1. Northern Colorado Eye Center Continuing Education Event Corneal Collagen Cross-linking September 20, 2014 S. Lance Forstot, MD, FACS Corneal Consultants of Colorado Founding Partner Clinical Professor of Ophthalmology University of Colorado Medical School

2. Corneal Collagen Cross-linking September 20, 2014 S. Lance Forstot, MD, FACS Corneal Consultants of Colorado Founding Partner Clinical Professor of Ophthalmology University of Colorado Medical School

3. Ultraviolet Light UVC –220-290nm –Blocked by ozone layer UVB –290-320nm UVA –320-340nm

4. Ultraviolet Light UVA –Can induce corneal endothelial damage with surface dose of 42.5 J/cm 2 –Typical dose for CXL only 5.4 J/cm 2 –Estimated dose received by cornea in 15-20 min of sun exposure on a summer day

5. All Exposed Tissues:  Spring 170-200J/cm 2 /day in 3-4 hrs outdoors  Fall ~60J/cm 2 /day of solar UVA Cornea:  5J/cm 2 in 15-20 min in Summer Real World UV Hawaii in Spring Australia in Summer

6. 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/cm ² 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

7. How much UV – light gets into the eye ? Radiant Energy is Below Damage Threshold

8. Safety of UVA-Riboflavin Cross-Linking of the Cornea Min pach of 400 μm protects endothelium, lens, retina Spoerl, et. al Cornea 2007; 26:385-389 300 µ

9. Riboflavin (Vitamin B2) Critical role in CXL Increases UVA absorption to 95% in saturated corneas (versus 32% w/o)

10. Riboflavin

11. Diabetics, KCN and CXL Diabetics don’t often develop adv KCN because of natural cross-linking from sugars and UV light Seiler T, Huhle S, Spoerl E, Manifest Diabetes and Keratoconus, Graefe’s Arch 2000

12. 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

13. CXL with Riboflavin ↑Rigidity In Europe since 1998 New Tx in US KCN, pellucid, ectasia, post-RK Scanning Electron Microscopy Stiffened Cornea Normal Cornea

14. CXL Mechanism –Not completely understood –Riboflavin known to generate active oxygen species (singlet oxygen and superoxide anion radicals)

15. 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 Microscopy

16. Crosslinks Between Collagen Fibers Strengthens Cornea like Ladder Rungs

17. 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

18. We All “Crosslink” as we Grow Up

19. 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)

20. CXL Technique Anesthetic drops, painless Prepare cornea Riboflavin drops for 30 mins UV light for 30 mins Bandage contact lens

21. Riboflavin 0.1% Drops

22. Patient’s View of UV Light

23. UV-A Light

24. CXL & Curvature Change Change in avg or steep K does not provide key info See diff maps to appreciate true curvature changes

25. PreopPostop 11 M Difference Map 5 D Steeper 3 D Flatter

26. Preop 6 M Postop 9 M Postop 12 M Postop 429 um 450 um 411 um ( 8.6%) 450 um Pachymetry Maps

27. Pre Op 6 months Post Op UCVACF100 BSCVA2520 Refraction-7.75+0.75x150 -3.75 +1.50 x 180 56 yr old male with Keratoconus: Epi-On CXL OS 6 monthsPreop Difference Map William Trattler, MD case

28. CXL: Epi-On v. Epi-Off

29. Post Op 3 Months Pre OpDifference Map ODUCVARefractionBSCVA Pre Op200-3.50+6.50x18030 3 Months50-0.75+1.75x17525 Epi-On Crosslinking for Ectasia 38 year-old male with post-Lasik ectasia William Trattler, MD case

30. BSCVA Comparison

32. 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

33. 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

34. 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

35. 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

36. 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

37. CXL Complications Infectious keratitis – bacterial, fungal Sterile ulceration Corneal haze HSV keratitis Corneal edema

38. Ring segments PRK Topo-guided PRK Better PKP Results? After CXL

39. 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

40. Topography Ablation More tissue removed

41. CXL Other Applications –Corneal edema –Infectious Keratitis –Radial Keratotomy

42. CXL and Ortho-K

43. CXL and the FDA Current status -Investigational Physician IND IRB Trials FDA Trials

44. Thank you for your attention

45. S. Lance Forstot, MD, FACS www. corneacolorado.com SL4STOT@aol.com