Current and new indications for corneal cross-linking in the therapy of corneal diseases Review article

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Katarzyna Przewłócka
Piotr Kanclerz


Corneal collagen cross-linking, a technique used in ophthalmology, involves the creation of new bonds between collagen fibers, thus leading to stabilization and corneal stiffening. The most common indication for corneal collagen cross-linking procedures is to prevent the progression of corneal ectasia,\ i.e., keratoconus, pellucid marginal degeneration, and ectasia after corneal refractive surgery. Clinical data also indicate that it is effective in the treatment of bacterial corneal infections and bullous keratopathy. Corneal collagen cross-linking was shown to inhibit the progression of corneal ectasia, and the treatment commonly leads to the improvement in visual acuity, decreases the maximum keratometry values, and improves the corneal topography image. In addition, it is possible to avoid or postpone the need for more complex and invasive surgery.


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Przewłócka K, Kanclerz P. Current and new indications for corneal cross-linking in the therapy of corneal diseases. Ophthatherapy [Internet]. 2021Sep.30 [cited 2022Oct.3];8(3):186-93. Available from:
Surgery and laser therapy


1. Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006; 17: 356-60.
2. Sherwin T, Brookes NH. Morphological changes in keratoconus: pathology or pathogenesis. Clin Exp Ophthalmol. 2004; 32: 211-7.
3. Wollensak G, Spörl E, Reber F et al. Corneal Endothelial Cytotoxicity of Riboflavin/UVA Treatment in vitro. Ophthalmic Res. 2003; 35: 324-8.
4. Spoerl E, Mrochen M, Sliney D et al. Safety of UVA-riboflavin cross-linking of the cornea. Cornea. 2007; 26: 385-9.
5. Hafezi F, Mrochen M, Iseli HP et al. Collagen crosslinking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas. J Cataract Refract Surg. 2009; 35: 621-4.
6. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003; 135: 620-7.
7. Caporossi A, Baiocchi S, Mazzotta C et al. Parasurgical therapy for keratoconus by riboflavin–ultraviolet type A rays induced cross-linking of corneal collagen. J Cataract Refract Surg. 2006; 32: 837-45.
8. Caporossi A, Mazzotta C, Baiocchi S et al. 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.
9. Asri D, Touboul D, Fournié P et al. Corneal collagen crosslinking in progressive keratoconus: Multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg. 2011; 37: 2137-43.
10. Kymionis GD, Mikropoulos DG, Portaliou DM et al. An overview of corneal collagen cross-linking (CXL). Adv Ther. 2013; 30: 858-69.
11. Hafezi F, Iseli HP. Pregnancy-related exacerbation of iatrogenic keratectasia despite corneal collagen crosslinking. J Cataract Refract Surg. 2008; 34: 1219-21.
12. Brancati F. A locus for autosomal dominant keratoconus maps to human chromosome 3p14-q13. J Med Genet. 2004; 41: 188-92.
13. Rabinowitz YS. Keratoconus. Surv Ophthalmol. 1998; 42: 297-319.
14. Asimellis G, Kaufman EJ. Keratoconus. StatPearls, Treasure Island (FL): StatPearls Publishing; 2020.
15. Ferdi AC, Nguyen V, Gore DM et al. Keratoconus Natural Progression: A Systematic Review and Meta-analysis of 11 529 Eyes. Ophthalmology. 2019; 126: 935-45.
16. Torres Netto EA, Al-Otaibi WM, Hafezi NL et al. Prevalence of keratoconus in paediatric patients in Riyadh, Saudi Arabia. Br J Ophthalmol. 2018; 102: 1436-41.
17. Gokul A, Patel DV, Watters GA et al. The natural history of corneal topographic progression of keratoconus after age 30 years in noncontact lens wearers. Br J Ophthalmol. 2017; 101: 839-44.
18. Piñero DP, Alio JL, Tomás J et al. Vector analysis of evolutive corneal astigmatic changes in keratoconus. Invest Ophthalmol Vis Sci. 2011; 52: 4054-62.
19. Walker RN, Khachikian SS, Belin MW. Scheimpflug photographic diagnosis of pellucid marginal degeneration. Cornea. 2008; 27: 963-6.
20. Krachmer JH. Pellucid marginal corneal degeneration. Arch Ophthalmol. 1978; 96: 1217-21.
21. Rodrigues MM, Newsome DA, Krachmer JH et al. Pellucid marginal corneal degeneration: a clinicopathologic study of two cases. Exp Eye Res. 1981; 33: 277-88.
22. Rodriguez-Prats J, Galal A, Garcia-Lledo M et al. Intracorneal rings for the correction of pellucid marginal degeneration. J Cataract Refract Surg. 2003; 29: 1421-4.
23. Sahu J, Raizada K. Pellucid Marginal Corneal Degeneration. StatPearls, Treasure Island (FL): StatPearls Publishing; 2020.
24. Wollensak G. Corneal collagen crosslinking: new horizons. Expert Rev Ophthalmol. 2010; 5: 201-15.
25. Spadea L. Corneal Collagen Cross-Linking with Riboflavin and UVA Irradiation in Pellucid Marginal Degeneration. J Refract Surg. 2010; 26: 375-7.
26. Stojanovic A, Zhang J, Chen X et al. Topography-Guided Transepithelial Surface Ablation Followed by Corneal Collagen Cross-Linking Performed in a Single Combined Procedure. J Refract Surg. 2010; 26: 145-52.
27. Kymionis GD, Karavitaki AE, Kounis GA et al. Management of pellucid marginal corneal degeneration with simultaneous customized photorefractive keratectomy and collagen crosslinking. J Cataract Refract Surg. 2009; 35: 1298-301.
28. Hassan Z, Nemeth G, Modis L et al. Collagen cross-linking in the treatment of pellucid marginal degeneration. Indian J Ophthalmol. 2014; 62: 367-70.
29. Rao SN, Epstein RJ. Early onset ectasia following laser in situ keratomileusus: case report and literature review. J Refract Surg. 2002; 18: 177-84.
30. Giri P, Azar DT. Risk profiles of ectasia after keratorefractive surgery. Curr Opin Ophthalmol. 2017; 28: 337-42.
31. Randleman JB, Woodward M, Lynn MJ et al. Risk assessment for ectasia after corneal refractive surgery. Ophthalmology. 2008; 115: 37-50.
32. Binder PS. Ectasia after laser in situ keratomileusis. J Cataract Refract Surg. 2003; 29: 2419-29.
33. O’Keefe M, Kirwan C. Laser epithelial keratomileusis in 2010 – a review. Clin Exp Ophthalmol. 2010; 38: 183-91.
34. Brenner LF, Alió JL, Vega-Estrada A et al. Indications for intrastromal corneal ring segments in ectasia after laser in situ keratomileusis. J Cataract Refract Surg. 2012; 38: 2117-24.
35. Tatar MG, Aylin Kantarci F, Yildirim A et al. Risk Factors in Post-LASIK Corneal Ectasia. J Ophthalmol. 2014; 2014: 204191.
36. Kanclerz P, Khoramnia R, Wang X. Current Developments in Corneal Topography and Tomography. Diagnostics. 2021; 11: 1466.
37. Hafezi F, Kanellopoulos J, Wiltfang R et al. 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.
38. Garg P, Das S, Roy A. Collagen Cross-linking for Microbial Keratitis. Middle East Afr J Ophthalmol. 2017; 24: 18-23.
39. Iseli HP, Thiel MA, Hafezi F et al. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea. 2008; 27: 590-4.
40. Sorkhabi R, Sedgipoor M, Mahdavifard A. Collagen cross-linking for resistant corneal ulcer. Int Ophthalmol. 2013; 33: 61-6.
41. Makdoumi K, Mortensen J, Crafoord S. Infectious keratitis treated with corneal crosslinking. Cornea. 2010; 29: 1353-8.
42. Shetty R, Nagaraja H, Jayadev C et al. Collagen crosslinking in the management of advanced non-resolving microbial keratitis. Br J Ophthalmol. 2014; 98: 1033-5.
43. Feizi S, Karimian F, Esfandiari H. Corneal crosslinking for the treatment of infectious keratitis: a review. Expert Rev Ophthalmol. 2021; 16: 287-95.
44. Papaioannou L, Miligkos M, Papathanassiou M. Corneal Collagen Cross-Linking for Infectious Keratitis: A Systematic Review and Meta-Analysis. Cornea. 2016; 35: 62-71.
45. Morishige N, Sonoda KH. Bullous keratopathy as a progressive disease: evidence from clinical and laboratory imaging studies. Cornea. 2013; 32(suppl 1): S77-83.
46. Gonçalves ED, Campos M, Paris F et al. [Bullous keratopathy: etiopathogenesis and treatment]. Arq Bras Oftalmol. 2008; 71: 61-4.
47. Pot SA, Gallhöfer NS, Walser-Reinhardt L et al. Treatment of bullous keratopathy with corneal collagen cross-linking in two dogs. Vet Ophthalmol. 2015; 18: 168-73.
48. Ghanem RC, Santhiago MR, Berti TB et al. Collagen crosslinking with riboflavin and ultraviolet-A in eyes with pseudophakic bullous keratopathy. J Cataract Refract Surg. 2010; 36: 273-6.
49. Krueger RR, Ramos-Esteban JC, Kanellopoulos AJ. Staged Intrastromal Delivery of Riboflavin With UVA Cross-linking in Advanced Bullous Keratopathy: Laboratory Investigation and First Clinical Case. J Refract Surg. 2008; 24(7): S730-6.
50. Wollensak G, Aurich H, Wirbelauer C et al. Potential use of riboflavin/UVA cross-linking in bullous keratopathy. Ophthalmic Res. 2009; 41: 114-7.
51. Choy BNK, Ng ALK, Zhu MM et al. Randomized Control Trial on the Effectiveness of Collagen Cross-linking on Bullous Keratopathy. Cornea. 2020; 39: 1341-7.
52. O’Brart DPS. Corneal collagen crosslinking for corneal ectasias: a review. Eur J Ophthalmol. 2017; 27: 253-69.
53. Wernli J, Schumacher S, Spoerl E et al. The Efficacy of Corneal Cross-Linking Shows a Sudden Decrease with Very High Intensity UV Light and Short Treatment Time. Invest Opthalmol Vis Sci. 2013; 54: 1176.
54. Aldahlawi NH, Hayes S, O’Brart DPS et al. Standard versus accelerated riboflavin–ultraviolet corneal collagen crosslinking: Resistance against enzymatic digestion. J Cataract Refract Surg. 2015; 41: 1989-96.