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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Asota, Fant, Edelhauser, and Stulting, unpublished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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