Results INTRA PROTOCOL ANALYSIS

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1 Results INTRA PROTOCOL ANALYSIS

0.35 0.3 BCVA logmar Pre op Post op 6m Post op 1y 0.25 0.2 0.15 0.1 0.05 0.3 0.21 0.17 0.15 0.2 0.17 0.15 0.16 0.22 0.21 0 0.18 0.13 0.14 0.15 0.2 3/30 9/10 18/5 30/3 TE p=0.

2 BCVA logmar Pre op Post op 6m Post op 1y /30 9/10 18/5 30/3 TE p=0.13 p=0.4 p=0.14 p=0.96 p=0.51 BCVA improved in all groups, but this improvement was not statistically significant from baseline

3 Spherical equivalent /30 9/10 18/5 30/3 TE p=0.57 p=0.14 p=0.17 Pre op Post op 6m Post op 1y p=0.67 p=0.44 SE decreased in all groups, but this decrease was not statistically significant from baseline

4 Thinnest pachymetry /30 9/10 18/5 30/3 TE Pre op Post op 6m Post op 1y P <0.01 P< 0.01 p=0.21 p= 0.5 p=0.31 Thinnest pachymetry reduced in all groups and the change from baseline to 1 year was statistically significant only in Group 1 and 2

52 51 50 49 48 47 46 45 44 43 42 Flat Keratometry 50.82 51.13 50.85 45.44 45.25 45.76 45.42 46.17 46.06 46.3 45.52 46.02 45.59 45.74 46.

5 Flat Keratometry /30 9/10 18/5 30/3 TE Pre op Post op 6m Post op 1y p=0.29 p=0.35 p=0.78 p=0.88 p=0.85 K1 flattened in all groups, but this flattening from baseline to 1 year was not statistically significant

Steep Keratometry 56 55 54 53 52 51 50 49 48 47 46 54.48 54.9 50.6 49.35 49.8 54.5 49.03 49.71 49.31 50 49.7 49.38 49.63 49.55 49.

6 Steep Keratometry /30 9/10 18/5 30/3 TE Pre op Post op 6m Post op 1y P = 0.25 p=0.49 p=0.76 p=0.88 p=0.73 K2 flattened in all groups, but this flattening was not statistically different from baseline to 1 year

7 Endothelial count /30 9/10 18/5 30/3 TE Pre op Post op 6m Post op 1y p=0.04 p=0.04 p=0.054 p=0.01 p=0.01 Endothelial count decreased in all groups, but this reduction was not statistically significant from baseline

Corneal densitometry 30 25 20 15 10 5 24.34 24.7 22.61 21.64 21.46 19.08 21.01 19.57 18.

39 Pre op Post op 6m Post op 1y 0 3 for 30 9 for 10 18 for 5 30 for 3 TE p < 0.05 p = 0.

8 Corneal densitometry Pre op Post op 6m Post op 1y 0 3 for 30 9 for for 5 30 for 3 TE p < 0.05 p = 0.01 p = 0.14 p = 0.02 p = 0.74 Change in Corneal densitometry was statistically different from baseline only in 3 for 30 (CXL) and 9 for 10 mins (ACXL) group.

9 Cornea.2013 May;32(5): Clinical Ophthalmology 2014: Transient haze was noted in 71% of the accelerated CXL cases and in 91% of the conventional CXL ACXL shows comparable results with conventional CXL in arresting the progression of KC

20% DEXTRAN (Vibex TM ) Polyglucose biopolymers Abundant hydrophilic hydroxyl groups---- >High affinity for water Viscosity---- > maintains a film of riboflavin to act as a

85% HPMC (Hydroxyl Propyl MethylCellulose) (Vibex Rapid TM, Vibex TM ) Alternative to dextran Water soluble viscoelastic polymer Faster diffusion of riboflavin.

10 20% DEXTRAN (Vibex TM ) Polyglucose biopolymers Abundant hydrophilic hydroxyl groups---- >High affinity for water Viscosity---- > maintains a film of riboflavin to act as a reservoir during the soak. Dehydrate and thin the cornea Draws water out of cornea Slows diffusion of riboflavin Extended soak time 0.85% HPMC (Hydroxyl Propyl MethylCellulose) (Vibex Rapid TM, Vibex TM ) Alternative to dextran Water soluble viscoelastic polymer Faster diffusion of riboflavin. The diffusivity of a 0.1% riboflavin and HPMC formulation (VibeX Rapid) is twice that of a 0.1% riboflavin formulation containing dextran (VibeX). The length of time required to reach a steady state concentration in the corneal stroma is reduced by half.

BENZALKONIUM CHLORIDE {BAC} (Paracel, Mediocross TE) Enhances epithelial-permeability Opens the epithelial tight junctions Impact of BAK - duration and concentration dependent.

11 BENZALKONIUM CHLORIDE {BAC} (Paracel, Mediocross TE) Enhances epithelial-permeability Opens the epithelial tight junctions Impact of BAK - duration and concentration dependent. Once the epithelial junctions have been sufficiently loosened, 0.25% riboflavin and saline may be used for rest of the procedure This reduces the duration of epithelial exposure to BAK. SALINE (Vibex Xtra TM ) Riboflavin 0.25% with NaCl TEKXL 1 st formulation - breach the corneal epithelium. ParaCel, a dextran-free, hypo-osmolar, 0.25% riboflavin 5 -phosphate containing epithelial-permeability enhancing agents including BAK 2 nd formulation - of 0.25% riboflavin and saline without permeability enhancers

Introduction Corneal collagen cross-linking (CXL) halts progression of keratoconus Accelerated cross linking (ACXL) aims To reduce patient discomfort To achieve more effective time management To

12 Introduction Corneal collagen cross-linking (CXL) halts progression of keratoconus Accelerated cross linking (ACXL) aims To reduce patient discomfort To achieve more effective time management To avoid the excessive corneal dehydration and thinning Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006; 17: Accelerated versus conventional corneal collagen cross-linking in the treatment of mild keratoconus: a comparative study. Clinical Ophthalmology 2014:

13 Riboflavin solutions MEDIO CROSS D 0.1% riboflavin solution with 20% Dextran (isotonic) 3,0ml: the standard solution for CXL. Epi-off 20min soak MedioCross TE CE TransEpithelial Solution MedioCross M 0.1% riboflavin solution with 1.1% HPMC Without Dextran MedioCross H Hypotonic Riboflavin Solution For Corneal Swelling (Thin corneas) MedioCross L 0.23% Riboflavin solution for LASIK and PRK

14 Transepithelial Riboflavin formulation Ricrolin TE (Sooft,Italy) Transepithelial Crosslinking Riboflavin Formulations Formulation composition 0.1% riboflavin-5-phosphate, 15% dextran T500, sodium edetate, trometamol, and NaCl UVA delivery device UV-X 1000, IROC Innocross, Switzerland Iontophoresis N/A Medio-cross (Peschke Meditrade GmbH, Germany) 0.25% riboflavin-5-phosphate hydroxypropyl methylcellulose, benzalkonium chloride, NaCl UV-X 1000, IROC Innocross, Switzerland N/A ParaCel (Avedor Inc, USA) Ricrolin+ (Sooft,Italy) VibeX Xtra (Avedro Inc, USA) 0.25% riboflavin-5-phosphate, hydroxypropyl methylcellulose, sodium edetate, trometamol, benzalkonium chloride, NaCL 0.1% riboflavin-5-phosphate, sodium edetate, trometamol, sodium dihydrogen phosphate dihydrate, and sodium phosphate dibasic dehydrate KXL, Avedro Inc., USA KXL, Avedro Inc., USA N/A I-ON CXL generator (Sooft, Italy) 0.25% riboflavin-5-phosphate and NaCl KXL, Avedro Inc., USA N/A

15 Transepithelial Crosslinking Comparing protocols Impact of various transepithelial protocols on corneal epithelium in regard to pain and epithelial integrity in the early postoperative period has been studied* *Taneri S, Oehler S, Lytle G, Dick HB, Evaluation of epithelial integrity with various transepithelial corneal cross-linking protocols for treatment of keratoconus. J Ophthalmol. 2014;2014: doi: /2014/ Epub 2014 Aug 12.

16 *Taneri S, Oehler S, Lytle G, Dick HB, Evaluation of epithelial integrity with various transepithelial corneal cross-linking protocols for treatment of keratoconus. J Ophthalmology 2014;2014: doi: /2014/ Incidence of pain & Epithelial defect post TECXL Percentage of eyes with postoperative pain following transepithelial CXL Percentage of eyes with postoperative epithelial defect following transepithelial CXL

Practices during Soak and Irradiation Effect of Speculum Comparing protocol alterations*

hypotonic treatment 20% dextran Lid speculum removed during with led to a significant

reduced the number of eyes requiring swelling before irradiation.

of corneal Pachymetry Pachymetry thickness after 30 increased by 1% increased by 11%

hypoosmolar Riboflavin Only 13% needed swelling None required swelling with Riboflavain

17 Practices during Soak and Irradiation Effect of Speculum Comparing protocol alterations* to the standard Dresden protocol Group1 Group 3 A standard CXL Group 2 Received hypotonic treatment 20% dextran Lid speculum removed during with led to a significant reduction in corneal pachymetry the 30 minutes of saturation riboflavin without isotonic riboflavin in with isotonic riboflavin. Closed eyelids during the riboflavin saturation phase significantly dextran 20% dextran reduced the number of eyes requiring swelling before irradiation. Need for the development of new riboflavin solutions with isooncotic 15% properties loss of corneal Pachymetry Pachymetry thickness after 30 increased by 1% increased by 11% minutes during the after 30 minutes saturation phase 90% needed swelling with hypoosmolar Riboflavin Only 13% needed swelling None required swelling with Riboflavain * Schmidinger G, Pachala M, Prager F. Pachymetry changes during corneal crosslinking: Effect of closed eyelids and hypotonic riboflavin solution. J Cataract Refract Surg 2013; 39:

18 Different Protocols Epithelium Riboflavin concentration Off 0.1% with 20% Dextran (conventional) Riboflavin impregnation Every 2 mins for 30 min, then every 5 min during fluence UV-A fluence (365nm) Irradiation time Total energy 3 mw/cm 2 30mins 5.4 J/cm 2 Off 0.1% with 20% Dextran (ACXL) Every 2 min for 20 mins 30mW/cm 2 3mins 5.4 J/cm 2 Off 0.1% with 20% Dextran (ACXL) Every 2 mins for 20 mins, then every 2 mins during fluence 18 mw/cm 2 5mins 5.4 J/cm 2 Off 0.1% with 20% Dextran (ACXL) On 0.25% with HPMC, NaCl, EDTA, Benzalkonium Chloride (TECXL) Off 0.5% with 0.9% NaCl (Hypoosmolar for corneal thickness <400 microns) Every 2 mins for 20 mins, then once after 5 mins Every 2 mins for 30 mins Every 3 mins for 30 mins, then every 20 secs for 5 mins 9 mw/cm 2 10mins 5.4 J/cm 2 45 mw/cm 2 2mins 40secs 7.2J.cm 2 3 mw/cm 2 30mins 5.4 J/cm 2

19 Transepithelial Riboflavin formulation Formulation composition UVA delivery device Iontophoresis Ricrolin TE (Sooft,Italy).1% riboflavin-5-phosphate, 15% dextran T500, sodium edetate, trometamol, and NaCl UV-X 1000, IROC Innocross, Switzerland N/A Medio-cross (Peschke Meditrade GmbH, Germany) 0.25% riboflavin-5-phosphate hydroxypropyl methylcellulose, benzalkonium chloride, NaCl UV-X 1000, IROC Innocross, Switzerland N/A ParaCel (Avedor Inc, USA) Ricrolin+ (Sooft,Italy) VibeX Xtra (Avedro Inc, USA) 0.25% riboflavin-5-phosphate, hydroxypropyl methylcellulose, sodium edetate, trometamol, benzalkonium chloride, NaCL 0.1% riboflavin-5-phosphate, sodium edetate, trometamol, sodium dihydrogen phosphate dihydrate, and sodium phosphate dibasic dehydrate KXL, Avedro Inc., USA KXL, Avedro Inc., USA 0.25% riboflavin-5-phosphate and NaCl KXL, Avedro Inc., USA N/A I-ON CXL generator (Sooft, Italy) N/A

Cutan Ocul Toxicol 2014 Jun;33(2):127-31 Resolution of

20 Cutan Ocul Toxicol 2014 Jun;33(2): Resolution of transient changes in Endothelial cell density indicate safe recovery

In a 400-μm-thick cornea, the irradiance at endothelial level was 0.

21 PURPOSE: To study potential damage to ocular tissue during CXL by means of the riboflavin/uva (370 nm) approach. RESULTS : Damage thresholds for keratocytes and endothelial cells are 0.45 and 0.35 mw/cm 2, respectively. In a 400-μm-thick cornea, the irradiance at endothelial level was 0.18 mw/cm 2 CONCLUSIONS : After CXL, repopulation of keratocytes in 300 μm depth takes up to 6 months. As long as the cornea treated has a minimum thickness of 400 μm, the corneal endothelium, lens & retina will not experience damage. The light source - homogenous irradiance, avoiding hot spots. Cornea 2007;26:

Riboflavin Solutions Standard Riboflavin Solution with Dextran for epi-off procedure (3ml) The Dresden Original:Time proven

1 % Riboflavin (Vitamin B2), 20 % dextran 500 Standard Riboflavin Solution without Dextran for epi-off procedure (3ml) Does not

22 Riboflavin Solutions Standard Riboflavin Solution with Dextran for epi-off procedure (3ml) The Dresden Original:Time proven Riboflavin solution with dextran Recommended instillation time: 20 minutes (1 drop every 2 minutes = 10 drops) Ingredients: 0.1 % Riboflavin (Vitamin B2), 20 % dextran 500 Standard Riboflavin Solution without Dextran for epi-off procedure (3ml) Does not reduce corneal thickness Recommended instillation time: 20 minutes (1 drop every 2 minutes = 10 drops) Ingredients: 0.1 % Riboflavin (Vitamin B2), 1.1 % HPMC Transepithelial Solution for epi-on procedure (2ml) Recommended instillation time: 20 minutes (1 drop every 2 minutes = 10 drops) Pre-loaded glass syringe containing 2.0 ml liquid Ingredients: 0.25 % Riboflavin (Vitamin B2), 1.2 % HPMC, 0.01 % Benzalkoniumchloride

μ Ingredients: 0.1 % Riboflavin (Vitamin B2) Riboflavin Solution for use with LASIK procedures on thin corneas (1.

23 Riboflavin Solutions Hypotonic Riboflavin Solution for corneal swelling (1.5ml) To swell thin corneas (< 400 μ) by means of osmotic effect Recommended instillation time: 1 drop every 5 seconds until corneal thickness has reached 400 μ Ingredients: 0.1 % Riboflavin (Vitamin B2) Riboflavin Solution for use with LASIK procedures on thin corneas (1.95ml) Recommended usage: after flap preparation and excimer treatment Put 3 5 drops on stroma, put flap back, wait 3 4 minutes, open flap Rinse off Riboflavin, put flap back and radiate with 1/2 of the recommended energy (1/2 of the time) Ingredients: > 0.23 % Riboflavin (Vitamin B2)

24 Corneal Cross linking with Isotonic solution* Hypotonic riboflavin 0.1 % solution) Begin dropping PESCHKE isotonic solution: 1 drop every 2 minutes for 20 minutes (= 10 drops). After 20 minutes - check at slit lamp with blue light whether anterior chamber is slightly yellow. If not, continue to drop isotonic solution until anterior chamber is yellow. If thinnest spot is under 400 μm without epithelium, apply hypotonic solution (using a 24 G cannula) to swell cornea. 1 drop every 5 seconds until corneal thickness isat least 400 μm. UV-illumination treatment set to 18 mw/cm2 for 5 min, focus distance between beam aperture and eye ~ 45 mm 55 mm and adjust beam diameter Post-op check-ups: 1 day 3 days 1 week 1 month 3 months 6 months yearly intervals. *Peschke Isotonic solution treatment information, Peschke trade GmbH.

25 Percentage of eyes with postoperative pain following transepithelial CXL Percentage of eyes with postoperative epithelial defect following transepithelial CXL Incidence of pain & Epithelial defect post TECXL

26 TOPOGRAPHY GUIDED PRK (TPRK) CENTERED CONE DECENTERED CONE

Riboflavin, Oxygen and Light. Sabine Kling, PhD, Farhad Hafezi, MD,PhD

Riboflavin, Oxygen and Light. Sabine Kling, PhD, Farhad Hafezi, MD,PhD Riboflavin, Oxygen and Light Sabine Kling, PhD, Farhad Hafezi, MD,PhD Corneal Cross-linking Increasing corneal stiffness to stop the progression of keratoconus 365 nm, 3mW/cm 2 30 min UV-light de-epithelialization