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Northern Colorado Eye CenterContinuing Education Event
Corneal Collagen Cross-linkingSeptember 20, 2014
S. Lance Forstot, MD, FACSCorneal Consultants of Colorado
Founding PartnerClinical Professor of Ophthalmology
University of Colorado Medical School
Ultraviolet Light
• UVC– 220-290nm– Blocked by ozone layer
• UVB– 290-320nm
• UVA– 320-340nm
Ultraviolet Light
• UVA– Can induce corneal endothelial damage
with surface dose of 42.5 J/cm2
– Typical dose for CXL only 5.4 J/cm2
– Estimated dose received by cornea in
15-20 min of sun exposure on a summer day
All Exposed Tissues: Spring 170-200J/cm2/day in 3-4 hrs outdoors Fall ~60J/cm2/day of solar UVA
Cornea:
5J/cm2 in 15-20 min in Summer
Real World UV Hawaii in Spring
Australia in Summer
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 threshold
3.00 mW/cm²
Safety of Cross-Linking
How much UV – light gets into the eye ?
0.65 J/cm2
70 J/cm2
70 J/cm2 7.7 J/cm2
Damage thresholds
0.46 J/cm2 (9 %)
0.33 J/cm2 (7 %)
0.14 J/cm2 (2.1%)
0.12 J/cm2 (1.9%)
Radiant exposures
5.4
J/cm
2
Radiant Energy is Below Damage
Threshold
Safety of UVA-Riboflavin Cross-Linking of the Cornea
Min pach of 400 μm
protects endothelium, lens, retina
Spoerl, Spoerl, et. al Cornea 2007; 26:385-389et. al Cornea 2007; 26:385-389
300 300 µµ
Riboflavin (Vitamin B2)
• Critical role in CXL
• Increases UVA absorption to 95% in
saturated corneas (versus 32% w/o)
Riboflavin
Diabetics, KCN and CXL
Diabetics don’t often develop adv KCN because of
natural cross-linking from sugars and UV
lightSeiler T, Huhle S, Spoerl E, Manifest Diabetes
and Keratoconus, Graefe’s Arch 2000
CXL – UVA+Riboflavin
• Results in increase in biomechanical rigidity (stiffening)
• Strongest effect in anterior 300u
– Which plays major role in maintaining corneal curvature
• Results in corneal flattening and and reduction in spherical equivalent
CXL with Riboflavin
• ↑Rigidity
• In Europe since 1998
• New Tx in US
• KCN, pellucid, ectasia, post-RK
Scanning Electron
Microscopy
Stiffened Cornea
Normal Cornea
CXL
• Mechanism– Not completely understood
– Riboflavin known to generate active oxygen species (singlet oxygen and superoxide anion radicals)
Pre op
6 m postop
3 m postop1 m postop
• Apoptosis 300 μm deep after CXL
• Repopulation takes 6 months
Courtesy of Dr. Caporossi,
Confocal MicroscopyConfocal Microscopy
Crosslinks Between Collagen Fibers Strengthens Cornea like Ladder
Rungs
Cross-Linking is Not New
• Hardening of polymers in materials science since 1930s (silicone oil→rubber ball)
• Dentists XL for decades• Normal aging of connective
tissue involves cross-linking and stiffening
• KCN progression ↓ with age
We All “Crosslink” as we Grow Up
History of CXL
• Basic research 1993-97 by Seiler & Spoerl
• First patients Txd in 1999
• Today over 400 centers worldwide
• Standard of care for KCN (in Europe as young as 9)
CXL Technique
• Anesthetic drops, painless
• Prepare cornea
• Riboflavin drops for 30 mins
• UV light for 30 mins
• Bandage contact lens
Riboflavin 0.1% Drops
Patient’s View of UV Light
UV-A Light
CXL & Curvature Change
Change in avg or steep K does not provide key
info
See diff maps to appreciate true
curvature changes
Preop Postop 11 M
Difference Map
5 D Steeper3 D
Flatter
PreopPreop 6 M Postop
9 M Postop 12 M Postop12 M Postop
429 um
450 um 411 um ( 8.6%)
450 um
Pachymetry Maps
Pre Op 6 months Post Op
UCVA CF 100
BSCVA 25 20
Refraction -7.75+0.75x150 -3.75 +1.50 x 180
56 yr old male with Keratoconus: Epi-On CXL OS
6 months Preop Difference MapWilliam Trattler, MD case
CXL: Epi-On v. Epi-Off
Post Op 3 Months Pre Op Difference Map
OD UCVA Refraction BSCVA
Pre Op 200 -3.50+6.50x180 30
3 Months 50 -0.75+1.75x175 25
Epi-On Crosslinking for Ectasia38 year-old male with post-Lasik ectasia
William Trattler, MD case
BSCVA Comparison
BSCVA Comparison
Summary of Epi-ON• EPI-On CXL
– Benefits:• Faster visual recovery/less pain• Reduced risk of pain/haze• Very good clinical results
– Even in keratoconus patients over the age of 35
– Downside: • Longer procedure (30-50 min longer)• Can not combine with simultaneous topo-guided PRK
William Trattler, MD
Final Points• Epi-On can be as effective as Epi-Off
– Technique differences can explain differences in results
• Age is not a major factor– Older patients can benefit from crosslinking
• Progression is not required for successful results with crosslinking– Non-progressive patients can achieve improvement in
corneal shape, UCVA, and BSCVA
Long-term Results
• 241 eyes• Follow-up 6 months to 6 years• Flattening: 2.68 D at 1 year; 4.84D at 3 years• BCVA improvement (> 1 line): 53% at 1 year• No BCVA lines lost• 2 patients had KCN prog and repeat CXL
(Also AJO April 2010)
Raiskup-Wolf, Hoyer, Spoerl. J Cat Ref Surg May 2008
Long Term Results
5 year study, 48 eyes (60 pts treated) No patient had prog of keratectasia. Postop avg improvement 2.87 D Improvement in BCSVA by 1.4 lines
Wollensak G. Crosslinking treatment of progressive keratoconus: New hope. Curr Opin Ophthalmol. 2006 Aug;17:356-60
CXL for KCN, Ectasia
• Shown safe and effective worldwide
• Arrests KCN progression (95+%)
• UCV, BCSVA, CL tolerance ↑ (60-80%)
• Ideal candidates ≤ 45 y/o, corneal thickness ≥ 400 µm, limited scarring
• Minimum age in Europe now 9 y/o
CXL Complications
• Infectious keratitis – bacterial, fungal
• Sterile ulceration
• Corneal haze
• HSV keratitis
• Corneal edema
• Ring segments
• PRK
• Topo-guided PRK
• Better PKP Results?
After CXL
Topographically-Guided Ablation
Developed by Theo Seiler
Over 22,000 curvature points on the cornea
Linked to excimer laser Main indications irreg
astig, decentered ablations, small OZ
Topography Ablation
More tissue removed
CXL Other Applications
– Corneal edema
– Infectious Keratitis
– Radial Keratotomy
CXL and Ortho-K
CXL and the FDA
• Current status -Investigational
• Physician IND
• IRB Trials
• FDA Trials
Thank you for your attention
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