Beyond the Dresden Protocol: Optimization of Corneal Cross-Linking for Visual Function

  • Grace Lytle
  • John Marshall


Corneal cross-linking (CXL) is a minimally invasive, conservative intervention for the treatment of progressive keratoconus that offers the opportunity to preserve visual function by slowing disease progression. A conventional treatment protocol, Dresden CXL, has been established as a first line treatment for keratoconus, and has been demonstrated to be safe and effective in randomized controlled clinical trials. This chapter provides an overview of modifications to the conventional Dresden CXL protocol aimed at shortening treatment time, improving clinical workflow, expanding access to the procedure to patients with thinner corneas, and targeting improved visual function in addition to stabilization. Parameter modifications discussed include adjustments to UVA irradiance, total energy dose, pulsed illumination and customized UV beam shaping. The chapter explores these modifications in the context of the photochemical mechanisms of cross-linking and evaluates the theoretical impact of each modification on the spatial distribution of cross-link bonds formed within the corneal stroma. Clinical evidence for the impact of each modification will be presented, and practical clinical implications are discussed.


Cross-linking Accelerated cross-linking Pulsed cross-linking Customized cross-linking Riboflavin Keratoconus Normalization CuRV PiXL Mosaic Photochemical mechanisms Demarcation line Oxygen UVA 


  1. 1.
    Rebenitsch RL, Kymes SM, Walline JJ, Gordon MO. The lifetime economic burden of keratoconus: a decision analysis using a markov model. Am J Ophthalmol. 2011;151(5):768–73.e2. Scholar
  2. 2.
    Rabinowitz YS. Keratoconus. Surv Ophthalmol. 1998;42(4):297–319. Scholar
  3. 3.
    Gomes JAP, Tan D, Rapuano CJ, et al. Global consensus on keratoconus and ectatic diseases. Cornea. 2015;34(4):359–69.CrossRefGoogle Scholar
  4. 4.
    Knox Cartwright NE, Tyrer JR, Marshall J. Age-related differences in the elasticity of the human cornea. Invest Ophthalmol Vis Sci. 2011;52(7):4324–9. Scholar
  5. 5.
    Chan E, Snibson GR. Current status of corneal collagen cross-linking for keratoconus: a review. Clin Exp Optom. 2013;17(Figure 2):1–10. Scholar
  6. 6.
    Ashwin PT, McDonnell PJ. Collagen cross-linkage: a comprehensive review and directions for future research. Br J Ophthalmol. 2009;94:965–70.CrossRefGoogle Scholar
  7. 7.
    Meek KM, Hayes S. Corneal cross-linking – a review. Ophthalmic Physiol Opt. 2013;33(2):78–93. Scholar
  8. 8.
    Raiskup F, Spoerl E. Corneal crosslinking with riboflavin and ultraviolet A. I. principles. Ocul Surf. 2013;11(2):65–74. Scholar
  9. 9.
    Knox Cartwright NE, Tyrer JR, Marshall J. In vitro quantification of the stiffening effect of corneal cross-linking in the human cornea using radial shearing speckle pattern interferometry. J Refract Surg. 2012;28(7):503–7. Scholar
  10. 10.
    Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res. 1998;66(1):97–103. Scholar
  11. 11.
    Spoerl E, Seiler T. Techniques for stiffening the cornea. J Refract Surg. 1999;15:711–3.PubMedGoogle Scholar
  12. 12.
    Wollensak G, Spoerl E, Reber F, Seiler T. Keratocyte cytotoxicity of riboflavin/UVA-treatment in vitro. Eye (Lond). 2004;18(7):718–22. Scholar
  13. 13.
    Wollensak G, Spörl E, Reber F, Pillunat L, Funk R. Corneal endothelial cytotoxicity of riboflavin/UVA treatment in vitro. Ophthalmic Res. 2003;35(6):324–8. Scholar
  14. 14.
    Wollensak G, Spoerl E, Wilsch M, Seiler T. Endothelial cell damage after riboflavin–ultraviolet-A treatment in the rabbit. J Cataract Refract Surg. 2003;29(9):1786–90. Scholar
  15. 15.
    Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135(5):620–7. Scholar
  16. 16.
    Wittig-Silva C, Chan E, Islam FM, Wu T, Whiting M, Snibson GR. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. Ophthalmology. 2014;121(4):812–21. Scholar
  17. 17.
    O’Brart DPS, Kwong TQ, Patel P, McDonald RJ, O’Brart N. Long-term follow-up of riboflavin/ultraviolet A (370 nm) corneal collagen cross-linking to halt the progression of keratoconus. Br J Ophthalmol. 2013. Scholar
  18. 18.
    Chang CY, Hersh PS. Corneal collagen cross-linking: a review of 1-year outcomes. Eye Contact Lens. 2014;40(6):345–52. Scholar
  19. 19.
    Raiskup F, Theuring A, Pillunat LE, Spoerl E. Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: 10-year results. J Cataract Refract Surg. 2015;41(1):41–6. Scholar
  20. 20.
    Hersh PS, Stulting RD, Muller D, et al. U.S. multicenter clinical trial of corneal collagen crosslinking for treatment of corneal ectasia after refractive surgery. Ophthalmology. 2017;124(10):1475–84. Scholar
  21. 21.
    Hersh PS, Stulting RD, Muller D, et al. United States multicenter clinical trial of corneal collagen crosslinking for keratoconus treatment. Ophthalmology. 2017;124(9):1259–70. Scholar
  22. 22.
    Lytle G. Advances in the technology of corneal cross-linking for keratoconus. Eye Contact Lens. 2014;0(0):1–7. Scholar
  23. 23.
    Chai D, Gaster RN, Roizenblatt R, Juhasz T, Brown DJ, Jester JV. Quantitative assessment of UVA-riboflavin corneal cross-linking using nonlinear optical microscopy. Invest Ophthalmol Vis Sci. 2011;52(7):4231–8. Scholar
  24. 24.
    Roy AS, Dupps WJ. Patient-specific computational modeling of keratoconus progression and differential responses to collagen cross-linking. Invest Ophthalmol Vis Sci. 2011;52(12):9174–87. Scholar
  25. 25.
    Greenstein S, Fry KL, Hersh PS. Effect of topographic cone location on outcomes of corneal collagen cross-linking for keratoconus and corneal ectasia. J Refract Surg. 2012;28(6):397–405. Scholar
  26. 26.
    Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg. 2009;35(8):1358–62. Scholar
  27. 27.
    Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008;34(5):796–801. Scholar
  28. 28.
    Ivarsen A, Hjortdal J. Collagen cross-linking for advanced progressive keratoconus. Cornea. 2013;0(0):1–4.Google Scholar
  29. 29.
    Vinciguerra R, Romano MR, Camesasca FI, et al. Corneal cross-linking as a treatment for keratoconus: 4-year morphologic and clinical outcomes with respect to patient age. Ophthalmology. 2013;120(5):908–16. Scholar
  30. 30.
    Buzzonetti L, Petrocelli G. Transepithelial corneal cross-linking in pediatric patients: early results. J Refract Surg. 2012;28(11):763–7. Scholar
  31. 31.
    Sung H-W, Chang W-H, Ma C-Y, Lee M-H. Crosslinking of biological tissues using genipin and/or carbodiimide. J Biomed Mater Res A. 2003;64(3):427–38. Scholar
  32. 32.
    Jaycock PD, Lobo L, Ibrahim J, Tyrer J, Marshall J. Interferometric technique to measure biomechanical changes in the cornea induced by refractive surgery. J Cataract Refract Surg. 2005;31(1):175–84. Scholar
  33. 33.
    Meek KM, Boote C. The use of X-ray scattering techniques to quantify the orientation and distribution of collagen in the corneal stroma. Prog Retin Eye Res. 2009;28(5):369–92. Scholar
  34. 34.
    Lewis PN, White TL, Young RD, Bell JS, Winlove CP, Meek KM. Three-dimensional arrangement of elastic fibers in the human corneal stroma. Exp Eye Res. 2016;146:43–53. Scholar
  35. 35.
    Winkler M, Chai D, Kriling S, et al. Nonlinear optical macroscopic assessment of 3-D corneal collagen organization and axial biomechanics. Invest Ophthalmol Vis Sci. 2011;52(12):8818–27. Scholar
  36. 36.
    Müller LJ, Pels E, Vrensen GF. The specific architecture of the anterior stroma accounts for maintenance of corneal curvature. Br J Ophthalmol. 2001;85(4):437–43. Scholar
  37. 37.
    White TL, Lewis PN, Young RD, et al. Elastic microfibril distribution in the cornea: differences between normal and keratoconic stroma. Exp Eye Res. 2017;159:40–8. Scholar
  38. 38.
    Meek KM, Tuft SJ, Huang Y, et al. Changes in collagen orientation and distribution in keratoconus corneas. Invest Ophthalmol Vis Sci. 2005;46(6):1948–56. Scholar
  39. 39.
    Roberts CJ, Dupps WJ. Biomechanics of corneal ectasia and biomechanical treatments. J Cataract Refract Surg. 2014;40(6):991–8. Scholar
  40. 40.
    Tian M, Ma P, Zhou W, Feng J, Mu G. Outcomes of corneal crosslinking for central and paracentral keratoconus. Med (United States). 2017;96(10):e6247. Scholar
  41. 41.
    Koller T, Schumacher S, Fankhauser F, Seiler T. Riboflavin/Ultraviolet a crosslinking of the paracentral cornea. Cornea. 2013;32(2):165–8. Scholar
  42. 42.
    Tomita M, Mita M, Huseynova T. Accelerated versus conventional corneal collagen crosslinking. J Cataract Refract Surg. 2014;40(6):1013–20. Scholar
  43. 43.
    Mita M, Waring GO, Tomita M. High-irradiance accelerated collagen crosslinking for the treatment of keratoconus: six-month results. J Cataract Refract Surg. 2014;40(6):1032–40. Scholar
  44. 44.
    Kamaev P, Friedman MD, Sherr E, Muller D. Photochemical kinetics of corneal cross-Linking with riboflavin. Invest Ophthalmol Vis Sci. 2012;53(4):2360–7. Scholar
  45. 45.
    Seiler T, Hafezi F. Corneal cross-linking-induced stromal demarcation line. Cornea. 2006;25(9):1057–9. Scholar
  46. 46.
    Mazzotta C, Caporossi T, Denaro R, et al. Morphological and functional correlations in riboflavin UV A corneal collagen cross-linking for keratoconus. Acta Ophthalmol. 2012;90:259–65. Scholar
  47. 47.
    Touboul D, Efron N, Smadja D, Praud D, Malet F, Colin J. Corneal confocal microscopy following conventional, transepithelial, and accelerated corneal collagen cross-linking procedures for keratoconus. J Refract Surg. 2012;28(11):769–76. Scholar
  48. 48.
    Kymionis G, Tsoulnaras K. Corneal stromal demarcation line determined with anterior segment optical coherence tomography following a very high intensity corneal collagen cross. Cornea. 2015;34:664–7.CrossRefGoogle Scholar
  49. 49.
    Medeiros CS, Giacomin NT, Bueno RL, Ghanem RC, Moraes HV, Santhiago MR. Accelerated corneal collagen crosslinking: technique, efficacy, safety, and applications. J Cataract Refract Surg. 2016;42(12):1826–35. Scholar
  50. 50.
    Liu Y, Liu Y, Zhang Y, et al. Systematic review and meta-analysis comparing modified cross-linking and standard cross-linking for progressive keratoconus. Int J Ophthalmol. 2017;10(9):1419–29. Scholar
  51. 51.
    Mazzotta C, Traversi C, Caragiuli S, Rechichi M. Pulsed vs continuous light accelerated corneal collagen crosslinking: in vivo qualitative investigation by confocal microscopy and corneal OCT. Eye (Lond). 2014;28(10):1179–83. Scholar
  52. 52.
    Mazzotta C, Traversi C, Paradiso AL, Latronico ME, Rechichi M. Pulsed light accelerated crosslinking versus continuous light accelerated crosslinking: 1-year results. J Ophthalmol. 2014;2014:1–6. Scholar
  53. 53.
    Jiang L, Jiang W, Qiu S. Conventional vs. pulsed-light accelerated corneal collagen cross-linking for the treatment of progressive keratoconus: 12-month results from a prospective study. Exp Ther Med. 2017;14:4238–44. Scholar
  54. 54.
    Mazzotta C, Baiocchi S, Bagaglia SA, Fruschelli M, Meduri A, Rechichi M. Accelerated 15 mW pulsed-light crosslinking to treat progressive keratoconus: 2-year clinical results. J Cataract Refract Surg. 2017;43(8):1081–8. Scholar
  55. 55.
    Peyman A, Nouralishahi A, Hafezi F, Kling S, Peyman M. Stromal Demarcation Line in Pulsed Versus Continuous Light Accelerated Corneal Cross-linking for Keratoconus. J Refract Surg. 2016;32(3):206–8. Scholar
  56. 56.
    Mazzotta C, Moramarco A, Traversi C, Baiocchi S, Iovieno A, Fontana L. Accelerated corneal collagen cross-linking using topography-guided UV-A energy emission: preliminary clinical and morphological outcomes. J Ophthalmol. 2016;2016:1–10. Scholar
  57. 57.
    Scott McCall A, Kraft S, Edelhauser HF, et al. Mechanisms of corneal tissue cross-linking in response to treatment with topical riboflavin and long-wavelength ultraviolet radiation (UVA). Investig Ophthalmol Vis Sci. 2010;51(1):129–38. Scholar
  58. 58.
    Muller D, Kamaev P, Friedman M, Sherr E, Eddington W. Accelerated UVA-RF corneal cross-linking through pulsed UVA illumination and oxygen rich environments. Invest Ophthalmol Vis Sci. 2013;54(15):5281.Google Scholar
  59. 59.
    Seiler TG, Fischinger I, Koller T, Zapp D, Frueh BE, Seiler T. Customized corneal cross-linking: one-year results. Am J Ophthalmol. 2016;166:14–21. Scholar
  60. 60.
    Cassagne M, Pierné K, Galiacy SD, Asfaux-Marfaing M-P, Fournié P, Malecaze F. Customized topography-guided corneal collagen cross-linking for keratoconus. J Refract Surg. 2017;33(5):290–7. Scholar
  61. 61.
    Nordström M, Schiller M, Fredriksson A, Behndig A. Refractive improvements and safety with topography-guided corneal crosslinking for keratoconus: 1-year results. Br J Ophthalmol. 2016; Scholar
  62. 62.
    Shetty R, Nethralaya N, Pahuja N, et al. Customized corneal crosslinking using different UVA beam profiles customized corneal crosslinking using different UVA beam profiles. J Refract Surg. 2017;33(10):676–82.CrossRefGoogle Scholar
  63. 63.
    Nordström M, Schiller M, Fredriksson A, et al. Refractive improvements and safety with topography-guided corneal crosslinking for keratoconus: 1-year results. Br J Ophthalmol. 2017;101:920–25.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Grace Lytle
    • 1
  • John Marshall
    • 2
  1. 1.AvedroWalthamUSA
  2. 2.Institute of Ophthalmology University College London in association with Moorfields Eye HospitalLondonUK

Personalised recommendations