ASCRS diams ASOA Symposium amp Congress

Technicians amp Nurses Program

May 6-10 2016 ndash New Orleans

462016

1

CORNEAL CROSSLINKING

BACKGROUND TECHNIQUES RESULTS JCAHPO

NEW ORLEANS 2016 James J Salz MD

Laser Vision Medical Group

Los Angeles CA

Clinical ProfessorOphthalmology

University of Southern California

(corneal cross linking is not FDA approved in US)

(many slides courtesy of Yaron Rabinowitz M D) ldquoHOT TOPICrdquo

MANY PUBLICATIONS

NOW IN THE LITERATURE UNDER FDA STUDY AT

SEVERAL CENTERS IN US

Cornea Genetic Institute near

Cedars-Sinai Hospital in Los Angeles PI Dr Yaron

Rabinowitz

2 basic techniques being

investigated

Classic- epithelium removed

ldquoEpi onrdquo epithelium not

removed

KERATOCONUS INCIDENCE 12000 PATIENTS IN U S

KERATOCONUS- BULGING

AND THINNING OF CORNEA USUALLY

INFERIORLY DUE TO WEAKENED CORNEAL COLLAGEN LAMELLAE

SIDE VIEW OF

KERATOCONUS

BACKGROUND

What is Crosslinking

1 Process well known in material sciences

2 The addition of molecular bonds to increase

the mechanical strength of tissue

3 An enzymatic process

bull Cross-links can be induced enzymatically by

means of aldehydes chemical fixatives and by

photosensitizing radiation

1) Photosensitizer 2) Chemicals 3) Aldehyde

+ light Fixatives Sugars

ie riboflavin + UV ie glutaraldehyde ie glucose

J Refract Surg 1999 15 711-713

Induction of cross-links in corneal tissue Spoerl E Huhle M Seiler T

Exp Eye Res 1998 Jan66(1)97-103

THEO SEILER M D

SWITZERLAND

FIRST TO PROPOSE COLLAGEN CROSS-

LINKING TO SLOW PROGRESSION OF

KERATOCONUS IN 1998

YARON RABINOWITZ MD

LOS ANGELES CA

Dr Rabinowitz first classified keratoconus by patterns on

topography

462016

1

CORNEAL CROSSLINKING

BACKGROUND TECHNIQUES RESULTS JCAHPO

NEW ORLEANS 2016 James J Salz MD

Laser Vision Medical Group

Los Angeles CA

Clinical ProfessorOphthalmology

University of Southern California

(corneal cross linking is not FDA approved in US)

(many slides courtesy of Yaron Rabinowitz M D) ldquoHOT TOPICrdquo

MANY PUBLICATIONS

NOW IN THE LITERATURE UNDER FDA STUDY AT

SEVERAL CENTERS IN US

Cornea Genetic Institute near

Cedars-Sinai Hospital in Los Angeles PI Dr Yaron

Rabinowitz

2 basic techniques being

investigated

Classic- epithelium removed

ldquoEpi onrdquo epithelium not

removed

KERATOCONUS INCIDENCE 12000 PATIENTS IN U S

KERATOCONUS- BULGING

AND THINNING OF CORNEA USUALLY

INFERIORLY DUE TO WEAKENED CORNEAL COLLAGEN LAMELLAE

SIDE VIEW OF

KERATOCONUS

BACKGROUND

What is Crosslinking

1 Process well known in material sciences

2 The addition of molecular bonds to increase

the mechanical strength of tissue

3 An enzymatic process

bull Cross-links can be induced enzymatically by

means of aldehydes chemical fixatives and by

photosensitizing radiation

1) Photosensitizer 2) Chemicals 3) Aldehyde

+ light Fixatives Sugars

ie riboflavin + UV ie glutaraldehyde ie glucose

J Refract Surg 1999 15 711-713

Induction of cross-links in corneal tissue Spoerl E Huhle M Seiler T

Exp Eye Res 1998 Jan66(1)97-103

THEO SEILER M D

SWITZERLAND

FIRST TO PROPOSE COLLAGEN CROSS-

LINKING TO SLOW PROGRESSION OF

KERATOCONUS IN 1998

YARON RABINOWITZ MD

LOS ANGELES CA

Dr Rabinowitz first classified keratoconus by patterns on

topography

462016

2

in vivo-experiments reveal UV-radiation and riboflavin to be the most effective and the least harmful procedure

Photo+Light Fixitive Sugars

1 Riboflavin (vit B2) + Ultraviolet radiation

2 Production of oxygen radicals

O2-

3 Induction of collagen cross-links -CH2-CH2-CH2-CH = NH-CH2-CH2-CH2-CH2-

collagen fibril collagen fibril

Basics in Crosslinking

Crosslinking

STEPS IN CROSSLINKING (CXL) Calibrate laser

Anesthesia- proparacaine 05

Debride central 7 mm epithelium

Use freshly prepared riboflavin solution (01)(10mg riboflavin-5-phosphate in 10 ml dextran 20 )

Apply every 2 minutes for 30 minutes prior to procedure

Check for Flare in AC

UV radiance of of 3mWcm2

and a wavelength of 370nm ndash 5 cm from eye homogenous

Cornea must be a least 400um

TECHNIQUE

APPLICATION OF RIBOFLAVIN

1 DROP Q 2 MINUTES FOR X 15

RIBOFLAVIN DIFFUSES INTO CORNEAL STROMA

UV RADIATION

U V LIGHT SYSTEM APPEARANCE OF CORNEA DURING UV LIGHT APPLICATION

LABORATORY STUDIES 2003- PRESENT

Biomechanical

Biochemical

Thermal

Morphological

Effect on keratocytes endothelium

462016

3

Crosslinking Extensiometry

RESEARCH - Extensiometry In-Vitro Testing of Corneal Stiffness

Sept 2003

Human Cornea

Porcine Cornea

rarr3289 increase of

rigidity in human cornea

LONG-TERM BIOMECHANICAL PROPERTIES OF RABBIT CORNEA AFTER PHOTODYNAMIC COLLAGEN CROSSLINKING

WOLLENSAK G IOMDINA E ACTA OPHTHALMOL 2008 JUN 11

In the treated rabbit cornea a decrease in

ultimate strain (of 057-784) were found over a

time period of up to 8 months after crosslinking treatment

RiboflavinUVA-induced collagen crosslinking

leads to a long term increase in biomechanical

rigidity which remains stable over time

COLLAGEN FIBER DIAMETER IN RABBIT CORNEAS WOLLENSAK G WILSCH M SPOERL E SEILER T

CORNEA 2004 JUL23(5)503-7

Cross linking using riboflavinUVA leads to a significant increase in corneal collagen diameter

Morphologic correlate of the cross linking process leading to an increase in biomechanical stability

Courtesy

Prof Wollensak

anterior effect

Increase by 12 in fiber diameter

Courtesy Prof Wollensak

CYTOTOXICITY OF CROSS-LINKING (CXL)

Rabbits irradiated with UVA 370 um

Cornea 2004 2343-49

RiboflavinUVA treatment leads to a dose-dependent

keratocyte damage that can be expected in human corneas

down to a depth of 300u repopulation occurs at 6 months

462016

3

Crosslinking Extensiometry

RESEARCH - Extensiometry In-Vitro Testing of Corneal Stiffness

Sept 2003

Human Cornea

Porcine Cornea

rarr3289 increase of

rigidity in human cornea

LONG-TERM BIOMECHANICAL PROPERTIES OF RABBIT CORNEA AFTER PHOTODYNAMIC COLLAGEN CROSSLINKING

WOLLENSAK G IOMDINA E ACTA OPHTHALMOL 2008 JUN 11

In the treated rabbit cornea a decrease in

ultimate strain (of 057-784) were found over a

time period of up to 8 months after crosslinking treatment

RiboflavinUVA-induced collagen crosslinking

leads to a long term increase in biomechanical

rigidity which remains stable over time

COLLAGEN FIBER DIAMETER IN RABBIT CORNEAS WOLLENSAK G WILSCH M SPOERL E SEILER T

CORNEA 2004 JUL23(5)503-7

Cross linking using riboflavinUVA leads to a significant increase in corneal collagen diameter

Morphologic correlate of the cross linking process leading to an increase in biomechanical stability

Courtesy

Prof Wollensak

anterior effect

Increase by 12 in fiber diameter

Courtesy Prof Wollensak

CYTOTOXICITY OF CROSS-LINKING (CXL)

Rabbits irradiated with UVA 370 um

Cornea 2004 2343-49

RiboflavinUVA treatment leads to a dose-dependent

keratocyte damage that can be expected in human corneas

down to a depth of 300u repopulation occurs at 6 months

462016

4

CORNEAL ENDOTHELIAL CYTOTOXICITY OF RIBOFLAVINUVA TREATMENT IN VITRO WOLLENSAK G SPOumlRL E REBER F PILLUNAT L FUNKR

OPHTHALMICRES 2003 NOV-DEC35(6)324-8

A cytotoxic effect on endothelial cells was demonstrated at a

thickness of lt 400um

Patients whose corneas are less than 400um should be excluded for treatment

Endothelial cell culture

YOPRO-stain

Courtesy Prof Wollensak

SLITLAMP APPEARANCE

Early mild diffuse Haze that dissipates with time

Likely due to the linking amp spacing of fibers

6 weeks after corneal collagen

cross-linking reveals bundles

of highly reflective striae

SAFETY OF UVA-RIBOFLAVIN CROSS-LINKING OF THE

CORNEA SPOERL E MROCHEN M SLINEY D TROKEL S SEILER T

CORNEA 2007 MAY26(4)385-9 REVIEW ARTICLE

The currently used UVA radiant exposure of 54 mJcm and the corresponding irradiance of 3 mWcm2 is below the known damage thresholds of UVA for the corneal endothelium lens and retina

CLINICAL STUDIES MAY 2003

22 patients ndash 2 to 4 yrs

no progression in all eyes

Improved in VA in 1522

flattening of Max K by 2D in 1622

eyes

CHANGE OF MAXIMAL K-VALUE

CROSSLINKING WITH RIBOFLAVIN AND ULTRAVIOLET-LIGHT IN

KERATOCONUS LONG-TERM RESULTS RAISKUP-WOLF ET AL 2008

J CATARACT REFRACT SURG 2008 796-801) DRESDEN 7-YEARS-RESULTS

Decrease of keratectasia year 1= 27D year 2 = 22D year 3 = 48D

Visual acuity improved by 1 line per year in 54 in first three years

2 patients had continued progression and were x-linked a 2nd time

462016

5

FIRST PROSPECTIVE RANDOMIZED CLINICAL TRIAL OF CROSSLINKING FOR KERATOCONUS

Progressive Keratoconus defined by increase in

Kmax by 10 D MR cyl by 10 D

MRSE by 05 D CL base curve by 01 mm

Exclusion for lt400 um scars or previous surgery

J Refract Surg 2008 (Sept) 24(7) S720-5

RISK FACTORSCOMPLICATION RATES SEILER 2009 117 EYES

Eyes losing gt2 lines BSCVA = 29

Continued progression after CXL =76

Sterile infiltrates 76

Central stromal scars 28

RARE CORNEAL HAZE COMPLICATION

USUALLY CLEARS SLOWLY OVER

TIME

SLIT LAMP APPEARANCE OCT STUDY

SHOULD EPITEHLIUM BE REMOVED

CURRENT CONSENSUS - YES 1 Research by Wollensak - 28 effect

2 Confocal Mic - no effect under epith

3 OCT - shows no changes wth epi on

4 Dangers of UV light without uniform absorption

5 Can use removing epithelium to your advantage

IMMUNOFLUORESCENT STAINING CONFOCAL (BOTTOS SCHOR amp CHAMON)

No stromal compaction

in presence of epithelium

or without UVA or Riboflavin

J Refract Surg 2008 (Sept) 24(7) S715-9

462016

6

ABSTRACT PURPOSE To present data on unhappy keratoconus patients

who presented to our office following C3R ldquoepi-onrdquo cross-linking

METHODS Retrospective chart review 1 year post procedure

RESULTS 13 eyes were identified Mean age was 33 yrs

(range 23 ndash 41) Mean uncorrected acuity was 20200

(range 2040-20200) Mean best-corrected acuity was 2060

(range 2030-20200) Mean central pachymetry was 435um

(range 380-485) Mean K value was 5027(range 43-58)

Mean I-S value was 425(range 184-1086) 4 eyes had

repeat cross-linking with the standard epi-off procedure 4 eyes

had corneal transplants and 5 eyes had no further treatment

CONCLUSIONS These data suggest that the ldquoepi-onrdquo C3R

procedure may not be optimal for treating keratoconus

EYE 2 - PRE OP AND 1 YEAR POST OP TOPOGRAPHY C3R - 8 D CHANGE

RESULTS

SUMMARY OF FINDINGS AT

PRESENTATION

413 (30) eyes had paracentral scars

913 (70) eyes had 1 additional surgery

613 (46) eyes had 2 additional surgeries

313 (23) eyes had 3 additional surgeries

CORNEAL CROSSLINKING (CXL) SINGLE CENTER CLINICAL TRIAL(IDE FROM FDA) - CXL VS INTACS + CXL

Currently enrolling patients

400 patients randomized to INTACS and no INTACS

Must Exhibit 1D of progression in past year

Can have Keratoconus or Ectasia after LASIK

For more information go to

wwwkeratoconuscom

EXCLUSION CRITERIA FOR CLX Corneas thinner than 400u

K reading of gt58D

Central corneal scar

Age gt 35 years stable

Preoperative BSCVA 2025 or better

Autoimmune disease Herpes Pregnant

Unrealistic expectations

ENTRY CRITERIA

18 years of age

Keratoconus or Ectasia

Demonstrate progression of Keratoconus in past year

Cornea must - 400um thick

K reading less than 58D

No central or paracentral scarring

462016

7

COLLAGEN CROSSLINKING RESULTS 12 MONTHS

PROGRESSIVE KERATOCONUS (N=77) CORNEA EYE INSTITUTE (JULY 2011--DR RABNINOWITZ)

UCVA BSCVA Average K

Gain in lines Gain in lines flattening

Mean 135 Mean 025 Mean 031D

Range -2 to 5 Range -2 to 4 Range -8 to 4

COLLAGEN CROSSLINKING RESULTS 12 MONTHS - SUMMARY AVERAGE K CORNEA EYE INSTITUTE

(JULY 2011)

93 flattened or did not change

62 flattened by 05D or more

31 did not change

15 steepened by 05D or more

COLLAGEN CROSSLINKING RESULTS 12 MONTHS - SUMMARY ACUITY CORNEA EYE INSTITUTE

(JUNE 2011)

61 of patients gained at least 1 line of acuity

42 of patients gained at least 2 lines of acuity

15 of patients lost at least 1 line of acuity

Prospective Randomized Study ndash 1 year results

Standard CXL vs Sham group( 70 eyes)rsquo

J Cat Ref Surg January 2011 Hersh PS et al

UCVA improved (20137) to (20117) (P = 04)

BSCVA improved (2045) to (2034) (Plt001)

211 gained and 14) 2 or more Snellen lines

Max K value decreased by 17 plusmn 39 diopters (D) (Plt001)

Max K decreased by 20D (310) increased by 20 D (42)

Keratoconus patients did better than ectasia patients

TOPOGRAPHY DRIVEN PRK + CORNEAL CROSSLINKING NOT APPROVED IN THE US

DR JOHN KANELLOPOULOS

NEW YORK AND ATHENS GREECE

ldquoTOPO LINK PRKrdquo TOPO LINK PRK + CXL

INDIAN JOURNAL OF OPHTHALMOLOGY 2014

PRE AND POSTOP TOPOGRAPHY OF PT IN INDIA OCT FROM PATIENT IN INDIA

462016

8

THANK YOU FOR YOUR ATTENTION

CROSSLINKING IS A MAJOR ADVANCE

THAT WILL DECREASE THE NEED FOR CORNEAL TRANSPLANTS FOR

THOUSANDS OF PATIENTS WORLD WIDE

• Cover Page - ASCRS 2016
• Salz_Corneal Cross Linking

462016

6

ABSTRACT PURPOSE To present data on unhappy keratoconus patients

who presented to our office following C3R ldquoepi-onrdquo cross-linking

METHODS Retrospective chart review 1 year post procedure

RESULTS 13 eyes were identified Mean age was 33 yrs

(range 23 ndash 41) Mean uncorrected acuity was 20200

(range 2040-20200) Mean best-corrected acuity was 2060

(range 2030-20200) Mean central pachymetry was 435um

(range 380-485) Mean K value was 5027(range 43-58)

Mean I-S value was 425(range 184-1086) 4 eyes had

repeat cross-linking with the standard epi-off procedure 4 eyes

had corneal transplants and 5 eyes had no further treatment

CONCLUSIONS These data suggest that the ldquoepi-onrdquo C3R

procedure may not be optimal for treating keratoconus

EYE 2 - PRE OP AND 1 YEAR POST OP TOPOGRAPHY C3R - 8 D CHANGE

RESULTS

SUMMARY OF FINDINGS AT

PRESENTATION

413 (30) eyes had paracentral scars

913 (70) eyes had 1 additional surgery

613 (46) eyes had 2 additional surgeries

313 (23) eyes had 3 additional surgeries

CORNEAL CROSSLINKING (CXL) SINGLE CENTER CLINICAL TRIAL(IDE FROM FDA) - CXL VS INTACS + CXL

Currently enrolling patients

400 patients randomized to INTACS and no INTACS

Must Exhibit 1D of progression in past year

Can have Keratoconus or Ectasia after LASIK

For more information go to

wwwkeratoconuscom

EXCLUSION CRITERIA FOR CLX Corneas thinner than 400u

K reading of gt58D

Central corneal scar

Age gt 35 years stable

Preoperative BSCVA 2025 or better

Autoimmune disease Herpes Pregnant

Unrealistic expectations

ENTRY CRITERIA

18 years of age

Keratoconus or Ectasia

Demonstrate progression of Keratoconus in past year

Cornea must - 400um thick

K reading less than 58D

No central or paracentral scarring

462016

7

COLLAGEN CROSSLINKING RESULTS 12 MONTHS

PROGRESSIVE KERATOCONUS (N=77) CORNEA EYE INSTITUTE (JULY 2011--DR RABNINOWITZ)

UCVA BSCVA Average K

Gain in lines Gain in lines flattening

Mean 135 Mean 025 Mean 031D

Range -2 to 5 Range -2 to 4 Range -8 to 4

COLLAGEN CROSSLINKING RESULTS 12 MONTHS - SUMMARY AVERAGE K CORNEA EYE INSTITUTE

(JULY 2011)

93 flattened or did not change

62 flattened by 05D or more

31 did not change

15 steepened by 05D or more

COLLAGEN CROSSLINKING RESULTS 12 MONTHS - SUMMARY ACUITY CORNEA EYE INSTITUTE

(JUNE 2011)

61 of patients gained at least 1 line of acuity

42 of patients gained at least 2 lines of acuity

15 of patients lost at least 1 line of acuity

Prospective Randomized Study ndash 1 year results

Standard CXL vs Sham group( 70 eyes)rsquo

J Cat Ref Surg January 2011 Hersh PS et al

UCVA improved (20137) to (20117) (P = 04)

BSCVA improved (2045) to (2034) (Plt001)

211 gained and 14) 2 or more Snellen lines

Max K value decreased by 17 plusmn 39 diopters (D) (Plt001)

Max K decreased by 20D (310) increased by 20 D (42)

Keratoconus patients did better than ectasia patients

TOPOGRAPHY DRIVEN PRK + CORNEAL CROSSLINKING NOT APPROVED IN THE US

DR JOHN KANELLOPOULOS

NEW YORK AND ATHENS GREECE

ldquoTOPO LINK PRKrdquo TOPO LINK PRK + CXL

INDIAN JOURNAL OF OPHTHALMOLOGY 2014

PRE AND POSTOP TOPOGRAPHY OF PT IN INDIA OCT FROM PATIENT IN INDIA

462016

8

THANK YOU FOR YOUR ATTENTION

CROSSLINKING IS A MAJOR ADVANCE

THAT WILL DECREASE THE NEED FOR CORNEAL TRANSPLANTS FOR

THOUSANDS OF PATIENTS WORLD WIDE

• Cover Page - ASCRS 2016
• Salz_Corneal Cross Linking

462016

7

COLLAGEN CROSSLINKING RESULTS 12 MONTHS

PROGRESSIVE KERATOCONUS (N=77) CORNEA EYE INSTITUTE (JULY 2011--DR RABNINOWITZ)

UCVA BSCVA Average K

Gain in lines Gain in lines flattening

Mean 135 Mean 025 Mean 031D

Range -2 to 5 Range -2 to 4 Range -8 to 4

COLLAGEN CROSSLINKING RESULTS 12 MONTHS - SUMMARY AVERAGE K CORNEA EYE INSTITUTE

(JULY 2011)

93 flattened or did not change

62 flattened by 05D or more

31 did not change

15 steepened by 05D or more

COLLAGEN CROSSLINKING RESULTS 12 MONTHS - SUMMARY ACUITY CORNEA EYE INSTITUTE

(JUNE 2011)

61 of patients gained at least 1 line of acuity

42 of patients gained at least 2 lines of acuity

15 of patients lost at least 1 line of acuity

Prospective Randomized Study ndash 1 year results

Standard CXL vs Sham group( 70 eyes)rsquo

J Cat Ref Surg January 2011 Hersh PS et al

UCVA improved (20137) to (20117) (P = 04)

BSCVA improved (2045) to (2034) (Plt001)

211 gained and 14) 2 or more Snellen lines

Max K value decreased by 17 plusmn 39 diopters (D) (Plt001)

Max K decreased by 20D (310) increased by 20 D (42)

Keratoconus patients did better than ectasia patients

TOPOGRAPHY DRIVEN PRK + CORNEAL CROSSLINKING NOT APPROVED IN THE US

DR JOHN KANELLOPOULOS

NEW YORK AND ATHENS GREECE

ldquoTOPO LINK PRKrdquo TOPO LINK PRK + CXL

INDIAN JOURNAL OF OPHTHALMOLOGY 2014

PRE AND POSTOP TOPOGRAPHY OF PT IN INDIA OCT FROM PATIENT IN INDIA

462016

8

THANK YOU FOR YOUR ATTENTION

CROSSLINKING IS A MAJOR ADVANCE

THAT WILL DECREASE THE NEED FOR CORNEAL TRANSPLANTS FOR

THOUSANDS OF PATIENTS WORLD WIDE

• Cover Page - ASCRS 2016
• Salz_Corneal Cross Linking

462016

8

THANK YOU FOR YOUR ATTENTION

CROSSLINKING IS A MAJOR ADVANCE

THAT WILL DECREASE THE NEED FOR CORNEAL TRANSPLANTS FOR

THOUSANDS OF PATIENTS WORLD WIDE

• Cover Page - ASCRS 2016
• Salz_Corneal Cross Linking