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305 - Corneal Cross-Linking and Beyond
Ryan McKinnis, OD, FAAO, FSLS
• Complete the course evaluation
• Hand in your course ticket at the conclusion of this course
Two Steps to Receive CE UnitsSpeaker DisclosuresCommercial Interest Nature of Relevant
Financial RelationshipTitle or Role
SynergEyes Honoraria Speaker
International Keratoconus Academy Honoraria Speaker
Reed Expositions (Vision Expo) Honoraria Speaker
Corneal Hydrops
Munson’s sign
Apical Scarring
Fleischer’s Ring
Vogt’s Striae
Irregular Mires
Abnormal Topography
Pachymetric anmolies
Post. Curvature/elevation
Biomechanical Weakness
???
EARLY
LATE
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KERATOCONUS: CAUSES
Genetics
➢ 1 in 10 chance of a blood relative of a keratoconic
patient developing keratoconus
➢ Environmental➢ Eye Rubbing
➢ Allergies
➢ Oxidative Stress
Cross-linking has been used for centuries to tan leather
Dentists have used it for 25 Years to stiffen plastic materials
Dermatologists have used it to tighten collagen fibers in sagging skin
Why not use it on weakened corneas to arrest keratectasias?
Corneal CXL is a medical procedure that incorporates photochemical principles
Light source + photoactivating agent
UVA absorption by riboflavin generates singlet oxygen essential for formations of new cross-links1
Cross-linking2:
Creates new corneal collagen cross-links
Early results show shortening & thickening of collagen fibrils
Leads to the stiffening of the cornea
CXL: Mechanism of Action
2Beshtawi IM, O’Donnell C, Radhakrishnan H. Biomechanical properties of corneal tissue after ultraviolet-A-riboflavin crosslinking. J Cataract Refract Surg. 2013;39(3):451–
62.
1Kamaev P, Friedman MD, Sherr E, Muller D. Photochemical kinetics of corneal cross-linking with riboflavin. Invest Ophthalmol Vis Sci. 2012;53:2360–7.
Anterior View
Riboflavin + UVA vs. Riboflavin Only (30min Treatment)
Asota, Fant, Edelhauser, and Stulting, unpublished
Posterior View
Average Change
Kmax = -1.6D
Gregor Wollensak ,
MD
CXL IN THE USA
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CXL IN THE USA
FINALLY APPROVED!!
RIBOFLAVIN
Avedro received FDA approval in 2016
Progressive KC (04/16)
Post-refractive surgery ectasia (07/16)
Photrexa Viscous/Photrexa + KXL System
CXL IN THE USA
INDICATION AND USAGE
Photrexa Viscous and Photrexa are photoenhancers indicated
for use with the KXL System in corneal collagen cross-linking
for the treatment of progressive keratoconus.
CONTRAINDICATIONS
None
WARNINGS AND PRECAUTIONS
Ulcerative keratitis can occur. Monitor for resolution of
epithelial defects.
ADVERSE REACTIONS
The most common ocular adverse reactions in any CXL-
treated eye were corneal opacity (haze), punctate keratitis,
corneal striae, corneal epithelium defect, eye pain, reduced
visual acuity, and blurred vision.
CXL IN THE USA
CXLUSA
• Evaluation of Epi-on vs. Epi-off
• Treatment of the following conditions:
• Keratoconus
• Pellucid Marginal Degeneration
• Post-refractive ectasia
• Post-RK Visual Fluctuation
CXL IN THE USA
CXLUSA also allows for CXL to be used in
conjunction with:
• Intacs
• Conductive Keratoplasty
• PRK
• Modification of Epi-on Technique
CXL IN THE USA
Epi-Off
• Removal of epithelium prior to application of
riboflavin
• Ensures penetration of riboflavin throughout
cornea
• Potential complications• Delayed healing time
• Increase in pain
• Potential for scarring
CXL IN THE USA
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EPI-OFF COMPLICATIONS
Retrospective review from 2007-2012 in Europe:
• 206 eyes in 180 patients
• 28 complications in 23 eyes
Delayed epithelial healing (4 eyes)
Hypertrophic epithelial healing (4 eyes)
Severe SPK >30 days (11 eyes)
Sterile infiltrates (4 eyes)
Microbial infiltrates (4 eyes)
Corneal Edema (1 eye)
Wajnsztajn D, Frenkel S, Frucht-Pery J. Early complications after crosslinking for keratoconus. Poster presented
at: American Academy of Ophthalmology Annual Meeting; November 12, 2012; Chicago, IL.
In 293 KC eyes, the most common ocular AE in CXL-treated eyes were
corneal opacity (haze*), punctate keratitis, corneal striae, corneal epithelium defect, eye pain, reduced visual acuity, and blurred vision
TX EMERGENT ADVERSE EVENTS
(TEAES)
During Mth 1: Majority of adverse events reported resolved
Up to Mth 6: Corneal epi-defect, corneal striae, punctate keratitis,
photophobia, dry eye and eye pain, and decreased visual acuity took up to 6
Mths to resolve
Up to Mth 12: Corneal opacity or haze took up to 12 Mths to resolve
In 1-2% of patients, corneal epithelium defect, corneal edema, corneal
opacity and corneal scar continued to be observed at 12 Mths
TX EMERGENT ADVERSE EVENTS
(TEAES)EPI-ON COMPLICATIONS
Question of Efficacy
• Up to 5X more corneal stiffening in lab animals with epi-off
• Progression of KCN noted in early retrospective review
Early Conclusions
• Loading time of 60-80 minutes required
• Questionable results
• Riboflavin mixed with Dextran cannot permeate the intact epithelium
EPI-ON: THE SOLUTION
Riboflavin
• Develop hypotonic formulations without Dextran
Treatment of Epithelium
• Break hemidesmosomes with pharmaceuticals
Patient Evaluation
• Evaluate patients for riboflavin penetration rather than
reliance on rigid timing rules
EPI-ON: THE PROCEDURE
Epi-On
• Epithelium is softened through application of anesthetic
• Riboflavin is alternated with the anesthetic for 45-60Min
• Patient is examined prior to treatment to ensure full
penetration of the riboflavin
Roy Rubinfeld, MD
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EPI-ON: OUR PROTOCOL
Modified Epi-On Procedure
• Removal of 5 microns of tissue with the excimer
laser
• 25 minutes of riboflavin loading
• Patient evaluation prior to treatment
• Epi-off required for corneal thicknesses less than 400
microns
• Ensures maximal stromal swelling to protect against UV
damage
3.00
mW/cm²
1.49
mW/cm²
0.74
mW/cm²
0.36
mW/cm²
0.18
mW/cm²
0.09mW/cm²
0.06
mW/cm²
0μm
100μm
200μm
300μm
400μm
500μm
600μm
100%
50%
25%
12%
6%
3%
2%
Endothelium
Damage threshold3.00 mW/cm²
SAFETY OF CXL
With Riboflavin loading
SELECTION OF CANDIDATES
Avedro (FDA criteria)
• 14 years of age or older
• Progressive keratoconus
• Ectasia post-refractive surgery
CXLUSA
• At least 8 years of age (mirrors European criteria)
• KCN/Ectasia/Pellucid
• Post-RK Visual Fluctuation
PRE-OPERATIVE MANAGEMENT
Management of Expectations
• No inherent refractive correction
• Stabilization of corneal structure
• Pain Management
PRE-OPERATIVE MANAGEMENT
Refractive/Contact Lenses
• No contacts for four days prior to final pre-op exam
• No contacts for 1 week prior to procedure
• No contacts for 10-14 days following the procedure
POST-OPERATIVE MANAGEMENT
The “Givens”
• Steroid
• NSAID
• Antibiotic
• Bandage CL
• Preservative-Free Artificial Tears
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POST-OPERATIVE MANAGEMENT
The “Nuances”
• When do you remove the bandage CL?
• How do you handle complications?
• What are effective pain management techniques?
• Does the type of procedure require alterations to the
treatment plan?
POST-OPERATIVE MANAGEMENT
Epi-Off CXL
• The use of the bandage lens is recommended until
re-epithelialization occurs
• Stop the NSAID after 1 week
• Stop the antibiotic once epithelium is intact
• Balance the use of the steroid so as to eliminate
scarring vs. inhibiting re-epithelialization
• Use copious amounts of artificial tears
POST-OPERATIVE MANAGEMENT
Epi-On CXL
• Bandage CL can typically be removed next day
• Stop the NSAID after 1 week
• Taper the steroid over 2 weeks
• Use artificial tears liberally
A 47 year old male reports for evaluation of keratoconus
OD>OS x 30 years
Pt reports decreased VA OD, OS still stable
BCVA
OD: +1.25 - 4.75 x075 20/30
OS: +0.25 -1.50 x095 20/20
The patient insisted on CXL OD alone BCVA:
OD: +3.50 -5.50 x090 20/30
OS: -0.50 -0.75 x135 20/30
OS untreated
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WHAT DO THE STUDIES SAY?
Patients who experienced the greatest improvement were those with:
• BCVA of LESS than 20/40
• Max Keratometry of >55D
• Centralized cones
Subjective Results after CXL
• Improvement in night driving, glare, halos, reading ability, and foreign body sensation
CXL Outcome in the US:A Single Center Review
Treatment Decision
Stable Disease
BSCVA > 20/40
Maximum K
< 55D
NO Independent Risk Factors
Independent Risk Factors
Maximum K
≥ 55D
BSCVA ≤ 20/40
Progressive Disease
Monitor? CXL? CXL? CXL CXL
Consider
BSCVA?PKP
Risk Factor?
Chang CY, Hersh PS. Corneal collagen cross-linking: a review of 1-year outcomes. Eye Contact Lens. 2014
Nov;40(6):345-52.
CXL: Algorithm in Progress
IN SEARCH OF THE HOLY GRAIL
Can we combine CXL with other procedures
to provide the best of both worlds?
• CXL & Intacs
• CXL & PRK
• CXL & CK
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CXL & INTACS
The Purpose of Intacs
• Provide structural reinforcement at weakened areas
• Reduce refractive error by flattening the apex
• Thought to be additive when coupled with CXL
CXL & INTACS
Reality vs Myths?
• Debate over whether procedures are additive
Legare et al. – ICRS vs. ICRS/CXL
• Controversy over proper time to place Intacs
Before or after CXL?
Same day vs. 6-12 months?
• Difficulties in refractive management with Intacs
Patients become more intolerant of corneal GPs
s/p CXL-Intacs
CL Tolerance at Presentation
48.1%*
CLF Success Post CXL + Intacs
100% (33/33)
LogMAR Habitual VA 0.44 (20/55.6)
LogMAR Final CLVA 0.17 (20/29.6)
A SINGLE CENTER POST-OP CL STUDY
Clark Chang, Angie Shin, Peter Hersh (Unpublished)
80.0%77.8%
50.0%
90.9%
75%
Clark Chang, Angie Shin, Peter Hersh (Unpublished)
A SINGLE CENTER POST-OP CL STUDY
INTACS CHANNEL CREATION POST-OPERATIVE MANAGEMENT
Typical Course
• Antibiotic/NSAID x 1 week
• Steroid tapered over 2-3 weeks
• Removal of corneal suture at 10-14 days
Management of Complications
• Longer taper of steroids for those with corneal haze
• Rarely issues with ICRS channel
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CXL & CK
Purpose
• Strategically place conductive keratoplasty spots on
the cornea to normalize corneal shape
• “Lock” the new shape into place using CXL
CXL & CK
First Hypothesis
• Place CK spots superiorly resulting in a “lifting” of
the inferior cone apex
• Lock the new corneal shape into place with CXL
ORA GUIDED CK SPOT PLACEMENT CXL & CK
Results
• Rapid topographic changes initially
• Regression back to original shape within 3 months
• No improvement in UCVA/BCVA
Kymionis GD, Kontadakis GA, Naoumidi TL, Kazakos DC, Giapitzakis I,
Pallikaris IG. Cornea. 2010 Feb;29(2):239-43. doi:
10.1097/ICO.0b013e3181a818ab.
CXL & CK
Second Hypothesis
• Place the CK spots on the physical apex of the cone
• Resulting corneal scar and shortening of collagen fibrils
will flatten the cone apex
**Cannot perform this if the apex is on the visual axis**
CXL ALONE
Pre-Op Topography December 2011
29 year old Male
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CXL ALONE
Post-Op Topography January 2014
Now 31 year old male
CXL & CK
Pre-Op Topography March 2014
31 year old male
CXL & CK
Post-Op Topography July 2014
31 year old male
CXL & CK
Post-Operative Management
• Mirrors that of the solo CXL procedure
• Subjective reports of increased foreign body sensation
during the first 24 hours
CXL & PRK
The Theory
• Utilize topography guided systems to normalize the
corneal shape
Patient Selection
• KCN patients without corneal scarring
• Forme fruste patients who wish to undergo refractive
surgery
CXL & PRK
“European” Method (Athens Protocol)
• “Debulk” the ectasia by reshaping the cornea
• Mild KCN = Better Results
• Patients will often still require specialized optical
correction
“American” Method (CXLUSA)
• Use as a safeguard in “forme fruste” KCN patients
undergoing refractive surgery
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CXL & PRK
The Procedure
• Remove the epithelium using traditional methods
• Perform PRK
KCN: Remove no more than 50 microns of stromal tissue while
eliminating 70% of pre-op Rx
Forme Fruste: Full PRK treatment unless contraindicated
• Soak cornea with riboflavin for 15 minutes
• Perform CXL for 15 minutes
CXL & PRK
Post-Operative Management
Patience is a Virtue
• Corneal Haze
• DELAYED Re-epithelialization
Not unusual to require steroids over 1-2 months
I.E. Pred Forte x 1 month, Lotemax x 1 month
• Role for Ambiodisk/Prokera?
Gomes JA, Tan D, Rapuano CJ, Belin MW, Ambrósio R Jr, Guell JL, Malecaze F, Nishida K, Sangwan VS; Group of Panelists for the Global Delphi
Panel of Keratoconus and Ectatic Diseases. Global consensus on keratoconus and ectatic diseases. Cornea. 2015 Apr;34(4):359-69.
POST-OP PEARLS
Most patients can be safely fit in contact
lenses 2-4 weeks post-CXL
Greatest refractive changes occur 6-24 months
post-CXL (procedure-dependent)
The type of contact lens utilized should be
based on axial AND elevation maps as well as
the type of procedure performed
POST-OP FITTING: CORNEAL GPS
Three-Point Touch
• Longstanding belief that the best fitting method was to
bear the weight of the lens equally between 3 points
POST-OP FITTING: CORNEAL GPS
CLEK Study
• RGP contact lenses appeared to increase risk of apical
scarring
• Thus, we can infer that three-point touch is not the
safest method
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POST-OP FITTING: CORNEAL GPS
Today’s Trends
• Corneal GPs 10mm or greater in diameter preferred
• Moving towards vaulting the corneal apex
Following CXL…
• Previous corneal GP wearers can go into their old lenses initially
• Prepare the patient for the potential need to change the fitting & Rx multiple times within the first two years
CORNEAL GPS: AFTER CXL
Immediate s/p CXL 1 Year s/p CXL
CORNEAL GPS: AFTER CXL
Properly fit corneal GPs remain a good option
Trend is to avoid them in corneas that have
undergone intracorneal ring implantation
unless the landing zone is outside of the rings
• Hypersensitive cornea
• Risk of epithelial breakdown over the rings
THOSE PESKY INTACS
Reserved for those patients that are contact
lens intolerant
Limits contact lens options
Interestingly, the majority of patients that
undergo Intacs do NOT return for contact
lenses
THOSE PESKY INTACS
If contact lenses must be fit after Intacs…
• Sclerals/Hybrids
• Specialty soft designs
• Large diameter GPs IF care can be taken to avoid
bearing on the cornea directly above the rings
EXAMPLE
49 year old contact lens intolerant male referred for Intacs
placement
Surgery is performed without incident
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EXAMPLE
Post-Op Fitting
• Kerasoft IC
OD: 8.4(STD)/14.5/-6.50 -4.50 x080 20/25
OS: 8.4(STD)/14.5/-3.50 -4.00 x095 20/25
SCLERALS
There has been an explosion of scleral designs
over the past five years
Currently 17 labs with a wide variety of designs for both normal
and irregular corneas
AFTER CXL…
Sclerals are a fantastic option as:
• They avoid direct contact with the corneal surface
• Are suitable for post-Intacs cases
• Allow for a more customizable Rx
Front toric
Multifocals
Aberration Control
HYBRIDS
Synergeyes KC →ClearKone→UltraHealth
What’s the difference?
SYNERGEYES ULTRAHEALTH
Improvements
• SiHy skirt with dK/t of 85
• Hyper dK RGP of 135
• Gentler internal landing zone
• Fitting with flatter skirts increases lens movement and tear exchange
Challenges
• No longer use the skirt to increase lens clearance
• Skirt can dry out quickly
• Still can be difficult to grasp the skirt for removal
AFTER CXL…
Hybrids are a good option for:
• Those previously intolerant of RGPs
• Uncomplicated CXL
• MAYBE post-Intacs
Caution is advised when:
• Apex of cone intersects with the internal landing zone
• Intacs segment interferes with the internal landing zone
• Patients prone to significant dry eye
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EyePrint Prosthetic
A customizable scleral shell designed to precisely fit each
eye
Obtain a mold of the globe
Mold is scanned by a high definition laser scanner
Design is limited only by what is physically capable to lathe
Obtaining a Mold
Examples of the EyePrint Lens CXL: SO NOW WHAT?
Treatment of Bullous Keratopathy
CXL: SO NOW WHAT?
Treatment of Infectious Keratitis
• UV light has been shown to successfully kill bacterial organisms
• May prove to be the answer to sight-threatening multi-drug resistant
bacteria
CXL: SO NOW WHAT?
Applications During Hyperopic LASIK
• A single drop of riboflavin under the flap
• 15 minutes of CXL
• Results
Non-CXL group regressed by +0.75D
CXL group regressed by +0.20D
Kanellopolous and Kahn. Topography-guided hyperopic LASIK with and without high
irradiance collagen cross-linking: initial comparative clinical findings in a contralateral
eye study of 34 consecutive patients. J Refract Surg. 2012 Nov;28(11 Suppl):S837-40.
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Thank You!
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