Mastering Corneal Collagen Cross-linking Techniques (C3-R/CCL/CxL)

Mastering Corneal Collagen Cross-linking Techniques (C3-R/CCL/CxL) System requirement: Windows XP or above Power DVD player (Software) Windows media player 10.0 version or above (Software) Accompanying DVD ROM is playable only in Computer and not in DVD player. Kindly wait for few seconds for DVD to autorun. If it does not autorun then please do the following: Click on my computer Click the DVD drive labelled JAYPEE and after opening the drive, kindly double click the file Jaypee

DVD Contents 1. Limited Topoguided PRK Followed by Collagen Cross-linking for Keratoconus. A John Kanellopoulos (Greece). 2. Riboflavin UV-A Induced Collagen Cross-linking In Keratoconus. C Banu Cosar, E Coskunseven (Turkey). 3. One Shot Epithelium Rhexis. Roberto Pinelli (Italy). 4. Tunnel Creation By Femtosecond Laser and the Implantation of Ferrara Ring Segments. Carlo Lovisolo (Italy) 5. Slit Lamp Video Wood Light Fluorescein Patterns of Custom Designed Reverse-Geometry Contact Lens in Keratoconus. Carlo Lovisolo (Italy).

Mastering Corneal Collagen Cross-linking Techniques (C3-R/CCL/CxL) with Video DVD Rom Roberto Pinelli Editors Ashok Garg MS PhD FIAO (Bel) FRSM, FAIMS, ADM, FICA International and National Gold Medalist Chairman and Medical Director Garg Eye Institute and Research Centre 235-Model Town, Dabra Chowk Hisar-125005 A John Kanellopoulos Director, Istituto Laser Microchirurgia Director, Laservision gr. Institute Oculare Crystal Palace, Via Cefalonia Mesogeion 2 and Vasilissis Sofias 70, 25124, Brescia Pyrgos Athinon Italy Building B, 11527-Athens Greece David O Brart Carlo F Lovisolo, FRCS, FRCOph Department of Ophthalmology Medical Director Kings College, London QuattroElle Eye Center The Rayne Institute Via Cusani, 709, 20121 St Thomas Hospital, London Milano UK Italy Foreword Eric D Donnenfeld JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi Ahmedabad Bengaluru Chennai Hyderabad Kochi Kolkata Lucknow Mumbai Nagpur St Louis (USA)

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Dedicated to My Respected Param Pujya Guru Sant Gurmeet Ram Rahim Singh Ji for his blessings and motivation. My Respected Parents, teachers, my wife Dr. Aruna Garg, son Abhishek and daughter Anshul for their constant support and patience during all these days of hard work. My dear friend Dr. Amar Agarwal, a renowned International Ophthalmologist for his constant support, guidance and expertise. Ashok Garg All patients affected by Keratoconus, in the hope that a near future will offer a solution avoiding for many of the them the corneal transplant. Roberto Pinelli My parents, the endless and willing teachers and my family : my wonderful wife Nathalie, and our children: Alexander, Angelina and Konstantine. A John Kanellopoulos My wife Elizabeth. David O. Brart My kids Alessandro and Luca Ghigo, the lastcomers, two potentially brilliant researchers in the field of nanotechnology. Carlo Francesco Lovisolo

Contributors A John Kanellopoulos Director, Laser Vision Gr. Institute Mesogeion 2 and Vasilissis Sofias Pyrgos Athinon (B Building) Athens 11527 Greece Amar Agarwal MS FRCS FRCOphth Agarwal s Eye Hospital 19 Cathedral Road Chennai - 600 086 Tamilnadu Antonio Calossi OD FAILAC FBCLA Studio Optometrico Calossi Via 2 Giugno, 37 50052 Certaldo (FI) Italy Antonio Leccisotti Istituto Laser Microchirurgia Oculare Crystal Palace, Via Cefalonia, 70 25124 Brescia Italy Arun C Gulani Director Gulani Vision Institute 8075 Gate Parkway (W) Suite 102, Jacksonvill Florida-32216 USA Ashok Garg MS PhD FRSM Chairman and Medical Director Garg Eye Institute and Research Centre 235-Model Town, Dabra Chowk Hisar-125005 Athiya Agarwal DO Agarwal s Eye Hospital 19 Cathedral Road Chennai - 600 086 Tamilnadu Aylin Ertan Kudret Goz Hastanesi Kennedy Caddesi No.71 Kavaklidere-Ankara Turkey Bahri Aydin Alparslan Turkes cad. No.57 Emek 06510 Ankara Turkey Belquiz A Nassaralla PhD Goiania Eye Instiute Department of Cornea and Refractive Surgery, Goiania, GO Brazil Brian Boxer Wachler Director Boxer Wachler Vision Institute 465 N, Roxbury, Dr. Suite 902 Los Angeles, CA 90210 USA Caitroina Kirwan MRC Ophth Department of Refractive Surgery Mater Private Hospital Eccles Street Dublin 7 Ireland Carina Koppen Department of Ophthalmology University Hospital Antwerp Wilrijkstraat 10, B-2650 Edegem (Antwerp) Belgium Carlo F Lovisolo Medical Director QuattroElle Eye Center via Cusani, 7-9, 20121 Milano Italy C Banu Cosar Associate Professor of Ophthalmology Sinpas Aqua City 1. Etap H Block D:13, Cekmekoy 34773 Istanbul Turkey Chitra Ramamurthy The Eye Foundation 582-A DB Road RS Puram Coimbatore-641002 Tamilnadu CS Siganos Deptt. of Ophthalmology Institute of Vision and Optics University of Crete Greece David PSO Brart FRCS FRCOphth Department of Ophthalmology St. Thomas Hospital, London UK

MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES viii D Ramamurthy Medical Director The Eye Foundation 582-A, DB Road R.S. Puram Coimbatore-641002 Tamilnadu Efekan Coskunseven Dunya Eye Hospital Istanbul Turkey Francisco Sanchez Leon Director Instituto Oftalmologico Novavision Av. Lomas Verdes 464 Naucalpan, Edo.Mexico Mexico CP53120 GD Kymionis PhD Deptt. of Ophthalmology, Institute of Vision and Optics University of Crete Greece Ioannis G Pallikaris PhD Director Deptt. of Ophthalmology Institute of Vision and Optics University of Crete Greece James Doutch BSc School of Optometry andvision Sciences, Cardiff, University Cardiff UK Jie Hou PhD Tianjin Eye Hospial and Eye Institute No. 4, Gansu Rd Tianjin 300020 China Joao J Nassaralla PhD Faculty of Health Sciences University of Brasilia, DF Goiania Eye Institute Department of Retina and Vitreosu Goiania, GO Brazil John Marshall PhD Department of Ophthalmology St. Thomas Hospital London UK Jorge L Alió PhD Professor and Chairman of Ophthalmology Instituto Oftalmologic De Alicante Avda. Denia 111, 03016 Edificio Vissum, Alicante Spain Kanxing Zhao PhD Tianjin Medical University Tianjin Eye Hospial and Eye Institute No.4, Gansu Rd, Tianjin 20020 China Keith M Meek PhD Chairman and Medical Director School of Optometry andvision Sciences, Cardiff, University Cardiff UK Konstantinos Samaras MRCOph Department of Ophthalmology St. Thomas Hosptial London UK Laure Gobin Department of Ophthalmology University Hospital Antwerp Wilrijkstraat 10, B-2650 Edegem (Antwerp) Belgium Lee T Nordan Gulani Vision Institute 8075 Gate Parkway (W) Suite 102, Jacksonvill Florida-32216 USA Liquing Liu Tianjin Eye Hospial and Eye Institute No.4, Gansu Rd Tianjin 300020 China Marie Jose Tassignon PhD Department of Ophthalmology University Hospital Antwerp Wilrijkstraat 10, B-2650 Edegem (Antwerp) Belgium Mesut Erdurmus Alparslan Turkes cad. No.57 Emek 06510 Ankara Turkey Michael O Keeffe FRCS Professor Department of Refractive Surgery Mater Private Hospital Eccles St, Dublin 7 Ireland Mohmed H Shabayek Instituto Oftalmologico De Alicante Avde. Denia 111, 03016 Edificio Vissum, Alicante Spain MS Sridhar SRIVISION Eye Hospital 225/A, Road No. Jubilee Hills Check Post Jubilee Hills Hyderabad-33

CONTRIBUTORS Nikos Tsiklis Deptt. of Ophthalmology Institute of Vision and Optics University of Crete Greece Nilesh Kanjiani DO FER Agarwal s Eye Hospital 19 Cathedral Road Chennai - 600 086 Tamilnadu Nurullah Cagil Ataturk Hastanesi Egitim ve Arastirma hastanesi, Goz Hastaliklari Lodumlu Yolu, No. 3 Bilkent Ankara Turkey Roberto o Pinelli Director Istituto Laser Microchirurgia Oculare Crystal Palace, Via Cefalonia, 70 25124 Brescia Italy Sally Hayes PhD School of Optometry and Vision Sciences, Cardiff, University Cardiff UK Soosan Jacob MS FRCS DNB MNAMS Agarwal s Eye Hospital 19 Cathedral Road, Chennai - 600 086 Tamilnadu Sunita Agarwal MS DO Agarwal s Eye Hospital 19 Cathedral Road, Chennai - 600 086 Tamilnadu Tarak ak Pujara Clinical Affairs Manager CustomVis, 9 Esmerelda Pass Darch, Western Australia-6065 Australia Tarek Elbeltagi Istituto Laser Microchirurgia Oculare Crystal Palace Via Cefalonia, 70 25124 Brescia Italy Yan Wang Professor, Tianjin Medical University Director Refractive Surgery Center Tianjin Eye Hospial and Eye Institute No.4, Gansu Rd Tianjin 300020 China ix

Foreword This is one of the most exciting times for ophthalmology in general, and cornea and refractive surgery in particular. The breakthroughs over the last several years are changing the way we approach the cornea and offering our patients new and exciting opportunities for visual rehabilitation. At present, there is no technology with more promise than corneal collagen cross-linking. It combines two relatively mundane entities: riboflavin or vitamin B 2, which is a naturally occurring photosensitizer found in all human cells, and ultraviolet light. A remarkable change occurs in the cornea stroma when riboflavin and ultraviolet light react together at the right concentrations and for the correct duration. The crosslinking of the corneal collagen fibrils strengthens the biomechanical properties of the cornea with a resultant increase in the tensile strength of the collagen fibrils. Although there may also be a slight flattening of the cornea, the most important effect of the cross-linking is that it stabilizes the corneal curvature and prevents further steepening and bulging of the corneal stroma. There is no significant change in the refractive index or the clarity of the cornea. The clinical applications of collagen cross-linking offers for the first time, a treatment for one of the most common corneal disorders, keratoconus, as well as the most dreaded complication of corneal refractive surgery, ectasia. Corneal ectasia is a rare but well-described complication of laser in-situ keratomileusis (LASIK) and an even more rare complication of photorefractive keratectomy (PRK). Over the last several years, risk factors for ectasia have been identified, which include high myopia, deep ablations, reduced residual corneal bed, young age, thin pachymetry, and most importantly, pre-operative corneal irregularity. However, ectasia may occur with no risk factors despite our best attempts to prevent it. Corneal ectasia is a condition in which the cornea is weakened by LASIK or PRK so that it protrudes irregularly and bows outward. This creates progressive steepening and thinning of the cornea, loss of uncorrected visual acuity, and loss of best spectacle-corrected visual acuity. The final results of ectasia may be as minimal as the need for the patient to return to the use of glasses. However, many patients may require a lifetime of rigid contact lenses, intracorneal ring segments, or penetrating keratoplasty for visual rehabilitation. Collagen cross-linking may arrest the progression of ectasia and when combined at the same time or subsequently with topographic or wavefront guided photoablation, may return uncorrected visual acuity. Patients at risk for ectasia may be prophylactically treated to prevent its occurrence. The elimination of corneal ectasia as a risk of LASIK and PRK has the potential to open an era of refractive surgery where the most dreaded complication has been eliminated. Keratoconus is a naturally occurring ocular condition similar to ectasia and characterized by progressive thinning and steepening of the central cornea. Keratoconus frequently affects patients in their teens and early twenties, progresses over the course of a decade, and leaves patients visually handicapped, often with high myopia, irregular astigmatism, and significant loss of best corrected visual acuity. Rigid contact lenses can be used to improve visual acuity in many patients, but keratoconus frequently progresses to the point that corneal transplantation is required to restore useful vision. It may recur following corneal transplantation and require further transplant surgery. The incidence of keratoconus in the general population is estimated to be approximately one in 2000 and in the United States, keratoconus is the third most common indication for penetrating keratoplasty. Corneal transplantation has undergone remarkable improvements, but it still has inherent risks

MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES that can result in permanent loss of vision, it significantly impacts the patient s quality of life during the surgical recovery phase, with lost work time, and it often requires permanent changes in lifestyle. Any modality, such as corneal collagen cross-linking that can delay or prevent corneal transplantation in patients with these conditions is of great benefit. The field of collagen cross-linking is advancing quickly. It offers for the first time a treatment for ectasia and keratoconus, two diseases that currently have no real treatment aside from corneal transplantation. There is a strong need to bring together the leading international investigators of collagen cross-linking to educate the ophthalmic community on recently published data, unpublished data, techniques, pitfalls, and personal observations. Drs. Ashok Garg, Roberto Pinelli, A. John Kanellopoulos, David Brat, and Carlo Lovisolo, the editors of Mastering Corneal Collagen Cross-linking have done exactly this. They have brought together the leading names in corneal collagen cross-linking and have created a wonderful resource for all of us to learn from their vast experience. The basic science of collagen cross-linking is explained, followed by chapters that expand our knowledge of ectasia and keratoconus. There are several chapters that describe the different techniques for employing corneal collagen cross-linking. There are also chapters on managing complications to help us avoid or treat untoward results. In addition, the DVD provides a visual representation of collagen cross-linking surgery which supplements the book beautifully. This book is an exceptional resource and the definitive book on corneal collagen cross-linking. Mastering Corneal Collagen Cross-linking should be required- reading for all of us with an interest in cornea and/or refractive surgery. Eric D Donnenfeld Professor of Ophthalmology New York University Medical Center Trustee Dartmouth Medical School 2000 N Village Ave Rockville Centre N.Y. 11570,USA Ph. 001-516766-2519 E-mail: eddoph@aol.com xii

Preface Corneal Collagen Cross-linking with Riboflavin and UV-A (C3-R) treatment is certainly a new and promising development in refractive surgery in recent times. The weakened cornea in form of Keratoconus or Post-Lasik/ PRK Corneal Ectasia (Keratoectasia) is one of the most challenging task for Ophthalmologists. Reduced corneal mechanical stability in Keratoconus and Corneal Ectasia can be treated by Photo-oxidative cross-linking of the Corneal Collagen. To achieve high absorption of irradiation energy in the cornea, Riboflavin at a concentration of 0.1% and UV-A light at a wavelength of 370 nm corresponding to the relative maximum of absorption of Riboflavin (Vitamin B 2 ) is used. Therapeutic C3-R cross-linking procedure causes decrease in corneal curvature of about 2D which leads not only to stabilization but also to an increase in visual acuity and more compact and stronger corneas. This book has been written with the aim of providing complete insight into this new technique for the benefit of refractive surgeons worldwide. Its 23 chapters have been written by International Experts of this technique and they cover all aspects of C3-R technique in a comprehensive manner. It deals with all steps mainly indications, contraindications, various surgical procedures, complications and their management. Video DVD given with this book shows the surgical steps of C3-R treatment by International Masters beautifully. Our sincere gratitude to publisher Shri Jitendar P Vij (CEO), M/s Jaypee Brothers Medical Publisher Pvt. Ltd. (), Mr Tarun Duneja (Director Publishing) and all staff members who took active interest and done hard work in timely preparation of this book, first of its kind in the world. C3-R treatment alone or combined with INTACS provide real hope for patients with progressive Keratoconus and Keratoectasia. We expect this book shall provide the complete information on C3-R procedures to refractive surgeons who are interested to master this technique for the benefits of patients. Editors

Contents 1. Corneal Collagen Cross-linking (C3-R) A Promising Technique.... 1 Ashok Garg () 2. Corneal Biomechanical Properties... 5 Jorge L Alio, Mohamed H Shabayek (Spain) 3. Assessment and Risk Factors for Corneal Ectasia following Laser in Situ Keratomileusis and its Assessment... 9 Yan Wang, Kanxing Zhao, Liquing Liu, Jie Hou (China) 4. Avoiding Keratoconus in Patients undergoing Refractive Surgery... 15 Michael O Keefe, Caitroina Kirwan (Ireland) 5. Clinical Significance of Collagen Corneal Cross-linking in Post-LASIK Corneal Ectasia... 21 Nurullah Cagil, Bahri Aydin, Mesut Erdurmus (Turkey) 6. Biophysical Aspects of Collagen, Corneal Cross-linking Covering Details about UV-A and Riboflavin and their Mechanism of Action on the Cornea... 25 MS Sridhar(), Tarak Pujara (Australia) 7. The Importance of Epithelial Debridement for Riboflavin Absorption Prior to Riboflavin/Ultraviolet-A (UV-A) Corneal Collagen Cross-linkage Therapy : A Laboratory Study Using Spectrophotometry in Porcine Corneas... 29 David PS O Brart, Konstantinos Samaras, James Doutch, Sally Hayes, John Marshall, Keith M Meek (UK) 8. Indications and Contraindications: Traditional Techniques Vs Transepithelial Technique... 38 Roberto Pinelli, Antonio Leccisotti, Tarek Elbeltagi (Italy) 9. Considerations on Endothelial Safety in UV-A Cross-linking Treatment... 44 Carina Koppen, Laure Gobin, Marie Jose Tassignon (Belgium) 10. Corneal Collagen Cross-linking with Riboflavin and Ultraviolet-A Light : Step by Step Technique... 51 Belquiz A Nassaralla, Joao J Nassaralla (Brazil) 11. Advances in Corneoplastique TM : Art of Laser Vision Surgery... 56 Arun C Gulani, Lee T Nordan (USA) 12. Applications of Collagen Corneal Cross-linking... 64 D Ramamurthy, Chitra Ramamurthy () 13. Cross-linking Plus Topography guided PRK for Post-LASIK Ectasia Management... 69 A John Kanellopoulos (Greece) 14. INTACS and Corneal Collagen Cross-linking with Riboflavin and Ultraviolet-A as a Combined Treatment for Irregular Astigmatism... 81 Nikos Tsiklis, GD Kymionis, E Coskunseven, CS Siganos, Ioannis. G Pallikaris (Greece) 15. Transepithelial Cross-linking for the Treatment of Keratoconus : Concepts... 87 Roberto Pinelli (Italy) 16. Corneal Collagen Cross-linking in Keratoconus... 92 C Banu Cosar, Efekan Coskunseven (Turkey)

MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES 17. Corneal Collagen Cross-linking with Riboflavin (C3-R) Combined with Intrastromal Ring Segment Implantation and Overnight Contact Lens Molding in Keratoconus... 98 Carlo F Lovisolo, Antonio Calossi (Italy) 18. Transepithelial Cross-linking Treatment in Eyes with INTACS... 110 Aylin Ertan (Turkey) 19. Re-shaping Keratoconus : Laser PRK followed by Corneal Cross-linking... 120 Arun C Gulani, Brian Boxer Wachler (USA) 20. Cross-linking in Keratoconus : Advantages and Disadvantages... 132 C Banu Cosar (Turkey) 21. Corneoplastics using Corneal Collagen Cross-linking and Intracorneal Rings of Keratoconus and Lasik Ectasia... 134 Francisco Sanchez Leon (Mexico) 22. Collagen Corneal Cross-linking Different Techniques... 140 Francisco Sanchez Leon (Mexico) 23. Posterior Corneal Changes in Refractive Surgery... 147 Amar Agarwal, Soosan Jacob, Sunita Agarwal, Athiya Agarwal, Nilesh Kanjiani () 24. Complications with the Use of Collagen Cross-linking... 156 A John Kanellopoulos (Greece) Index... 159 xvi