Corneal Cross Linking for Keratoconus and Ectasia Paul M. Karpecki, OD, FAAO Corneal Services and Ocular Disease Research Koffler Vision Group - Lexington KY 1 Paul M. Karpecki, OD, FAAO Financial Disclosures: AMO Alcon Labs Allergan Inc Bausch & Lomb Inc Cyanacon Ocusoft Eyemaginations Focus Laboratories Inspire Pharmaceuticals Ista Pharmaceuticals Konan Medical LCA Vision Inc. Pixel Optics PRN Nutrition Odyssey Medical OfficeMate Optometric Medical Solutions Rapid Pathogen Screening Science Based Health TearLab TelScreen Inc Topcon TruVision Vmax Keratoconus Responsible for 15% of all corneal transplants in the US About 22% of patients with keratoconus require a PKP with a mean duration of 8.8 years Develops during the ages of 12-20 most commonly Males = Females Bilateral and asymmetric 3 Corneal Cross Linking for Keratoconus and Ectasia CA-200 Basic module Fast and comfortable image acquisition High quality of keratoscopic images Normalized scale: Map is presented within the maximum scale measured of the cornea. This map shows immediately the actual astigmatism. More then 3 colors present a suspected high astigmatism. 1
Axial Absolute Normalized Tangential Tangential Absolute Normalized 4 combinations of mapping Axial Keratoconus Apical Curvature. This index repre- sents the power of the apical cornea. Apical Curvature Gradient. AGC higher kerato values than 2 D/mm show s possible compatibility with keratoconus. SI is a vertical asymmetric index. Positive values means top hemi- sphere more curved than the bottom one, and vice versa. KPI: Keratoconus Probability Index. Value in Green: Not compatible with Keratoconus. Value in Yellow: Suspected keratoconus. Value in red: Compatible with keratoconus. Elevation Maps of the cornea (BFS) Steep center Ectasia Diagnosis and Management Post-op Flat periphery The normal cornea is prolate, Q < 1, meaning that meridional curvature decreases from center to periphery. Prolateness of the normal cornea causes it to rise centrally above the reference sphere. The result is a central hill. Immediately surrounding the central hill is an annular sea where the cornea dips below the reference surface. In the far periphery, the prolate cornea again rises above the reference surface, producing peripheral highlands. With courtesy from Prof. Michael Belin 9 Note: central pach 514 Thinnest pach: 507 Normal topography (left lower map) Yet elevated and eccentric posterior elevation (right upper map) Pre-op Pre-op 17 months post-op Post-op 11 12 2
Belin/Ambrosio Enhanced Ectasia Differences in fitting the sphere Belin/Ambrosio Enhanced Ectasia A normal cornea looks pretty same, independent which fitting method is used An abnormal cornea looks different. With the enhanced fitting the cone is more pronounced 13 14 Standard BFS distance in vector notation Enhanced BFS progression index Difference between normal and enhanced BFS traffic light green = ok yellow = susp. red = abnormal Belin/Ambrosio Enhanced Ectasia 15 Belin/Ambrosio Enhanced Ectasia 16 1. Topography- inferior steepening 2. Wavefront RMS elevated Especially peripheral aberrations 3. Irregularity index (e.g. IS or Rabinowitz) (pachymetry) 6. Steep K s (>47D) 17 18 Belin/Ambrosio Enhanced Ectasia 3
CA-200 Topography of a patient with Keratoconus itrace of a patient with Keratoconus A case of advanced keratoconus PMD 22 PMD 1. Topography- inferior steepening 2. Wavefront RMS elevated Especially peripheral aberrations 3. Irregularity index (e.g. IS) 6. Steep K s (>47D) 23 24 4
Radial order 2nd Order Interaction: From Higher to Lower Lower Order Aberrations astigmatism defocus astigmatism 3rd trefoil coma coma trefoil Higher Order Aberrations 4th quadrafoil secondary spherical ab. secondary quadrafoil 25 astigmatism astigmatism 26 1. Topography- inferior steepening 2. Wavefront RMS elevated Especially peripheral aberrations 3. Irregularity index (e.g. IS-Rabinowitz) 6. Steep K s (>47D) 27 28 Peripheral Thickness Comparisons 1. Topography- inferior steepening 2. Wavefront RMS elevated Especially peripheral aberrations 3. Irregularity index (e.g. IS) 6. Steep K s (>47D) If peripheral pachs are not > 20 microns from central this is a sign of potential keratoconus 29 30 5
Orbscan FF Keratoconus Indices Variance Between Eyes 1. Number of Abnormal maps 2. Posterior surface float (difference) > 0.050D 3. 3MM and 5MM irregularity 6. Steep K s Astigmatism > 1.00D between eyes 31 32 NORMAL EYE KERATOCONUS EYE TOPOGRAPHY MAP 1. Topography- inferior steepening 2. Wavefront RMS elevated Especially peripheral aberrations 3. Irregularity index (e.g. IS) 6. Steep K s (>47D) EPITHELIAL THICKNESS MAP STEEPEST POINT = THICKEST POINT STEEPEST POINT = THINNEST POINT 33 CXL Treatment Options 36 6
Corneal Cross-Linking First introduced by Theo Seiler MD Involves saturating the cornea with riboflavin (Vit B2) Expose cornea to UV light (370 nm) for 30 minutes Riboflavin absorbs UV light and produces singlet oxygen Causes cross-linking of collagen fibers and extracellular matrix proteins To protect the endothelium: Soak cornea for 30 minutes prior Debride corneal epithelium 37 Ensure riboflavin has penetrated to the AC Corneal Collagen Cross- Linking Riboflavin prevents penetration of uv light Older corneas vs. younger corneas and progression of keratoconus CXL appears to be the first technology than can halt the progression of ectasia 38 CORNEAL CROSSLINKING with Riboflavin 0.1% (Vit B2) increases corneal rigidity by 328,9% CORNEAL EPITHELIUM = LYPO-SOLUBLE BARRIER can accept only lypo-soluble molecules smaller than about 500 Dalton RIBOFLAVIN (Vit B2) =376 Dalton HYDRO-SOLUBLE MOLECULE Increased rigidity of the cornea caused by intrastromal cross-linking Ophthalmologe. 1997 Dec;94(12):902-6 Spörl E, Huhle M, Kasper 39 M, Seiler T. 40 RIBOFLAVIN cannot pass beyond the CORNEAL EPITHELIUM Corneal cross-linking in vivo and ex vivo Riboflavin concentration determined by HPCL chromatography in corneal stroma exposed with and without epithelium (Caporossi A. et al. J Cataract Refract Surg. 2009 May;35(5):893-9.) Biomechanical and histological changes after corneal crosslinking with and without epithelial debridment (Wollensak G. et al. J Cataract & Refract Surg 2009, 35.540-546) Role of benzalkonium chloride (BAK) on the corneal epithelium Corneal epithelium tight junctions are the most important barrier for Riboflavin permeability BAK (=contained in many eye drop concentrations 0.0075%-0.02) loosens epithelial tight junctions and enhances permeability for pharmaceutical agents MC Carey B. In vivo corneal epithelial permeability following treatment with prostaglandin analogs with or without benzalkonium chloride J. Ocul Pharmacol Ther 2007;23:445-451 Cha SH, lee JS,Oum BS, Kim CD, Corneal epithelial cellular dysfunction from benzalkonium chloride (BAC) in vitro. Clin Experiment Ophthalmol 2004,32: 180-184 Burstein NL. Preservative alteration of corneal permeability in humans and rabbits. Invest Ophthalmol Vis Sci 1984;25:1453-1457 RICROLIN TE = Hypotonic ophthalmic solution containing Riboflavin o.1% and enhancers helping the Riboflavin pass through the intact corneal epithelium 41 42 7
RIBOFLAVIN 0,1% TE (TRANSEPITHELIAL) PENETRATION" INTO THE ANTERIOR STROMA (89-99 microns by PENTACAM)" 43 44 NORMAL EYE KERATOCONUS EYE UVA -Riboflavin TOPOGRAPHY MAP STEEPEST POINT = THICKEST POINT STEEPEST POINT = THINNEST POINT 30 minutes of drops and UV radiation exposure Strengthen collagen bonds EPITHELIAL THICKNESS MAP RIBOFLAVIN MAY PENETRATE EASIER WHERE THE EPITHELIUM IS THINNER (with better effect on the apex of the cone) 45 UVA -Riboflavin: Post-operative Care Interim Results from a multicenter clinical trial on CXL in the US Shows that CXL halts keratoconus and ectasia after LASIK Improves vision UVA -Riboflavin: Ongoing US Clinical Trials Interim Results from a multicenter clinical trial on CXL in the US Shows that CXL halts keratoconus and ectasia after LASIK Improves vision 8
UVA -Riboflavin: Ongoing US Clinical Trials Interim Results from a multicenter clinical trial on CXL in the US Shows that CXL halts keratoconus and ectasia after LASIK Improves vision UVA -Riboflavin: Ongoing US Clinical Sites Penny Asbell - New York, NY David Hardten - Bloomington, MN Ron Krueger - Cleveland OH Tom Mauger - Columbus, OH George Waring - Columbus, OH Gregory Pamel - New York, NY Robert Rivera - Phoenix, AZ Stephen Slade - Houston, TX Doyle Stulting - Atlanta, GA Steven Dell - Austin, TX Mark Speaker - New York, NY Darcy Wolsey - Salt Lake City, UT UVA -Riboflavin: Ongoing US Clinical Trials Cornea is stronger and increased stiffness but: also thinner (compacted?) 292 patients enrolled, 3 & 6 month data: 182 keratoconus eyes and 139 post-lasik ectasia 1:2 sham group statistical improvement in average corneal curvature values UVA -Riboflavin: Ongoing US Clinical Trials No change in manifest Rx Statistical improvement in BCVA Complications in 321 eyes treated: 4 infiltrates 4 delayed re-epithelialization 1 case of uveitis No cases of corneal haze in the clinical trial but occurs occasionally in international experience: resolves with time UVA -Riboflavin: Longer term data Other potential applications 71 eyes of 58 patients (KCN and ectasia) treated 41 received a sham but were treated at 3 months for ethical considerations 1 year - statistical improvement in UDVA and BCDVA Stabilization curve noted On average K s flattened by 1.7D Results were best for keratoconus > post-lasik ectasia > control Raiskup Wolf F, Hoyer A et al. Collagen cross linking with riboflavin and uv-a light in keratoconus long-term results. J. of Cataract and Refractive Surgery. 2008 ;34:796-801 Combine CXL with Intacs ICR has been shown to flatten the cornea in 80% of the cases CXL has been shown to halt progression of the disease 9
Intacs for Keratoconus Other potential applications Physician sponsored IND for infectious keratitis treatment Ulcers limited to 250 microns May also help with infectious load Treatment of corneal edema Cross linking reduces imbibition pressure Internationally it appears to work for 3 mo to 12 mo duration Conclusions Diagnosing keratoconus early is critical to effective treatment CXL is likely to become the standard of care for ectasia management Patients are more educated than in the past and expect to see doctors who know the answers to their eye care questions and can communicate that knowledge THANK YOU Paul@Karpecki.com 10