraldehyde and Karnovsky's solution treatment resulted in significantly increased stiffness of the cornea (p < 0.05). The biomechanical behaviour of the cornea can be altered by low-concentration glutaraldehyde, Karnovsky's solution, and by riboflavin and UV irradiation, which offers potential conservative treatment of keratoconus. To optimize this effect further investigation is necessary regarding the dose-effect relation and the in-vivo conditions.
Article
Full-text available
To compare the results of ultrasonic and Orbscan pachymetry in corneal haze not related to surgery. An institutionally based, prospective, controlled clinical trial included 40 eyes of 40 consecutive patients with corneal haze not related to surgery. Fifty normal eyes were used as a control group to calculate the customized acoustic factor. Corneal haze was graded with slit-lamp by a single examiner. Ultrasonic and Orbscan II pachymetry measurements were obtained. Paired t- and Kruskal-Wallis tests were used to evaluate the difference between ultrasonic and Orbscan pachymetry measurements. Correlation of the two methods and haze grade were determined with Kendall's tau-b correlation analysis. Eighty-five percent of patients had moderate haze. With the customized acoustic factor, Orbscan values were significantly smaller than ultrasonic pachymetry measurements (p = 0.001, paired samplet-test). Increased haze grade resulted in smaller Orbscan pachymetry measurements however, this difference was insignificant (p = 0.444, Kruskal-Wallis test). A positive correlation was found between two methods, though insignificant (p = 0.064, Kendall's tau-b correlation). When grouped in respect of diagnoses, differences in pachymetry measurements as well as the correlation were not significant (p > 0.05). An insignificant positive correlation was found between the two methods in the presence of corneal haze. Orbscan measurements were inversely related to haze grading, and were significantly lower than ultrasonic pachymetry. According to our results, we recommend that clinicians should not count on Orbscan topography alone in the presence of corneal haze.
Article
Full-text available
The purpose of this study was to investigate the continuous and real-time influence of ophthalmic ingredients on rabbit cornea by monitoring electrophysiological characteristics. The tight junctional permeabilities of FITC-dextran 4,400 (FD-4) was also determined through the cornea in the presence of ophthalmic ingredients. Intact cornea showed approximately one k-ohmxcm(2) of transepithelial electrical resistance (TEER) and extremely low permeability of FD-4. The ophthalmic ingredients used in the present study were benzalkonium chloride (BK; 0.002%, 0.01%, 0.05%), ethylenediaminetetraacetic acid (EDTA; 0.5%), capric acid (C10; 0.25%), saponin (SP; 0.1%), taurocholic acid (TA; 1.0%) and sodium dodecyl sulfate (SDS; 0.01%). They were previously reported to be effective on corneal penetrations of various drugs at those concentrations without severe toxicity. These ingredients decreased TEER and increased corneal permeability of FD-4. BK reduced TEER in a concentration-dependent manner. There was a significant correlation (gamma=0.860) between the permeability coefficient (Papp) of FD-4 and conductance (Gm), which is the reciprocal value of TEER. It was also indicated that Papp and Gm have a relationship with the corneal cytotoxicity of the ingredients. In conclusion, an electrophysiological method using isolated cornea was very useful to determine the continuous and real-time influence of ophthalmic ingredients on the cornea. In this method, electrophysiological conductance must be able to predict corneal tight junction permeability and the corneal cytotoxicity of ingredients.
Article
Full-text available
To evaluate the importance of complete epithelial removal before riboflavin-ultraviolet-A (UVA) corneal collagen crosslinking therapy. School of Optometry and Vision Sciences, Cardiff University, Wales, United Kingdom. Riboflavin eyedrops were applied at 5-minute intervals for 35 minutes to the anterior corneal surface of 36 porcine eyes (12 with no epithelial trauma but treated with tetracaine eyedrops, 12 with superficial epithelial trauma but with an intact basal epithelium, and 12 with a fully removed epithelium). The corneal surface of 6 tetracaine-treated eyes, 6 eyes with superficial epithelial trauma, and 6 eyes with a fully removed epithelium was exposed to UVA light for 30 minutes during riboflavin administration. The light transmission spectra of the enucleated corneas were analyzed with a spectrophotometer and compared with those of 9 untreated porcine corneas. Corneas with a fully removed epithelium treated with riboflavin showed an abnormal dip in the transmission spectrum between 400 nm and 510 nm (P<.01). This was attributed to the presence of riboflavin in the corneal stroma. The spectra of riboflavin-treated corneas with no epithelial trauma but tetracaine administration and those with superficial epithelial trauma did not differ from those of the non-riboflavin-treated controls. Exposure to UVA following riboflavin administration did not alter corneal light transmission. Complete removal of the corneal epithelium is an essential component of riboflavin-UVA crosslinking therapy as superficial epithelial trauma and tetracaine administration alone are not sufficient to permit the penetration of riboflavin into the corneal stroma. Failure to achieve adequate stromal absorption of riboflavin may impair the efficacy of the crosslinking process.
Article
To compare early corneal healing following conventional, transepithelial, and accelerated corneal collagen cross-linking (CXL) protocols. Twenty-four patients with progressive keratoconus were divided into three groups to receive conventional, transepithelial, or accelerated CXL. In vivo corneal confocal microscopy was performed on each patient preoperatively and at 1, 3, and 6 months postoperatively. Closure of the epithelial wound was complete 3 days following conventional and accelerated CXL. The subbasal nerve plexus was essentially obliterated immediately following conventional and accelerated CXL, and virtually no nerve fibers had regenerated by 6 months. The anterior stroma showed significant changes 1 month following conventional CXL; these changes were similar but more pronounced following accelerated CXL. Observed stromal changes included complete obliteration of keratocytes, increased tissue reflectivity, a honeycomb-like appearance, and circular lacunae. Some recovery of keratocyte density was noted after 6 months. These changes were less pronounced in the mid-stroma, and there were no apparent changes to the posterior stroma or endothelium. The cornea appeared to be unaltered following transepithelial CXL. In vivo corneal confocal microscopy analysis of the postoperative impact of CXL on the cornea revealed clear differences among conventional, accelerated, and transepithelial CXL protocols. Accelerated CXL had a greater impact than conventional CXL on the anterior cornea, whereas transepithelial CXL did not appear to alter corneal morphology.
Article
To report 18-month follow-up after transepithelial cross-linking (CXL) in young patients. Thirteen eyes with keratoconus were evaluated (mean patient age: 14.4±3.7 years [range: 8 to 18 years]). Corrected distance visual acuity (CDVA); spherical equivalent refraction; keratometry (K); coma, spherical aberration, and higher order aberrations (HOAs) for a 5.0-mm pupil; and thinnest point were measured preoperatively and 1, 3, 6, 9, 12, and 18 months postoperatively by Scheimplflug camera. Endothelial cell density and anterior segment optical coherence tomography were also evaluated. Paired Student t test was used to compare preoperative and 12- and 18-month postoperative data. P<.05 was considered significant. Eighteen months after treatment, CDVA improved significantly, whereas K readings and HOAs showed statistically significant worsening (P<.05). Spherical equivalent refraction, sphere and cylinder, coma, spherical aberration, thinnest point, and endothelial cell density did not show statistically significant changes (P>.05). The mean demarcation line depth was 105 μm. No side effects were observed. Transepithelial CXL appears to be a safe treatment in children. Although improved CDVA was noted 18 months after treatment, this technique does not effectively halt keratoconus progression in children compared to standard CXL.
Article
Purpose: To compare efficiency and safety of epithelium-off corneal cross-linking (CXL) and transepithelial cross-linking (TE-CXL) in pediatric patients with progressive keratoconus. Methods: Uncorrected and corrected visual acuity, corneal topography and pachymetry (Pentacam; Oculus Pentacam), and in vivo confocal microscopy (HRT II, Rostock Cornea Module, Heidelberg Engineering, Heidelberg, Germany) were evaluated at baseline and at 3, 6, and 12 months. Results: In the epithelium-off CXL group (19 patients, 23 eyes; mean age, 14.75 ± 2.1 years), a significant improvement at month 12 was present for Kmax [-1.11 diopters (D), P = 0.01], Kmin (-3.2 D, P = 0.001), mean K (-1.47 D, P = 0.01), surface asymmetry index (-0.64 D, P = 0.001), inferior-superior symmetry index (-0.54 D, P = 0.01), index of height asymmetry (-2.97, P = 0.03), and anterior elevation at the thinnest location (-2.82 D, P = 0.01) and at the apex (-2.27 D, P = 0.01). Postoperative corneal edema lasted 3 months in 16 eyes (69.5%) and more than 6 months in 2 eyes (8.7%). In the TE-CXL group (10 patients, 14 eyes; mean age, 15 ± 4.2 years), a significant improvement at month 12 was present for Kmax (-1.14 D, P = 0.02), Kmin (-2.04 D, P = 0.01), mean K (-1.63 D, P = 0.01), surface asymmetry index (-0.86 D, P = 0.001), inferior-superior symmetry index (-0.55 D, P = 0.001), index of height asymmetry (-2.95, P = 0.01), and anterior elevation at the thinnest location (-2.96 D, P = 0.01) and at the apex (-2.19 D, P = 0.01). No postoperative corneal edema after TE-CXL was observed. Changes at month 12 from baseline were not significantly different between the 2 groups (P > 0.05). TE-CXE was significantly less painful than epithelium-off CXL. Conclusions: In pediatric patients with progressive keratoconus, TE-CXL was less painful, provided similar effectiveness and fewer complications than epithelium-off CXL at 12-month follow-up.
Article
Purpose: To increase the stability of the cornea by artificial cross-linking (radiation or chemical agents) and to investigate a future therapy for keratoconus. Materials and methods: The epithelium of enucleated porcine eyes was removed. Ten eyes in each of eight test groups were treated with UV light (λ = 254 nm), 0.5 % riboflavin and UV light (365 nm), blue light (436 nm) and sunlight, and the chemical agents glutaraldehyde (1 % and 0.1 %, 10 min) and Karnovsky's solution (0.1 %, 10 min). Strips of 5 mm in width and 9 mm in length were cut from each cornea and the stress-strain behaviour of the strips was measured. For comparison, eight groups of ten untreated corneas each were measured by the same method. Results: Compared to untreated corneas riboflavin and UV irradiation as well as glutaraldehyde and Karnovsky's solution treatment resulted in significantly increased stiffness of the cornea (p < 0.05). Conclusions: The biomechanical behaviour of the cornea can be altered by low-concentration glutaraldehyde, Karnovsky's solution, and by riboflavin and UV irradiation, which offers potential conservative treatment of keratoconus. To optimize this effect further investigation is necessary regarding the dose-effect relation and the in-vivo conditions.
Article
To evaluate the effect of benzalkonium chloride-assisted (BAC) transepithelial collagen crosslinking (CXL) in eyes with progressive keratoconus and a minimum follow-up of 6 months. Department of Ophthalmology, Antwerp University Hospital, Antwerp, Belgium. Cohort study. Eyes with progressive keratoconus had CXL treatment without epithelial debridement. The standard CXL irradiation was preceded by instillation of proparacaine drops 0.5% preserved with BAC 0.005% every 5 minutes for 30 minutes. Selected parameters of refraction assessed by Placido disk (Eyesys) and Scheimpflug (Pentacam) examinations were compared before CXL and after CXL at 6, 12, and 18 months. The study enrolled 53 eyes of 38 patients. Sphere, cylinder, as well as maximum keratometry (K max) simulated K values (steep, flat, astigmatism), and refractive power values (steep, flat, astigmatism) measured using the Placido disk device remained stable over the 18-month follow-up. Only corrected distance visual acuity showed a statistically significant improvement at 6 months and 12 months. The Scheimpflug device measurements of maximum K and pachymetry at the thinnest point showed statistically significant progression throughout the study. No patient developed corneal haze or other complications. Transepithelial CXL using proparacaine drops 0.5% preserved with BAC 0.005% was less effective than standard CXL in stabilizing progressive keratoconus.
Article
The purposes of this study are to characterize the pathophysiological effects of benzalkonium chloride and gentamicin on corneal epithelial cells and to determine the concentration dependent effect of these agents on membrane currents of these cells. Rabbit corneal epithelial cells were isolated and subdivided into small, medium and large cells according to their cell capacitance. Using whole cell clamp technique, potassium current of corneal epithelial cells was recorded. Transmembrane current was measured again after bathing in benzalkonium chloride 1, 3, 10, 30 and 100 μ m ml−1for 3 min. The effect of gentamicin was tested at concentrations of 0.4, 1.0, 2.0, 4.0 and 10 mg ml−1. Synergistic effect of gentamicin of the above mentioned concentrations in the presence of benzalkonium chloride 1 μ g ml−1was also measured. We found that small corneal epithelial cells had the highest depolarization-gated, outward potassium current density and large cells had the lowest current density, while medium cells had a current density in between. Benzalkonium chloride induced a concentration dependent increase in the leak current with increasing concentration from 1 to 100 μ g ml−1. The increase of leak current in medium and large cells was less than that in the small cells. Gentamicin also caused a concentration dependent increase in leak current density from 0.4 to 10.0 mg ml−1. The increase in leak current density was statistically significant when the concentration was 2.0 mg ml−1or higher in small corneal epithelial cells and 1.0 mg ml−1or higher in the medium and large cells. Benzalkonium chloride 1.0 μ g ml−1augmented the effect of gentamicin on epithelial cell membrane. The extent of enhancement was more prominent in larger than smaller cells. Using whole-cell clamp technique, we were able to determine the threshold concentration of gentamicin and benzalkonium chloride on the integrity of corneal epithelial cell membrane. The toxic action of both agents is mediated by an increase in leak current. We propose that the whole-cell clamp technique is a sensitive and useful tool in determining cytotoxic effects of various agents.
Article
To evaluate the efficacy of transepithelial collagen crosslinking (CXL) in patients with bilateral progressive keratoconus. Outpatient ophthalmic clinic. Cohort study. Patients with a history of bilateral progressive keratoconus were recruited. The worst eye was treated with transepithelial CXL, while the fellow eye was left untreated as a control. Transepithelial CXL was performed by applying an enhanced riboflavin solution (riboflavin 0.1%, dextrane T500 with trometamol [Tris-hydroxymethyl aminomethane] and EDTA [ethylenediaminetetraacetic] sodium salt) on the intact corneal epithelium for 30 minutes before irradiation with ultraviolet A (370 nm at 3 mW/cm(2)) for 30 minutes. Follow-up was 18 months in all eyes. The study enrolled 20 patients. Transient hyperemia and mild foreign-body sensation occurred in 8 eyes (40%) after treatment; both resolved after 24 hours. In treated eyes, there were statistically significant improvements in uncorrected and corrected visual acuity and topography-derived keratometry, cone apex power, and higher-order aberrations (P<.05). In untreated control eyes, there was a general trend toward worsening of these parameters. No complications were reported. Transepithelial CXL treatment appeared to halt keratoconus progression, with a statistically significant improvement in visual and topographic parameters. The treatment was safe and well tolerated. Its noninvasive nature makes it potentially useful in cases in which epithelial debridement is ideally avoided, such as pediatric cases, uncooperative patients, and thin corneas with thicknesses nearing 380 μm.
Article
Management of patients with lung cancer continues to pose a considerable challenge to today's oncologist. While treatment may be curative in the early stages of the disease, the majority of patients are not diagnosed until the tumor has progressed beyond the primary site. Most patients face an intensive and invasive treatment regimen comprising surgery, radiotherapy, or chemotherapy, or combinations thereof depending on disease stage/performance status. Most will require chemotherapy even if their initial surgery is potentially curative; for those with advanced disease, chemotherapy may be their only treatment option. Moreover, the majority of patients will require multiple lines of therapy as their cancer cells acquire resistance to the chemotherapeutic agents to which they are exposed. Resistance to current chemotherapeutics available for the management of non-small cell lung cancer (NSCLC) represents one of the most significant barriers to improving long-term outcomes for this vulnerable patient group. Future management may lie in individualizing therapy through careful selection of appropriate agents based on the likelihood of response and the development of resistance. A number of biomarkers are emerging that predict response to current therapeutics; work is ongoing to develop appropriate algorithms based on such markers to guide treatment selection. In addition, novel chemotherapeutics are in development including new platinum analogs such as picoplatin (a cisplatin analog), ABT-751 (a sulfonamide) and tubulin binding agents (TBAs) such as the epothilones, providing hope for the future.
Article
To evaluate intrastromal concentrations of riboflavin with and without epithelium to ensure the efficacy and safety of corneal crosslinking (CXL) by the standard and transepithelial procedures. Department of Ophthalmology and Department of Pharmacology G. Segre, Siena University, Siena, Italy. This study comprised keratoconic patients enrolled for penetrating keratoplasty (PKP) and warm-stored sclerocorneal rings unsuitable for transplantation. Half the PKP specimens were debrided, and half were left with the epithelium in situ. One of the latter and 1 debrided sample were not exposed to riboflavin (controls). Samples in both groups were soaked with 0.1% riboflavin-dextran 20% solution instilled every 2 minutes for 5, 15, and 30 minutes. Riboflavin concentrations were determined by high-performance liquid chromatography (HPLC). The study evaluated 14 PKP specimens and 16 sclerocorneal rings. Control samples did not show a riboflavin emission peak. In exposed samples with epithelium, the mean riboflavin concentration was 91.88 ng/g after 5 minutes of exposure, 95.60 ng/g after 15 minutes, and 94.92 ng/g after 30 minutes. In the debrided samples, the mean riboflavin concentration was 14.42 microg/g, 20.92 microg/g, and 24.06 microg/g, respectively. No differences were seen between the in vivo samples and the ex vivo samples. The HPLC quantitative study showed that stromal concentrations of riboflavin increased with exposure time only if the epithelium was removed. A theoretically safe and effective riboflavin concentration of 15 microg/g was obtained for ultraviolet A-induced CXL only after the epithelium was removed and after at least 10 minutes of riboflavin application every 2 minutes.
Article
To investigate the effects of benzalkonium chloride (BAK) on the human reconstituted corneal epithelial model (HCE) and to optimize the operating potential of this model in the field of ophthalmic toxicology. The HCEs were treated with 0.001% to 0.5% BAK for 24 hours followed or not by a 24-hour postincubation period. To complete the histologic analysis, the authors designed a new MTT procedure to assess cellular viability. Frozen sections were analyzed by using fluorescence confocal microscopy for the presence of TUNEL, activated caspase-3, Ki67, ICAM-1, HLA-DR, E-cadherin, and occludin. Occludin gene expression was also investigated by using quantitative RT-PCR. The MTT test revealed a dose-dependent response of BAK with significant toxic effects for concentrations as low as 0.005%. Increasing BAK concentrations induced an increased number of apoptotic cells, found from the superficial to the deeper layers, with the activation of caspase-3 at 0.01% and 0.02% concentrations. The number of Ki67- and ICAM-1-positive cells increased with 0.01% BAK and with 0.001% to 0.01% BAK, respectively. BAK induced the dose-dependent disappearance of occludin in the superficial layers while increasing its gene expression up to the 0.02% BAK concentration. Fluorescence techniques conjugated with confocal microscopy on 3D-reconstructed corneal epithelia were well suited for the investigation of toxicological markers such as cell junction alteration, apoptosis, cell activation, and proliferation and gave relevant results compared with the known human data. They complement the new sensitive MTT test and improve the operating potential of this new, valuable 3D model in ophthalmic toxicology.
Article
Keratoconus is a bilateral noninflammatory corneal ectasia with an incidence of approximately 1 per 2,000 in the general population. It has well-described clinical signs, but early forms of the disease may go undetected unless the anterior corneal topography is studied. Early disease is now best detected with videokeratography. Classic histopathologic features include stromal thinning, iron deposition in the epithelial basement membrane, and breaks in Bowman's layer. Keratoconus is most commonly an isolated disorder, although several reports describe an association with Down syndrome, Leber's congenital amaurosis, and mitral valve prolapse. The differential diagnosis of keratoconus includes keratoglobus, pellucid marginal degeneration and Terrien's marginal degeneration. Contact lenses are the most common treatment modality. When contact lenses fail, corneal transplant is the best and most successful surgical option. Despite intensive clinical and laboratory investigation, the etiology of keratoconus remains unclear. Clinical studies provide strong indications of a major role for genes in its etiology. Videokeratography is playing an increasing role in defining the genetics of keratoconus, since early forms of the disease can be more accurately detected and potentially quantified in a reproducible manner. Laboratory studies suggest a role for degradative enzymes and proteinase inhibitors and a possible role for the interleukin-1 system in its pathogenesis, but these roles need to be more clearly defined. Genes suggested by these studies, as well as collagen genes and their regulatory products, could potentially be used as candidate genes to study patients with familial keratoconus. Such studies may provide the clues needed to enable us to better understand the underlying mechanisms that cause the corneal thinning in this disorder.
Article
In animal eyes, a significant increase in corneal biomechanical stiffness has been found after collagen crosslinking by combined riboflavin/ultraviolet-A (UVA) treatment. The aim of the present study was to evaluate the clinical usefulness of riboflavin/UVA-induced collagen crosslinking for bringing the progression of keratoconus to a halt. Prospective, nonrandomized clinical pilot study. Twenty-three eyes of 22 patients with moderate or advanced progressive keratoconus (maximum K value, 48-72 diopters) were included. After central corneal abrasion, photosensitizing riboflavin drops were applied and the eyes exposed to UVA (370 nm, 3 mW/cm(2)) in a 1-cm distance for 30 minutes. Postoperative examinations were performed in 6-month intervals, including visual acuity testing, corneal topography, slit-lamp examination, measurement of endothelial cell density, and photographic documentation. The follow-up time was between 3 months and 4 years. In all treated eyes, the progression of keratoconus was at least stopped. In 16 eyes (70%) regression with a reduction of the maximal keratometry readings by 2.01 diopters and of the refractive error by 1.14 diopters was found. Corneal and lens transparency, endothelial cell density, and intraocular pressure remained unchanged. Visual acuity improved slightly in 15 eyes (65%). Collagen crosslinking may be a new way for stopping the progression of keratectasia in patients with keratoconus. The need for penetrating keratoplasty might then be significantly reduced in keratoconus. Given the simplicity and minimal costs of the treatment, it might also be well-suited for developing countries. Long-term results are necessary to evaluate the duration of the stiffening effect and to exclude long term side-effects.
Article
To evaluate the biomechanical effect of combined riboflavin-ultraviolet A (UVA) treatment on porcine and human corneas. Department of Ophthalmology, Technical University of Dresden, Dresden, Germany. Corneal strips from 5 human enucleated eyes and 20 porcine cadaver corneas were treated with the photosensitizer riboflavin and irradiated with 2 double UVA diodes (370 nm, irradiance = 3 mW/cm2) for 30 minutes. After cross-linking, static stress-strain measurements of the treated and untreated corneas were performed using a microcomputer-controlled biomaterial tester with a prestress of 5 x 10(3) Pa. There was a significant increase in corneal rigidity after cross-linking, indicated by a rise in stress in treated porcine corneas (by 71.9%) and human corneas (by 328.9%) and in Young's modulus by the factor 1.8 in porcine corneas and 4.5 in human corneas. The mean central corneal thickness was 850 microm +/- 70 (SD) in porcine corneas and 550 +/- 40 microm in human corneas. Riboflavin-UVA-induced collagen cross-linking led to an increase in mechanical rigidity in porcine corneas and an even greater increase in human corneas. As collagen cross-linking is maximal in the anterior 300 microm of the cornea, the greater stiffening effect in human corneas can be explained by the relatively larger portion of the cornea being cross-linked in the overall thinner human cornea.
Article
This study was conducted to clarify the penetration properties of 4-[1-hydroxy-1-methylethyl]-2-propyl-1-[4-[2-[tetrazole-5-yl]phenyl]phenyl]methylimidazole-5-carboxylic acid monohydrate (CS-088), an ophthalmic agent, and the mechanism of the permeability-enhancing effect of EDTA and boric acid (EDTA/boric acid) on the corneal penetration of CS-088. In the absence of additives, corneal permeability decreased with increasing concentration of CS-088 as CS-088 monomers self-associate to form dimers. Presence of EDTA/boric acid caused no significant changes in the physicochemical properties of CS-088, the apparent partition coefficient or the mean particle size of CS-088. EDTA/boric acid induced only a slight change in the zeta potential of liposomes used as a model of the biological membrane. On the other hand, EDTA/boric acid significantly increased membrane fluidity of liposomes, whereas other buffering agents tested did not. This effect was synergistic and concentration-dependent for both EDTA and boric acid as was observed in in vitro corneal penetration of CS-088. In accordance with the result, the rate of CS-088 permeation into the liposomes significantly increased by the addition of EDTA/boric acid. Therefore, it was demonstrated that EDTA/boric acid promotes corneal penetration of CS-088 through the transcellular pathway by increasing membrane fluidity. Conversely, other buffering agents decreased corneal permeability of CS-088 by inducing further self-association of CS-088 aggregates.
Article
The purpose of this research was to optimize the formulation factors for maximum in vitro permeation of gatifloxacin from aqueous drops through excised goat cornea and to evaluate the permeation characteristics of drug from selected marketed eyedrop formulations. Permeation studies were conducted by putting 1 mL of formulation on the cornea (0.67 cm(2)) fixed between the donor and receptor compartments of an all-glass modified Franz diffusion cell and measuring gatifloxacin concentration in the receptor (containing normal saline under stirring) by spectrophotometry at 291.5 nm, after 120 minutes. Raising the drug concentration of the drops increased the drug permeation but decreased the percent permeation and the in vitro ocular availability. Raising the pH of the formulation from pH 5 to 7.2 increased both the drug permeation and the in vitro ocular availability. Eyedrops containing benzalkonium chloride (BAK; 0.01% wt/vol) and disodium edetate (EDTA; 0.01% wt/vol) showed maximum permeation, followed by Zymar, BAK (0.01% wt/vol), Gatilox, Gatiquin, and Gate (statistically significant P < .05 compared with control). In vitro titration of the formulations with 0.1N NaOH indicated the presence of a buffer in Zymar (pH 6) and Gate (pH 5.8), which may cause irritation and induce lacrimation, resulting in reduced ocular availability in vivo. Thus, formulation with BAK and EDTA, which is unbuffered, has a better likelihood of being absorbed in vivo. The BAK-EDTA formulation significantly (P < .05) increased the permeation of gatifloxacin through paired excised corneas of goat, sheep, and buffalo, compared with the control formulation. The goat cornea showed the greatest increase in permeation, followed by the sheep and buffalo corneas.
Article
The overall objective of this study was to evaluate the effect of chitosan, benzalkonium chloride (BAK) and disodium ethylendiaminetetraacetic acid (EDTA), alone and in combination, on permeation of acyclovir (ACV) across excised rabbit cornea. Corneas of male New Zealand White rabbits were used in these studies. Transcorneal permeation studies were conducted at 34 degrees C using a side-bi-side diffusion apparatus. In the presence of 0.01% BAK, transcorneal permeability of ACV was observed to increase almost 10.5-fold, from 3.5x10(-6) to 37.4x10(-6)cm/s. At 0.005% BAK, permeability of ACV was almost 3-fold higher than control. Combination of BAK 0.005% and EDTA 0.01% increased transcorneal penetration of ACV by 2.5-fold. Chitosan 0.2 and 0.1% increased corneal permeability of ACV by 5.8- and 3.1-fold, respectively, whereas, at 0.02%, chitosan did not exhibit a statistically significant effect. BAK at 0.005%, in combination with 0.01% EDTA and 0.1% chitosan, increased transcorneal ACV permeation by 5.5-fold. This study suggests that a judicious combination of chitosan, BAK and EDTA can lead to a significant increase in ACV's transcorneal permeability and that chitosan can enhance diffusion of hydrophilic agents across the corneal membrane. Further in vivo evaluation is warranted.
Article
Acute corneal permeability change after instillation of benzalkonium chloride (BAC) was evaluated using a newly developed in vivo corneal transepithelial electric resistance (TER) measurement method. Corneal TER was measured by Ag/AgCl electrodes placed in the anterior aqueous chamber and on the cornea of live rabbit eyes. TER was measured and TER change after instillation of 0.05% BAC solution was monitored. After TER measurement, cornea was excised and fixed for transmission and scanning electron microscopy. For the control study, physiologic saline was used instead of BAC. The TER of normal rabbit cornea was 602.3 +/- 195.0 Omega cm(2). TER decreased instantly after instillation of 0.05% BAC. In 5 s, TER decreased to 58.3 +/- 5.2%. In 60 s, TER decreased to 18.5 +/- 3.2%. At all time points, TER after instillation of 0.05% BAC was significantly lower than that of the control (p < 0.0001). Dissociation of tight junctions and the destruction of superficial cell membranes were observed under electron microscopy. Corneal epithelial change with increased permeability is rapid and intense after the instillation of highly concentrated BAC solution, accompanied by disorder of tight junctions and cell membranes of superficial cells. The newly developed in vivo corneal TER measurement method is suitable for assessing acute corneal change after drug instillation.
Effect of chitosan, benzalkonium chloride, and EDTA on permeation of acyclovir across isolated rabbit cornea
  • S Majumdar
  • K Hippalgaonkar
  • Ma
Majumdar S, Hippalgaonkar K, Repka MA. Effect of chitosan, benzalkonium chloride, and EDTA on permeation of acyclovir across isolated rabbit cornea. Int J Pharm 2008;348:175—8.
  • Y S Rabinowitz
  • Keratoconus
Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998;42: 297-319.
Electrophysiological characterization of tight junctional pathway of rabbit cornea treated with ophthalmic ingredients
  • T Nakamura
  • M Yamada
  • M Teshima
  • M Nakashima
  • H To
  • N Ishikawa
Nakamura T, Yamada M, Teshima M, Nakashima M, To H, Ishikawa N, et al. Electrophysiological characterization of tight junctional pathway of rabbit cornea treated with ophthalmic ingredients. Biol Pharm Bull 2007;30:2360-4.
Transepithelial corneal collagen crosslinking: bilateral study
  • M Filippello
  • E Stagni
  • O Brart
Filippello M, Stagni E, O'Brart D. Transepithelial corneal collagen crosslinking: bilateral study. J Cataract Refract Surg 2012;38:283-91.