Results

INTRA PROTOCOL ANALYSIS

BCVA logMAR

0.3

0.17 0.2 0.17

0.22

0.21

0.15 0.15 0.16

0.21

0.18 0.13 0.14 0.15 0.2 0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

3/30 9/10 18/5 30/3 TE

Pre op

Post op 6m

Post op 1y

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

Spherical equivalent

-4.11 -4.3 -4.06 -3.76 -3.99

-3.64 -3.99 -3.01 -3.24 -3.77

-2.82 -3.4

-2.88 -3.47 -3.72

-5

-4.5

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

3/30 9/10 18/5 30/3 TE

Pre op Post op 6m Post op 1y

p=0.44 p=0.67 p=0.17 p=0.14 p=0.57

SE decreased in all groups, but this decrease was not statistically significant from baseline

447.28 451.38 463 458.59

422.17

431.39 440.16

448.82 456.77

417.08

423.67 427.43

449.33 448.96

406.48

370

380

390

400

410

420

430

440

450

460

470

3/30 9/10 18/5 30/3 TE

Pre op Post op 6m Post op 1y

Thinnest pachymetry

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

46.3 46.02 45.76 46.06

51.13

45.52 45.74

45.59 46.08

50.85

45.44 45.25 45.42 46.17

50.82

42

43

44

45

46

47

48

49

50

51

52

3/30 9/10 18/5 30/3 TE

Pre op Post op 6m Post op 1y

Flat Keratometry

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

50.6 50 49.71 49.7

54.9

49.38 49.63 49.55 49.74

54.5 49.35 49.03 49.31

49.8

54.48

46

47

48

49

50

51

52

53

54

55

56

3/30 9/10 18/5 30/3 TE

Pre op Post op 6m Post op 1y

p=0.88 p=0.73 p=0.76 P = 0.25 p=0.49

Steep Keratometry

K2 flattened in all groups, but this flattening was not statistically different from baseline to 1 year

27

45

.88

26

84

.67

27

34

.06

27

59

.85

27

28

.9

26

39

.7

25

32

.04

25

84

.3

26

41

.2

26

45

.95

25

67

.76

25

46

.16

25

40

.35

24

59

.62

26

65

.93

2300

2350

2400

2450

2500

2550

2600

2650

2700

2750

2800

3/30 9/10 18/5 30/3 TE

Pre op

Post op 6m

Post op 1y

Endothelial count

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

0

5

10

15

20

25

30

3 for 30 9 for 10 18 for 5 30 for 3 TE

19.57 18.1 18.56

24.7 22.61

27.39 21.67 19.96

23.71

20.65

24.34

21.64 21.46 19.08 21.01

Pre op

Post op 6m

Post op 1y

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.

Cornea.2013 May;32(5):597-601

Transient haze was noted in 71% of the accelerated CXL cases and in 91% of the conventional CXL

Clinical Ophthalmology 2014:8 1435–1440

ACXL shows comparable results with conventional CXL in arresting the progression of KC

20% DEXTRAN (VibexTM) • 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 RapidTM, VibexTM)

• 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. • 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 XtraTM)

• Riboflavin 0.25% with NaCl • TEKXL –

• 1st formulation - breach the corneal epithelium. • ParaCel, a dextran-free, hypo-osmolar, 0.25% riboflavin 5’-phosphate containing epithelial-permeability

enhancing agents including BAK • 2nd 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

•Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006; 17:356–360. • Accelerated versus conventional corneal collagen cross-linking in the treatment of mild keratoconus: a comparative study. Clinical Ophthalmology 2014:8 1435–1440

To reduce patient discomfort

To achieve more effective time management

To avoid the excessive corneal dehydration and

thinning

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

Transepithelial Crosslinking Riboflavin Formulations

Transepithelial Riboflavin

formulation

Formulation composition UVA delivery device

Iontophoresis

Ricrolin TE (Sooft,Italy) 0.1% 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) 0.25% riboflavin-5-phosphate, hydroxypropyl methylcellulose, sodium edetate, trometamol, benzalkonium chloride, NaCL

KXL, Avedro Inc., USA N/A

Ricrolin+ (Sooft,Italy) 0.1% riboflavin-5-phosphate, sodium edetate, trometamol, sodium dihydrogen phosphate dihydrate, and sodium phosphate dibasic dehydrate

KXL, Avedro Inc., USA I-ON CXL generator (Sooft,

Italy)

VibeX Xtra (Avedro Inc, USA)

0.25% riboflavin-5-phosphate and NaCl

KXL, Avedro Inc., USA N/A

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;2014:614380. doi: 10.1155/2014/614380. Epub 2014 Aug 12.

Percentage of eyes with postoperative pain following transepithelial CXL

Incidence of pain & Epithelial defect post TECXL

Percentage of eyes with postoperative epithelial defect following transepithelial CXL

*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;2014:614380. doi: 10.1155/2014/614380.

Practices during Soak and Irradiation – Effect of Speculum Comparing protocol alterations* to the standard Dresden protocol

Group1

A standard CXL treatment with

isotonic riboflavin in

20% dextran

Group 2 Lid speculum removed during the 30 minutes of saturation

with isotonic riboflavin.

Group 3 Received hypotonic riboflavin without

dextran

15% loss of corneal thickness after 30

minutes

90% needed swelling with hypoosmolar

Riboflavin

Pachymetry increased by 1%

during the saturation phase

Only 13%

needed swelling

Pachymetry increased by 11% after 30 minutes

None required swelling with

Riboflavain

20% dextran led to a significant reduction in corneal pachymetry

Closed eyelids during the riboflavin saturation phase significantly reduced the number of eyes requiring swelling before irradiation.

Need for the development of new riboflavin solutions with isooncotic properties

*Schmidinger G, Pachala M, Prager F. Pachymetry changes during corneal crosslinking: Effect of closed eyelids and hypotonic riboflavin solution. J Cataract Refract Surg 2013; 39:1179–1183

Different Protocols Epithelium Riboflavin

concentration Riboflavin

impregnation UV-A

fluence (365nm)

Irradiation time

Total energy

Off 0.1% with 20% Dextran

(conventional)

Every 2 mins for 30 min, then every 5

min during fluence

3 mW/cm2 30mins 5.4 J/cm2

Off 0.1% with 20% Dextran (ACXL)

Every 2 min for 20 mins

30mW/cm2

3mins 5.4 J/cm2

Off 0.1% with 20% Dextran (ACXL)

Every 2 mins for 20 mins, then every 2

mins during fluence

18 mW/cm2

5mins 5.4 J/cm2

Off 0.1% with 20% Dextran (ACXL)

Every 2 mins for 20 mins, then once

after 5 mins

9 mW/cm2 10mins 5.4 J/cm2

On 0.25% with HPMC, NaCl, EDTA,

Benzalkonium Chloride (TECXL)

Every 2 mins for 30 mins

45 mW/cm2

2mins 40secs 7.2J.cm2

Off 0.5% with 0.9% NaCl (Hypoosmolar

for corneal thickness <400

microns)

Every 3 mins for 30 mins, then every 20

secs for 5 mins

3 mW/cm2 30mins 5.4 J/cm2

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) 0.25% riboflavin-5-phosphate, hydroxypropyl methylcellulose, sodium edetate, trometamol, benzalkonium chloride, NaCL

KXL, Avedro Inc., USA

N/A

Ricrolin+ (Sooft,Italy) 0.1% riboflavin-5-phosphate, sodium edetate, trometamol, sodium dihydrogen phosphate dihydrate, and sodium phosphate dibasic dehydrate

KXL, Avedro Inc., USA

I-ON CXL generator (Sooft,

Italy)

VibeX Xtra (Avedro Inc, USA)

0.25% riboflavin-5-phosphate and NaCl

KXL, Avedro Inc., USA

N/A

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

Resolution of transient changes in Endothelial cell density indicate safe recovery

PURPOSE: To study potential damage to ocular tissue during CXL by means of the riboflavin/UVA (370 nm) approach.

Cornea 2007;26:385–389

RESULTS : Damage thresholds for keratocytes and endothelial cells are 0.45 and 0.35

mW/cm2, respectively. In a 400-μm-thick cornea, the irradiance at endothelial level was 0.18

mW/cm2

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.

Riboflavin Solutions

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

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

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

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 Solutions

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)

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.

Corneal Cross linking with Isotonic solution*

*Peschke Isotonic solution treatment information, Peschke trade GmbH.

Percentage of eyes with postoperative pain following transepithelial CXL

Incidence of pain & Epithelial defect post TECXL

Percentage of eyes with postoperative epithelial defect following transepithelial CXL

TOPOGRAPHY GUIDED PRK (TPRK)

CENTERED CONE

DECENTERED CONE