Corneal Crosslinking for Keratoconus and Corneal Ectasia

  • Peter S. HershEmail author
  • Steven A. Greenstein


Corneal collagen crosslinking (CXL) is a treatment designed to decrease the progression of keratoconus, in particular, and other corneal thinning processes such as post-LASIK and PRK ectasia. CXL may have beneficial vision and optical effects as well. In the CXL procedure, riboflavin (Vitamin B2) is administered in conjunction with ultraviolet A (UVA – 370 nm) producing a photochemical reaction in the corneal stroma with consequent mechanical stiffening of the cornea. Studies suggest that crosslinking is effective in decreasing progression of keratoconus and corneal ectasias. Maximum keratometry generally flattens by 1D to 3D 1 year after CXL. Similarly, corneal topography indices, higher-order aberrations, and subjective visual function generally improve after CXL. In addition, best-corrected visual acuity improves by about 1 Snellen line, on average. After crosslinking, clinical outcomes appear to worsen at 1 month and improve between 3 and 12 months. During the wound healing course, there is a typical crosslinking-associated corneal haze, which peaks at 1 month, and improves between 3 and 12 months, postoperatively. From the viewpoint of clinical decision-making, it is reasonable to consider all eyes with progressive keratoconus or corneal ectasia for crosslinking; however, eyes with good visual acuity (better than 20/40) may be somewhat more susceptible to a loss of 1 Snellen line of acuity after CXL. New clinical studies are underway to investigate transepithelial, accelerated, and customized crosslinking procedures as well as crosslinking as an adjunctive treatment with other procedures such as intracorneal ring segments and PRK.


Corneal collagen crosslinking Keratoconus Post-Lasik and PRK ectasia Maximum keratometry Crosslinking-associated corneal haze Riboflavin Ultraviolet light Intracorneal ring segments Photorefractive keratectomy 


  1. 1.
    Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620–7.CrossRefGoogle Scholar
  2. 2.
    Vinciguerra P, Camesasca FI, Albe E, Trazza S. Corneal collagen cross-linking for ectasia after excimer laser refractive surgery: 1-year results. J Refract Surg. 2009:1–12.Google Scholar
  3. 3.
    Seiler T, Koufala K, Richter G. Iatrogenic keratectasia after laser in situ keratomileusis. J Refract Surg. 1998;14:312–7.Google Scholar
  4. 4.
    Salgado JP, Khoramnia R, Lohmann CP, Winkler von Mohrenfels C. Corneal collagen crosslinking in post-LASIK keratectasia. Br J Ophthalmol. 2011;95(4):493–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Hafezi F, Kanellopoulos J, Wiltfang R, Seiler T. Corneal collagen crosslinking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis. J Cataract Refract Surg. 2007;33:2035–40.CrossRefPubMedGoogle Scholar
  6. 6.
    Brooks NO, Greenstein S, Fry K, Hersh PS. Patient subjective visual function after corneal collagen crosslinking for keratoconus and corneal ectasia. J Cataract Refract Surg. 2012;38:615–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Greenstein SA, Fry KL, Bhatt J, Hersh PS. Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg. 2010;36:2105–14.CrossRefPubMedGoogle Scholar
  8. 8.
    Greenstein SA, Fry KL, Hersh MJ, Hersh PS. Higher-order aberrations after corneal collagen crosslinking for keratoconus and corneal ectasia. J Cataract Refract Surg. 2012;38:292–302.CrossRefPubMedGoogle Scholar
  9. 9.
    Greenstein SA, Fry KL, Hersh PS. Corneal topography indices after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37:1282–90.CrossRefPubMedGoogle Scholar
  10. 10.
    Greenstein SA, Fry KL, Hersh PS. In vivo biomechanical changes after corneal collagen cross-linking for keratoconus and corneal ectasia: 1-year analysis of a randomized, controlled, clinical trial. Cornea. 2012;31:21–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Greenstein SA, Hersh PS. Characteristics influencing outcomes of corneal collagen crosslinking for keratoconus and ectasia: implications for patient selection. J Cataract Refract Surg. 2013;39:1133–40.CrossRefPubMedGoogle Scholar
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37:149–60.CrossRefPubMedGoogle Scholar
  14. 14.
    Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking. J Cataract Refract Surg. 2003;29:1780–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Hayes S, Kamma-Lorger CS, Boote C, et al. The effect of riboflavin/UVA collagen cross-linking therapy on the structure and hydrodynamic behaviour of the ungulate and rabbit corneal stroma. PLoS One. 2013;8:e52860.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sawaguchi S, Yue BY, Chang I, Sugar J, Robin J. Proteoglycan molecules in keratoconus corneas. Invest Ophthalmol Vis Sci. 1991;32:1846–53.PubMedGoogle Scholar
  17. 17.
    Wollensak J, Buddecke E. Biochemical studies on human corneal proteoglycans--a comparison of normal and keratoconic eyes. Graefes Arch Clin Exp Ophthalmol. 1990;228:517–23.CrossRefPubMedGoogle Scholar
  18. 18.
    Sawaguchi S, Yue BY, Sugar J, Gilboy JE. Lysosomal enzyme abnormalities in keratoconus. Arch Ophthalmol. 1989;107:1507–10.CrossRefPubMedGoogle Scholar
  19. 19.
    Wollensak G, Iomdina E. Long-term biomechanical properties of rabbit cornea after photodynamic collagen crosslinking. Acta Ophthalmol. 2009;87:48–51.CrossRefPubMedGoogle Scholar
  20. 20.
    Ahearne M, Yang Y, Then KY, Liu KK. Non-destructive mechanical characterisation of UVA/riboflavin crosslinked collagen hydrogels. Br J Ophthalmol. 2008;92:268–71.CrossRefPubMedGoogle Scholar
  21. 21.
    Hatami-Marbini H, Jayaram SM. UVA/riboflavin collagen crosslinking stiffening effects on anterior and posterior corneal flaps. Exp Eye Res. 2018;176:53–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Dias J, Diakonis VF, Kankariya VP, Yoo SH, Ziebarth NM. Anterior and posterior corneal stroma elasticity after corneal collagen crosslinking treatment. Exp Eye Res. 2013;116:58–62.CrossRefPubMedGoogle Scholar
  23. 23.
    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(4):585–93.CrossRefPubMedGoogle Scholar
  24. 24.
    Vinciguerra P, Albe E, Trazza S, et al. Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology. 2009;116:369–78.CrossRefPubMedGoogle Scholar
  25. 25.
    Hersh PS, Stulting RD, Muller D, Durrie DS, Rajpal RK, Group USCS. U.S. Multicenter clinical trial of corneal collagen crosslinking for treatment of corneal ectasia after refractive surgery. Ophthalmology. 2017;124:1475–84.CrossRefPubMedGoogle Scholar
  26. 26.
    Hersh PS, Stulting RD, Muller D, Durrie DS, Rajpal RK, United States Crosslinking Study G. United States multicenter clinical trial of corneal collagen crosslinking for keratoconus treatment. Ophthalmology. 2017;124:1259–70.CrossRefPubMedGoogle Scholar
  27. 27.
    Hersh PS, Issa R, Greenstein SA. Corneal crosslinking and intracorneal ring segments for keratoconus: A randomized study of concurrent versus sequential surgery. J Cataract Refract Surg 2019;45:830–9.CrossRefGoogle Scholar
  28. 28.
    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.CrossRefPubMedGoogle Scholar
  29. 29.
    Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Parasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of corneal collagen: preliminary refractive results in an Italian study. J Cataract Refract Surg. 2006;32:837–45.CrossRefPubMedGoogle Scholar
  30. 30.
    Koller T, Pajic B, Vinciguerra P, Seiler T. Flattening of the cornea after collagen crosslinking for keratoconus. J Cataract Refract Surg. 2011;37:1488–92.CrossRefPubMedGoogle Scholar
  31. 31.
    Henriquez MA, Villegas S, Rincon M, Maldonado C, Izquierdo L Jr. Long-term efficacy and safety after corneal collagen crosslinking in pediatric patients: three-year follow-up. Eur J Ophthalmol. 2018;28:415–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Mazzotta C, Traversi C, Baiocchi S, et al. Corneal collagen cross-linking with riboflavin and ultraviolet A light for pediatric keratoconus: ten-year results. Cornea. 2018;37:560–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Raiskup F, Theuring A, Pillunat LE, Spoerl E. Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. J Cataract Refract Surg. 2015;41:41–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Seifert J, Hammer CM, Rheinlaender J, et al. Distribution of Young’s modulus in porcine corneas after riboflavin/UVA-induced collagen cross-linking as measured by atomic force microscopy. PLoS One. 2014;9:e88186.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Goldich Y, Barkana Y, Morad Y, Hartstein M, Avni I, Zadok D. Can we measure corneal biomechanical changes after collagen cross-linking in eyes with keratoconus?--a pilot study. Cornea. 2009;28:498–502.CrossRefPubMedGoogle Scholar
  36. 36.
    Vinciguerra P, Albe E, Mahmoud AM, Trazza S, Hafezi F, Roberts CJ. Intra- and postoperative variation in ocular response analyzer parameters in keratoconic eyes after corneal cross-linking. J Refract Surg. 2010:1–8.Google Scholar
  37. 37.
    Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg. 2005;31:156–62.CrossRefPubMedGoogle Scholar
  38. 38.
    Bak-Nielsen S, Pedersen IB, Ivarsen A, Hjortdal J. Dynamic Scheimpflug-based assessment of keratoconus and the effects of corneal cross-linking. J Refract Surg. 2014;30:408–14.CrossRefPubMedGoogle Scholar
  39. 39.
    Terai N, Raiskup F, Haustein M, Pillunat LE, Spoerl E. Identification of biomechanical properties of the cornea: the ocular response analyzer. Curr Eye Res. 2012;37:553–62.CrossRefPubMedGoogle Scholar
  40. 40.
    Vinciguerra R, Romano V, Arbabi EM, et al. In vivo early corneal biomechanical changes after corneal cross-linking in patients with progressive keratoconus. J Refract Surg. 2017;33:840–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Kucumen RB, Sahan B, Yildirim CA, Ciftci F. Evaluation of corneal biomechanical changes after collagen crosslinking in patients with progressive keratoconus by ocular response analyzer. Turk J Ophthalmol. 2018;48:160–5.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Scarcelli G, Pineda R, Yun SH. Brillouin optical microscopy for corneal biomechanics. Invest Ophthalmol Vis Sci. 2012;53:185–90.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Webb JN, Su JP, Scarcelli G. Mechanical outcome of accelerated corneal crosslinking evaluated by Brillouin microscopy. J Cataract Refract Surg. 2017;43:1458–63.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Yun SH, Chernyak D. Brillouin microscopy: assessing ocular tissue biomechanics. Curr Opin Ophthalmol. 2018;29:299–305.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Seiler T, Hafezi F. Corneal cross-linking-induced stromal demarcation line. Cornea. 2006;25:1057–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Mazzotta C, Balestrazzi A, Baiocchi S, Traversi C, Caporossi A. Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation. Clin Exp Ophthalmol. 2007;35:580–2.CrossRefPubMedGoogle Scholar
  47. 47.
    Mazzotta C, Hafezi F, Kymionis G, et al. In vivo confocal microscopy after corneal collagen crosslinking. Ocul Surf. 2015;13:298–314.CrossRefPubMedGoogle Scholar
  48. 48.
    Greenstein SA, 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;28:397–405.CrossRefPubMedGoogle Scholar
  49. 49.
    Caporossi A, Mazzotta C, Paradiso AL, Baiocchi S, Marigliani D, Caporossi T. Transepithelial corneal collagen crosslinking for progressive keratoconus: 24-month clinical results. J Cataract Refract Surg. 2013;39:1157–63.CrossRefPubMedGoogle Scholar
  50. 50.
    Zhang ZY, Zhang XR. Efficacy and safety of transepithelial corneal collagen crosslinking. J Cataract Refract Surg. 2012;38:1304; author reply -5CrossRefPubMedGoogle Scholar
  51. 51.
    Koppen C, Wouters K, Mathysen D, Rozema J, Tassignon MJ. Refractive and topographic results of benzalkonium chloride-assisted transepithelial crosslinking. J Cataract Refract Surg. 2012;38:1000–5.CrossRefPubMedGoogle Scholar
  52. 52.
    Caporossi A, Mazzotta C, Baiocchi S, Caporossi T, Paradiso AL. Transepithelial corneal collagen crosslinking for keratoconus: qualitative investigation by in vivo HRT II confocal analysis. Eur J Ophthalmol. 2012;22(Suppl 7):S81–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Hersh PS, Lai MJ, Gelles JD, Lesniak SP. Transepithelial corneal crosslinking for keratoconus. J Cataract Refract Surg. 2018;44:313–22.CrossRefPubMedGoogle Scholar
  54. 54.
    Stulting RD, Trattler WB, Woolfson JM, Rubinfeld RS. Corneal crosslinking without epithelial removal. J Cataract Refract Surg. 2018;44:1363–70.CrossRefPubMedGoogle Scholar
  55. 55.
    Mazzotta C, Bagaglia SA, Vinciguerra R, Ferrise M, Vinciguerra P. Enhanced-fluence pulsed-light iontophoresis corneal cross-linking: 1-year morphological and clinical results. J Refract Surg. 2018;34:438–44.CrossRefPubMedGoogle Scholar
  56. 56.
    Rosenblat E, Hersh PS. Intraoperative corneal thickness change and clinical outcomes after corneal collagen crosslinking: standard crosslinking versus hypotonic riboflavin. J Cataract Refract Surg. 2016;42:596–605.CrossRefPubMedGoogle Scholar
  57. 57.
    Ehmke T, Seiler TG, Fischinger I, Ripken T, Heisterkamp A, Frueh BE. Comparison of corneal riboflavin gradients using dextran and HPMC solutions. J Refract Surg. 2016;32:798–802.CrossRefPubMedGoogle Scholar
  58. 58.
    Rapuano PB, Mathews PM, Florakis GJ, Trokel SL, Suh LH. Corneal collagen crosslinking in patients treated with dextran versus isotonic hydroxypropyl methylcellulose (HPMC) riboflavin solution: a retrospective analysis. Eye Vis (Lond). 2018;5:23.CrossRefGoogle Scholar
  59. 59.
    Fischinger I, Seiler TG, Santhirasegaram K, Pettenkofer M, Lohmann CP, Zapp D. Corneal crosslinking (CXL) with 18-mW/cm(2) irradiance and 5.4-J/cm(2) radiant exposure-early postoperative safety. Graefes Arch Clin Exp Ophthalmol. 2018;256:1521–5.CrossRefPubMedGoogle Scholar
  60. 60.
    Mazzotta C, Baiocchi S, Bagaglia SA, Fruschelli M, Meduri A, Rechichi M. Accelerated 15 mW pulsed-light crosslinking to treat progressive keratoconus: two-year clinical results. J Cataract Refract Surg. 2017;43:1081–8.CrossRefPubMedGoogle Scholar
  61. 61.
    Bao F, Zheng Y, Liu C, et al. Changes in corneal biomechanical properties with different corneal cross-linking irradiances. J Refract Surg. 2018;34:51–8.CrossRefPubMedGoogle Scholar
  62. 62.
    Males JJ, Viswanathan D. Comparative study of long-term outcomes of accelerated and conventional collagen crosslinking for progressive keratoconus. Eye (Lond). 2018;32:32–8.CrossRefGoogle Scholar
  63. 63.
    Elbaz U, Shen C, Lichtinger A, et al. Accelerated (9 mW/cm2) corneal collagen crosslinking for keratoconus--a 1-year follow-up. Cornea. 2015;34:e1–2.CrossRefPubMedGoogle Scholar
  64. 64.
    Zhu Y, Reinach PS, Zhu H, et al. Continuous-light versus pulsed-light accelerated corneal crosslinking with ultraviolet-A and riboflavin. J Cataract Refract Surg. 2018;44:382–9.CrossRefPubMedGoogle Scholar
  65. 65.
    Fida A, Humayun S, Fatima I, Basit I, Ishaq M, Hussain F. Safety of high intensity accelerated corneal collagen cross-linking in keratoconus patients on basis of endothelial cell density. J Ayub Med Coll Abbottabad. 2018;30:501–5.PubMedGoogle Scholar
  66. 66.
    Vega-Estrada A, Alio JL, Brenner LF, et al. Outcome analysis of intracorneal ring segments for the treatment of keratoconus based on visual, refractive, and aberrometric impairment. Am J Ophthalmol. 2013;155:575–84 e1.CrossRefPubMedGoogle Scholar
  67. 67.
    Saelens IE, Bartels MC, Bleyen I, Van Rij G. Refractive, topographic, and visual outcomes of same-day corneal cross-linking with Ferrara intracorneal ring segments in patients with progressive keratoconus. Cornea. 2011;30:1406–8.CrossRefPubMedGoogle Scholar
  68. 68.
    Alio JL, Shabayek MH, Artola A. Intracorneal ring segments for keratoconus correction: long-term follow-up. J Cataract Refract Surg. 2006;32:978–85.CrossRefPubMedGoogle Scholar
  69. 69.
    Kwitko S, Severo NS. Ferrara intracorneal ring segments for keratoconus. J Cataract Refract Surg. 2004;30:812–20.CrossRefPubMedGoogle Scholar
  70. 70.
    Spadea L. Collagen crosslinking for ectasia following PRK performed in excimer laser-assisted keratoplasty for keratoconus. Eur J Ophthalmol. 2012;22:274–7.CrossRefPubMedGoogle Scholar
  71. 71.
    Nattis A, Donnenfeld ED, Rosenberg E, Perry HD. Visual and keratometric outcomes of keratoconus patients after sequential corneal crosslinking and topography-guided surface ablation: early United States experience. J Cataract Refract Surg. 2018;44:1003–11.CrossRefGoogle Scholar
  72. 72.
    Sakla H, Altroudi W, Munoz G, Albarran-Diego C. Simultaneous topography-guided partial photorefractive keratectomy and corneal collagen crosslinking for keratoconus. J Cataract Refract Surg. 2014;40:1430–8.CrossRefPubMedGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Cornea and Laser Eye Institute-Hersh Vision Group, CLEI Center for Keratoconus, Teaneck, NJ, Department of Ophthalmology, Rutgers - NJ Medical SchoolNewarkUSA

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