Individualized Corneal Cross-linking With Riboflavin and UV-A in Ultrathin Corneas: The Sub400 Protocol

Hafezi, Farhad; Kling, Sabine; Gilardoni, Francesca; Hafezi, Farhad; Hillen, Mark; Abrishamchi, Reyhaneh; Gomes, José Álvaro Pereira; Mazzotta, Cosimo; Randleman, J. Bradley; Torres-Netto, Emílio A.

doi:10.1016/j.ajo.2020.12.011

Cited by 90 publications

(88 citation statements)

References 40 publications

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“…The algorithm was published in 2017 and based on this algorithm, a pilot study of 39 eyes with corneal stromal thickness ranging from 214 μm to 398 μm showed that 90% of eyes established topographical stability at 12 months, while no eyes experienced endothelial decompensation ( Kling and Hafezi, 2017 ). There was a significant improvement in corneal maximum keratometry values (−2.06 ± 3.66 diopters), but there were no changes in corrected distance visual acuity ( Hafezi et al, 2020 ). This individualised approach is a promising new addition to existing treatment modalities for thin corneas, especially since this can be accomplished using standard CXL equipment.…”

Section: Reducing Riboflavin/ultraviolet-a Toxicity For the Treatment Of Thin Corneasmentioning

confidence: 89%

“…A study by Hafezi et al introduced the sub400 individualised fluence CXL protocol which allows CXL to be performed on corneas with thickness of less than 400 µm ( Hafezi et al, 2020 ). This aimed to circumvent disadvantages of reduced cross-linking efficacy conferred by earlier approaches that induced corneal swelling through hypoosmolar riboflavin or contact lens-assisted corneal cross-linking, and the need for specialised equipment for techniques such epi-Off-Lenticule-on and pachymetry based corneal cross-linking ( Stojanovic et al, 2014 ).…”

Section: Reducing Riboflavin/ultraviolet-a Toxicity For the Treatment Of Thin Corneasmentioning

confidence: 99%

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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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Section: Reducing Riboflavin/ultraviolet-a Toxicity For the Treatment Of Thin Corneasmentioning

confidence: 89%

Section: Reducing Riboflavin/ultraviolet-a Toxicity For the Treatment Of Thin Corneasmentioning

confidence: 99%

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

Lim

et al. 2021

Front. Pharmacol.

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“…From clinical and economic perspectives, two critical decisions must be made in KC: when to schedule the next visit and whether a patient would benefit from CXL, which can halt KC progression in 90%–95% of the treated cases [ 32 , 33 ] in a cost-effective way [ 34 , 35 ]. CXL, however, is not without risks [ 36 ], and national reimbursement protocols often require proof of progression prior to treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Aiming for a more personalized approach to KC management is, in our opinion, the way to go, and previous studies have been carried out with that objective in mind [ 33 , 45 , 46 ]. Here, we presented another step forward, a predictive system with the prospect of a platform-independent generalization.…”

Section: Discussionmentioning

confidence: 99%

Forecasting Progressive Trends in Keratoconus by Means of a Time Delay Neural Network

Jiménez‐García

Issarti

Kreps

et al. 2021

JCM

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Early and accurate detection of keratoconus progression is particularly important for the prudent, cost-effective use of corneal cross-linking and judicious timing of clinical follow-up visits. The aim of this study was to verify whether a progression could be predicted based on two prior tomography measurements and to verify the accuracy of the system when labelling the eye as stable or suspect progressive. Data from 743 patients measured by Pentacam (Oculus, Wetzlar, Germany) were available, and they were filtered and preprocessed to data quality needs. The time delay neural network received six features as input, measured in two consecutive examinations, predicted the future values, and determined the classification (stable or suspect progressive) based on the significance of the change from the baseline. The system showed a sensitivity of 70.8% and a specificity of 80.6%. On average, the positive and negative predictive values were 71.4% and 80.2%. Including data of less quality (as defined by the software) did not significantly worsen the results. This predictive system constitutes another step towards a personalized management of keratoconus. While the results obtained were modest and perhaps insufficient to decide on a surgical procedure, such as cross-linking, they may be useful to customize the timing for the patient’s next follow-up.

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“…The safety and efficacy issues of corneal collagen crosslinking (CXL) have been reported theoretically [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. The critical parameters influencing the efficacy of CXL include: initial concentration and diffusion depth of riboflavin (RF) (for type-I CXL) and oxygen (for type-II CXL), quantum yield, UV light intensity, dose and irradiation duration [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Critical Analysis of Corneal Cross-linking (Part-I): Formulas for Efficacy, Safety Dose, Minimum Thickness, Demarcation Line Depth and the Role of Oxygen

Cheng¹,

Lin²

2021

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Purpose: To update and derive formulas for the efficacy and kinetics of corneal collagen crosslinking (CXL) including both type-I and oxygen-mediated type-II mechanisms, the role of oxygen, the initiator regeneration, safety dose, minimum corneal thickness and demarcation line depth. Study Design: Modeling the kinetics of CXL in UV light and using riboflavin as the photosensitizer. Place and Duration of Study: Taipei, Taiwan, between June, 2021 and July, 2021. Methodology: Coupled kinetic equations are derived under the quasi-steady state condition for the 2-pathway mechanisms of CXL. For type-I CXL, the riboflavin (RF) triplet state [T] may interact directly with the stroma collagen substrate [A] to form radical (R) and regenerate initiator. For type-II process, [T] interacts with oxygen to form a singlet oxygen [1O2]. Both reactive radical (R) and [1O2], can interact with the substrate [A]) for crosslinking. Based on a safety dose and a threshold dose, formulas for the minimum corneal thickness and demarcation line depth (DLD) are derived. Results: Our updated theory/modeling showed that oxygen plays a limited and transient role in the process, in consistent with that of Kamave. In contrary, Kling et al believed that type-II is the predominant mechanism, which however conflicting with the epi-on CXL results. For both type-I and type-II, a transient state conversion (crosslink) efficacy in an increasing function of light intensity (or dose), whereas, its steady state efficacy is a deceasing function of light intensity. RF depletion in type-I is compensated by the RF regeneration term (RGE) which is a decreasing function of oxygen. For the case of perfect regeneration case (or when oxygen=0), RF is a constant due to the catalytic cycle. Unlike the conventional Dresden rule of 400 um thickness, thin cornea CXL is still safe as far as the dose is under a threshold dose (E*), based on our minimum thickness formula (Z*). Our formula for thin cornea is also clinically shown by Hafez et al for ultra thin (214 nm) CXL. Conclusion: For both type-I and type-II, the transient state conversion (crosslink) efficacy in an increasing function of light intensity (or dose), whereas, its steady state efficacy is a deceasing function of light intensity. CXL for ultra thin corneas are still safe, as far as it is under a threshold dose (E*), based on our minimum thickness (Z*) formula, which has a similar tend as that of demarcation line depth (Z').

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Individualized Corneal Cross-linking With Riboflavin and UV-A in Ultrathin Corneas: The Sub400 Protocol

Cited by 90 publications

References 40 publications

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

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

Forecasting Progressive Trends in Keratoconus by Means of a Time Delay Neural Network

Critical Analysis of Corneal Cross-linking (Part-I): Formulas for Efficacy, Safety Dose, Minimum Thickness, Demarcation Line Depth and the Role of Oxygen

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