CXL
Derek N. Cunningham, O.D., FAAO
Disclosure
• In the last 12 month I have had relations with the following companies:
• Abbott • Alcon • Allergan • B+L • Reichert • Arctic Dx • Tearlab
• Avedro
• Innovision
• TearScience
• Lumenis
background
Keratoconus basics
• Collagen fibers are highly uniform in
diameter (25-35 nm)
• The distance between two corneal fibers is also highly uniform (41.5nm)
Keratoconus and Post-LASIK ectasia
Keratoconus:
• Non-inflammatory, degenerative disorder of the cornea characterized by progressive ectasia and stromal thinning.
• Reported prevalence of 1 in 2000 in the general population.[1]
Post-LASIK corneal ectasia:
• Corneal weakening after a LASIK procedure, creating
progressive steepening and thinning of the cornea and loss of BSCVA.
• Incidence of post-LASIK ectasia estimated to be 1 in 1000
cases of LASIK surgery.
[1] Feder RS, Kshettry P. Non-inflammatory ectatic disorders. [book auth.] Mannis MJ, Holland EJ, eds Krachmer JH. Cornea. Philadelphia : Elsevier Mosby, 2005:956, Vol. Chapter 78.
Typical Cone
Cone? 28 y/o female – 10 year dx of KC
Cone?
28 y/o female – 10 year dx of KC
41 y/o female – 20 year dx KC
41 y/o female – 20 year dx KC
Newly Diagnose Keratoconic
25 y/o white female
• Upset with the sudden diagnosis
• Very upset with the contact lens cost
• Went on line and did DAYS of research
• Came to us for crosslinking (was not told
about crosslinking)
Referring Docs Scans
Other Options?
A.Try a different less expensive lens
C. Corneal Transplant
• B. Crosslink
• D. Monitor
One week later
Lotemax QID Restasis BID Omega 3 supplements
1 week later
6 Months later
First, Fix the Surface…
• Better pre-op data, better quality post-op
– Artificial Tears. All pts.
– O-3 FA. Almost all pts.
– Topical Cyclosporin.
– Topical Azithromycin
– Topical steroids
– Plugs.
Ectasia
CXL - Basics
Basics
• Soaking the cornea with riboflavin (vitamin B2) and then exposing the cornea
to ultraviolet (UV) light with a 370-nm
wavelength at 15 - 45 mW/cm2.
Riboflavin (vitamin B2)
• Water soluble, not stored
• Helps metabolism of carbs, fat and
protein
• Important for skin, hair, eyes, and liver
• RDA = 1.5mg/day
UV absorbtion
Cross-linking
Corneal collagen cross-linking
The figures above show the parallel corneal layers (white) and the collagen cross-linking (red) which are increased after Corneal Cross-Linking treatment.
Cross-Linking:
• Improves the biomechanical properties of the cornea by strengthening the corneal tissue in the anterior stroma.
• The only procedure available to specifically stop the progression of keratoconus and strengthen the individual collagen fibers in the cornea.
• Corneal cross-linking (also know as CXL) is a procedure that has been in global clinical use since 1997.
Cross-linking – First Procedures
Standard CXL, developed by Eberhard Spoerl and Theo Seiler in 1997.[2]
CXL procedure includes:
• Removal of corneal epithelium and then pre-treating with riboflavin 0.1% ophthalmic solution (0.1% diluted in 20% Dextran) for 30 minutes.
• Cornea then irradiated with 3 mW/cm2 of UVA (365 nm) for 30 minutes delivering a total radiant exposure of 5.4 J/cm2.
Exposure of cornea to the combination of UVA light with riboflavin photosensitizer induces cross-linking of the corneal collagen fibrils with a resultant increase in tensile strength and diameter of the collagen fibrils.
[2] Conservative therapy of keratoconus by enhancement of collagen cross-links. Seiler T, Spoerl E, Huhle M, Kamouna A. s.l. : Invest. Ophthalmol. Vis. Sci., Vol. 37. S1017.
Result
• STIFF OLD
Risks
• Pain
• Blurred vision
• Delayed healing
• Infection
• Inflammation
• Corneal haze
• Dry eye
Method
• Remove cornea
Video
Avedro’s Cross-Linking Products
The VibeX™ / KXL™ System is not approved for sale in the United States MA-000178 Rev. C
• FDA Approved • FDA Orphan Drug Designation
RFID Card & Riboflavin
KXLTM System
© 2012 Avedro
Avedro’s KXL System
The VibeX™ / KXL™ System is not approved for sale in the United States MA-000178 Rev. C© 2012 Avedro
Post op
• Handle like a surface ablation patient
• Steroid, antibiotic, NSAID
• Bandage lens for 1 week
Clinical Course
• Gets worse initially
Method
• Epithelium on?
5 minutes post “disruption”
1 day p/o
1 day p/o
1 day p/o
ACOS-KXL-001:
Cross-linking Trial in Patients with Keratoconus or Corneal Ectasia following
Refractive Surgery
© 2012 Avedro The VibeX™ / KXL™ System is not approved for sale in the United States MA-000178 Rev. C
Overall Study Design
Sponsor: ACOS
Title: A Multi-Center, Randomized, Controlled Evaluation of the Safety and Efficacy of the KXL System with VibeX (Riboflavin Ophthalmic Solution) for Corneal Collagen Cross-Linking in Eyes with Keratoconus or Corneal Ectasia after Refractive Surgery
Phase: III
Planned Sample Size: up to 2000 primary eyes with keratoconus and up to 2000 primary eyes with corneal ectasia at 100 sites randomized in 1:1:1 ratio between 3 active treatment groups.
Primary Efficacy Criteria: Mean change in maximum corneal curvature (Kmax) from baseline to 6 months or from baseline to 12 months (within subject comparison). Each treatment condition (keratoconus and corneal ectasia) and treatment group will be evaluated independently.
Schedule of Assessments: Screening/baseline, Day 0 (randomization/treatment day), 1 day, 1 week, and 1, 3, 6 and 12 months after treatment.
The VibeX™ / KXL™ System is not approved for sale in the United States MA-000178 Rev. C© 2012 Avedro
Inclusion Criteria
Presence of central or inferior steepening on the topographic map
BSCVA better than 1 and worse than 80 letters on the Early Treatment of Diabetic Retinopathy Study [ETDRS] chart
At least 12 years of age
For corneal ectasia patients only: • Diagnosis of corneal ectasia after refractive surgery • Axial topography consistent with corneal ectasia
For keratoconus patients only:
• Topographic evidence of keratoconus with a diagnosis of mild, moderate or severe keratoconus
• Maximum corneal curvature as measured by steepest keratometry (Kmax) value ≥ 47.00 D
Contact lens wearers only: manifest refraction must be stable between two visits which occur at least 7 days apart
The VibeX™ / KXL™ System is not approved for sale in the United States MA-000178 Rev. C© 2012 Avedro
Exclusion Criteria
Eyes classified as either normal, atypical normal (except corneal ectasia),
or keratoconus suspect on the severity grading scheme
A history of previous corneal surgery (other than LASIK or PRK for subjects with corneal ectasia) or the insertion of Intacs in the eye(s) to be treated
Corneal pachymetry that is < 375 microns prior to epithelial debridement at the thinnest point in the eye to be treated
Eyes which are aphakic or pseudophakic and do not have a UV blocking lens implanted
A history of delayed epithelial healing in the eye(s) to be treated
Patients with nystagmus or any other condition that would have prevented
a steady gaze during the CXL treatment or other diagnostic tests
The VibeX™ / KXL™ System is not approved for sale in the United States MA-000178 Rev. C© 2012 Avedro
Treatment Groups
15mW/cm2 for 8 minutes
Epithelial removal
0.12% riboflavin 1 gtt/2 mins for 20 mins
Irradiated at 15 mW/cm2 for 8 minutes (7.2 J/cm2)
30mW/cm2
for 4 minutes
Epithelial removal
0.12% riboflavin 1 gtt/2 mins for 20 mins
Irradiated at 30 mW/cm2 for 4 minutes (7.2 J/cm2)
45mW/cm2
for 2 minutes and 40 seconds
Epithelial removal
0.12% riboflavin 1 gtt/2 mins for 20 mins
Irradiated at 45 mW/cm2 for 2 min 40 sec (7.2 J/cm2
The VibeX™ / KXL™ System is not approved for sale in the United States MA-000178 Rev. C© 2012 Avedro
Goals and Key Benefits
• Provide patients access to treatment for current unmet medical need in an orphan population
• Greatly increase patient comfort during treatment due to
shorter UVA irradiation time
• Allow qualified contralateral eyes to be treated
• Gain deeper understanding of safety and efficacy of higher powers of UVA irradiation for corneal collagen cross-linking
The VibeX™ / KXL™ System is not approved for sale in the United States MA-000178 Rev. C© 2012 Avedro
FDA STUDY
• 2 year follow-up
General success
Great Success!!! Consensus of literature
• CXL prevents further vision loss in over 95% of patients
• 60-70% of patients having improved vision
Complications
13 y/o white male – 5 days p/0 – lost bcl 2 days ago
Father brought son in because eye
seemed red
Child reports no pain – F/U BCL for 2 days
No improvement with BCL for 2 days, 1
days post pressure patch
29 year old black male
• Very poor bcva
• OS worse than OD
Initial presentation
Tough case 1
Do We Dare?
2 months post cxl
2 months post cxl
3.5 Diopters of flattening
2.5 Diopters of corneal flattening
15 year old Hispanic Male
1 day post op
1 week p/o
Studies
• Being investigated for a treatment of
infectious keratitis
• Effective treatment depth of 300 microns may limit effectiveness
Studies
• Treating corneal edema
• How long will the effect last
Studies
• Combining CXL with thermal or microwave procedures that transiently modify
corneal shape
Studies
• CXL for post-RK ectasia and vision
fluctuations
ARVO 2013
• Topographically Guided Corneal Cross-Linking • David B. Usher
– Uses eye tracker and mirror system to control corneal illumination
• Patterned collagen crosslinking had an effect on corneal astigmatism.
• Finite Element Analysis of Treatment of Corneal Astigmatism with Collagen Crosslinking IBRAHIM SEVEN1
PIXEL
• Photorefrative Intrasromal Crosslinking
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The Future of
Corneal Cross-Linking for Refractive Correction
• Potential applications reach beyond the single goal of stabilizing corneas with keratoconus
• The ability to change the biomechanical properties of the cornea presents opportunities for refractive indications
• To apply CXL to refractive surgery, the procedure must be predictable and customizable
The Mosaic System is not approved for sale in the United States
Redistribution of Corneal Stress
• Recent biomechanical studies strengthen the theory that corneal ectasia develops from
focal weakening of the cornea1
• Finite element analysis modeling demonstrates the potential for
optimization of cross-linking through focal stiffening of the cornea2
• Preferentially stiffening the weakest zone of the cornea = Redistribution of corneal stress 1. Roberts, C., Dupps, WJ. Biomechanics of corneal ectasia and biomechanical treatments. J
Cataract Refract Surg 2014: 40:991-998
2. Roy, AS., Dupps, WJ. Patient specific computational modeling of keratoconus progression
and differential responses to collagen cross-linking. Invest Ophthal Vis Sci 2011: 52: 9174-87
The Mosaic System is not approved for sale in the United States
What is Photorefractive Intrastromal
Cross-Linking (PiXL)?
• Corneal cross-linking (CXL) was first introduced in 1998 as a treatment for progressive
keratoconus1
• Laboratory2 and clinical studies
3 have demonstrated that CXL stiffens the cornea
(alters corneal biomechanics)
• PiXL is the application of zonal CXL using spatial application of UVA
• The goal of PiXL is to introduce controlled corneal shape change using patterned UVA
CXL, without ablation
1. Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal
tissue. Exp. Eye Res. 1998;66(1):97–103. 2. Spoerl E, Seiler T. Techniques for Stiffening the Cornea. J.
Refract. Surg. 1999;15:711–713 3. Goldich Y, et al. Clinical and corneal biomechanical changes
after collagen cross-linking with riboflavin and UV irradiation in patients with progressive keratoconus: results after 2 years of follow-up. Cornea. 2012;31(6):609–14.
Sharply defined edges
✓ Eye Tracking to compensate for
patient eye movement
Complex patterning
✓ Digitial Micromirror Device
(DMD) to project UVA pattern of
any design
More stiffening than standard
technology
✓ Pulsed Illumination
✓ Higher Energy Doses
✓ Supplemental Oxygen
Requirements for PiXL derived from the FEA Model: Solutions
The Mosaic System is not approved for sale in the United States
Riboflavin is applied to the corneal
surface
The patient is
positioned under the
Mosaic device, and an iris tracker
precisely aligns the
device with the patient’s eye
A customized
treatment pattern is applied using the
Mosaic system
Refractive correction with customized cross-linking
PiXL: Photorefractive Intrastromal
Cross-linking
The Mosaic System is not approved for sale in the United States
PiXL for Myopia: Basic Principle
! Specific UVA patterning is applied to the center
(myopia) of the riboflavin-soaked cornea
! Focal stiffening is achieved in the treatment zone
! Redistribution of biomechanical stresses occurs
in response to normal intraocular pressure
! “Bulging” of the cornea in untreated regions
results in central flattening: reduction of myopia
Images Adapted From: Professor John Marshall, MBE, PhD
The Mosaic System is not approved for sale in the United States
Post-OP Pre-Op Difference
Epithelium-Off PiXL Case Example– 38 year old
Myope
Pre-OP: -1.75-0.75x175 UCVA: 20/50 BCVA: 20/20
1 Month Post-Op: -0.00-1.00x156 UCVA: 20/25 BCVA: 20/20
6 Months Post-OP: -0.25-0.50x160 UCVA: 20/25 BCVA: 20/20
12 Months Post-OP: -0.25 -0.50x180 UCVA: 20/20 BCVA: 20/20
Professor H. Burkhard Dick Dr. Matthias Elling
Ruhr University Bochum, Germany
Ongoing Clinical Studies
Transepi PiXL in Healthy Myopic Eyes
• Intended correction: -0.75 to -2.0D
sphere • No prior corneal surgery
Principal Investigators: • Prof. H. Burkhard Dick, Ruhr
University, Bochum, Germany • Prof. François Malecaze, Hôpital
Purpan, Toulouse, France
• Prof. Anders Behndig, Umea
University, Umea, Sweden
University-Based European Clinical Trials of
Transepithelial PiXL with Oxygen
for Treatment of Low Myopia
The Mosaic System is not approved for sale in the United States
Enhanced Crosslinking
• Breathing new life into CXL
• Pulse light therapy
99
Is this a surgery?
?
