Istanbul (Turkey) January 19th, 2011

Luca Gualdi D.O.M.A. srl Rome (Italy) www.gualdi.it luca@gualdi.it

CORNEAL CROSSLINKING with Riboflavin 0.1% (Vit B2) increase corneal rigidity by 328,9%

Increased rigidity of the cornea caused by intrastromal cross-linking Ophthalmologe. 1997 Dec;94(12):902-6 Sprl E, Huhle M, Kasper M, Seiler T.

CONVENTIONAL CXL SIDE EFFECTS

- Post-operative pain - Post-operative foggy vision - Prolonged theraphy (expecially corticoides) - Risk of infection (due to the epithelial debridment)

How to riduce these side effects ???

...through the corneal epithelium...

CORNEAL EPITHELIUM = LYPO-SOLUBLE BARRIER

can accept only lypo-soluble molecules smaller than about 500 Dalton

RIBOFLAVIN (Vit B2) =376 Dalton HYDRO-SOLUBLE MOLECULE

RIBOFLAVIN cannot pass beyond the CORNEAL EPITHELIUM

Corneal cross-linking in vivo and ex vivo Riboflavin concentration determined by HPCL chromatography in corneal stroma exposed with and without epithelium (Caporossi A. et al. J Cataract Refract Surg. 2009 May;35(5):893-9.) Biomechanical and histological changes after corneal crosslinking with and without epithelial debridment (Wollensak G. et al. J Cataract & Refract Surg 2009, 35.540-546)

Role of benzalkonium chloride (BAK) on corneal epithelium

Corneal epithelium tight junctions are the most important barrier for Riboflavin permeability BAK (=contained in many eye drop concentrations 0.0075%-0.02) loosens epithelial tight junctions and enhances permeability for pharmaceutical agents

MC Carey B. In vivo corneal epithelial permeability following treatment with prostaglandin analogs with or without benzalkonium chloride J. Ocul Pharmacol Ther 2007;23:445-451

Cha SH, lee JS,Oum BS, Kim CD, Corneal epithelial cellular dysfunction from benzalkonium chloride (BAC) in vitro. Clin Experiment Ophthalmol 2004,32: 180-184
Burstein NL. Preservative alteration of corneal permeability in humans and rabbits. Invest Ophthalmol Vis Sci 1984;25:1453-1457

Rabbit corneal epithelium treated with a product preserved with sodium perborate q.i.d. for 7 days. The tissue reveals a mostly normal epithelium with extensive microvilli and tight epithelial cell to cell junctions (32,000X).

Rabbit corneal epithelium treated with a product preserved with 0.001% polyquaternium-1 q.i.d. for 7 days. The tissue reveals extensive superficial epithelial erosion and lack of protruding microvilli (32,000X).

Role of benzalkonium chloride (BAK) on corneal epithelium

CXL with BAK suggested by Pinelli and Boxer Walcher success only by stable visual acuity and corneal topographies

Pinelli R. Corneal Cross-linking with riboflavin:enteriging a new era in ophthalmology. Ophthalmology Times Europe 2006:2-36-38 Pinelli R. Mometto C. Corneal abrasion for CCL contra. 3rd internatonal congress of corneal cross linking. Zurich, 7-8 Dec 2007

Boxer Wachler B. Corneal collagen crosslinking with riboflavin. Cataract & Refractive Surg Today. 2006, 1:73-74

RICROLIN TE

Hypotonic ophthalmic solution containing Riboflavin o.1% and enhancers helping the Riboflavin pass through the intact corneal epithelium
=

TRANSEPITELIAL CROSS-LINKING
RICROLIN TE

0373 = Riboflavin 0,1% + Enhancers

Enhancers

Trometamol Amino-alcohol which improves the pharmacodynamics and bioavability of Riboflavin and increases its passage into the corneal stroma.

Sodic ETDA Helps to break cell-cell bonds,to facilitate the penetration of Riboflavin.

INTRACELLULAR ROUTE (predominantly LIPOPHILIC DRUGS)

PARACELLULAR ROUTE (predominantly HYDROPHILIC DRUGS)

The Enhancers increase ocular penetration of hydrophilic drugs by transiently relaxing EPITHELIAL TIGHT JUNCTIONS, temporarily opening a paracellular route for drug adsorption

Corneal epithelium

CORNEAL EPITHELIUM 30 min. after CXL TE

With courtesy of Dr. Cosimo Mazzotta

RIBOFLAVIN 0,1% TE (TRANSEPITELIAL) PENETRATION INTO THE ANTERIOR STROMA (89-99 microns by PENTACAM)

ANTERIOR CROSS-LINKING

Courtesy of F. Hafezi

No keratocytes apoptosis

Less biomechanical effect?

THE EPITHELIAL MAP

The earliest abnormalities of keratoconus occur in the epithelial basement membrane and Bowman's layer. The basement membrane may be disrupted (arrow 6) and duplicated. Bowman's layer (arrow 3) is disrupted (arrow 4) and fibrous tissue is interposed between the epithelial basement membrane and Bowman' layer (arrows 5). There is also stromal scarring.

ARTEMIS Digital Ultrasound

Corneal epithelial thickness profile in the diagnosis of keratoconus

Dan Z. Reinstein Journal of Refractive Surgry Vol. 25, July 2009

EPITHELIAL MAP
Epithelial doughnut pattern characterized by epithelial thinning sourronded by anulus of thicker epithelium coincident with an eccentric posterior elevation BSS apex, is consistent with KERATOCONUS

EPITEHELIAL THINNING

EPITHELIAL THICKENING

NORMAL EYE

KERATOCONUS EYE

TOPOGRAPHY MAP

STEEPEST POINT = THICKEST POINT

STEEPEST POINT = THINNEST POINT

EPITHELIAL THICKNESS MAP

RIBOFLAVIN MAY PENETRATE EASIER WHERE THE EPITHELIUM IS THINNER

(with better effect on the apex of the cone)

PERSONAL EXPERIENCE with CXL TE

PRE-POST OP:
BUVA/BCVA Topography (CSO,OPD-scan ), Tomography (PENTACAM , VISANTE ), Corneal histeresis and corneal resistence factor (Ocular Response Analyzer ), Corneal endotelial count (CSO ), Confocal microscopy (CONFOSCAN ), Aberrometry (CSO , OPD-scan )

MATHERIALS: 48 eyes (20 with follow-up > 1 year)

OXIBUPROCAINE (0,02 % BENZALCHONIUM CLORIDE) VEGA CROSS-LINKER RICROLIN TE

METHODS:

1HOUR pre-instillation of oxibuprocaine (0,02 % benzalchonium cloride) and RICROLIN TE >10 min. with the patient in supine position before UVA irradiation with the anulus, 30 min. IRRADIATION TIME (9mm diameter): UVA 370 nm at 3.0 mW/cm2 (dose:% 5.4 J/cm2) 2 RICROLIN TE DROPS EVERY 2.5 MINUTES

PERSONAL EXPERIENCE
CONVENTIONAL CXL NUMBER OF CASES 64 eyes (from May 2007 to today) TRANSEPITELIAL CXL (TE) 48 eyes (from september 2009 to today)

FOLLOW-UP GAINED LINES OF BUVA

GAINED LINES OF BCVA LOST LINES OF BUVA and BCVA STEEPEST K AVERAGE DECREASE

43 months 0,9
0,6 0 -1,74 D

17 months 0,7
0,2 0 -1,04 D

MEAN RMS ERROR DECREASE

DISCOMFORT EVALUATION (0-5) CORNEAL HISTERESIS (CH) CORNEAL RESISTENT FACTOR (CRF) DEMARCATION LINE ENDOTHELIAL CELL LOSS

-1,27
4
No statistical significant difference (range -0.4 mmHg/ +0.5 mmHg) No statistical significant difference (range -0.4v mmHg/ -0.5 mm Hg)

-0,77
0,5
No statistical significant difference (range -0.4 mm Hg / +0.6 Mm Hg) No statistical significant difference (range -0.5 mmHg/ +0.5 mm Hg)

170 to 380 micron None

50 to 150 micron None

MEAN TOPOGRAPHIC INDEX (EYETOP/CSO)

CSO EYE TOP:Mean SIMK imrovement pre-post surgery
46,20

CSO EYE TOP:Mean AK improvement prepostsurgery

54,45 54,40 54,35 54,42

46,00
45,80 45,60

Simk pre

Simk post

54,30 54,25

AK pre 54,27 Ak post

45,40
45,20 45,00

54,20 54,15

44,80

CSO EYE TOP:Mean SAI imrovement pre-post surgery

4,25 4,20 4,15 4,10 4,05 4,00 3,95 3,90 3,85 3,80 Sai preop 3,95 Sai postop 4,21

CSO EYE TOP:Mean COMA improvement prepostsurgery

1,382666667

COMA pre

1,209796296

COMA post

CSO EYE TOP:Mean LSA pre-postsurgery

-1,70

-1,80 -1,90
-2,00 -2,10

-1,92
LSA pre LSA post

-2,20 -2,30
-2,40

-2,28

MEAN KLYCES INDEX CHANGES (OPD-Scan II )

NIDEK OPS Scan II: Mean SIMK1, SIMK2 e MINK improvement pre-postsurgery
50,00 48,00 46,00 44,00 42,00 40,00 38,00 44,57 48,57

47,97 SIMK1 pre SIMK1 post 44,14 42,64 41,83 SIMK2 pre SIMK2 post MINK pre MINK post

NIDEK OPD Scan II:Mean SAI and IAI prepostsurgery

2,50

2,00
1,50 1,00

1,95 1,65
SAI pre SAI post IAI pre IAI post

0,56 0,50

0,51

0,00

NIDEK OPD Scan II:Mean CYL pre-postsurgery

4,00 3,90 3,80 3,70 3,60 3,50 3,40 3,30 3,20 1 3,49 CYL pre CYL post

NIDEK OPD Scan II:Mean % AA and D CVP improvement pre-postsurgery

80,00 70,00 60,00 50,00 40,00
30,00 20,00 10,00 0,00

3,90

70,80

67,83
55,98

51,62

AA pre AA post CVP pre CVP post

NIDEK OPD Scan II:Mean CEI improvement prepostsurgery

0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,20 0,10 0,00
0,85 0,90 1,10 1,05

NIDEK OPD Scan II:Mean SRI and SRC prepostsurgery

1,08 1,03 1,02 SRI pre SRI post 0,93 SRC pre SRC post

0,79

0,52 CEI pre CEI post

1,00 0,95

MEAN ABERROMETRIC CHANGES (OPD-Scan II / Nidek)

NIDEK OPD Scan II:Mean COMA improvement pre-postsurgery

1,20 1,00 0,80 COMA pre 0,60 0,40 0,20 0,00 COMA post 1,13 0,90

NIDEK OPD Scan II:Mean LSA improvement prepostsurgery

0,00 -0,02 -0,04 -0,06 -0,08 -0,10 -0,12 -0,14 -0,16 -0,18 -0,17 -0,08 LSA pre LSA post

MEAN TOMOGRAPHIC AMBROSIOS INDEX (Pentacam / Oculus )

OCULUS PENTACAM:Mean IHA improvement pre-postsurgery
20,00 18,00 16,00 14,00 12,00 10,00 8,00 6,00 4,00 2,00 0,00 13,72 17,85

OCULUS PENTACAM:Mean CKI improvement pre-post surgery

1,024 1,022 1,020
IHA pre IHA post

1,023

1,018 1,016 1,016 1,014 1,012

CKI pre CKI post

OCULUS PENTACAM:Mean IVA improvement prepsurgery

0,68 0,66 0,64 0,62 0,60 0,60 0,58 0,56 IVA pre IVA post 0,67

THINNEST POINT (Pentacam / Oculus)

OCULUS PENTACAM: Mean Thinnest point change pre-postsurgery

500.00 490.00 480.00 470.00 478.53 487.53

460.00
450.00 440.00 430.00 420.00 410.00 400.00
Thinnest point post Thinnest point pre

NO SIGNIFICANT CHANGE= +9 micron

(range -11/ +15 micron)

OCULAR RESPONSE ANALYSER (Reichert)

Mean CH pre-op=9,2 mmHg Mean CRF pre-op=9,7 mmHg Mean CH post-op= +0,1mmHg
(range=-0,4/+0,5 mmHg) (range=-0,4/ +0,7 mmHg)

Mean CRF post-op= +0,2mm Hg

PRE-OP

POST-OP

NO SIGNIFICANT CHANGE ON PEAKS, CH AND CRF

CORNEAL ENDOTHELIUM
PRE-OP POST-OP

NO SIGNIFICANT CHANGE IN POLIMEGATHISM, PLEIOMORFISM AND n.CELLS

QUANTITY OF VISION
UCVA and BCVA average improvement pre vs post surgery
1 0,8 0,6 0,4 0,2 0 -0,2 -0,4 -0,6 -0,8 -1 0,73

0,21

Mean Average UCVA improvement Mean average BCVA improvement

Mean UCVA improvement= +0,73 lines (range -0,5/+2) Mean BCVA improvement= +0,21 lines (range -0,5/+1)

QUALITY OF VISION
PRE-OP POST-OP

SPECIAL CASES

PELLUCIDA MARGINAL DEGENERATION

PRE-OP

POST-OP

TRISOMY 21 PATIENT

FRUST KERATOCONUS

PRE-OP

POST-OP

PEDIATRIC PATIENT

CORNEAL ECTASIA

TRANSEPITELIAL CROSS-LINKING (CXL TE)

PRO=
- Allowed treatments also for corneal thickness < 400 micron
- No post-operative pain - No visual worsening due to corneal opacity (expecially in the 1 month) - No discomfort - Rapid visual recovery - No complications or risk of infection due to epithelium removal - No long term theraphy (expecially for corticoids) - No necessairly need to be performed in the surgery theatre - Easier bilateral procedure - Less costs (no surgery theatre,no massive and prolonged therapy less post-operative consultants, no LAC, etc.)

CONTRA=

- Less Riboflavin penetration into the posterior stroma

CONCLUSIONS
TRANSEPITHELIAL CXL with RICROLIN TE is an effective way to stop or reduce ectasic disease such as: keratoconus, PMD and post-lasik ectasia. The penetration of RICROLIN TE into the anterior stroma was confirmed by many diagnostic instruments (VISANTE,PENTACAM, CONFOSCAN). The effects were confirmed from pre-op to post-op BUVA, BAVC and by topo-aberrometrical stability or decreasing of the apex of the cone (CSO, OPD,
PENTACAM).

Anyway the amount of RICROLIN TE doesnt reach the posterior stroma and this could lead to less stiffening effect.

RIBOFLAVIN 0,1% TE (TRANSEPITELIAL) PENETRATION INTO THE ANTERIOR STROMA (about 150 microns)

CONVENTIONAL RIBOFLAVIN 0,1% PENETRATION INTO THE ANTERIOR AND POSTERIOR STROMA (about 380 microns)

WHICH CROSS-LINKING? CONVENTIONAL CXL or TRANSEPIELIAL CXL

CONCLUSIONS
To have a deeper penetration also in the posterior stroma, further studies and longer follow-up will help to modify: - Fluence of UVA irradiation - Time of exposion - Wavelight CONVENTIONAL AND TRANSEPITHELIAL CXL TODAY MUST COHESIST (The ophthalmologist have to address the patient to the best way because each case, each person, each ectasic disorder, is different).

THANK YOU !

luca@gualdi.it

THANK YOU
luca@gualdi.it