Abstract
Purpose
To assess the safety and the efficacy of the “Sub-400 corneal cross-linking (CXL) protocol” for progressive keratoconus (KC) in ultrathin corneas.
Methods
The study included thirty four patients with progressive KC, who underwent CXL using the “Sub-400” protocol due to intraoperative thinnest corneal pachymetry ranging from 295 to 398 μm after epithelial removal. After the epithelium was removed, the following ultraviolet A irradiation was applied at a fluence of 3 mW/cm2 and the duration was adjusted based on the specific corneal stromal thickness. In addition to slit-lamp microscopy and visual acuity assessment, our evaluation included measurements of the maximal anterior keratometry value (Kmax), mean anterior and posterior K values (Kmean), thinnest corneal thickness (TCT), central corneal thickness, intraoperative pachymetry, and corneal endothelial cell density (ECD) preoperatively and 1 year postoperatively. Stromal demarcation line depth (DL) was measured in the first postoperative month.
Results
At the first year postoperative follow-up visit, 88% (30 eyes) exhibited tomographic stability, with average values of change in Kmax (ΔKmax) 0.61 ± 6.45 D after CXL. None of the eyes showed signs of endothelial decompensation. The mean DL depth was 250.76 ± 44.05 μm. Moderate positive correlations were observed between DL and ultraviolet A irradiation time, DL, and intraoperative stromal thickness (r = 0.473, p = 0.005 and r = 0.517, p = 0.002, respectively). ΔKmax was negatively correlated with preoperative Kmax (r = − 0.559, P = 0.001) and positively correlated with preoperative TCT (r = 0.373, P = 0.030).
Conclusion
The “Sub-400 protocol” for CXL has a broad application possibility for ultrathin corneas with KC and has shown promising results.
Access this article
Rent this article via DeepDyve
Similar content being viewed by others
Data Availability
The data that support the findings of this study are available from the corresponding author [EEK] upon reasonable request.
References
Rabinowitz YS (1998) Keratoconus. Surv Ophthalmol 42(4):297–319
Jankov Ii MR, Jovanovic V, Nikolic L, Lake JC, Kymionis G, Coskunseven E (2010) Corneal collagen cross-linking. Middle East Afr J Ophthalmol 17(1):21–27
Wollensak G, Spoerl E, Seiler T (2003) Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 135(5):620–627
Srivatsa S, Jacob S, Agarwal A (2020) Contact lens assisted corneal cross linking in thin ectatic corneas - A review. Indian J Ophthalmol 68(12):2773–2778
Wollensak G, Sporl E, Reber F, Pillunat L, Funk R (2003) Corneal endothelial cytotoxicity of ribo avin/UVA treatment in vitro. Ophthalmic Res 35:324–328
Hafezi F, Kling S, Gilardoni F, Hafezi N, Hillen M, Abrishamchi R, Gomes JAP, Mazzotta C, Randleman JB, Torres-Netto EA (2021) Individualized corneal cross-linking with riboflavin and UV-A in ultrathin corneas: The Sub400 Protocol. Am J Ophthalmol 224:133–142
Belin MW, Kundu G, Shetty N, Gupta K, Mullick R, Thakur P (2020) ABCD: A new classi cation for keratoconus. Indian J Ophthalmol 68:2831–2834
Kymionis GD, Kounis GA, Portaliou DM, Grentzelos MA, Karavitaki AE, Coskunseven E, Jankov MR, Pallikaris IG (2009) Intraoperative pachymetric measurements during corneal collagen cross-linking with riboflavin and ultraviolet A irradiation. Ophthalmology 116(12):2336–2339
Schmidinger G, Pachala M, Prager F (2013) Pachymetry changes during corneal crosslinking: effect of closed eyelids and hypotonic riboflavin solution. J Cataract Refract Surg 39(8):1179–1183
Hafezi F, Mrochen M, Iseli HP, Seiler T (2009) Collagen crosslinking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas. J Cataract Refract Surg 35(4):621–624
Koc M, Uzel MM, Koban Y, Tekin K, Taspinar AG, Ylmazbas P (2016) Accelerated Corneal Cross-Linking with a Hypoosmolar riboflavin dolution in keratoconic thin corneas: Short-term Results. Cornea 35(3):350–354
Kymionis GD, Diakonis VF, Coskunseven E, Jankov M, Yoo SH, Pallikaris IG (2009) Customized pachymetric guided epithelial debridement for corneal collagen cross linking. BMC Ophthalmol 9:10
Kaya V, Utine CA, Yilmaz OF (2011) Efficacy of corneal collagen cross-linking using a custom epithelial debridement technique in thin corneas: a confocal microscopy study. J Refract Surg 27(6):444–450
Filippello M, Stagni E, O’Brart D (2012) Transepithelial corneal collagen crosslinking: bilateral study. J Cataract Refract Surg 38(2):283–291
Koppen C, Wouters K, Mathysen D, Rozema J, Tassignon MJ (2012) Refractive and topographic results of benzalkonium chloride-assisted transepithelial crosslinking. J Cataract Refract Surg 38(6):1000–1005
Soeters N, Wisse RP, Godefrooij DA, Imhof SM, Tahzib NG (2015) Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: a randomized controlled trial. Am J Ophthalmol 159(5):821-828 e3
Jacob S, Kumar DA, Agarwal A, Basu S, Sinha P, Agarwal A (2014) Contact lens-assisted collagen cross-linking (CACXL): A new technique for cross-linking thin corneas. J Refract Surg 30(6):366–372
Kling S, Richoz O, Hammer A, Tabibian D, Jacob S, Agarwal A (2015) Hafezi FJJoRS Increased biomechanical efficacy of corneal cross-linking in thin corneas due to higher oxygen availability. J Refract Surg 31(12):840–846
Richoz O, Hammer A, Tabibian D, Gatzioufas Z (2013) Hafezi FJTvs, technology The biomechanical effect of corneal collagen cross-linking (CXL) with riboflavin and UV-A is oxygen dependent. Transl Vis Sci Technol 2(7):6–6
Kasai K, Kato N, Konomi K, Shinzawa M, Shimazaki J (2017) Flattening effect of corneal cross-linking depends on the preoperative severity of keratoconus. Medicine (Baltimore) 96(40):e8160
Chan TCY, Tsui RWY, Chow VWS, Lam JKM, Wong VWY, Wan KH (2022) Accelerated corneal collagen cross-linking in progressive keratoconus: Five-year results and predictors of visual and topographic outcomes. Indian J Ophthalmol 70(8):2930–2935
Hersh PS, Stulting RD, Muller D, Durrie DS, Rajpal RK, Binder PS, Donnenfeld ED, Durrie D, Hardten D, Hersh PJO (2017) United States multicenter clinical trial of corneal collagen crosslinking for keratoconus treatment. Ophthalmology 124(9):1259–1270
Greenstein SA (2021) Hersh PSJT Corneal crosslinking for progressive keratoconus and corneal ectasia: summary of US multicenter and subgroup clinical trials. Transl Vis Sci Technol 10(5):13–13
Author information
Authors and Affiliations
Contributions
E.E.K. and Y.A. wrote the main manuscript. E.E.K. and O.E.K. made substantial contributions to the conception or design of the work and interpretation of data. Y.A. O.E.K. and D.M.U. made contributions to data collection. E.E.K prepared the figures D.M.U. prepared the tables. O.E.K. made the literature search. All authors drafted the work and revised it critically for important intellectual content; All authors approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Corresponding author
Ethics declarations
Conflict of interests
The authors declare that there are no conflicts of interest or funding for this study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Karaca, E.E., Asfuroğlu, Y., Ulusoy, D.M. et al. Evaluating the safety and effectiveness of the sub-400 corneal cross-linking protocol: initial clinical and morphological findings. Int Ophthalmol 45, 16 (2025). https://doi.org/10.1007/s10792-024-03371-8
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s10792-024-03371-8