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

Soeters, Nienke; Wisse, Robert P. L.; Godefrooij, Daniël A.; Imhof, Saskia M.; Tahzib, Nayyirih G.

doi:10.1016/j.ajo.2015.02.005

Cited by 167 publications

(158 citation statements)

References 31 publications

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“…6,[25][26][27][28] Twelve-month results from one recently published randomized controlled trial 6 concluded that transepithelial CXL using Ricrolin TE (Sooft Italia S.p.A.) was not effective at stabilizing corneal shape compared with epithelium-off treatment. For iontophoresis, up to 15-month followup data have been published, with reported cessation of disease progression and improvements in keratometric and visual parameters.…”

Section: Discussionmentioning

confidence: 99%

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Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model

Gore

O’Brart

French

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Gore DM, O'Brart D, French P, Dunsby C, Allan BD. Transepithelial riboflavin absorption in an ex vivo rabbit corneal model. Invest Ophthalmol Vis Sci. 2015;56:5006-5011. DOI:10.1167/iovs.15-16903 PURPOSE. To measure depth-specific riboflavin concentrations in corneal stroma using twophoton fluorescence microscopy and compare commercially available transepithelial corneal collagen cross-linking (CXL) protocols. METHODS.Transepithelial CXL riboflavin preparations-MedioCross TE, Ribocross TE, Paracel plus VibeX Xtra, and iontophoresis with Ricrolinþ-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-lm 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.RESULTS. Peak riboflavin concentration of 0.09% (60.01) was observed within the most superficial stroma (stromal depth 0-10 lm) in positive controls (epithelium-off). At the same depth, peak stromal riboflavin concentrations for MedioCross TE, Ricrolinþ, Paracel/Xtra, and Ribocross TE were 0.054% (60.01), 0.031% (0.003), 0.021% (60.001), and 0.015% (60.004), respectively. At a depth of 300 lm (within the demarcation zone commonly seen after corneal cross-linking), the stromal concentration in epithelium-off positive controls was 0.075% (60.006), while at the same depth MedioCross TE and Ricrolinþ achieved 0.018% (60.006) and 0.016% (0.002), respectively. None of the remaining transepithelial protocols achieved concentrations above 0.005% at this same 300-lm depth. Overall, MedioCross TE was the best-performing transepithelial formulation.CONCLUSIONS. 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.

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Section: Discussionmentioning

confidence: 99%

“…However, the only published randomized controlled trial of this newer technique 6 recently concluded that it was not effective compared with epithelium-off CXL. Most commercially available riboflavin formulations for transepithelial CXL are designed to enhance epithelial permeability by the addition of epithelial-toxic agents (Table).…”

mentioning

confidence: 99%

Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model

Gore

O’Brart

French

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…Indeed, as for other transepithelial protocols, iontophoresis does not seem to ensure an improvement in topographic indices in pediatric patients 33 . This absence of efficacy can be explained by limited riboflavin and UVA penetration with the epithelium in situ 11,[34][35][36] . Indeed, the epithelium is a physical barrier for both riboflavin and UVA penetration, limiting the depth of apoptosis and thus of corneal biomechanical effects 11 .…”

Section: Discussionmentioning

confidence: 99%

Three Different Protocols of Corneal Collagen Crosslinking in Keratoconus: Conventional, Accelerated and Iontophoresis

Bouheraoua

Jouve

Borderie

et al. 2015

JoVE

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Keratoconus is a bilateral and progressive corneal ectasia. In order to slow down its progression, corneal collagen cross-linking (CXL) has recently been introduced as an efficient treatment option. In biological and chemical sciences, crosslinking refers to new chemical bonds formed between reactive molecules. Hence, the aim of corneal collagen CXL is to synthetically increase the formation of crosslinks between collagen fibrils in the corneal stroma. Despite the fact that the efficiency of the conventional CXL (C-CXL) protocol has already been shown in several clinical studies, it might benefit from improvements in duration of the procedure and removal of corneal epithelium. Hence, in order to provide a coherent evaluation of two new and optimized CXL protocols, we studied keratoconus patients who had undergone one of the three CXL treatments: iontophoresis (I-CXL), accelerated CXL (A-CXL), and conventional CXL (C-CXL). A-CXL is a 6 time faster CXL procedure using a ten time higher UVA irradiance but still including an epithelium removal. Iontophoresis is a transepithelial non-invasive technique in which a small electric current is applied to improve riboflavin penetration throughout the cornea. Using anterior segment optical coherence tomography (AS OCT) and in vivo confocal microscopy (IVCM), we conclude that regarding the depth of treatment penetration, conventional CXL protocol remains the standard for treating progressive keratoconus. Accelerated CXL seems to be a quick, effective and safe alternative to treat thin corneas. The use of iontophoresis is still being investigated and should be considered with greater caution. Video LinkThe video component of this article can be found at

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“…The original dextran-containing solutions have been shown in both laboratory and clinical studies to be ineffective for transepithelial cross-linking. [9][10][11][12] A number of formulations of riboflavin designed to facilitate penetration across an intact corneal epithelium are currently marketed. 13 Most contain toxic agents to increase epithelial permeability, including benzalkonium chloride (BAC), highconcentration sodium chloride, sodium ethylenediaminetetraacetic acid (EDTA), or trometamol.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

Section: Methodsmentioning

confidence: 99%

A Comparison of Different Corneal Iontophoresis Protocols for Promoting Transepithelial Riboflavin Penetration

Gore

O’Brart

French

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Gore DM, O'Brart DP, French P, Dunsby C, Allan BD. A comparison of different corneal iontophoresis protocols for promoting transepithelial riboflavin penetration. Invest Ophthalmol Vis Sci. 2015;56:7908-7914. DOI:10.1167/iovs.15-17569 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 lm 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-BACcontaining 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.

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

Cited by 167 publications

References 31 publications

Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model

Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model

Three Different Protocols of Corneal Collagen Crosslinking in Keratoconus: Conventional, Accelerated and Iontophoresis

A Comparison of Different Corneal Iontophoresis Protocols for Promoting Transepithelial Riboflavin Penetration

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