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

CXL optimization

Goal:

Shorter treatment time More effective CXL

UV intensity

Optimized beam profile

Local riboflavin concentration

Additionalsubstances

Purpose

Stop keratoconus progression by increasing corneal strength

Relative portion cross-linked determines overall strength

Cross-linking larger corneal tissue volume

How to maximize cross-linked volume?

Goal:

More effective CXL

Gregor Wollensak, Eberhard Spoerl, Theo SeilerStress-strain measurements of human and porcine corneas after riboflavin–ultraviolet-A-induced cross-linkingJournal of cataract and refractive surgery, 2003

Higher overall strength Lower overall strength

Demarcation line 1 month after CXL with UV-X 1000

Courtesy of T. Seiler

Demarcation line 1 month after CXL with VEGA CBM X-linker

Doors et al.Use of Anterior Segment Optical CoherenceTomography to Study Corneal Changes AfterCollagen Cross-linking.Am J Ophthalmol, 2009

Corneal thickness profile

Ambrósio R, Alonso R, Luz A. Corneal-thickness spatial profile and corneal-volume distribution: Tomographic indices to detect keratoconus. J Cataract Refract Surg 2006

Normal eyesCentral: 540 µm3.5 mm: + 30 µm5 mm: + 50 µm

Keratoconic eyesCentral: 430 µm3.5 mm: + 70 µm5 mm: + 110 µm

3.5 mm: + 50 µm

Average corneal thickness

0

100

200

300

400

500

600

700

800

0 1 2 3 4 5 6 7 8 9

Distance to thinnest point (mm)

Co

rnea

l th

ickn

ess

(um

)

Normal eyes Keratoconus eyes

450

470

490

510

530

550

570

590

610

3 3.5 4 4.5 5 5.5

Cross-linking depth

Gregor Wollensak, Eberhard Spoerl, Michaela Wilsch, and Theo SeilerKeratocyte Apoptosis After Corneal Collagen Cross-linking Using Riboflavin/UVA TreatmentCornea 2004

50 µm deeper CXL 30% higher intensity

Maximize cross-linking volume

Effect parallel to posterior corneal surface Effect parallel to anterior corneal surface

Optimized beam profile

Peripheral intensity 30% higher than ENERGY DOSE (not intensity)

=Increased biomechanical strengthening of the cornea

=improved corneal flattening

High intensity CXLBunsen 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

3mW/cm2

30 min 10 min

9mW/cm2 30mW/cm2

3 min

90mW/cm2

1 min

Same CXL effect in theory…really?

VISION - OPTICS - LIGHT we focus your ideas!

Reduced effect at higher intensities

CXL Process

UV - light

RiboflavinOxygen

10 mW/cm230 mW/cm2

High levels of peroxide might occur

Hypoxia?

Pulsed mode

UV - light

RiboflavinOxygen

Pulsed mode might result in longer treatment time or less effect

No clinical data available

Epithelium on vs. epithelium off-an ongoing controversy?

Epi-Off vs. Epi-On CXLEpi-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)

The problemEpi-Off CXL• During standard DRESDEN

protocol for CXL, the corneal epithelium is mechanically removed after surface anesthesia and prior to riboflavin application.

Epi-On CXL• 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.

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

Diffusion Findings

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

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.

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.

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; 38:283–291Touboul 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.

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