Transepithelial versus Epithelium-off Corneal Collagen Cross-linking for Corneal Ectasia

Nath, Siddharth; Shen, Carl; Koziarz, Alex; Banfield, Laura; Nowrouzi‐Kia, Behnam; Fava, Mark; Hodge, William

doi:10.1016/j.ophtha.2020.12.023

Cited by 33 publications

(36 citation statements)

References 35 publications

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“…16 Despite this observed discrepancy in topographical metrics between standard epi-off CXL and the current epi-on CXL protocols, the same systematic review by Nath et al also confirmed that epi-on CXL, to date, produced UCVA and BCVA outcomes comparable to those obtained with epioff CXL and also offered potential advantages in terms of providing better patient comfort, quicker post-operative recovery, and reduced incidences of adverse events. 16 A major limitation of current approaches to epi-on CXL, including the present study, may stem from the impedance of the epithelial barrier on more than just riboflavin diffusion, but also on the transmission of UVA and oxygen, two other key components of cross-linking photochemistry. [26][27][28] In addition to optimized riboflavin formulations, advanced epi-on treatment protocols may include pulsed, accelerated, UVA irradiation protocols to reduce the rate of oxygen consumption 29,30 and, most recently, the addition of supplemental oxygen at the corneal surface to increase the rate of oxygen diffusion to the corneal stroma in an attempt to improve the photochemical efficiency of the procedure.…”

Section: Discussionmentioning

confidence: 91%

“…15 A recent systematic review and meta-analysis demonstrated that, while the studies of various epithelium-on techniques demonstrated reduced rates of postoperative complications, they were also associated with an increased rate of post-operative disease progression. 16 While several transepithelial riboflavin formulations are available outside of the US, to date, there is no US FDA approved riboflavin formulation indicated for use in epi-on CXL. 17 A proposed alternative to these transepithelial riboflavin formulations is the application of a standard riboflavin solution in combination with a topical anesthetic (proparacaine with 0.01% benzalkonium chloride) which is designed to facilitate epithelial permeability.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Beckman¹

2021

OPTH

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Introduction: Epithelium-off cross-linking (epi-off CXL) has long been established as the gold standard treatment for progressive keratoconus. Several protocols for epithelium-on (epi-on) CXL have been proposed to help reduce post-operative pain and facilitate visual recovery, but there is no epi-on treatment approach that is currently approved in the United States. The hydrophilic and macromolecular characteristics of conventional epi-off riboflavin formulations may create clinical challenges for absorption through an intact epithelium. This study investigates the clinical efficacy of a dextran-free hypotonic riboflavin ophthalmic solution (Photrexa, Glaukos, Burlington, MA, USA), approved for epi-off CXL, in a novel epi-on CXL protocol. Methods: Twenty-five eyes of 17 patients were treated in this prospective, single-arm study using a hypotonic riboflavin formulation without dextran and low irradiance UVA (3mW/ cm 2 ) for epi-on CXL. Visual acuity, as well as refractive and keratometry outcomes, were observed over 12 months. Results: At 12 months, Kmax was stable with no clinically or statistically significant change from a mean pre-op of 55.4D to 55.9D (p=0.13). Uncorrected and best corrected logMAR visual acuity significantly improved from 0.77 to 0.62 and from 0.17 to 0.12, respectively. There were no significant adverse safety events. Conclusion:Patients who underwent epi-on CXL with dextran-free hypotonic riboflavin demonstrated improvements in uncorrected and best corrected visual acuity with stable keratometry at 12 months post-operatively. The efficacy is consistent with other epi-on studies to date but remains lower than standard epi-off CXL. New technologies, including supplemental oxygen and transepithelial riboflavin ophthalmic solutions, are currently under clinical evaluation and may offer a path forward for epi-on CXL in the USA.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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

Beckman¹

2021

OPTH

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“…Meta-analyses performed by Li and Wang, and Nath et al confirmed that epithelium-on protocols were less effective. Li and Wang demonstrated that standard epithelium-off protocols were more effective at reducing maximum corneal curvature than epithelium-on protocols ( Li and Wang, 2017 ), while Nath et al reported that 7% of patients undergoing epithelium-on CXL experienced disease progression within the first year, compared to 2% of patients in the epithelium-off group ( p -value = 0.022) ( Nath et al, 2020 ). As a result, several modifications to epithelium-on CXL have been proposed.…”

Section: Maximising Pharmacokinetic Properties Of Riboflavin/ultraviolet-a In the Treatment Of Keratoconusmentioning

confidence: 99%

Corneal Cross-Linking: The Evolution of Treatment for Corneal Diseases

Lim

et al. 2021

Front. Pharmacol.

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Corneal cross-linking (CXL) using riboflavin and ultraviolet A (UVA) light has become a useful treatment option for not only corneal ectasias, such as keratoconus, but also a number of other corneal diseases. Riboflavin is a photoactivated chromophore that plays an integral role in facilitating collagen crosslinking. Modifications to its formulation and administration have been proposed to overcome shortcomings of the original epithelium-off Dresden CXL protocol and increase its applicability across various clinical scenarios. Hypoosmolar riboflavin formulations have been used to artificially thicken thin corneas prior to cross-linking to mitigate safety concerns regarding the corneal endothelium, whereas hyperosmolar formulations have been used to reduce corneal oedema when treating bullous keratopathy. Transepithelial protocols incorporate supplementary topical medications such as tetracaine, benzalkonium chloride, ethylenediaminetetraacetic acid and trometamol to disrupt the corneal epithelium and improve corneal penetration of riboflavin. Further assistive techniques include use of iontophoresis and other wearable adjuncts to facilitate epithelium-on riboflavin administration. Recent advances include, Photoactivated Chromophore for Keratitis-Corneal Cross-linking (PACK-CXL) for treatment of infectious keratitis, customised protocols (CurV) utilising riboflavin coupled with customised UVA shapes to induce targeted stiffening have further induced interest in the field. This review aims to examine the latest advances in riboflavin and UVA administration, and their efficacy and safety in treating a range of corneal diseases. With such diverse riboflavin delivery options, CXL is well primed to complement the armamentarium of therapeutic options available for the treatment of a variety of corneal diseases.

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“…In addition to the study of accelerated crosslinking protocols, there has been considerable study in the field on the comparative effects of epithelial-on (transepithelial) versus epithelial-off (de-epithelialized) riboflavin / UV-A crosslinking protocols. 147 These studies have concluded that although transepithelial CXL results in reduced healing time and improved best-corrected visual acuity, it is less effective (in most implementations studied) at halting the progression of keratoconus.…”

Section: Measurement Of Biomechanical Change Induced By Crosslinkingmentioning

confidence: 99%

Biomechanics of Ophthalmic Crosslinking

Blackburn

Rollins

Dupps

2021

Trans. Vis. Sci. Tech.

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Crosslinking involves the formation of bonds between polymer chains, such as proteins. In biological tissues, these bonds tend to stiffen the tissue, making it more resistant to mechanical degradation and deformation. In ophthalmology, the crosslinking phenomenon is being increasingly harnessed and explored as a treatment strategy for treating corneal ectasias, keratitis, degenerative myopia, and glaucoma. This review surveys the multitude of exogenous crosslinking strategies reported in the literature, both “light” (involving light energy) and “dark” (involving non-photic chemical processes), and explores their mechanisms, cytotoxicity, and stage of translational development. The spectrum of ophthalmic applications described in the literature is then discussed, with particular attention to proposed therapeutic mechanisms in the cornea and sclera. The mechanical effects of crosslinking are then discussed in the context of their proposed site and scale of action. Biomechanical characterization of the crosslinking effect is needed to more thoroughly address knowledge gaps in this area, and a review of reported methods for biomechanical characterization is presented with an attempt to assess the sensitivity of each method to crosslinking-mediated changes using data from the experimental and clinical literature. Biomechanical measurement methods differ in spatial resolution, mechanical sensitivity, suitability for detecting crosslinking subtypes, and translational readiness and are central to the effort to understand the mechanistic link between crosslinking methods and clinical outcomes of candidate therapies. Data on differences in the biomechanical effect of different crosslinking protocols and their correspondence to clinical outcomes are reviewed, and strategies for leveraging measurement advances predicting clinical outcomes of crosslinking procedures are discussed. Advancing the understanding of ophthalmic crosslinking, its biomechanical underpinnings, and its applications supports the development of next-generation crosslinking procedures that optimize therapeutic effect while reducing complications.

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Transepithelial versus Epithelium-off Corneal Collagen Cross-linking for Corneal Ectasia

Cited by 33 publications

References 35 publications

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

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

Corneal Cross-Linking: The Evolution of Treatment for Corneal Diseases

Biomechanics of Ophthalmic Crosslinking

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