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Protokół nr 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. 

Protokół nr 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. 

Protokół nr 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. 

Protokół nr 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. 

Protokół nr 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. 

Protokół nr 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 (7.2 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.