cornea, cross linking, trans epithelium, riboflavin, high intensity, short treatment time, clinical results, Theo Seiler, Eberhard Spoerl, Arthur Cummings, Michael Mrochen

1. Higher fluence, irradiation
profiles, epi-on
Michael Mrochen, PhD

2. CXL optimization
Goal:
Shorter treatment time
UV
intensity
Local riboflavin
concentration
More effective CXL
Additional
substances
Optimized
beam profile

3. Goal:
Purpose
More effective CXL
Stop keratoconus progression by
increasing corneal strength
Relative portion cross-linked
determines overall strength
Cross-linking larger corneal tissue
volume

5. Corneal thickness profile
Normal eyes
Central: 540 µm
3.5 mm: + 30 µm
5 mm: + 50 µm
Average corneal thickness
800
Corneal thickness (um)
700
600
500
400
610
300
590
Keratoconic eyes
Central: 430 µm
3.5 mm: + 70 µm
5 mm: + 110 µm
200
570
100
550
0
0
1
2
3
4
5
6
7
8
9
530
Distance to thinnest point (mm)
510
Normal eyes
Keratoconus eyes
490
470
450
3
3.5
4
4.5
5
5.5
Ambrósio R, Alonso R, Luz A.
Corneal-thickness spatial profile and corneal-volume distribution: Tomographic indices to detect keratoconus.
J Cataract Refract Surg 2006
 3.5 mm: + 50 µm

6. Cross-linking depth
50 µm deeper CXL 
30% higher intensity
Gregor Wollensak, Eberhard Spoerl, Michaela Wilsch, and Theo Seiler
Keratocyte Apoptosis After Corneal Collagen Cross-linking Using Riboflavin/UVA Treatment
Cornea 2004

7. Maximize cross-linking volume

8. Optimized beam profile

9. High intensity CXL
Bunsen reciprocity law:
Photochemical processes depend
on the absorbed energy dose
Energy dose:
Energy dose = Intensity x Time
Energy dose of standard protocol:
3 mW/cm2 x 30 min = 5.4 J/cm2
Same CXL effect in theory…really?
30 min
3mW/cm2
10 min
9mW/cm2
3 min
30mW/cm2
1 min
90mW/cm2

10. Reduced effect at higher intensities
VISION - OPTICS - LIGHT
we focus your ideas!

11. CXL Process
10 mW/cm2
30 mW/cm2
UV - light
Riboflavin
Oxygen
Hypoxia?
High levels of
peroxide might occur

12. Pulsed mode
UV - light
Riboflavin
Oxygen
No clinical
data available
Pulsed mode might result in longer treatment time or less effect

13. Epithelium on vs. epithelium off
-an ongoing controversy?

14. Epi-Off vs. Epi-On CXL
Epi-Off CXL
• Established surgical
procedure
• Long term data showing
stabilization
• New CXL applications
continually advancing:
Shorter treatment time etc.
Epi-On CXL
• Less painful for patient
• Reduced risk of infection
• Suitable for thinner corneas
(˂
400µm)

15. The problem
Epi-Off CXL
Epi-On CXL
• During standard DRESDEN
protocol for CXL, the corneal
epithelium is mechanically
removed after surface
anesthesia and prior to riboflavin
application.
• The intact corneal
epithelium, with its tight
junctions, is considered the most
significant barrier to riboflavin
permeability resulting in less
effective riboflavin diffusion
Baiocchi S, Mazzotta C, Cerretani D, Caporossi T, CaporossiA.
Corneal crosslinking: riboflavin concentration in corneal stroma
exposed with and without epithelium. J Cataract Refract Surg.
2009;35:893–899
Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue.
Exp Eye Res. 1998;66:97–103.

16. Possible solutions
Modified formulations:
• Benzalkonium chloride
(BAC)
• Tetracaine, pilocarpinecare
• EDTA
• Ribomycin drops containing
gentamycin,
• EDTA and BAC with
Oxybuprocaine drops
Modified applications
• Iontophoresis
• Micro-needle injections
• FS – laser pockets

17. Diffusion Findings
Frederik Raiskup1, Roberto Pinelli2, and Eberhard Spoerl1 Current Eye Research, 37(3), 234–238, 2012

18. Review Of Epi-On Cases
In-Vitro Studies:
• 20% biomechanical effect compared to Epi-Off
• Reduction in riboflavin absorption without epithelial
debridement
Wollensak G, Iomdina E. Biomechanical and histological changes after corneal
crosslinking with and without epithelial debridement. J Cataract Refract Surg.
2009;35:540-546.
Baiocchi S, Mazzotta C, Cerretani D ,Caporossi T, Caporossi A. Corneal Cross-Linking:
riboflavin concentration in corneal stroma exposed with and without epithelium. J
Cataract Refract Surg. 2009;35:893-899.

19. Clinical findings Epi-on
Caporossi et al. Transepithelial corneal collagen crosslinking for progressive keratoconus:
24-month clinical results. J Cataract Refract Surg 2013; 39: 1157-1163.

20. Trans-epithelium results
In-Vivo Studies:
•
Improvement in corneal curvature at 3 and 6 months post-op
•
Stability ONLY up to 12 months
•
Increase in K-max from baseline and loss of UDVA in 12-24 months
•
No modifications to corneal morphology after treatment under confocal microscope
Caporossi A, Mazzotta C, Paradiso AL, Baiocchi S, Marigliani D, Caporossi T. Transepithelial corneal collagen crosslinking for progressive
keratoconus: 24-month clinical results. J Cataract Refract Surg. 2013 ;39:1157-63.
Transepithelial corneal collagen crosslinking: Bilateral study Massimo Filippello, MD, PhD, Edoardo Stagni, MD, David
O’Brart, MD, FRCS, FRCOphth. J Cataract Refract Surg 2012; 38:283–291
Touboul D, Efron N, Smada D, Praud D, Malet F, Colin J. Corneal confocal microscopy following conventional, transepithelial, and
acceleratedcorneal collagen cross-linking procedures for keratoconus.

21. Summary
• 2nd generation beam profiles allow a large
volume CXL
• Limitations of high intensity CXL need to be
understood
• Trans-Epi CXL has not shown to be effective