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Keratoconus 1

  • The so-called «Dresden protocol» is the original epi-off CXL protocol that started corneal cross-linking in 1999.
  • The «Dresden protocol» currently (2020) represents the benchmark in terms of biomechanical stiffness effect in CXL
  • This protocol is most often used for the following Indications when the strongest biomechanical effect is needed:
    • Aggressive progression of keratoconus
    • Keratoconus in children and adolescents
    • Pellucid marginal degeneration
    • Ectasia after LASIK/PRK/SMILE
    • Bullous keratopathy
    • Sterile corneal melting

1. Wollensak G, Spoerl E, and Seiler T, Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol, 2003. 135(5): p. 620-7. 

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

3. Spoerl E, Wollensak G, and Seiler T, Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res, 2004. 29(1): p. 35-40. 

4. Spoerl E, Mrochen M, Sliney D, Trokel S, and Seiler T, Safety of UVA-riboflavin cross-linking of the cornea. Cornea, 2007. 26(4): p. 385-9. 

5. Mackool RJ, Crosslinking for iatrogenic keratectasia after LASIK and for keratoconus. Journal of cataract and refractive surgery, 2008. 34(6): p. 879; author reply 879. 

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

7. Koller T, Mrochen M, and Seiler T, Complication and failure rates after corneal crosslinking. J Cataract Refract Surg, 2009. 35(8): p. 1358-62. 

8. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T, Denaro R, and Balestrazzi A, Riboflavin-UVA-induced corneal collagen cross-linking in pediatric patients. Cornea, 2012. 31(3): p. 227-31. 

9. Chatzis N and Hafezi F, Progression of Keratoconus and Efficacy of Corneal Collagen Cross-linking in Children and Adolescents. J Refract Surg, 2012. 28(11): p. 753-8. 

10. Raiskup F and Spoerl E, Corneal crosslinking with riboflavin and ultraviolet A. I. Principles. Ocul Surf, 2013. 11(2): p. 65-74. 

11. Raiskup F, Theuring A, Pillunat LE, and Spoerl E, Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. J Cataract Refract Surg, 2015. 41(1): p. 41-6. 

12. Khairy HA, Elsawy MF, Said-Ahmed K, Zaki MA, and Mandour SS, Accelerated versus standard corneal cross linking in the treatment of ectasia post refractive surgery and penetrating keratoplasty: a medium term randomized trial. Int J Ophthalmol, 2019. 12(11): p. 1714-1719. 

13. Lang PZ, Hafezi NL, Khandelwal SS, Torres-Netto EA, Hafezi F, and Randleman JB, Comparative Functional Outcomes After Corneal Crosslinking Using Standard, Accelerated, and Accelerated With Higher Total Fluence Protocols. Cornea, 2019. 38(4): p. 433-441. 

Keratoconus 2

  • Accelerated epi-off CXL protocol with 10 minutes irradiation time and standard fluence (5.4 J/cm2).
  • This protocol is most often used for the following indications:
    • Moderately progressive keratoconus in adults
    • Pellucid marginal degeneration
    • Ectasia after LASIK/PRK/SMILE

1. Richoz O, Hammer A, Tabibian D, Gatzioufas Z, and Hafezi F. The Biomechanical Effect of Corneal Collagen Cross-Linking (CXL) With Riboflavin and UV-A is Oxygen Dependent. Transl Vis Sci Technol. 2013. 2(7): 6 

2. Hammer A, Richoz O, Mosquera S, Tabibian D, Hoogewoud F, and Hafezi F. Corneal biomechanical properties at different corneal collagen cross-linking (CXL) Irradiances. Invest Ophthalmol Vis Sci. 2014. 55(5): 2881-4

3. Kymionis GD, Tsoulnaras KI, Grentzelos MA, Plaka AD, Mikropoulos DG, Liakopoulos DA, Tsakalis NG, and Pallikaris IG. Corneal stroma demarcation line after standard and high-intensity collagen crosslinking determined with anterior segment optical coherence tomography. J Cataract Refract Surg. 2014. 40(5): 736-40

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

5. Marino GK, Torricelli AA, Giacomin N, Santhiago MR, Espindola R, and Netto MV. Accelerated Corneal Collagen Cross-linking for Postoperative LASIK Ectasia: Two-Year Outcomes. J Refract Surg. 2015. 31(6): 380-4

6. Pahuja N, Kumar NR, Francis M, Shanbagh S, Shetty R, Ghosh A, and Roy A. Correlation of Clinical and Biomechanical Outcomes of Accelerated Crosslinking (9 mW/cm in 10 minutes) in Keratoconus with Molecular Expression of Ectasia-Related Genes. Curr Eye Res. 2016. 41(11): 1419-23

7. Hagem AM, Thorsrud A, Sandvik GF, Raen M, and Drolsum L. Collagen crosslinking with conventional and accelerated ultraviolet-A irradiation using riboflavin with hydroxypropyl methylcellulose. J Cataract Refract Surg. 2017. 43(4):  511-517

8. Hashemi H, Asgari S, Mehravaran S, Miraftab M, Ghaffari R, and Fotouhi A. Corneal Biomechanics After Accelerated Cross-linking: Comparison Between 18 and 9 mW/cm2 Protocols. J Refract Surg. 2017. 33(8): 558-562

9. Ulusoy DM, Goktas E, Duru N, Ozkose A, Atas M, Yuvaci I, Arifoglu HB, and Zararsiz G. Accelerated corneal crosslinking for treatment of progressive keratoconus in pediatric patients. Eur J Ophthalmol. 2017: 27(3): 319-25 

10. Lang PZ, Hafezi NL, Khandelwal SS, Torres-Netto EA, Hafezi F, Randleman JB. Comparative Functional Outcomes After Corneal Crosslinking Using Standard, Accelerated, and Accelerated With Higher Total Fluence Protocols. Cornea. 2019. 38(4):  433-41. 

11. Akkaya S, Ulusoy DM, Duru Z, and Demirtas AA. Long-term Outcomes of Accelerated Corneal Cross-linking in the Treatment of Keratoconus: Comparison of Hypotonic Riboflavin Solution With Standard Riboflavin Solution. J Refract Surg. 2020. 36(2): 110-117

12. Kobashi H and Tsubota K. Accelerated Versus Standard Corneal Cross-Linking for Progressive Keratoconus: A Meta-Analysis of Randomized Controlled Trials. Cornea. 2019. 39(2): 172-80

13. Mazzotta C, Raiskup F, Hafezi F, Torres-Netto EA, Armia Balamoun A, Giannaccare G, Bagaglia SA. Long term results of accelerated 9 mW corneal crosslinking for early progressive keratoconus: the Siena Eye-Cross Study 2. Eye Vis (Lond). 2021. 8(1): 16

Keratoconus 3

  • Accelerated epi-off CXL protocol with 5 minutes irradiation time and standard fluence (5.4 J/cm2).
  • This protocol is most often used for the following indications:
    • Moderately progressive keratoconus in adults
    • Pellucid marginal degeneration
    • Ectasia after LASIK/PRK/SMILE

1. Gatzioufas Z, Richoz O, Brugnoli E, and Hafezi F. Safety profile of high-fluence corneal collagen cross-linking for progressive keratoconus: preliminary results from a prospective cohort study. J Refract Surg. 2013. 29(12): 846-8 

2. Alnawaiseh M, Rosentreter A, Bohm MR, Eveslage M, Eter N, and Zumhagen L. Accelerated (18 mW/cm2) Corneal Collagen Cross-Linking for Progressive Keratoconus. Cornea, 2015. 34(11): 1427-31

3. Hashemi H, Miraftab M, Seyedian MA, Hafezi F, Bahrmandy H, Heidarian S, Amanzadeh K, Nikbin H, Fotouhi A, Asgari S. Long-term Results of an Accelerated Corneal Cross-linking Protocol (18 mW/cm2) for the Treatment of Progressive Keratoconus. Am J Ophthalmol, 2015. 160(6): 1164-1170 e1 

4. Kymionis GD, Tsoulnaras KI, Liakopoulos DA, Skatharoudi CA, Grentzelos MA, Tsakalis NG. Corneal Stromal Demarcation Line Depth Following Standard and a Modified High Intensity Corneal Cross-linking Protocol. J Refract Surg, 2016. 32(4): 218-22 

5. Khairy HA, Elsawy MF, Said-Ahmed K, Zaki MA, Mandour SS. Accelerated versus standard corneal cross linking in the treatment of ectasia post refractive surgery and penetrating keratoplasty: a medium term randomized trial. Int J Ophthalmol, 2019. 12(11): 1714-19

6. Agca A, Tulu B, Yasa D, Kepez Yildiz B, Sucu ME, Genc S, Fazil K, Yildirim Y. Accelerated corneal crosslinking in children with keratoconus: 5-year results and comparison of 2 protocols. J Cataract Refract Surg. 2020. 46(4): 517-23

7. Kobashi H and Tsubota K. Accelerated Versus Standard Corneal Cross-Linking for Progressive Keratoconus: A Meta-Analysis of Randomized Controlled Trials. Cornea, 2019. 39(2): 172-80

8. Ozulken K, Aksoy Aydemir G, Aydemir E, Kiziltoprak H, Yuksel E. Comparison of Two Different Accelerated Corneal Cross-linking Procedures Outcomes in Patients with Keratoconus. Balkan Med J, 2020. 37(3): 131-37

Keratoconus 4

  • Accelerated and high-fluence epi-off CXL protocol (7.2 J/cm2).
  • This new protocol has been introduced to provide more stiffening effect than Protocol 02, especially in patients with more agressive forms of corneal ectasia.

1. Kang Y, Li S, Liu C, Xu M, Shi S, Liu Y. Accelerated Epithelium-off Corneal Cross-linking With High Ultraviolet Energy Dose (7.2 J/cm(2)) for Progressive Keratoconus: 2-Year Results in a Chinese Population. J Refract Surg. 2020. 36(11): 731-39

Keratoconus 5

  • Accelerated pulsed epi-off CXL protocol with standard fluence (5.4 J/cm2).
  • This protocol is most often used for the following Indications:
    • Moderately progressive keratoconus in adults
    • Pellucid marginal degeneration
    • Ectasia after LASIK/PRK/SMILE

Krueger RR, Herekar S, and Spoerl E. First proposed efficacy study of high versus standard irradiance and fractionated riboflavin/ultraviolet a cross-linking with equivalent energy exposure. Eye Contact Lens, 2014. 40(6): 353-7 

Keratoconus 6

  • Accelerated pulsed epi-on CXL protocol with high fluence (7.0 J/cm2).
  • This protocol is most often used for the following indications: :
    • Progressive keratoconus in adults
    • Pellucid marginal degeneration

1. Mazzotta C, Bagaglia SA, Vinciguerra R, Ferrise M, and Vinciguerra P. Enhanced-Fluence Pulsed-Light Iontophoresis Corneal Cross-linking: 1-Year Morphological and Clinical Results. J Refract Surg, 2018. 34(7):  438-44

2. Mazzotta C, Wollensak G, Raiskup F, Pandolfi AM, Spoerl E. The meaning of the demarcation line after riboflavin-UVA corneal collagen crosslinking. Expert Review of Ophthalmology. 2019. 14(2): 115-31

3. Mazzotta C, Bagaglia SA, Sgheri A, Di Maggio A, Fruschelli M, Romani A, Vinciguerra R, Vinciguerra P, Tosi GM. Iontophoresis Corneal Cross-linking With Enhanced Fluence and Pulsed UV-A Light: 3-Year Clinical Results. J Refract Surg, 2020. 36(5): 286-292

Keratoconus 7

  • Accelerated pulsed epi-on CXL protocol with high fluence (7.0 J/cm2).
  • This protocol is most often used for the following indications: :
    • Progressive keratoconus in adults
    • Pellucid marginal degeneration

1. 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 

2. 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

3. Belviranli S, Oltulu R. Efficacy of pulsed-light accelerated crosslinking in the treatment of progressive keratoconus: Two-year results. Eur J Ophthalmol. 2020:  30(6): 1256-60

Keratoconus 8

  • The «sub400» protocol can be used to treat thin and ultrathin corneas.
  • This protocol can be used for the following indications:
    • Keratoconus
    • Postoperative ectasia
    • PMD
    • Keratoglobus
    • Terrien Marginal Degeneration (TMD)

1. Hafezi F, Gatzioufas Z, Seiler TG, Seiler T. Corneal collagen cross-linking for Terrien marginal degeneration. J Refract Surg. 2014. 30(7): 498-500

2. Richoz O, Tabibian D, Hammer A, Majo F, Nicolas M, Hafezi F. The effect of standard and high-fluence corneal cross-linking (CXL) on cornea and limbus. Invest Ophthalmol Vis Sci. 2014. 55(9): 5783-7

3. Kling S, Hafezi F. An Algorithm to Predict the Biomechanical Stiffening Effect in Corneal Cross-linking. J Refract Surg. 2017. 33(2): 128-36

4. Hafezi F, Kling S, Gilardoni F, Hafezi N, Hillen M, Abrishamchi R, Gomes JAP, Mazzotta C, Randleman JB, Torres-Netto EA. Individualized Corneal Cross-linking With Riboflavin and UV-A in Ultrathin Corneas: The Sub400 Protocol. Am J Ophthalmol. 2021. 224: 133-42

Keratitis 1

  • Accelerated high-fluence PACK-CXL protocol with high fluence (7.2 J/cm2).
  • This protocol is currently most often used in:
    • Infectious keratitis of bacterial and fungal origin
    • Sterile corneal melting
    • Other uses include CXL applications for the treatment of ectasia.

1. 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 

2. 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 

3. Ozgurhan EB, Kara N, Cankaya KI, Kurt T, and Demirok A. Accelerated corneal cross-linking in pediatric patients with keratoconus: 24-month outcomes. J Refract Surg. 2014. 30(12): 843-9 

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

5. 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

6. 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

7. Knyazer B, Krakauer Y, Baumfeld Y, Lifshitz T, Kling S, Hafezi F. Accelerated Corneal Cross-Linking With Photoactivated Chromophore for Moderate Therapy-Resistant Infectious Keratitis. Cornea. 2018. 37(4): 528-31

8. Lang PZ, Hafezi NL, Khandelwal SS, Torres-Netto EA, Hafezi F, Randleman JB. Comparative Functional Outcomes After Corneal Crosslinking Using Standard, Accelerated, and Accelerated With Higher Total Fluence Protocols. Cornea. 2019. 38(4):  433-41 

9. Salah Y, Omar K, Sherif A, Azzam S. Study of Demarcation Line Depth in Transepithelial versus Epithelium-Off Accelerated Cross-Linking (AXL) in Keratoconus. J Ophthalmol. 2019. 2019: 3904565

10. Agca A, Tulu B, Yasa D, Kepez Yildiz B, Sucu ME, Genc S, Fazil K, Yildirim Y. Accelerated corneal crosslinking in children with keratoconus: 5-year results and comparison of 2 protocols. J Cataract Refract Surg. 2020. 46(4): 517-23

11. Kling S, Hufschmid FS, Torres-Netto EA, Randleman JB, Willcox M, Zbinden R, Hafezi F. High Fluence Increases the Antibacterial Efficacy of PACK Cross-Linking. Cornea. 2020. 39(8): 1020-26

Keratitis 2

  • Accelerated high-fluence PACK-CXL protocol with high fluence (10.0 J/cm2).
    • Recent evidence shows that the corneal endothelium is more resistant to UV-A irradiation than previously assumed, especially in a less transparent keratitis cornea.
    • Infectious keratitis of bacterial and fungal origin
    • Sterile corneal melting

1. Seiler TG, Batista A, Frueh BE, Koenig K. Riboflavin Concentrations at the Endothelium During Corneal Cross-Linking in Humans. Invest Ophthalmol Vis Sci. 2019. 60(6): 2140-45

2. Kling S, Hufschmid FS, Torres-Netto EA, Randleman JB, Willcox M, Zbinden R, Hafezi F. High Fluence Increases the Antibacterial Efficacy of PACK Cross-Linking. Cornea. 2020. 39(8): 1020-26

3. Li M, Yu T, Gao X, Wu XY. Accelerated corneal collagen cross-linking in clinical management of infectious keratitis. J Int Med Res. 2020. 48(6): 300060520926411

Refractive 1

  • High-intensity low-fluence accelerated CXL
  •  Indications include:
    • LASIK Xtra
    • SMILE Xtra
    • PRK Xtra

1. Ganesh S, Brar S. Clinical Outcomes of Small Incision Lenticule Extraction with Accelerated Cross-Linking (ReLEx SMILE Xtra) in Patients with Thin Corneas and Borderline Topography. J Ophthalmol. 2015. 2015: 263412

2. Kanellopoulos AJ, Asimellis G, Salvador-Culla B, Chodosh J, Ciolino JB. High-irradiance CXL combined with myopic LASIK: flap and residual stroma biomechanical properties studied ex-vivo. Br J Ophthalmol. 2015. 99(6): 870-4

3. Ng AL, Kwok PS, Wu RT, Jhanji V, Woo VC, Chan TC. Comparison of the Demarcation Line on ASOCT After Simultaneous LASIK and Different Protocols of Accelerated Collagen Crosslinking: A Bilateral Eye Randomized Study. Cornea. 2017. 36(1): 74-77

4. Randleman JB, Su JP, Scarcelli G. Biomechanical Changes After LASIK Flap Creation Combined With Rapid Cross-Linking Measured With Brillouin Microscopy. J Refract Surg. 2017. 33(6): 408-14

5. Lim EWL, Lim L. Review of Laser Vision Correction (LASIK, PRK and SMILE) with Simultaneous Accelerated Corneal Crosslinking – Long-term Results. Curr Eye Res. 2019. 44(11): 1171-80

6. Osman IM, Helaly HA, Abou Shousha M, AbouSamra A, Ahmed I. Corneal Safety and Stability in Cases of Small Incision Lenticule Extraction with Collagen Cross-Linking (SMILE Xtra). J Ophthalmol. 2019. 2019: 6808062

7. Kohnen T, Lwowski C, Hemkeppler E, de’Lorenzo N, Petermann K, Forster R, Herzog M, Bohm M. Comparison of Femto-LASIK With Combined Accelerated Cross-linking to Femto-LASIK in High Myopic Eyes: A Prospective Randomized Trial. Am J Ophthalmol. 2020. 211: 42-55

Protocolo 2

  • Accelerated epi-off CXL protocol with 10 minutes irradiation time and standard fluence (5.4 J/cm2).
  • This protocol is most often used for the following indications:
    • Moderately progressive keratoconus in adults
    • Pellucid marginal degeneration
    • Ectasia after LASIK/PRK/SMILE

1. Lang PZ, Hafezi NL, Khandelwal SS, Torres-Netto EA, Hafezi F, and Randleman JB, Comparative Functional Outcomes After Corneal Crosslinking Using Standard, Accelerated, and Accelerated With Higher Total Fluence Protocols. Cornea, 2019. 38(4): p. 433-441. 

2. Richoz O, Hammer A, Tabibian D, Gatzioufas Z, and Hafezi F, The Biomechanical Effect of Corneal Collagen Cross-Linking (CXL) With Riboflavin and UV-A is Oxygen Dependent. Transl Vis Sci Technol, 2013. 2(7): p. 6. 

3. Hammer A, Richoz O, Mosquera S, Tabibian D, Hoogewoud F, and Hafezi F, Corneal biomechanical properties at different corneal collagen cross-linking (CXL) Irradiances. Invest Ophthalmol Vis Sci, 2014. 55(5): p. 2881-4. 

4. Kymionis GD, Tsoulnaras KI, Grentzelos MA, Plaka AD, Mikropoulos DG, Liakopoulos DA, Tsakalis NG, and Pallikaris IG, Corneal stroma demarcation line after standard and high-intensity collagen crosslinking determined with anterior segment optical coherence tomography. J Cataract Refract Surg, 2014. 

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

6. Marino GK, Torricelli AA, Giacomin N, Santhiago MR, Espindola R, and Netto MV, Accelerated Corneal Collagen Cross-linking for Postoperative LASIK Ectasia: Two-Year Outcomes. J Refract Surg, 2015. 31(6): p. 380-4. 

7. Pahuja N, Kumar NR, Francis M, Shanbagh S, Shetty R, Ghosh A, and Roy AS, Correlation of Clinical and Biomechanical Outcomes of Accelerated Crosslinking (9 mW/cm in 10 minutes) in Keratoconus with Molecular Expression of Ectasia-Related Genes. Curr Eye Res, 2016: p. 1-5. 

8. Ulusoy DM, Goktas E, Duru N, Ozkose A, Atas M, Yuvaci I, Arifoglu HB, and Zararsiz G, Accelerated corneal crosslinking for treatment of progressive keratoconus in pediatric patients. Eur J Ophthalmol, 2016: p. 0. 

9. Hagem AM, Thorsrud A, Sandvik GF, Raen M, and Drolsum L, Collagen crosslinking with conventional and accelerated ultraviolet-A irradiation using riboflavin with hydroxypropyl methylcellulose. J Cataract Refract Surg, 2017. 43(4): p. 511-517. 

10. Hashemi H, Asgari S, Mehravaran S, Miraftab M, Ghaffari R, and Fotouhi A, Corneal Biomechanics After Accelerated Cross-linking: Comparison Between 18 and 9 mW/cm2 Protocols. J Refract Surg, 2017. 33(8): p. 558-562. 

11. Kobashi H and Tsubota K, Accelerated Versus Standard Corneal Cross-Linking for Progressive Keratoconus: A Meta-Analysis of Randomized Controlled Trials. Cornea, 2019.

12. Akkaya S, Ulusoy DM, Duru Z, and Demirtas AA, Long-term Outcomes of Accelerated Corneal Cross-linking in the Treatment of Keratoconus: Comparison of Hypotonic Riboflavin Solution With Standard Riboflavin Solution. J Refract Surg, 2020. 36(2): p. 110-117. 

13. Ozulken K, Aksoy Aydemir G, Aydemir E, Kiziltoprak H, and Yuksel E, Comparison of Two Different Accelerated Corneal Cross-linking Procedures Outcomes in Patients with Keratoconus. Balkan Med J, 2020. 

Protocolo 3

  • Accelerated epi-off CXL protocol with 5 minutes irradiation time and standard fluence (5.4 J/cm2).
  • This protocol is most often used for the following indications:
    • Moderately progressive keratoconus in adults
    • Pellucid marginal degeneration
    • Ectasia after LASIK/PRK/SMILE

1. Kobashi H and Tsubota K, Accelerated Versus Standard Corneal Cross-Linking for Progressive Keratoconus: A Meta-Analysis of Randomized Controlled Trials. Cornea, 2019.

2. Khairy HA, Elsawy MF, Said-Ahmed K, Zaki MA, and Mandour SS, Accelerated versus standard corneal cross linking in the treatment of ectasia post refractive surgery and penetrating keratoplasty: a medium term randomized trial. Int J Ophthalmol, 2019. 12(11): p. 1714-1719. 

3. Ozulken K, Aksoy Aydemir G, Aydemir E, Kiziltoprak H, and Yuksel E, Comparison of Two Different Accelerated Corneal Cross-linking Procedures Outcomes in Patients with Keratoconus. Balkan Med J, 2020. 

4. Gatzioufas Z, Richoz O, Brugnoli E, and Hafezi F, Safety profile of high-fluence corneal collagen cross-linking for progressive keratoconus: preliminary results from a prospective cohort study. J Refract Surg, 2013. 29(12): p. 846-8. 

5. Alnawaiseh M, Rosentreter A, Bohm MR, Eveslage M, Eter N, and Zumhagen L, Accelerated (18 mW/cm2) Corneal Collagen Cross-Linking for Progressive Keratoconus. Cornea, 2015. 

6. Hashemi H, Miraftab M, Seyedian MA, Hafezi F, Bahrmandy H, Heidarian S, Amanzadeh K, Nikbin H, Fotouhi A, and Asgari S, Long-term Results of an Accelerated Corneal Cross-linking Protocol (18 mW/cm2) for the Treatment of Progressive Keratoconus. Am J Ophthalmol, 2015. 160(6): p. 1164-1170 e1. 

7. Kymionis GD, Tsoulnaras KI, Liakopoulos DA, Skatharoudi CA, Grentzelos MA, and Tsakalis NG, Corneal Stromal Demarcation Line Depth Following Standard and a Modified High Intensity Corneal Cross-linking Protocol. J Refract Surg, 2016. 32(4): p. 218-22. 

Protocolo 4

  • Accelerated high-fluence PACK-CXL protocol with high fluence (7.2 J/cm2).
  • This protocol is currently used in:
    • Infectious keratitis of bacterial and fungal origin
    • Sterile corneal melting

1. Lang PZ, Hafezi NL, Khandelwal SS, Torres-Netto EA, Hafezi F, and Randleman JB, Comparative Functional Outcomes After Corneal Crosslinking Using Standard, Accelerated, and Accelerated With Higher Total Fluence Protocols. Cornea, 2019. 38(4): p. 433-441. 

2. Mazzotta C, Traversi C, Caragiuli S, and 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): p. 1179-83. 

3. Mazzotta C, Traversi C, Paradiso AL, Latronico ME, and Rechichi M, Pulsed Light Accelerated Crosslinking versus Continuous Light Accelerated Crosslinking: One-Year Results. J Ophthalmol, 2014. 2014: p. 604731. 

4. Ozgurhan EB, Kara N, Cankaya KI, Kurt T, and Demirok A, Accelerated corneal cross-linking in pediatric patients with keratoconus: 24-month outcomes. J Refract Surg, 2014. 30(12): p. 843-9. 

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

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

7. Peyman A, Nouralishahi A, Hafezi F, Kling S, and Peyman M, Stromal Demarcation Line in Pulsed Versus Continuous Light Accelerated Corneal Cross-linking for Keratoconus. J Refract Surg, 2016. 32(3): p. 206-208. 

8. Knyazer B, Krakauer Y, Baumfeld Y, Lifshitz T, Kling S, and Hafezi F, Accelerated Corneal Cross-Linking With Photoactivated Chromophore for Moderate Therapy-Resistant Infectious Keratitis. Cornea, 2018. 37(4): p. 528-531. 

9. Salah Y, Omar K, Sherif A, and Azzam S, Study of Demarcation Line Depth in Transepithelial versus Epithelium-Off Accelerated Cross-Linking (AXL) in Keratoconus. J Ophthalmol, 2019. 2019: p. 3904565. 

Protocolo 5

  • Accelerated pulsed epi-off CXL protocol with standard fluence (5.4 J/cm2).
  • This protocol is most often used for the following Indications:
    • Moderately progressive keratoconus in adults
    • Pellucid marginal degeneration
    • Ectasia after LASIK/PRK/SMILE

Krueger RR, Herekar S, and Spoerl E, First proposed efficacy study of high versus standard irradiance and fractionated riboflavin/ultraviolet a cross-linking with equivalent energy exposure. Eye Contact Lens, 2014. 40(6): p. 353-7. 

Protocolo 6

  • Accelerated pulsed epi-on CXL protocol with high fluence (7.2 J/cm2).
  • This protocol is most often used for the following indications: :
    • Progressive keratoconus in adults
    • Pellucid marginal degeneration

1. Mazzotta C, Bagaglia SA, Vinciguerra R, Ferrise M, and Vinciguerra P, Enhanced-Fluence Pulsed-Light Iontophoresis Corneal Cross-linking: 1-Year Morphological and Clinical Results. J Refract Surg, 2018. 34(7): p. 438-444. 

2. Mazzotta C, Bagaglia SA, Sgheri A, Di Maggio A, Fruschelli M, Romani A, Vinciguerra R, Vinciguerra P, and Tosi GM, Iontophoresis Corneal Cross-linking With Enhanced Fluence and Pulsed UV-A Light: 3-Year Clinical Results. J Refract Surg, 2020. 36(5): p. 286-292. 

Protocol 7

  • Accelerated pulsed epi-on CXL protocol with high fluence (7.0 J/cm2).
  • This protocol is most often used for the following indications: :
    • Progressive keratoconus in adults
    • Pellucid marginal degeneration

1. Mazzotta C, Traversi C, Paradiso AL, Latronico ME, and Rechichi M, Pulsed Light Accelerated Crosslinking versus Continuous Light Accelerated Crosslinking: One-Year Results. J Ophthalmol, 2014. 2014: p. 604731. 

2. Mazzotta C, Traversi C, Caragiuli S, and 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): p. 1179-83. 

3. Belviranli S and Oltulu R, Efficacy of pulsed-light accelerated crosslinking in the treatment of progressive keratoconus: Two-year results. Eur J Ophthalmol, 2019: p. 1120672119872375. 

Protocolo 1

  • The so-called «Dresden protocol» is the original epi-off CXL protocol that started corneal cross-linking in 1999.
  • The «Dresden protocol» currently (2020) represents the benchmark in terms of biomechanical stiffness effect in CXL
  • This protocol is most often used for the following Indications when the strongest biomechanical effect is needed:
    • Aggressive progression of keratoconus
    • Keratoconus in children and adolescents
    • Pellucid marginal degeneration
    • Ectasia after LASIK/PRK/SMILE
    • Bullous keratopathy
    • Sterile corneal melting

1. Wollensak G, Spoerl E, and Seiler T, Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol, 2003. 135(5): p. 620-7. 

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

3. Spoerl E, Wollensak G, and Seiler T, Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res, 2004. 29(1): p. 35-40. 

4. Spoerl E, Mrochen M, Sliney D, Trokel S, and Seiler T, Safety of UVA-riboflavin cross-linking of the cornea. Cornea, 2007. 26(4): p. 385-9. 

5. Mackool RJ, Crosslinking for iatrogenic keratectasia after LASIK and for keratoconus. Journal of cataract and refractive surgery, 2008. 34(6): p. 879; author reply 879. 

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

7. Koller T, Mrochen M, and Seiler T, Complication and failure rates after corneal crosslinking. J Cataract Refract Surg, 2009. 35(8): p. 1358-62. 

8. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T, Denaro R, and Balestrazzi A, Riboflavin-UVA-induced corneal collagen cross-linking in pediatric patients. Cornea, 2012. 31(3): p. 227-31. 

9. Chatzis N and Hafezi F, Progression of Keratoconus and Efficacy of Corneal Collagen Cross-linking in Children and Adolescents. J Refract Surg, 2012. 28(11): p. 753-8. 

10. Raiskup F and Spoerl E, Corneal crosslinking with riboflavin and ultraviolet A. I. Principles. Ocul Surf, 2013. 11(2): p. 65-74. 

11. Raiskup F, Theuring A, Pillunat LE, and Spoerl E, Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. J Cataract Refract Surg, 2015. 41(1): p. 41-6. 

12. Khairy HA, Elsawy MF, Said-Ahmed K, Zaki MA, and Mandour SS, Accelerated versus standard corneal cross linking in the treatment of ectasia post refractive surgery and penetrating keratoplasty: a medium term randomized trial. Int J Ophthalmol, 2019. 12(11): p. 1714-1719. 

13. Lang PZ, Hafezi NL, Khandelwal SS, Torres-Netto EA, Hafezi F, and Randleman JB, Comparative Functional Outcomes After Corneal Crosslinking Using Standard, Accelerated, and Accelerated With Higher Total Fluence Protocols. Cornea, 2019. 38(4): p. 433-441.