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Corneal Collagen Cross-Linking for Corneal Ectasias

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Keratoconus

Abstract

The aim of this chapter is to review the published literature on corneal collagen cross-linking (CXL). Emphasis has been placed on seminal publications, systemic reviews, meta-analyses and randomized controlled trials. Where such evidence does not exist, large series cohort studies, case-controlled studies and case series with follow-up greater than 12 months were included. Riboflavin/Ultraviolet A (UVA) corneal collagen cross-linking (CXL) is the first therapeutic intervention capable of arresting the progression of ectatic disorders of the cornea. In addition, the majority of investigators report significant improvements in visual, keratometric and topographic measurements 12 months after surgery. Its precise mode of action at a molecular level has not been fully determined. Follow-up is limited to 5–10 years but suggests sustained stability and enhancement in corneal shape with time. Virtually all published long-term data and comparative studies are with epithelium-off techniques. Epithelium-on CXL investigations suggest some efficacy but less than with the epithelium-off treatments and long-term data are not available. Accelerated techniques with higher UVA fluencies and shorter treatments times are the subject of current investigation, with some studies suggesting reduced efficacy compared to the standard 3 milli-watt per square centimetre (mW/cm2) for 30 min irradiation procedure. Research into other CXL methodologies is being undertaken.

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References

  1. Krachmer JH, Feder RS, Belin MW. Keratoconus and related non-inflammatory corneal thinning disorders. Surv Ophthalmol. 1984;28:293–322.

    Article  CAS  PubMed  Google Scholar 

  2. Rabinowitz YS. Keratoconus. Surv Ophthalmol. 1998;42(4):297–319.

    Article  CAS  PubMed  Google Scholar 

  3. Kennedy RH, Bourne WM, Dyer JA. A 48-year clinical and epidemiological study of keratoconus. Am J Ophthalmol. 1986;101(3):267–73.

    Article  CAS  PubMed  Google Scholar 

  4. Kymes SM, Walline JJ, Zadnik K, Sterling J, Gordon MO. Changes in the quality of life of people with keratoconus. Am J Ophthalmol. 2004;138:527.

    Article  PubMed  Google Scholar 

  5. Hammerstein W. Zur genetic des keratoconus. Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1974;190:293–308.

    Article  CAS  PubMed  Google Scholar 

  6. Zhou L, Sawaguchi S, Twining SS, Sugar J, Feder RS, Yue BY. Expression of degradative enzymes and protease inhibitors in corneas with keratoconus. Invest Ophthalmol Vis Sci. 1998;39:1117–24.

    CAS  PubMed  Google Scholar 

  7. Andreassen T, Simonsen AH, Oxlund H. Biomechanical properties of keratoconus and normal corneas. Exp Eye Res. 1980;31(4):435–41.

    Article  CAS  PubMed  Google Scholar 

  8. Seiler T, Quurke AW. Iatrogenic keratectasia after LASIK in a case of forme fruste keratoconus. J Cataract Refract Surg. 1998;24(7):1007–9.

    Article  CAS  PubMed  Google Scholar 

  9. Randleman JB, Russell B, Ward MA, Thompson KP, Stulting RD. Risk factors and prognosis for corneal ectasia after LASIK. Ophthalmology. 2003;110(2):267–75.

    Article  PubMed  Google Scholar 

  10. Pallikaris IG, Kymionis GD, Astyrakakis NI. Corneal ectasia induced by laser in situ keratomileusis. J Cataract Refract Surg. 2001;27(11):1796–802.

    Article  CAS  PubMed  Google Scholar 

  11. Duffey RJ, Leaming D. US trends in refractive surgery: 2004 ISRS/AAO survey. J Refract Surg. 2005;21(6):742–8.

    PubMed  Google Scholar 

  12. Twa MD, Nichols JJ, Joslin CE, Kollbaum PS, Edrington TB, Bullimore MA, Mitchell GL, Cruickshanks KJ, Schanzlin DJ. Characteristics of corneal ectasia after LASIK for myopia. Cornea. 2004;23(5):447–57.

    Article  PubMed  Google Scholar 

  13. Randleman JB, Woodward M, Lynn MJ, Stulting RD. Risk assessment for ectasia after corneal refractive surgery. Ophthalmology. 2008;115(1):37–50.

    Article  PubMed  Google Scholar 

  14. Shaikh S, Shaikh NM, Manche E. Iatrogenic keratoconus as a complication of radial keratotomy. J Cataract Refract Surg. 2002;28(3):553–5.

    Article  PubMed  Google Scholar 

  15. Rabinowitz YS. Ectasia after laser in situ keratomileusis. Curr Opin Ophthalmol. 2006;17(5):421–6.

    Article  PubMed  Google Scholar 

  16. Jinabhai A, Radhakrishnan H, O’Donnell C. Pellucid corneal marginal degeneration: a review. Cont Lens Anterior Eye. 2011;34(2):56–63.

    Article  PubMed  Google Scholar 

  17. Sridhar MS, Mahesh S, Bansal AK, Nutheti R, Rao GN. Pellucid marginal corneal degeneration. Ophthalmology. 2004;111(6):1102–7.

    Article  CAS  PubMed  Google Scholar 

  18. Lee BW, Jurkunas UV, Harissi-Dagher M, Poothullil AM, Tobaigy FM, Azar DT. Ectatic disorders associated with a claw-shaped pattern on corneal topography. Am J Ophthalmol. 2007;144(1):154–6.

    Article  PubMed  Google Scholar 

  19. Mandell RB. Keratoconus. In: Mandell RB, editor. Contact lens practice. 4th ed. Springfield: Charles C. Thomas; 1988. p. 824–49.

    Google Scholar 

  20. Kirkness CM, Ficker LA, Steele AD, Rice NS. The success of penetrating keratoplasty for keratoconus. Eye. 1990;4:673–88.

    Article  PubMed  Google Scholar 

  21. Spoerl E, Huhle M, Seiler T. Erhohung der Festigkeit der Horn haut durch Vernetzung. Ophthalmologe. 1997;94(12):902–6.

    Article  Google Scholar 

  22. Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res. 1998;66(1):97–103.

    Article  CAS  PubMed  Google Scholar 

  23. Spoerl E, Schreiber J, Hellmund K, et al. Untersuchungen zur Verfestigung der Hornhaut am kaninchen. Ophthalmologe. 2000;97(3):203–6.

    Article  Google Scholar 

  24. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol. 2003;135(5):620–7.

    Article  CAS  PubMed  Google Scholar 

  25. McCall AS, 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). Invest Ophthalmol Vis Sci. 2010;51(1):129–38.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hayes S, Kamma-Lorger CS, Boote C, Young RD, Quantock AJ, Rost A, Khatib Y, Harris J, Yagi N, Terrill N, Meek KM. 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(1), e52860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine cornea after riboflavin/ultraviolet-a-induced crosslinking. J Cataract Refract Surg. 2003;29:1780–5.

    Article  PubMed  Google Scholar 

  28. Wollensak G, Iomdina E. Long-term biomechanical properties of rabbit cornea after photodynamic collagen crosslinking. Acta Ophthalmol. 2009;87:48–51.

    Article  PubMed  Google Scholar 

  29. Kohlhaas M, Spoerl E, Schilde T, Unger G, Wittig C, Pillunat LE. Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light. J Cataract Refract Surg. 2006;3292:279–83.

    Article  Google Scholar 

  30. Spoerl E, Wollensak G, Dittert DD, Seiler T. Thermomechanical behavior of collagen-cross-linked porcine cornea. Ophthalmologica. 2004;218(2):136–40.

    Article  CAS  PubMed  Google Scholar 

  31. Spoerl E, Wollensak G, Seiler T. Increased resistance of cross linked cornea against enzymatic digestion. Curr Eye Res. 2004;29(1):35–40.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang Y, Mao X, Schwend T, Littlechild S, Conrad GW. Resistance of corneal RFUVA–cross-linked collagens and small leucine-rich proteoglycans to degradation by matrix metalloproteinases. Invest Ophthalmol Vis Sci. 2013;54(2):1014–25. doi:10.1167/iovs.12-11277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wollensak G, Wilsch M, Spoerl E, Seiler T. Collagen fiber diameter after riboflavin/UVA induced collagen-crosslinking in the rabbit cornea. Cornea. 2004;23(5):503–7.

    Article  PubMed  Google Scholar 

  34. Wollensak G, Aurich H, Pham DT, Wirbelauer C. Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A. J Cataract Refract Surg. 2007;33(3):516–21.

    Article  PubMed  Google Scholar 

  35. Hayes S, Boote C, Kamma-Lorger CS, Rajan MS, Harris J, Dooley E, Hawksworth N, Hiller J, Terill NJ, Hafezi F, Brahma AK, Quantock AJ, Meek KM. Riboflavin/UVA collagen cross-linking-induced changes in normal and keratoconus corneal stroma. PLoS One. 2011;6(8), e22405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wollensak G, Redl B. Gel electrophoretic analysis of corneal collagen after photodynamic cross-linking treatment. Cornea. 2008;27(3):353–6.

    Article  PubMed  Google Scholar 

  37. Wollensak G, Spoerl E, Reber F, Seiler T. Keratocyte cytotoxicity of Riboflavin/UVA-treatment in vitro. Eye. 2004;18(7):718–22.

    Article  CAS  PubMed  Google Scholar 

  38. Wollensak G, Sporl E, Reber F, Pillunat L, Funk R. Corneal endothelial cytotoxicity of riboflavin/UVA treatment in vitro. Ophthalmic Res. 2003;35(6):324–8.

    Article  CAS  PubMed  Google Scholar 

  39. Wollensak G, Spoerl E, Wilsch M, Seiler T. Endothelial damage after riboflavin-ultraviolet-A treatment in the rabbit. J Cataract Refract Surg. 2003;29(9):1786–90.

    Article  PubMed  Google Scholar 

  40. Spoerl E, Mrochen M, Sliney D, et al. Safety of UVA riboflavin cross-linking of the cornea. Cornea. 2007;26(4):385–9.

    Article  PubMed  Google Scholar 

  41. Scnitzler E, Sporl E, Seiler T. Crosslinking of the corneal collagen by UV radiation with riboflavin for the mode of treatment melting ulcer of the cornea, first results of four patients. Klin Monbl Augenheilkd. 2000;217(3):190–3.

    Article  Google Scholar 

  42. Caporossi A, Baiocchi S, Mazzotta C, et al. Parasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of the corneal collagen; preliminary refractive results in an Italian study. J Cataract Refract Surg. 2006;32(5):837–45.

    Article  PubMed  Google Scholar 

  43. Vinciguerra P, Albe E, Trazza S, et al. Refractive, topographic, tomographic, and abberometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology. 2009;116(3):369–78.

    Article  PubMed  Google Scholar 

  44. Coskunseven E, Jankov 2nd MR, Hafezi F. Contralateral eye study of corneal collagen cross-linking with riboflavin and UVA radiation in patients with keratoconus. J Refract Surg. 2009;25(4):371–6.

    Article  PubMed  Google Scholar 

  45. Agrawal VB. Corneal collagen cross-linking with riboflavin and ultraviolet—a light for keratoconus: results in Indian eyes. Indian J Ophthalmol. 2009;57(2):111–4.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Arbelaez MC, Sekito MB, Vidal C, Choudhury SR. Collagen cross-linking with riboflavin and ultraviolet-a light in keratoconus: one-year results. Oman J Ophthalmol. 2009;2(1):33–8.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Vinciguerra P, Albè E, Trazza S, Seiler T, Epstein D. Intraoperative and postoperative effects of corneal collagen cross-linking on progressive keratoconus. Arch Ophthalmol. 2009;127(10):1258–65.

    Article  PubMed  Google Scholar 

  48. Fournié P, Galiacy S, Arné JL, Malecaze F. [Corneal collagen cross-linking with ultraviolet-A light and riboflavin for the treatment of progressive keratoconus]. J Fr Ophtalmol. 2009;32(1):1–7.

    Article  PubMed  Google Scholar 

  49. Henriquez MA, Izquierdo Jr L, Bernilla C, Zakrzewski PA, Mannis M. Riboflavin/Ultraviolet A corneal collagen cross-linking for the treatment of keratoconus: visual outcomes and Scheimpflug analysis. Cornea. 2011;30(3):281–6.

    Article  PubMed  Google Scholar 

  50. Kampik D, Koch M, Kampik K, Geerling G. Corneal riboflavin/UV-A collagen cross-linking (CXL) in keratoconus: two-year results. Klin Monbl Augenheilkd. 2011;228(6):525–30.

    Article  CAS  PubMed  Google Scholar 

  51. Goldich Y, Marcovich AL, Barkana Y, Mandel Y, Hirsh A, Morad Y, Avni I, Zadok D. Clinical and corneal biomechanical changes after collagen cross-linking with riboflavin and UV irradiation in patients with progressive keratoconus: results after 2 years of follow-up. Cornea. 2012;31(6):609–14.

    Article  PubMed  Google Scholar 

  52. Asri D, Touboul D, Fournié P, Malet F, Garra C, Gallois A, Malecaze F, Colin J. Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg. 2011;37(12):2137–43.

    Article  PubMed  Google Scholar 

  53. Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37(1):149–60.

    Article  PubMed  Google Scholar 

  54. Arora R, Gupta D, Goyal JL, Jain P. Results of corneal collagen cross-linking in pediatric patients. J Refract Surg. 2012;28(11):759–62.

    Article  PubMed  Google Scholar 

  55. Vinciguerra P, Albé E, Frueh BE, Trazza S, Epstein D. Two-year corneal cross-linking results in patients younger than 18 years with documented progressive keratoconus. Am J Ophthalmol. 2012;154(3):520–6.

    Article  PubMed  Google Scholar 

  56. Ivarsen A, Hjortdal J. Collagen cross-linking for advanced progressive keratoconus. Cornea. 2013;32(7):903–6.

    Article  PubMed  Google Scholar 

  57. 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(12):2035–40.

    Article  PubMed  Google Scholar 

  58. Vinciguerra P, Camesasca FI, Albè E, Trazza S. Corneal collagen cross-linking for ectasia after excimer laser refractive surgery: 1-year results. J Refract Surg. 2010;26(7):486–97.

    Article  PubMed  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. Richoz O, Mavrakanas N, Pajic B, Hafezi F. Corneal collagen cross-linking for ectasia after LASIK and photorefractive keratectomy: long-term results. Ophthalmology. 2013;120(7):1354–9.

    Article  PubMed  Google Scholar 

  61. Spadea L. Corneal collagen cross-linking with riboflavin and UVA irradiation in pellucid marginal degeneration. J Refract Surg. 2010;26(5):375–7.

    Article  PubMed  Google Scholar 

  62. Hassan Z, Nemeth G, Modis L, Szalai E, Berta A. Collagen cross-linking in the treatment of pellucid marginal degeneration. Indian J Ophthalmol. 2013;10.

    Google Scholar 

  63. Bayraktar S, Cebeci Z, Oray M, Alparslan N. Corneal collagen cross-linking in pellucid marginal degeneration: 2 patients, 4 eyes. Case Rep Ophthalmol Med. 2015;2015:840687.

    PubMed  PubMed Central  Google Scholar 

  64. O’Brart DP, 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(11):1519–24.

    Article  PubMed  Google Scholar 

  65. Wittig-Silva C. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus; preliminary results. J Refract Surg. 2008;24(7):S720–5.

    PubMed  Google Scholar 

  66. 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.

    Article  PubMed  Google Scholar 

  67. Chang CY, Hersh PS. Corneal collagen cross-linking: a review of 1-year outcomes. Eye Contact Lens. 2014;40(6):345–52.

    Article  PubMed  Google Scholar 

  68. 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(7):1282–90.

    Article  PubMed  Google Scholar 

  69. Lang SJ, Messmer EM, Geerling G, Mackert MJ, Brunner T, Dollak S, Kutchoukov B, Böhringer D, Reinhard T, Maier P. Prospective, randomized, double-blind trial to investigate the efficacy and safety of corneal cross-linking to halt the progression of keratoconus. BMC Ophthalmol. 2015;15:78.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Seyedian MA, Aliakbari S, Miraftab M, Hashemi H, Asgari S, Khabazkhoob M. Corneal collagen cross-linking in the treatment of progressive keratoconus: a randomized controlled contralateral eye study. Middle East Afr J Ophthalmol. 2015;22(3):340–5.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Sharma N, Suri K, Sehra SV, Titiyal JS, Sinha R, Tandon R, Vajpayee RB. Collagen cross-linking in keratoconus in Asian eyes: visual, refractive and confocal microscopy outcomes in a prospective randomized controlled trial. Int Ophthalmol. 2015;35(6):827–32.

    Article  PubMed  Google Scholar 

  72. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen cross-linking with riboflavin and ultraviolet A light in keratoconus: long term results. J Cataract Refract Surg. 2008;34(5):796–801.

    Article  PubMed  Google Scholar 

  73. 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.

    Article  CAS  PubMed  Google Scholar 

  74. O’Brart DP, Kwong TQ, Patel P, McDonald RJ, O’Brart NA. Long-term follow-up of riboflavin/ultraviolet A (370 nm) corneal collagen cross-linking to halt the progression of keratoconus. Br J Ophthalmol. 2013;97(4):433–7.

    Article  PubMed  Google Scholar 

  75. Hashemi H, Seyedian MA, Miraftab M, Fotouhi A, Asgari S. Corneal collagen cross-linking with riboflavin and ultraviolet A irradiation for keratoconus: long-term results. Ophthalmology. 2013;120(8):1515–20.

    Article  PubMed  Google Scholar 

  76. Poli M, Lefevre A, Auxenfans C, Burillon C. Corneal collagen cross-linking for the treatment of progressive corneal ectasia: 6-year prospective outcome in a French population. Am J Ophthalmol. 2015;160(4):654–62.

    Article  PubMed  Google Scholar 

  77. Theuring A, Spoerl E, Pillunat LE, Raiskup F. Corneal collagen cross-linking with riboflavin and ultraviolet-A light in progressive keratoconus. Results after 10-year follow-up. Ophthalmologe. 2015;112(2):140–7.

    Article  CAS  PubMed  Google Scholar 

  78. 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(1):41–6.

    PubMed  Google Scholar 

  79. O’Brart DP, Patel P, Lascaratos G, Wagh VK, Tam C, Lee J, O’Brart NA. Corneal cross-linking to halt the progression of keratoconus and corneal ectasia: seven-year follow-up. Am J Ophthalmol. 2015;160(6):1154–63.

    Article  PubMed  Google Scholar 

  80. Javadi MA, Motlagh BF, Jafarinasab MR, et al. Outcomes of penetrating keratoplasty in keratoconus. Cornea. 2005;24:941–6.

    Article  PubMed  Google Scholar 

  81. Gore D, Margineanu A, French P, O’Brart D, Dunsby C, Allan D. Two-photon fluorescence microscopy of corneal riboflavin absorption. Invest Ophthamol Vis Sci. 2014;55(4):2476–81.

    Article  CAS  Google Scholar 

  82. Jain V, Gazali Z, Bidayi R. Isotonic riboflavin and HPMC with accelerated cross-linking protocol. Cornea. 2014;33(9):910–3.

    Article  PubMed  Google Scholar 

  83. Verma S, Corbett MC, Marshall J. A prospective, randomized, double-masked trial to evaluate the role of topical anesthetics in controlling pain after photorefractive keratectomy. Ophthalmology. 1995;102(12):1918–24.

    Article  CAS  PubMed  Google Scholar 

  84. Croxatto JO, Tytiun AE, Argento CJ. Sequential in vivo confocal microscopy study of corneal wound healing after cross-linking in patients with keratoconus. J Refract Surg. 2009;24:1–8.

    Google Scholar 

  85. Mazzotta C, Balestrazzi A, Traversi C, et al. Treatment of progressive keratoconus by riboflavin UVA induced cross linking of corneal collagen: ultrastructural analysis by Heidelberg retinal tomography II in vivo confocal microscopy in humans. Cornea. 2007;26(4):390–7.

    Article  PubMed  Google Scholar 

  86. Mazzotta C, Balestrazzi A, Baiocchi S. Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation. Clin Exp Ophthalmol. 2007;35(6):580–2.

    Article  PubMed  Google Scholar 

  87. Seiler T, Hafezi F. Corneal cross-linking induced stromal demarcation line. Cornea. 2006;25(9):1057–9.

    Article  PubMed  Google Scholar 

  88. Mencucci R, Marini M, Paladini I, Sarchielli E, Sgambati E, Menchini U, Vannelli GB. Effects of riboflavin/UVA corneal cross-linking on keratocytes and collagen fibres in human cornea. Clin Experiment Ophthalmol. 2010;38(1):49–56.

    Article  PubMed  Google Scholar 

  89. Akhtar S, Almubrad T, Paladini I, Mencucci R. Keratoconus corneal architecture after riboflavin/ultraviolet A cross-linking: ultrastructural studies. Mol Vis. 2013;19:1526–37.

    PubMed  PubMed Central  Google Scholar 

  90. Messmer EM, Meyer P, Herwig MC, Loeffler KU, Schirra F, Seitz B, Thiel M, Reinhard T, Kampik A, Auw-Haedrich C. Morphological and immunohistochemical changes after corneal cross-linking. Cornea. 2013;32(2):111–7.

    Article  PubMed  Google Scholar 

  91. Hayes S, O’Brart DP, Lamdin LS, Doutch J, Samaras K, Meek KM, Marshall J. An investigation into the importance of complete epithelial debridement prior to riboflavin/ultraviolet A (UVA) corneal collagen cross-linkage therapy. J Cat Ref Surg. 2008;34:557–61.

    Article  Google Scholar 

  92. Samaras K, O’Brart DPS, Doutch J, Hayes S, Marshall J, Meek K. Effect of epithelial retention and removal on riboflavin absorption in porcine corneas. J Refract Surg. 2009;25(9):771–5.

    Article  PubMed  Google Scholar 

  93. Tariq AA, O’Brart DPS, O’Brart AL, Meek KM. An investigation of trans-epithelial stromal Riboflavin absorption with Ricrolin TE ® (Riboflavin 0.1% with trometamol and sodium EDTA) using spectrophotometry. J Cat Ref Surg. 2012;38:884–9.

    Article  Google Scholar 

  94. Chan C, Sharma M, Wachler B. Effect of inferior segment Intacs with and without C3-R on keratoconus. J Cataract Refract Surg. 2007;33(1):75–80.

    Article  PubMed  Google Scholar 

  95. Filippello M, Stagni E, O’Brart D. Trans-epithelial corneal collagen cross-linking: a bilateral, prospective study. J Cat Ref Surg. 2012;38(2):283–91.

    Article  Google Scholar 

  96. Kissner A, Spoerl E, Jung R, Spekl K, Pillunat LE, Raiskup F. Pharmacological modification of the epithelial permeability by benzalkonium chloride in UVA/Riboflavin corneal collagen cross-linking. Curr Eye Res. 2010;35(8):715–21.

    Article  CAS  PubMed  Google Scholar 

  97. Samaras KE, Lake DB. Corneal collagen cross linking: a review. Int Ophthalmol Clin. 2010;50(3):89–100.

    Article  PubMed  Google Scholar 

  98. Vinciguerra R, Spoerl E, Romano MR, Rosetta P, Vinciguerra P. Comparative stress strain measurements of human corneas after Transepithelial UV-A induced cross-linking: impregnation with iontophoresis, different riboflavin solutions and irradiance power. Invest Ophthalmol Vis Sci. 2012;53:1518 [ARVO 2012 Abstract].

    Google Scholar 

  99. Raiskup F, Pinelli R, Spoerl E. Riboflavin osmolar modification for transepithelial corneal cross-linking. Curr Eye Res. 2012;37(3):234–8.

    Article  CAS  PubMed  Google Scholar 

  100. Rechichi M, Daya S, Scorcia V, Meduri A, Scorcia G. Epithelial-disruption collagen crosslinking for keratoconus: one-year results. J Cataract Refract Surg. 2013;39(8):1171–8.

    Article  PubMed  Google Scholar 

  101. Hashemi H, Miraftab M, Hafezi F, Asgari S. Matched comparison study of total and partial epithelium removal in corneal cross-linking. J Refract Surg. 2015;31(2):110–5.

    Article  PubMed  Google Scholar 

  102. Razmjoo H, Rahimi B, Kharraji M, Koosha N, Peyman A. Corneal haze and visual outcome after collagen crosslinking for keratoconus: a comparison between total epithelium off and partial epithelial removal methods. Adv Biomed Res. 2014;3:221.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Salman AG. Transepithelial corneal collagen crosslinking for progressive keratoconus in a pediatric age group. J Cataract Refract Surg. 2013;39(8):1164–70.

    Article  PubMed  Google Scholar 

  104. Magli A, Forte R, Tortori A, Capasso L, Marsico G, Piozzi E. Epithelium-off corneal collagen cross-linking versus transepithelial cross-linking for pediatric keratoconus. Cornea. 2013;32(5):597–601.

    Article  PubMed  Google Scholar 

  105. Buzzonetti L, Petrocelli G. Transepithelial corneal cross-linking in pediatric patients: early results. J Refract Surg. 2012;28(11):763–7.

    Article  PubMed  Google Scholar 

  106. 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(8):1157–63.

    Article  PubMed  Google Scholar 

  107. Leccisotti A, Islam T. Transepithelial corneal collagen cross-linking in keratoconus. J Refract Surg. 2010;26(12):942–8.

    Article  PubMed  Google Scholar 

  108. 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(6):1000–5.

    Article  PubMed  Google Scholar 

  109. Yuksel E, Novruzlu S, Ozmen MC, Bilgihan K. A study comparing standard and transepithelial collagen cross-linking riboflavin solutions: epithelial findings and pain scores. J Ocul Pharmacol Ther. 2015;31(5):296–302.

    Article  CAS  PubMed  Google Scholar 

  110. Rossi S, Orrico A, Santamaria C, Romano V, De Rosa L, Simonelli F, De Rosa G. Standard versus trans-epithelial collagen cross-linking in keratoconus patients suitable for standard collagen cross-linking. Clin Ophthalmol. 2015;9:503–9. doi:10.2147/OPTH.S73991 [eCollection 2015].

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Nawaz S, Gupta S, Gogia V, Sasikala NK, Panda A. Trans-epithelial versus conventional corneal collagen crosslinking: a randomized trial in keratoconus. Oman J Ophthalmol. 2015;8(1):9–13.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Al Fayez MF, Alfayez S, Alfayez Y. Transepithelial versus epithelium-Off corneal collagen cross-linking for progressive keratoconus: a prospective randomized controlled trial. Cornea. 2015;34 Suppl 10:S53–6.

    Article  PubMed  Google Scholar 

  113. Soeters N, Wisse RP, Godefrooij DA, Imhof SM, Tahzib NG. Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: a randomized controlled trial. Am J Ophthalmol. 2015;159(5):821–8.

    Article  PubMed  Google Scholar 

  114. Kocak I, Aydin A, Kaya F, Koc H. Comparison of transepithelial corneal collagen crosslinking with epithelium-off crosslinking in progressive keratoconus. J Fr Ophtalmol. 2014;37(5):371–6.

    Article  CAS  PubMed  Google Scholar 

  115. Gore DM, French P, O’Brart D, Dunsby C, Allan BD. Two-photon fluorescence microscopy of corneal riboflavin absorption through an intact epithelium. Invest Ophthamol Vis Sci. 2015;56(2):1191–2.

    Article  Google Scholar 

  116. Gore DM, O’Brart D, Dunsby C, French P, Allan BD. Transepithelial riboflavin absorption in an ex-vivo rabbit corneal model. Invest Ophthamol Vis Sci. 2015;56(8):5006–11.

    Article  CAS  Google Scholar 

  117. Cassagne M, Laurent C, Rodrigues M, Galinier A, Spoerl E, Galiacy SD, Soler V, Fournié P, Malecaze F. Iontophoresis transcorneal delivery technique for transepithelial corneal collagen crosslinking with riboflavin in a rabbit model. Invest Ophthalmol Vis Sci. 2016;57:594–603. doi:10.1167/iovs.13-12595 [Epub ahead of print].

    Article  CAS  PubMed  Google Scholar 

  118. Vinciguerra P, Mencucci R, Romano V, Spoerl E, Camesasca FI, Favuzza E, Azzolini C, Mastropasqua R, Vinciguerra R. Imaging mass spectrometry by matrix-assisted laser desorption/ionization and stress-strain measurements in iontophoresis transepithelial corneal collagen cross-linking. Biomed Res Int. 2014;2014:404587. doi:10.1155/2014/404587 [Epub 2014 Sep 2].

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Mastropasqua L, Lanzini M, Curcio C, Calienno R, Mastropasqua R, Colasante M, Mastropasqua A, Nubile M. Structural modifications and tissue response after standard epi-off and iontophoretic corneal crosslinking with different irradiation procedures. Invest Ophthalmol Vis Sci. 2014;55(4):2526–33.

    Article  PubMed  Google Scholar 

  120. Lombardo M, Serrao S, Rosati M, Ducoli P, Lombardo G. Biomechanical changes in the human cornea after transepithelial corneal crosslinking using iontophoresis. J Cataract Refract Surg. 2014;40(10):1706–15.

    Article  PubMed  Google Scholar 

  121. Bikbova G, Bikbov M. Transepithelial corneal collagen cross-linking by iontophoresis of riboflavin. Acta Ophthalmol. 2014;92(1):e30–4.

    Article  CAS  PubMed  Google Scholar 

  122. Vinciguerra P, Randleman JB, Romano V, Legrottaglie EF, Rosetta P, Camesasca FI, Piscopo R, Azzolini C, Vinciguerra R. Transepithelial iontophoresis corneal collagen cross-linking for progressive keratoconus: initial clinical outcomes. J Refract Surg. 2014;30(11):746–53.

    Article  PubMed  Google Scholar 

  123. Li N, Fan Z, Peng X, Pang X, Tian C. Clinical observation of transepithelial corneal collagen cross-linking by lontophoresis of riboflavin in treatment of keratoconus. Eye Sci. 2014;29(3):160–4.

    PubMed  Google Scholar 

  124. Buzzonetti L, Petrocelli G, Valente P, Iarossi G, Ardia R, Petroni S. Iontophoretic transepithelial corneal cross-linking to halt keratoconus in pediatric cases: 15-month follow-up. Cornea. 2015;34(5):512–5.

    Article  PubMed  Google Scholar 

  125. Hayes S, Morgan S, O’Brart D P, O’Brart N, Meek KM. A study of stromal riboflavin absorption using new and existing delivery protocols for corneal cross-linking. Acta Ophthalmol. 2016 Mar;94(2):e109–17.

    Google Scholar 

  126. Gore DM, O’Brart D, Dunsby C, French P, Allan BD. A comparison of different corneal iontophoresis protocols for promoting transepithelial riboflavin penetration. Invest Ophthalmol Vis Sci. 2015;56(13):7908–14.

    Article  PubMed  Google Scholar 

  127. Lamy R, Chan E, Zhang H, Salgaonkar VA, Good SD, Porco TC, Diederich CJ, Stewart JM. Ultrasound-enhanced penetration of topical riboflavin into the corneal stroma. Invest Ophthalmol Vis Sci. 2013;54(8):5908–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Bottos KM, Oliveira AG, Bersanetti PA, Nogueira RF, Lima-Filho AA, Cardillo JA, Schor P, Chamon W. Corneal absorption of a new riboflavin-nanostructured system for transepithelial collagen cross-linking. PLoS One. 2013;8(6), e66408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Ostacolo C, Caruso C, Tronino D, Troisi S, Laneri S, Pacente L, Del Prete A, Sacchi A. Enhancement of corneal permeation of riboflavin-5’-phosphate through vitamin E TPGS: a promising approach in corneal trans-epithelial cross linking treatment. Int J Pharm. 2013;440(2):148–53.

    Article  CAS  PubMed  Google Scholar 

  130. Kanellopoulos AJ. Collagen cross-linking in early keratoconus with riboflavin in a femtosecond laser-created pocket: initial clinical results. J Refract Surg. 2009;25(11):1034–7.

    Article  PubMed  Google Scholar 

  131. Beshtawi IM, Akhtar R, Hillarby MC, O’Donnell C, Zhao X, Brahma A, Carley F, Derby B, Radhakrishnan H. Biomechanical properties of human corneas following low- and high-intensity collagen cross-linking determined with scanning acoustic microscopy. Invest Ophthalmol Vis Sci. 2013;54(8):5273–80.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Schumacher S, Oeftiger L, Mrochen M. Equivalence of biomechanical changes induced by rapid and standard corneal cross-linking, using riboflavin and ultraviolet radiation. Invest Ophthalmol Vis Sci. 2011;52(12):9048–52.

    Article  PubMed  Google Scholar 

  133. Wernli J, Schumacher S, Spoerl E, Mrochen M. The efficacy of corneal cross-linking shows a sudden decrease with very high intensity UV light and short treatment time. Invest Ophthalmol Vis Sci. 2013;54(2):1176–80.

    Article  PubMed  Google Scholar 

  134. Cınar Y, Cingü AK, Turkcu FM, Yüksel H, Sahin A, Yıldırım A, Caca I, Cınar T. Accelerated corneal collagen cross-linking for progressive keratoconus. Cutan Ocul Toxicol. 2014;33(2):168–71.

    Article  PubMed  CAS  Google Scholar 

  135. Shetty R, Nagaraja H, Jayadev C, Pahuja NK, Kurian Kummelil M, Nuijts RM. Accelerated corneal collagen cross-linking in pediatric patients: two-year follow-up results. Biomed Res Int. 2014;2014:894095.

    PubMed  PubMed Central  Google Scholar 

  136. Marino GK, Torricelli AA, Giacomin N, Santhiago MR, Espindola R, Netto MV. Accelerated corneal collagen cross-linking for postoperative LASIK ectasia: two-year outcomes. J Refract Surg. 2015;31(6):380–4.

    Article  PubMed  Google Scholar 

  137. Elbaz U, Shen C, Lichtinger A, Zauberman NA, Goldich Y, Chan CC, Slomovic AR, Rootman DS. Accelerated (9-mW/cm2) corneal collagen crosslinking for keratoconus-A 1-year follow-up. Cornea. 2014;33(8):769–73.

    Article  PubMed  Google Scholar 

  138. Ng AL, Chan TC, Cheng AC. Conventional versus accelerated corneal collagen cross-linking in the treatment of keratoconus. Clin Experiment Ophthalmol. 2015. doi:10.1111/ceo.12571 [Epub ahead of print].

    Google Scholar 

  139. Brittingham S, Tappeiner C, Frueh BE. Corneal cross-linking in keratoconus using the standard and rapid treatment protocol: differences in demarcation line and 12-month outcomes. Invest Ophthalmol Vis Sci. 2014;55(12):8371–6.

    Article  PubMed  Google Scholar 

  140. Kanellopoulos AJ. Long term results of a prospective randomized bilateral eye comparison trial of higher fluence, shorter duration ultraviolet A radiation, and riboflavin collagen cross linking for progressive keratoconus. Clin Ophthalmol. 2012;6:97–101.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Hashemian H, Jabbarvand M, Khodaparast M, Ameli K. Evaluation of corneal changes after conventional versus accelerated corneal cross-linking: a randomized controlled trial. J Refract Surg. 2014;30(12):837–42.

    Article  PubMed  Google Scholar 

  142. Hashemi H, Fotouhi A, Miraftab M, Bahrmandy H, Seyedian MA, Amanzadeh K, Heidarian S, Nikbin H, Asgari S. Short-term comparison of accelerated and standard methods of corneal collagen crosslinking. J Cataract Refract Surg. 2015;41(3):533–40.

    Article  PubMed  Google Scholar 

  143. Shetty R, Pahuja NK, Nuijts RM, Ajani A, Jayadev C, Sharma C, Nagaraja H. Current protocols of corneal collagen cross-linking: visual, refractive, and tomographic outcomes. Am J Ophthalmol. 2015;160(2):243–9.

    Article  PubMed  Google Scholar 

  144. Sherif AM. Accelerated versus conventional corneal collagen cross-linking in the treatment of mild keratoconus: a comparative study. Clin Ophthalmol. 2014;8:1435–40.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Nada H, Aldahlawi AH, Hayes S, O’Brart DPS, Meek KM. Standard versus accelerated riboflavin/ultraviolet corneal cross-linking: resistance against enzymatic digestion. J Cataract Refract Surg. 2015;41(9):1989–96.

    Article  Google Scholar 

  146. Kymionis GD, Tsoulnaras KI, Grentzelos MA, Liakopoulos DA, Tsakalis NG, Blazaki SV, Paraskevopoulos TA, Tsilimbaris MK. Evaluation of corneal stromal demarcation line depth following standard and a modified-accelerated collagen cross-linking protocol. Am J Ophthalmol. 2014;158(4):671–5.

    Article  PubMed  Google Scholar 

  147. Mazzotta C, Traversi C, Paradiso AL, Latronico ME, Rechichi M. Pulsed light accelerated crosslinking versus continuous light accelerated crosslinking: One-year results. J Ophthalmol. 2014;2014:604731.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Moramarco A, Iovieno A, Sartori A, Fontana L. Corneal stromal demarcation line after accelerated crosslinking using continuous and pulsed light. J Cataract Refract Surg. 2015;41(11):2546–51.

    Article  PubMed  Google Scholar 

  149. Raiskup F, Spoerl E. Corneal cross-linking with hypo-osmolar riboflavin solution in thin keratoconic corneas. Am J Ophthalmol. 2011;152(1):28–32.

    Article  CAS  PubMed  Google Scholar 

  150. Nassaralla BA, Vieira DM, Machado ML, Figueiredo MN, Nassaralla Jr JJ. Corneal thickness changes during corneal collagen cross-linking with UV-A irradiation and hypo-osmolar riboflavin in thin corneas. Arq Bras Oftalmol. 2013;76(3):155–8.

    Article  PubMed  Google Scholar 

  151. Kymionis GD, Portaliou DM, Diakonis VF, Kounis GA, Panagopoulou SI, Grentzelos MA. Corneal collagen cross-linking with riboflavin and ultraviolet-A irradiation in patients with thin corneas. Am J Ophthalmol. 2012;153(1):24–8.

    Article  CAS  PubMed  Google Scholar 

  152. Hafezi F. Limitation of collagen cross-linking with hypoosmolar riboflavin solution: failure in an extremely thin cornea. Cornea. 2011;30(8):917–9.

    Article  PubMed  Google Scholar 

  153. Spadea L, Mencucci R. Transepithelial corneal collagen cross-linking in ultrathin keratoconic corneas. Clin Ophthalmol. 2012;6:1785–92. doi:10.2147/OPTH.S37335 [Epub 2012 Nov 2].

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Jacob S, Kumar DA, Agarwal A, Basu S, Sinha P, Agarwal A. Contact lens-assisted collagen cross-linking (CACXL): a new technique for cross-linking thin corneas. J Refract Surg. 2014;30(6):366–72.

    Article  PubMed  Google Scholar 

  155. Mazzotta C, Ramovecchi V. Customized epithelial debridement for thin ectatic corneas undergoing corneal cross-linking: epithelial island cross-linking technique. Clin Ophthalmol. 2014;8:1337–43.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Reinstein DZ, Gobbe M, Archer TJ, Silverman RH, Coleman DJ. Epithelial, stromal, and total corneal thickness in keratoconus: three-dimensional display with artemis very-high frequency digital ultrasound. J Refract Surg. 2010;26(4):259–71.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Kapasi M, Baath J, Mintsioulis G, Jackson WB, Baig K. Phototherapeutic keratectomy versus mechanical epithelial removal followed by corneal collagen crosslinking for keratoconus. Can J Ophthalmol. 2012;47(4):344–7.

    Article  PubMed  Google Scholar 

  158. Kymionis GD, Grentzelos MA, Kounis GA, Diakonis VF, Limnopoulou AN, Panagopoulou SI. Combined transepithelial phototherapeutic keratectomy and corneal collagen cross-linking for progressive keratoconus. Ophthalmology. 2012;119(9):1777–84.

    Article  PubMed  Google Scholar 

  159. Kymionis GD, Grentzelos MA, Kankariya VP, Liakopoulos DA, Karavitaki AE, Portaliou DM, Tsoulnaras KI, Pallikaris IG. Long-term results of combined transepithelial phototherapeutic keratectomy and corneal collagen crosslinking for keratoconus: Cretan protocol. J Cataract Refract Surg. 2014;40(9):1439–45.

    Article  PubMed  Google Scholar 

  160. Kanellopoulos AJ, Binder PS. Management of corneal ectasia after LASIK with combined, same-day, topography-guided partial transepithelial PRK and collagen cross-linking: the athens protocol. J Refract Surg. 2011;27(5):323–31.

    Article  PubMed  Google Scholar 

  161. Kymionis GD, Portaliou DM, Diakonis VF, Karavitaki AE, Panagopoulou SI, Jankov Ii MR, Coskunseven E. Management of post laser in situ keratomileusis ectasia with simultaneous topography guided photorefractive keratectomy and collagen cross-linking. Open Ophthalmol J. 2011;5:11–3.

    Article  PubMed  PubMed Central  Google Scholar 

  162. Krueger RR, Kanellopoulos AJ. Stability of simultaneous topography-guided photorefractive keratectomy and riboflavin/UVA cross-linking for progressive keratoconus: case reports. J Refract Surg. 2010;26(10):S827–32.

    Article  PubMed  Google Scholar 

  163. Alessio G, L’abbate M, Sborgia C, La Tegola MG. Photorefractive keratectomy followed by cross-linking versus cross-linking alone for management of progressive keratoconus: two-year follow-up. Am J Ophthalmol. 2013;155(1):54–65.

    Article  PubMed  Google Scholar 

  164. Lin DT, Holland S, Tan JC, Moloney G. Clinical results of topography-based customized ablations in highly aberrated eyes and keratoconus/ectasia with cross-linking. J Refract Surg. 2012;28(11 Suppl):S841–8.

    Article  PubMed  Google Scholar 

  165. Sakla H, Altroudi W, Muñoz G, Albarrán-Diego C. Simultaneous topography-guided partial photorefractive keratectomy and corneal collagen crosslinking for keratoconus. J Cataract Refract Surg. 2014;40(9):1430–8.

    Article  PubMed  Google Scholar 

  166. Labiris G, Giarmoukakis A, Sideroudi H, Gkika M, Fanariotis M, Kozobolis V. Impact of keratoconus, cross-linking and cross-linking combined with photorefractive keratectomy on self-reported quality of life. Cornea. 2012;31(7):734–9.

    Article  PubMed  Google Scholar 

  167. Kanellopoulos AJ, Asimellis G. Keratoconus management: long-term stability of topography-guided normalization combined with high-fluence CXL stabilization (the Athens Protocol). J Refract Surg. 2014;30(2):88–93.

    Article  PubMed  Google Scholar 

  168. Kymionis GD, Portaliou DM, Diakonis VF, Kontadakis GA, Krasia MS, Papadiamantis AG, Coskunseven E, Pallikaris AI. Posterior linear stromal haze formation after simultaneous photorefractive keratectomy followed by corneal collagen cross-linking. Invest Ophthalmol Vis Sci. 2010;51(10):5030–3.

    Article  PubMed  Google Scholar 

  169. Güell JL, Verdaguer P, Elies D, Gris O, Manero F. Late onset of a persistent, deep stromal scarring after PRK and corneal cross-linking in a patient with forme fruste keratoconus. J Refract Surg. 2014;30(4):286–8.

    Article  PubMed  Google Scholar 

  170. Coskunseven E, Jankov 2nd MR, Grentzelos MA, Plaka AD, Limnopoulou AN, Kymionis GD. Topography-guided transepithelial PRK after intracorneal ring segments implantation and corneal collagen CXL in a three-step procedure for keratoconus. J Refract Surg. 2013;29(1):54–8.

    Article  PubMed  Google Scholar 

  171. Ertan A, Karacal H, Kamburoğlu G. Refractive and topographic results of transepithelial cross-linking treatment in eyes with intacs. Cornea. 2009;28(7):719–23.

    Article  PubMed  Google Scholar 

  172. Renesto Ada C, Melo Jr LA, Sartori Mde F, Campos M. Sequential topical riboflavin with or without ultraviolet a radiation with delayed intracorneal ring segment insertion for keratoconus. Am J Ophthalmol. 2012;153(5):982–93.

    Article  PubMed  CAS  Google Scholar 

  173. El-Raggal TM. Sequential versus concurrent KERARINGS insertion and corneal collagen cross-linking for keratoconus. Br J Ophthalmol. 2011;95(1):37–41.

    Article  PubMed  Google Scholar 

  174. Kanellopoulos AJ. Long-term safety and efficacy follow-up of prophylactic higher fluence collagen cross-linking in high myopic laser-assisted in situ keratomileusis. Clin Ophthalmol. 2012;6:1125–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Celik HU, Alagöz N, Yildirim Y, Agca A, Marshall J, Demirok A, Yilmaz OF. Accelerated corneal crosslinking concurrent with laser in situ keratomileusis. J Cataract Refract Surg. 2012;38(8):1424–31.

    Article  PubMed  Google Scholar 

  176. Kanellopoulos AJ, Kahn J. Topography-guided hyperopic LASIK with and without high irradiance collagen cross-linking: initial comparative clinical findings in a contralateral eye study of 34 consecutive patients. J Refract Surg. 2012;28(11 Suppl):S837–40.

    Article  PubMed  Google Scholar 

  177. Kanellopoulos AJ, Asimellis G. Combined laser in situ keratomileusis and prophylactic high-fluence corneal collagen crosslinking for high myopia: two-year safety and efficacy. J Cataract Refract Surg. 2015;41(7):1426–33.

    Article  PubMed  Google Scholar 

  178. Rocha KM, Ramos-Esteban JC, Qian Y, et al. Comparative study of riboflavin-UVA cross-linking and “flash-linking” using wave elastometry. J Refract Surg. 2008;24(7):S748–51.

    PubMed  Google Scholar 

  179. Paik D, Wen Q, Braunstein RE, et al. Initial studies using ali phatic ß-nitro alcohols for therapeutic corneal cross linking. Invest Ophthalmol Vis Sci. 2009;50(3):1098–105.

    Article  PubMed  Google Scholar 

  180. Cherfan D, Verter EE, Melki S, Gisel TE, Doyle Jr FJ, Scarcelli G, Yun SH, Redmond RW, Kochevar IE. Collagen cross-linking using rose bengal and green light to increase corneal stiffness. Invest Ophthalmol Vis Sci. 2013;54(5):3426–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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David P.S. O’Brart declares that he has no conflict of interest. He holds a non-commercial grant from Alcon Inc for research into Femto-second laser assisted cataract surgery. No human or animal studies were carried out by the author for this review.

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O’Brart, D. (2017). Corneal Collagen Cross-Linking for Corneal Ectasias. In: Alió, J. (eds) Keratoconus. Essentials in Ophthalmology. Springer, Cham. https://doi.org/10.1007/978-3-319-43881-8_19

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