Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A comparison of keratoconus progression following collagen cross-linkage using standard or personalised keratometry thresholds

Eye (2024)Cite this article

Subjects

Abstract

Objective

To define how estimates of keratoconus progression following collagen cross-linking (CXL) vary according to the parameter selected to measure corneal shape.

Materials and methods

We estimated progression following CXL in 1677 eyes. We compared standard definitions of keratoconus progression based on published thresholds for Kmax, front K2, or back K2, or progression of any two of these three parameters, with the option of an increased threshold for Kmax values ≥ 55D. As corneal thickness reduces unpredictably after CXL, it was excluded from the principal analysis. We then repeated the analysis using novel adaptive estimates of progression for Kmax, front K2, or back K2, developed separately using 6463 paired readings from keratoconus eyes, with a variation of the Bland–Altman method to determine the 95% regression-based limits of agreement (LoA). We created Kaplan-Meier survival plots for both standard and adaptive thresholds. The primary outcome was progression five years after a baseline visit 9–15 months following CXL.

Results

Progression rates were 8% with a standard (≥ 1.5D) threshold for K2 or 6% with the static multi-parameter definition. With a ≥ 1D threshold for Kmax, the progression was significantly higher at 29%. With adaptive Kmax or K2, the progression rates were similar (20%) but less than with the adaptive multi-parameter method (22%).

Conclusions

Estimates of keratoconus progression following CXL vary widely according to the reference criteria. Using adaptive thresholds (LoA) to define the repeatability of keratometry gives estimates for progression that are markedly higher than with the standard multi-parameter method.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2: Bland–Altman plots for Kmax, front K2, back K2, and minimum pachymetry with 95% limit of agreement for 6463 paired readings.
Fig. 3: Kaplan-Meier survival curves based on 1677 eyes following corneal cross-linking and using six different definitions of progression.

Similar content being viewed by others

Data availability

Additional data are available from the corresponding author on reasonable request.

References

  1. Papaliʼi-Curtin AT, Cox R, Ma T, Woods L, Covello A, Hall RC. Keratoconus prevalence among high school students in New Zealand. Cornea. 2019;38:1382–9.

    Article  PubMed  Google Scholar 

  2. Chan E, Chong EW, Lingham G, Stevenson LJ, Sanfilippo PG, Hewitt AW, et al. Prevalence of keratoconus based on Scheimpflug imaging: the raine study. Ophthalmology. 2021;128:515–21.

    Article  PubMed  Google Scholar 

  3. Godefrooij DA, de Wit GA, Uiterwaal CS, Imhof SM, Wisse RPL. Age-specific incidence and prevalence of keratoconus: a nationwide registration study. Am J Ophthalmol. 2017;175:169–72.

    Article  PubMed  Google Scholar 

  4. Tur VM, MacGregor C, Jayaswal R, O’Brart D, Maycock N. A review of keratoconus: diagnosis, pathophysiology, and genetics. Surv Ophthalmol. 2017;62:770–83.

    Article  Google Scholar 

  5. Ferdi AC, Nguyen V, Gore DM, Allan BD, Rozema JJ, Watson SL. Keratoconus natural progression: a systematic review and meta-analysis of 11529 Eyes. Ophthalmology. 2019;126:935–45.

    Article  PubMed  Google Scholar 

  6. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T. Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol. 2010;149:585–93.

    Article  CAS  PubMed  Google Scholar 

  7. Gore DM, Leucci MT, Koay S-Y, Kopsachilis N, Nicolae MN, Malandrakis MI, et al. Accelerated pulsed high-fluence corneal cross-linking for progressive keratoconus. Am J Ophthalmol. 2021;221:9–16.

    Article  PubMed  Google Scholar 

  8. O’Brart DPS, Chan E, Samaras K, Patel P, Shah SP. A randomised, prospective study to investigate the efficacy of riboflavin/ultraviolet A (370 nm) corneal collagen cross-linkage to halt the progression of keratoconus. Br J Ophthalmol. 2011;95:1519–24.

    Article  PubMed  Google Scholar 

  9. Nicula C, Nicula D, Pop RN. Results at 7years after cross-linking procedure in keratoconic patients. J Fr Ophtalmol. 2017;40:535–41.

    Article  CAS  PubMed  Google Scholar 

  10. Larkin DFP, Chowdhury K, Burr JM, Raynor M, Edwards M, Tuft SJ, et al. Effect of corneal cross-linking versus standard care on keratoconus progression in young patients: The KERALINK Randomized Controlled Trial. Ophthalmology. 2021;128:1516–26.

    Article  PubMed  Google Scholar 

  11. Ferdi A, Nguyen V, Kandel H, Tan JCK, Arnalich-Montiel F, Abbondanza M, et al. Predictors of progression in untreated keratoconus: a Save Sight Keratoconus Registry study. Br J Ophthalmol. 2021;106:1206–11.

    Article  PubMed  Google Scholar 

  12. Achiron A, El-Hadad O, Leadbetter D, Hecht I, Hamiel U, Avadhanam V, et al. Progression of pediatric keratoconus after corneal cross-linking: a systematic review and pooled analysis. Cornea. 2022;41:874–8.

    Article  PubMed  Google Scholar 

  13. Ng SM, Ren M, Lindsley KB, Hawkins BS, Kuo IC. Transepithelial versus epithelium-off corneal crosslinking for progressive keratoconus. Cochrane Database Syst Rev. 2021;3:CD013512.

    PubMed  Google Scholar 

  14. Flynn TH, Sharma DP, Bunce C, Wilkins MR. Differential precision of corneal pentacam HR measurements in early and advanced keratoconus. Br J Ophthalmol. 2016;100:1183–7.

    Article  PubMed  Google Scholar 

  15. Flockerzi E, Häfner L, Xanthopoulou K, Daas L, Munteanu C, Langenbucher A, et al. Reliability analysis of successive corneal visualization Scheimpflug technology measurements in different keratoconus stages. Acta Ophthalmol. 2022;100:e83–90.

    Article  PubMed  Google Scholar 

  16. Kreps EO, Jimenez-Garcia M, Issarti I, Claerhout I, Koppen C, Rozema JJ. Repeatability of the pentacam HR in various grades of keratoconus. Am J Ophthalmol. 2020;219:154–62.

    Article  PubMed  Google Scholar 

  17. Seiler TG, Mueller M, Mendes Baiao T. Repeatability and comparison of corneal tomography in mild to severe keratoconus between the anterior segment OCT MS-39 and Pentacam HR. J Refract Surg. 2022;38:250–5.

    Article  PubMed  Google Scholar 

  18. Greenstein SA, Shah VP, Fry KL, Hersh PS. Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37:691–700.

    Article  PubMed  Google Scholar 

  19. Mencucci R, Paladini I, Virgili G, Giacomelli G, Menchini U. Corneal thickness measurements using time-domain anterior segment OCT, ultrasound, and Scheimpflug tomographer pachymetry before and after corneal cross-linking for keratoconus. J Refract Surg. 2012;28:562–6.

    Article  PubMed  Google Scholar 

  20. Shafik Shaheen M, Lolah MM, Piñero DP. The 7-year outcomes of epithelium-off corneal cross-linking in progressive keratoconus. J Refract Surg. 2018;34:181–6.

    Article  PubMed  Google Scholar 

  21. Tzamalis A, Diafas A, Vinciguerra R, Ziakas N, Kymionis G. Repeated corneal cross-linking (CXL) in keratoconus progression after primary treatment: updated perspectives. Semin Ophthalmol. 2021;36:526–30.

    Article  Google Scholar 

  22. Bland JM. How do I estimate limits of agreement when the mean or SD of differences is not constant? https://www-users.york.ac.uk/~mb55/meas/glucose.htm (2009).

  23. Flockerzi E, Elzer B, Daas L, Xanthopoulou K, Eppig T, Langenbucher A, et al. The reliability of successive Scheimpflug imaging and anterior segment optical coherence tomography measurements decreases with increasing keratoconus severity. Cornea. 2021;40:1433–9.

    Article  PubMed  Google Scholar 

  24. Vinciguerra R, Belin MW, Borgia A, Piscopo R, Montericcio A, Confalonieri F, et al. Evaluating keratoconus progression prior to crosslinking: maximum keratometry vs the ABCD grading system. J Cataract Refract Surg. 2021;47:33–9.

    Article  PubMed  Google Scholar 

  25. Lenk J, Herber R, Oswald C, Spoerl E, Pillunat LE, Raiskup F. Risk factors for progression of keratoconus and failure rate after corneal cross-linking. J Refract Surg. 2021;37:816–23.

    Article  PubMed  Google Scholar 

  26. Mazzotta C, Raiskup F, Hafezi F, Torres-Netto EA, Armia Balamoun A, Giannaccare G, et al. Long term results of accelerated 9 mW corneal crosslinking for early progressive keratoconus: the Siena Eye-Cross Study 2. Eye Vis. 2021;8:16.

    Article  Google Scholar 

  27. Lombardo M, Serrao S, Lombardo G, Schiano-Lomoriello D. Two-year outcomes of a randomized controlled trial of transepithelial corneal crosslinking with iontophoresis for keratoconus. J Cataract Refract Surg. 2019;45:992–1000.

    Article  PubMed  Google Scholar 

  28. Iqbal M, Elmassry A, Saad H, Am Gad A, Ibrahim O, Hamed N, et al. Standard cross-linking protocol versus accelerated and transepithelial cross-linking protocols for treatment of paediatric keratoconus: a 2-year comparative study. Acta Ophthalmol. 2020;98:e352–62.

    Article  PubMed  Google Scholar 

  29. Jouve L, Borderie V, Sandali O, Temstet C, Basli E, Laroche L, et al. Conventional and iontophoresis corneal cross-linking for keratoconus: efficacy and assessment by optical coherence tomography and confocal microscopy. Cornea. 2017;36:153–62.

    Article  PubMed  Google Scholar 

  30. Shajari M, Kolb CM, Agha B, Steinwender G, Müller M, Herrmann E, et al. Comparison of standard and accelerated corneal cross‐linking for the treatment of keratoconus: a meta‐analysis. Acta Ophthalmol. 2019;97:e22–35.

    Article  PubMed  Google Scholar 

  31. Kobashi H, Tsubota K. Accelerated versus standard corneal cross-linking for progressive keratoconus: a meta-analysis of randomized controlled trials. Cornea. 2020;39:172–180.

    Article  PubMed  Google Scholar 

  32. Kandel H, Abbondanza M, Gupta A, Mills R, Watson AS, Petsoglou C, et al. Comparison of standard versus accelerated corneal collagen cross-linking for keratoconus: 5-year outcomes from the Save Sight Keratoconus Registry. Eye. 2023;8:95–102. https://doi.org/10.1038/s41433-023-02641-6.

    Article  Google Scholar 

  33. Seifert FK, Theuersbacher J, Schwabe D, Lamm O, Hillenkamp J, Kampik D. Long-term outcome of corneal collagen crosslinking with riboflavin and UV-A irradiation for keratoconus. Curr Eye Res. 2022;47:1472–8.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Mary Fortune provided statistical advice. Moorfields Eye Charity is supported in part by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology.

Funding

HM was funded by a Moorfields Eye Charity PhD Studentship (GR001147). NP is funded by a Moorfields Eye Charity Career Development Award (R190031A). ST, BA and DG acknowledge that a proportion of their financial support is from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The sponsor or funding organisation had no role in the design or conduct of this research.

Author information

Author notes

  1. These authors contributed equally: Ji-Peng Olivia Li, Howard P. Maile.

Authors and Affiliations

  1. Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London, EC1V 2PD, UK

    Ji-Peng Olivia Li, Catey Bunce, Marcello T. Leucci, Bruce D. Allan, Stephen J. Tuft & Daniel M. Gore

  2. UCL Institute of Ophthalmology, 11-43 Bath Street, London, EC1V 9EL, UK

    Howard P. Maile, Catey Bunce, Lynn Kandakji, Bruce D. Allan, Stephen J. Tuft, Nikolas Pontikos & Daniel M. Gore

  3. National Institute for Health and Care Research (NIHR) BRC at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London, UK

    Catey Bunce

Authors
  1. Ji-Peng Olivia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Howard P. Maile
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Catey Bunce
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lynn Kandakji
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marcello T. Leucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bruce D. Allan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stephen J. Tuft
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nikolas Pontikos
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daniel M. Gore
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

OL, HM, ST, DG conceptualization; OL, HM, ML, ST, NP, DG methodology; HM, LK, ML, NP software; OL, HM, validation; HM, CB formal analysis; ML, NK, ST, BA, DG resources; HM, ML data curation; OL, HM, ST, DG writing; all authors approved the final draft.

Corresponding author

Correspondence to Stephen J. Tuft.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, JP.O., Maile, H.P., Bunce, C. et al. A comparison of keratoconus progression following collagen cross-linkage using standard or personalised keratometry thresholds. Eye (2024). https://doi.org/10.1038/s41433-024-02994-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41433-024-02994-6

Search

Advanced search

Quick links