Mastering Corneal Collagen Cross-linking Techniques (C3-R/CCL/CxL)
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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 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 India
Roberto Pinelli
A John Kanellopoulos
MD
MD
Director, Istituto Laser Microchirurgia Oculare Crystal Palace, Via Cefalonia 70, 25124, Brescia Italy
Director, Laservision gr. Institute Mesogeion 2 and Vasilissis Sofias Pyrgos Athinon Building B, 11527-Athens Greece
David O Brart
Carlo F Lovisolo
MD, FRCS, FRCOph
MD
Department of Ophthalmology Kings College, London The Rayne Institute St Thomas Hospital, London UK
Medical Director QuattroElle Eye Center Via Cusani, 709, 20121 Milano Italy
Foreword Eric D Donnenfeld ®
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Mastering Corneal Collagen Cross-linking Techniques © 2009, Editors All rights reserved. No part of this publication and Video DVD Rom should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the editors and the publisher. This book has been published in good faith that the material provided by contributors is original. Every effort is made to ensure accuracy of material, but the publisher, printer and editors will not be held responsible for any inadvertent error(s). In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only.
First Edition: 2009 ISBN 978-81-8448-493-9 Typeset at JPBMP typesetting unit Printed at Ajanta Press
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
Athiya Agarwal
Carina Koppen
MD
MD DO
MD
Director, Laser Vision Gr. Institute Mesogeion 2 and Vasilissis Sofias Pyrgos Athinon (B Building) Athens 11527 Greece
Agarwal’s Eye Hospital 19 Cathedral Road Chennai - 600 086 Tamilnadu India
Department of Ophthalmology University Hospital Antwerp Wilrijkstraat 10, B-2650 Edegem (Antwerp) Belgium
Amar Agarwal
Aylin Ertan
Carlo F Lovisolo
MD
MD
Kudret Goz Hastanesi Kennedy Caddesi No.71 Kavaklidere-Ankara Turkey
Medical Director QuattroElle Eye Center via Cusani, 7-9, 20121 Milano Italy
MS FRCS FRCOphth
Agarwal’s Eye Hospital 19 Cathedral Road Chennai - 600 086 Tamilnadu India Antonio Calossi OD FAILAC FBCLA Studio Optometrico Calossi Via 2 Giugno, 37 50052 Certaldo (FI) Italy
Bahri Aydin
Antonio Leccisotti
Belquiz A Nassaralla
MD
MD PhD
Istituto Laser Microchirurgia Oculare Crystal Palace, Via Cefalonia, 70 25124 Brescia Italy Arun C Gulani MD
MD
Alparslan Turkes cad. No.57 Emek 06510 Ankara Turkey
Goiania Eye Instiute Department of Cornea and Refractive Surgery, Goiania, GO Brazil Brian Boxer Wachler
Director Gulani Vision Institute 8075 Gate Parkway (W) Suite 102, Jacksonvill Florida-32216 USA
MD
Ashok Garg
Caitroina Kirwan
MS PhD FRSM
MRC Ophth
Chairman and Medical Director Garg Eye Institute and Research Centre 235-Model Town, Dabra Chowk Hisar-125005 India
Department of Refractive Surgery Mater Private Hospital Eccles Street Dublin 7 Ireland
Director Boxer Wachler Vision Institute 465 N, Roxbury, Dr. Suite 902 Los Angeles, CA 90210 USA
C Banu Cosar MD
Associate Professor of Ophthalmology Sinpas Aqua City 1. Etap H Block D:13, Cekmekoy 34773 Istanbul Turkey Chitra Ramamurthy MD
The Eye Foundation 582-A DB Road RS Puram Coimbatore-641002 Tamilnadu India CS Siganos MD
Deptt. of Ophthalmology Institute of Vision and Optics University of Crete Greece David PSO’ Brart MD FRCS FRCOphth
Department of Ophthalmology St. Thomas’ Hospital, London UK
MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES D Ramamurthy
Joao J Nassaralla
Lee T Nordan
MD
MD PhD
MD
Medical Director The Eye Foundation 582-A, DB Road R.S. Puram Coimbatore-641002 Tamilnadu India
Faculty of Health Sciences University of Brasilia, DF Goiania Eye Institute Department of Retina and Vitreosu Goiania, GO Brazil
Gulani Vision Institute 8075 Gate Parkway (W) Suite 102, Jacksonvill Florida-32216 USA
John Marshall Efekan Coskunseven MD
Dunya Eye Hospital Istanbul Turkey Francisco Sanchez Leon MD
Department of Ophthalmology St. Thomas Hospital London UK Jorge L Alió MD PhD
Director Instituto Oftalmologico Novavision Av. Lomas Verdes 464 Naucalpan, Edo.Mexico Mexico CP53120
Professor and Chairman of Ophthalmology Instituto Oftalmologic De Alicante Avda. Denia 111, 03016 Edificio Vissum, Alicante Spain
GD Kymionis
Kanxing Zhao
MD PhD
MD PhD
Deptt. of Ophthalmology, Institute of Vision and Optics University of Crete Greece
Tianjin Medical University Tianjin Eye Hospial and Eye Institute No.4, Gansu Rd, Tianjin 20020 China
Ioannis G Pallikaris
Keith M Meek
MD 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
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PhD
PhD
Chairman and Medical Director School of Optometry andVision Sciences, Cardiff, University Cardiff UK Konstantinos Samaras MD MRCOph
Department of Ophthalmology St. Thomas Hosptial London UK
Liquing Liu MD
Tianjin Eye Hospial and Eye Institute No.4, Gansu Rd Tianjin 300020 China Marie Jose Tassignon MD PhD
Department of Ophthalmology University Hospital Antwerp Wilrijkstraat 10, B-2650 Edegem (Antwerp) Belgium Mesut Erdurmus MD
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 MD
Instituto Oftalmologico De Alicante Avde. Denia 111, 03016 Edificio Vissum, Alicante Spain MS Sridhar
Laure Gobin
MD
Jie Hou
MD
PhD
Department of Ophthalmology University Hospital Antwerp Wilrijkstraat 10, B-2650 Edegem (Antwerp) Belgium
SRIVISION Eye Hospital 225/A, Road No. Jubilee Hills Check Post Jubilee Hills Hyderabad-33 India
Tianjin Eye Hospial and Eye Institute No. 4, Gansu Rd Tianjin 300020 China
CONTRIBUTORS Nikos Tsiklis
Robert o Pinelli Roberto
Tar ak Pujara Tarak
MD
MD
MD
Deptt. of Ophthalmology Institute of Vision and Optics University of Crete Greece
Director Istituto Laser Microchirurgia Oculare Crystal Palace, Via Cefalonia, 70 25124 Brescia Italy
Clinical Affairs Manager CustomVis, 9 Esmerelda Pass Darch, Western Australia-6065 Australia
Sally Hayes
Tarek Elbeltagi
PhD
MD
School of Optometry and Vision Sciences, Cardiff, University Cardiff UK
Istituto Laser Microchirurgia Oculare Crystal Palace Via Cefalonia, 70 25124 Brescia Italy
Nilesh Kanjiani DO FER
Agarwal’s Eye Hospital 19 Cathedral Road Chennai - 600 086 Tamilnadu India Nurullah Cagil MD
Ataturk Hastanesi Egitim ve Arastirma hastanesi, Goz Hastaliklari Lodumlu Yolu, No. 3 Bilkent Ankara Turkey
Soosan Jacob MS FRCS DNB MNAMS
Agarwal’s Eye Hospital 19 Cathedral Road, Chennai - 600 086 Tamilnadu India Sunita Agarwal MS DO
Agarwal’s Eye Hospital 19 Cathedral Road, Chennai - 600 086 Tamilnadu India
Yan Wang MD
Professor, Tianjin Medical University Director Refractive Surgery Center Tianjin Eye Hospial and Eye Institute No.4, Gansu Rd Tianjin 300020 China
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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 B2, 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 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 surgery.
Eric D Donnenfeld MD
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:
[email protected]
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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 B2) 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. (India), 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 (India) 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 PostLASIK Corneal Ectasia ..................... 21 Post-LASIK 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(India), 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 CorneoplastiqueTM: 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 (India) 13. Cross-linking Plus Topography guided PRK for PostLASIK Ectasia Management .............................. 69 Post-LASIK 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 (India) 24. Complications with the Use of Collagen Cross-linking ..................................................................... 156 A John Kanellopoulos (Greece)
Index ..................................................................................................................................................... 159
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CORNEAL COLLAGEN CROSS-LINKING (C3-R)–A PROMISING TECHNIQUE
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
INTRODUCTION In last one decade Corneal Refractive Surgery has advanced rapidly with excellent visual results worldwide. Refractive surgeons have come across the problem of Post Refractive Keratectasia or Corneal ectasia. Due to effect of Excimer Laser photoablation on the corneal biomechanical properties a significant decrease in the bio mechanical assets was found after surgery. This implies that due to creation of flap and subsequent corneal thinning by ablation weakens the cornea and decreases its elastic properties. This leads later to corneal ectasia. This is indicator for the clinical significance of evaluating corneal biomechanical properties specifically the corneal hysteresis and resistance factor in screening refractive surgery patients. Similarly in Keratoconus (a progressive non inflammatory cone like Ectasia) the corneal hysteresis (CH) and corneal resistance factor (CRF) are significantly lower than in the normal eyes and post Lasik surgery corneas Low values of CH means that the cornea is less capable of absorbing the energy of the air pulse whereas low values of CRF indicates that corneal rigidity is lower than normal. The corneal biomechanical properties are primarily determined by the collagen fibres and the degree of interfibrillar linkage. Corneal Ectatic conditions whether inflammatory or non inflammatory have weak interfibrillar linkage strength. WHAT IS CROSS-LINKING?
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Cross-linking of human Collagen is a physiologic process. Corneal Collagen Cross-linking also known as C3-R/CCL/CxL treatment is a new approach to increase the mechanical and chemical stability of corneal tissue. The primary aim of this treatment is to create additional chemical bonds inside the corneal stroma by means of a highly localized photopolymerization while minimizing exposure to the surrounding structure of the eye. This procedure was first developed by Prof. Theo Seiler, Prof. Wollensak and Prof. Eberhard Spoerl in 1998 at the University of Dresdan, Germany. They did this procedure in cases of progressive Keratoconus and Post Refractive Corneal Ectasia. Followed this other studies undertaken by Dr A Caporossi, Dr Roberto Pinelli and their colleagues (Italy) and Dr Brian Boxer in USA.
There are several different techniques of crosslinking. The most promising technique in cornea is use of UV light and Riboflavin (Vitamin B2 solution) for inducing cross-linking to increase biomedical rigidity of the cornea. This slows down or even stops the progressive thinning of the cornea. In this Photopolymerisation is performed by means of a nontoxic and soluble photo mediator (Riboflavin) and a wavelength which was absorbed strongly enough to protect deeply layers of the eye. (Riboflavin - UVA technique). PHYSIOLOGY OF COLLAGEN CORNEAL CROSS-LINKING In this procedure custom made Riboflavin eye drops are applied to the cornea which is then activated by ultraviolet light. Using UVA at 370 nm, the photosenstizer Riboflavin is excited into its triplet state generating reactive oxygen species (ROS) which is mainly singlet oxygen and to a much less degree superoxide anion radicals. The ROS can react further with various molecules including chemical covalent bonds bridging amino groups collagen fibrils / type II photochemical reaction (Fig. 1.1 and 1.2). The wavelength of 370 mm of UVA is chosen because of an absorption peak of Riboflavin at this wavelength Biomechanical studies have shown an increase in the corneal rigidity of 328.9% in human cornea after crosslinking (Fig. 1.3). The increase on biomechanical rigidity after C3-R is probably caused by an increase
Figure 1.1: Bonding tissues and cross-linking
CORNEAL COLLAGEN CROSS-LINKING (C3-R)–A PROMISING TECHNIQUE
PARAMETERS FOR C3-R TREATMENT • • • •
Disorder should be progressive in nature Thinnest corneal pachymetry higher than 400 um No central corneal scarring Maximum corneal curvature should not exceed 60 D.
PREOPERATIVE WORK UP FOR C3-R TREATMENT
Figure 1.2: Strengthening of corneal fibres by C3-R Treatment
Figure 1.3: UV-XTM Illumination system
in the collagen fiber diameter due to interfibrillar and Intrafibrillar covalent bonds by photosensitized oxidation cross-linking. The cross-linking results in more compact stronger corneas that are more resistant to biomechanical deformation or ectasia.
• Visual acuity assessment (UCVA, BCVA, Contrast senstivitiy) • Intra ocular pressure recording • Detailed Slit Lamp Examination specially for Vogts Striae, Fleischer’s ring and corneal scarring • Slit lamp photographs of corneal changes • Pentacam evaluation for central corneal thickness and thinnest pachymetry • Corneal Topography • OCT Examination. STEPS OF C3-R TECHNIQUE (FIG. 1.4) The procedure takes place ambulatory and takes about one hour. • First eye is anesthelized with Topical proparacaine 0.5 eye drops. Then Manual debridement of corneal epithelium. (Thin surface layer) is abrased in the
INDICATIONS FOR C3-R TREATMENT • Progressive keratoconus • Iatrogenic post refractive keratectasia (Post Lasik Ectasia) • Pellucid marginal degeneration. EXCLUSION CRITERIA • Corneal thinkness less than 400 um at thinnest position • Keratometric readings above 60 Diopter • Active ocular disease • Herpes Keratitis • Diabetes • Pregnancy • Previous ocular surgery other than Laser refractive surgery • Immunocompromised Patients • Patients with known sensitivity.
Figure 1.4: Corneal collagen cross-linking (controlled UVA radiation is applied to corneal stroma to stiffen the cornea
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
central 7 mm of cornea in order to allow penetration of stroma. Riboflavin solution containing 0.1% Riboflavin, 20% Dextran T 500 in isotonic sodium chloride solution (ph 7.0) is applied every 3 minute for the first 30 minutes. This is followed by irradiation of cornea with 365 nm UVA using UV-XTM for 30 minutes. Riboflavin drops are then continued for another 30 minutes at the interval of every 5 minutes as the eye is exposed to a UVA light positioned above the cornea to deliver predetermined dose of UVA light. The distance between the UV delivery system and cornea should be 5 cm (50 mm) so as to deliver a dose of 3 mw/cm2 (Total of 5.4 J/cm2 in 30 mts). As the UVA light interacts with the Riboflavin chemical bonds (cross links) form between the Corneal Collagen molecules and make the Cornea stiffer. As a result the corneal collagen tissue is stronger and can more uniformly retains its natured curved shape rather than bow forward into the cone like shape that is hallmark of Keratoconus and corneal ectasia. At the end of treatment the cornea is flushed with BSS and a bandage contact lens is placed over the cornea. POSTOPERATIVE FOLLOW-UP Patient is prescribed Topical antibiotics, nonsteroidal anti inflammatory and Lubricating eye drops in the postoperative period. Eye may be little painful after the treatment and it may take off after 48 hours. Till the closure of epithelial defect the patient is followed
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up everyday. Bandage contact lens is taken off when epithelial defect heals. Subsequent follow-up should be taken at 1 week, 4 weeks, 12 weeks, 24 weeks and 1 year. On each follow-up Refraction, Keratometry, Slit lamp and Pentacam Examination is mandatory. OCT is done at the one month visit and subsequent visits. FUTURE PROSPECTS Corneal Collagen Cross-linking with Riboflavin and UVA for the treatment of progressive keratoconus and post refractive keratectasia are relatively safe and effective treatment. The ability to permanently strengthen the inherently weakned cornea is a major advancement and achievement of this technique. C3-R treatment alone or combined with intacs implantation in Keratoconus are allowing improved vision and comfort to the patients. C3-R is a simple, safe and effective procedure in the management of progressive ectatic disorders of the cornea. C3-R treatment shall become a standard treatment in near future. A lot of clinical research works is going on for the further improvement and wider applications of this treatment, New Clinical research works have started for possible combining of C3-R treatment with topography guided advanced surface ablation, intacs, orthokeratology and conductive keratoplasty. Possible C3-R treatment applications in treating corneal edema, bullous Keratopathy are also being investigated with lot of hope and promise.
CORNEAL BIOMECHANICAL PROPERTIES
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
INTRODUCTION Corneal refractive surgery advanced rapidly during the past two decades, due to the encouraging, predictable and stable results of corneal remodelling by photoablation using excimer lasers. A result of such advancement a new frontier of diagnostic equipments and tools became accessible to ophthalmic surgeon such as; corneal topographer, wavefront sensors, very high frequency optical coherence tomography (VHF OCT), and confocal microscopy. This technology aided in analysing not only the optical but also the structural properties of the cornea. Recently the biomechanical properties of the cornea have been introduced as a new parameter in corneal refractive surgery, parameter that evaluates corneal characteristics from the biomechanical perspective; such as the corneal resistance factor, and corneal hysteresis. These parameters can be helpful for diagnosing certain corneal pathologies especially corneal ectatic diseases, were the biomechanical corneal characteristics are different from normal corneas. TERMINOLOGY Corneal Hysteresis The term “Hysteresis” is derived from an ancient Greek word which means “coming behind”. It was first introduced into scientific vocabulary in 1890 by the Scottish physicist, Sir James Alfred Ewing. Hysteresis is a property of physical systems that do not instantly follow the forces applied to them, but react slowly, or do not return completely and instantaneously to their original state.
Figure 2.1: Corneal resistance factor which is the amount of pressure needed to flatten the anterior corneal surface
applanation. Pallikaris et al 6 measured the ocular rigidity in living human eyes increasing the intraocular pressure by injecting a saline solution into the anterior chamber; while, Grabner et al7 used the dynamic corneal imaging method by central indentation to assess the individual elastic properties of eyes. Where as, Luce8 determined the biomechanical properties of the cornea using the Reichert ocular response analyzer (ORA), based on a dynamic bidirectional applanation process. OCULAR RESPONSE ANALYZER ORA The Ocular Response Analyzer, (ORA Reichert Ophthalmic Instruments, Depew NY) (Fig. 2.2) measures the corneal biomechanical properties by using a dynamic bidirectional air applanation process (non invasive method). It is composed of an air pump which applies a force on the anterior corneal surface (specific point) through a pressure transducer while an infrared light emitter is focused on the same point
Corneal Resistance Factor
6
The static resistance component of the cornea which indicates the overall corneal resistance or simply the pressures “force” needed to applanate “deform” the cornea, this deformation is proportional to applied force and is expressed in mmHg (Fig. 2.1). However, measuring the biomechanical properties in vivo is a challenging task, and has been approached by several methods,1-8 whether invasive as anterior Chamber saline injection and measuring ocular rigidity or non invasive as dynamic corneal imaging with central indentation and dynamic bidirectional air
Figure 2.2: Ocular response analyzer (ORA)
CORNEAL BIOMECHANICAL PROPERTIES
and the reflection of this infrared beam is monitored by a light intensity detector. This system records two applanation pressure measurements; one while the cornea is moving inward, and the other as the cornea returns. Due to its biomechanical properties, the cornea resists the dynamic air puff causing delays in the inward and outward applanation events, resulting in two different pressure values (Figs 2.3 and 2.4).
Figure 2.3: The infrared light intensity is maximally detected when the anterior corneal surface is applanated
Figure 2.4: ORA graph showing the difference in pressure between the In signal peek and the out signal peek which evaluates the viscoelastic property of the cornea (corneal hysteresis)
properties in normal non complaining individual and keratoconic eyes using the ocular response analyzer ORA. The study included a total of 250 eyes divided into three groups: 164 normal eyes, 21 keratoconic eyes and 65 eyes that had undergone a corneal refractive surgery procedure to evaluate the effect of LASIK on the corneal biomechanical properties. The author’s inclusion criteria were: for normal and post-refractive surgery groups, patients with any irregular patterns of corneal topography or history of ocular disease were not included; and for keratoconus group, only eyes with keratoconus with at least one clinical sign that was confirmed by corneal topography. Results of this study, demonstrated that in the normal group, a decrease in the corneal biomechanical properties was observed in elder patients. This implies a loss of the elastic properties of the cornea with age, which coincides with the increase of ocular rigidity found by Pallikaris et al.6 As for the post LASIK surgery group, or the effect of excimer laser photoablation on the corneal biomechanical properties, a significant decrease in the biomechanical properties was found after the surgery. This result coincides with other studies 1,7,10 and implies that the creation of the flap and the corneal thinning by ablation weaken the cornea and decreases its elastic properties. This could lead later to corneal ectasia after refractive surgery11,12. This can be an indicator for the importance of evaluating corneal biomechanical properties precisely the corneal hysteresis and resistance factor in screening refractive surgery candidates. In keratoconic eyes, the corneal hysteresis (CH) and the corneal resistance factor (CRF) were significantly lower than in normal eyes and post LASIK surgery corneas. Low values of CH imply that the cornea is less capable of absorbing the energy of the air pulse, where as, low values of CRF, indicates the cornea rigidity is lower than normal. REFERENCES
CORNEAL BIOMECHANICAL PROPERTIES IN NORMAL, KERATOCONIC EYES AND POSTLASIK EYES In Prospective, conventional, comparative, interventional study,9 that reported the corneal biomechanical
1. Jaycock PD, Lobo L, Ibrahim J, et al. Interferometric technique to measure biomechanical changes in the cornea induced by refractive surgery. J Cataract Refract Surg 2005;31:175-84. 2. Mamelok AE, Posner A. Measurements of corneal elasticity in relation to disease, using the Wiegersma elastometer. Am J Ophthalmol 1955;39:817-21.
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES 3. Vaughan JM, Randall JT. Brillouin scattering, density and elastic properties of the lens and cornea of the eye. Nature 1980;284:489-91. 4. Kasprzak H, Forster W, von BG. Measurement of elastic modulus of the bovine cornea by means of holographic interferometry. Part I. Method and experiment. Optom Vis Sci 1993;70:535-44. 5. Wang H, Prendiville PL, McDonnell PJ, Chang WV. An ultrasonic technique for the measurement of the elastic moduli of human cornea. J Biomech 1996;29:1633-36. 6. Pallikaris IG, Kymionis GD, Ginis HS, et al. Ocular rigidity in living human eyes. Invest Ophthalmol Vis Sci 2005;46:409-14. 7. Grabner G, Eilmsteiner R, Steindl C, et al. Dynamic corneal imaging. J Cataract Refract Surg 2005;31:163-74.
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8. Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg 2005;31:156-62. 9. Ortiz D, Piñero D, Shabayek MH, et al. Corneal biomechanical properties in normal, post-laser in situ keratomileusis, and keratoconic eyes. J Cataract Refract Surg 2007;33:1371–75. 10. Kamiya K, Miyata K, Tokunaga T, et al. Structural analysis of the cornea using scanning-slit corneal topography in eyes undergoing excimer laser refractive surgery. Cornea 2004;23:S59-S64. 11. Dupps WJ, Jr. Biomechanical modeling of corneal ectasia. J Refract Surg 2005;21:186-90. 12. Guirao A. Theoretical elastic response of the cornea to refractive surgery: Risk factors for keratectasia. J Refract Surg 2005;21:176-85.
ASSESSMENT AND RISK FACTORS FOR CORNEAL ECTASIA FOLLOWING LASER IN SITU KERATOMILEUSIS AND ITS ASSESSMENT
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
INTRODUCTION Although corneal ectasia (keratectasia) after laser in situ keratomileusis (LASIK) is reported uncommon, which is estimated to be 0.1%1to 0.66%,2 it is still an enigmatic and potentially devastating complication following laser in situ keratomileusis (LASIK). 3 Abnormal collagen in addition to thin corneas may lead to progressive inferior corneal steepening, increase in myopia, irregular astigmatism, and loss of best corrected visual acuity. Unfortunately, the etiology of corneal ectasia is not fully known. When contact lenses are no longer effective in preventing ectasia progression, there are some surgical management available, such as lamellar keratoplasty and intrastromal corneal ring segments. Various medical therapies did not differ significantly in decreasing the progression of ectasia. Hence, penetrating keratoplasty is another commonly performed surgical procedure for ectatic corneas. However, it is associated with many complications.4 Recently, Crosslinking seems to be one of the more effective means in the management of mild to severe cases. It is essential that before the clinical treatment, the surgeon must correctly identify, assess, and understand the risk factors of corneal ectasia following laser in situ keratomileusis. Precise assessment is crucial in the management of corneal ectasia after laser in situ keratomileusis. ASSESSMENT
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Accurate detection of corneal ectasia is very important. A precise diagnosis of corneal ectasia may explain a patient’s symptoms postoperatively. A regression of refractive power may alter the postoperative management and treatment. Corneal ectasia is a direct contraindication for any enhancement surgeries and may detriment the cornea even further. There may be no clinical symptoms in early stages. Although in some advanced cases, astigmatism may appear which may be detected by a refractive examination. Some patients may report acute onset of blurred vision. In the postoperative period, patients may frequently notice dramatic fluctuations in their vision3 and experience regression of their refractive surgical outcome. Like early keratoconus, corneal ectasia is difficult to detect using clinical tests. A useful tool for early
detection of keratoconus or keratectasia is pachymetry, which shows the relationship of the apical, central and thinnest part of the cornea. Corneal topography provides useful and accurate information with regards to the position of the ectasia. It also allows to detect the progression, and for early cases. Corneal topography is a diagnostic tool for corneal ectasia. CORNEAL TOPOGRAPHY Corneal ectasia has a similar clinical entity and topography with keratoconus and forme fruste keratoconus. Therefore, after LASIK, corneal ectasia has been reported in patients with keratoconus,5 and forme fruste keratoconus (FFKC). 6,7 Also, the progression of ectasia can be most effectively evaluated via analysis of a series of corneal topographies. Most diagnoses and assessments for keratoconus are based on anterior corneal curvature and elevation data derived from Placido-based corneal topography. But some mild degrees of post-LASIK keratectasia may be better detected at the level of the posterior corneal surface. The posterior corneal shape is mainly used for early recognition of this pathologic condition. Thus, it is prudent to be able to accurately evaluate any changes in the posterior cornea after LASIK.8,9 ORBSCAN The Orbscan corneal topography system, which uses a placido device, can obtain the corneal curvature and has been used in refractive surgery for many years. It takes 40 slit sections of the cornea during two scans. The anterior and posterior corneal height profiles are reconstructed from these sections using threedimensional ray tracing with 9600 points. The Orbscan has been proven to provide useful and accurate information regarding the morphology and topographic changes related to keratoconus. 10 Posterior topographic changes after LASIK are obviously, which has been well investigated.11,12 The risk of ectasia, which is highly suspected as corneal ectasia or keratoconus, is suggested as follows:13 • A variance of more than 1.00D in astigmatism between the eyes. • Keratometric or corneal steepness on the mean power map.
ASSESSMENT AND RISK FACTORS FOR CORNEAL ECTASIA FOLLOWING LASER IN SITU KERATOMILEUSIS AND ITS ASSESSMENT
Figure 3.1: This Orbscan quad map shows a posterior float of approximately 0.065 mm, a strong red flag for forme fruste keratoconus
• The posterior surface float is greater than 0.05 mm (The difference between the highest and lowest spots). Near the center of the posterior elevation map appears a dark reddish color. Wang et al12 have shown that the posterior elevation increases after LASIK. The increase is correlated with residual corneal bed thickness (Figure 3.1). • Irregularity at 3 mm to 5 mm of the central cornea. • The thinnest area of corneal thickness is more than 20 μm thinner than the thickness of the central cornea. • The number of abnormal maps using the normal band scale. One abnormal map does not indicate forme fruste keratoconus or corneal ectasia. It is necessary to check after a few months. Two abnormal maps may indicate early keratoconus or corneal ectasia. Recently however, some studies showed that Orbscan fails to correctly identify the posterior corneal
surface and can give incorrect diagnosis of post LASIK ectasia. 14,15 We believe that corneal topography is an important complementary tool in the diagnosis of post LASIK ectasia. To fully evaluate these measurements, the clinician must look at the indices as a whole rather than at each individual values separately. The three components that are displayed (The elevation, curvature, and pachymetry) are designed to help in the analysis by comparing each one to another. PENTACAM Previous studies have reported that the Pentacam has a high degree of repeatability for the measurement of the posterior corneal curvature.16 The Pentacam is a rotating Scheimpflug camera with a higher depth of focus. It assesses the anterior chamber of the eye, the topographic corneal thickness,
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
Figure 3.2: This Pentacam quad map shows corneal ectasia after LASIK. Each abnormal part of on the 3 maps (A, B, C) is at the same point
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corneal curvature, anterior chamber angle, and volume and height from up to 25,000 true elevation points. The system takes 50 pictures in a maximum of two seconds while rotating around a central point with a moveable eye. Scheimpflug imaging differs from the Placido-based system in that it allows for the measurement of both the anterior and posterior corneal surfaces and the computation of a complete pachymetric map. The method of depicting elevation data and the subtracted reference shapes commonly uses a best-fit-sphere (BFS) and identifies a 4 mm optical zone centered on the thinnest portion of the cornea (exclusion zone). BFS is defined by utilizing all the valid data from within the 9 mm central cornea with the exception of the exclusion zone.17 The proposed screening parameters are:18,19 • Anterior elevation differences < +12μm are normal. • Anterior elevation differences > +15μm are indicative of keratoconus.
• Anterior elevation differences + 12 ~ +15μm are suspicious. • Similar numbers (about 5μm higher) apply to posterior elevation. The confirmation can be made for forme fruste keratoconus when the hot spot on the tangential map, relative pachymetry map and back elevation map, using the toric ellipsoid, are all at the same point. By Holliday’s experience,18 exceed -3.0% are significant for relative pachymetry, also for elevations of more than 15μm above the toric ellipsoid on the back elevation map (Fig. 3.2). Other indices of the ectasia are the position of the thinnest point. At the beginning of the ectasia, the thinnest point is at central position. The thinnest point can transform from central position toward an eccentric position. Several other parameters could also be extracted from corneal tomography examination. These include a faster and a more abrupt increase of the corneal
ASSESSMENT AND RISK FACTORS FOR CORNEAL ECTASIA FOLLOWING LASER IN SITU KERATOMILEUSIS AND ITS ASSESSMENT
Figure 3.3: Pentacam map shows a steep and abrupt increase of the corneal thickness spatial profile and percentage of increase in thickness. The patient was suspected as keratoconus level 1 after LASIK
thickness spatial profile and the percentage of increase of thickness relative to normal corneas.17 Figure 3.3 shows a particular case of a patient with post-LASIK ectasia. All of these can be used in a series of follow-up exams of the posterior corneal curvature in post-LASIK eyes. This will help to identify and predict keratectasia following LASIK. However, whether these measurements are more sensitive and specific than the classic Placido-based topography needs further investigation. RISK FACTORS After LASIK, there are many risk factors that may increase the probability of corneal ectasia. None of these factors are absolute predictors of corneal ectasia, but are correlated with its occurrence. Also, LASIK is not necessarily a causative or contributing factor to corneal ectasia seen postoperatively.20 Possible risk factors analyzed by Randleman et al3 include high
myopia, and thin preoperative corneal thickness. Some possible risk factors include: • Forme fruste keratoconus (FFKC): Some ectasia after LASIK has been reported in patients with forme fruste keratoconus.6,7 One study showed 88% of affected eyes met the FFKC criteria. 3 Therefore, screening and identifying patients with FFKC preoperatively is necessary. • Keratoconus in one eye or a family history of keratoconus. Eyes with keratoconus are known to produce unpredictable refractive results and scarring after LASIK.21,22 • Residual stromal bed thickness after laser ablation was less than 250μm. Many studies have showed that the residual stromal bed thickness of more than 250μm would possibly be safe. 1 • High myopia: Patients with high myopia require more tissue ablation during LASIK. This leaves them with a lower residual stromal bed thickness than patients with low myopia, increasing the risk for developing ectasia.
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• Patients that have underwent enhancement after LASIK surgery. It has been proposed that multiple enhancements were correlated with ectasia .23 Enhancement after LASIK surgery may make residual stromal bed thinner. • Asymmetrical cornea steepening. • Asymmetrical astigmatism. • High keratometric measurements: A higher risk of keratoectasia is suggested by K readings of 46D or more at the steepest point.13 • Age: With aging, the structure and shape of the cornea changes and may attribute to the development of ectasia. • Patients who have genetic corneal dystrophies.24 Clinically, some of the patients who developed corneal ectasia may have multiple risk factors. As technology continually advancing, the knowledge for assessing corneal ectasia following laser in situ keratomileusis continues to grow and criterion may be changed. Further studies are needed to provide more accurate and predictable treatment outcomes. ACKNOWLEDGMENTS We thank John Barkley OD, Thanh Nguyen OD and Tran Nguyen OD (Nova Southeastern University, FL, USA) for providing generous assistance and attentive correction of the language. REFERENCES
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1. Kim TH, Lee D, Lee HI. The safety of 250μm residual stromal bed in preventing keratectasia. J Korean Med Sci 2007;22:142-45. 2. Pallikaris IG, Kymionis GD, Astyrakakis NI. Corneal ectasia induced by laser in situ keratomileusis. J Cataract Refract Surg 2001;27:1796-1802. 3. Randleman JB, Russell B, Ward MA, et al. Risk factors and prognosis for corneal ectasia after LASIK. Ophthalmology 2003;110(2):267-75. 4. Tan BU, Purcell TL, Torres LF, et al. New surgical approaches to the management of keratoconus and post-LASIK ectasia. Trans Am Ophthalmol Soc 2006;104:212-20. 5. Clair-Florent M, Schmitt-Bernard C, Lesage C, Arnaud B. Keratectasia induced by laser in situ keratomileusis in keratoconus. J Refract Surg 2000;16:368-70. 6. Argento C, Cosentino MJ, Tytiun A, et al. Corneal ectasia after laser in situ keratomileusis. J Cataract Refract Surg 2001;27:1440–48. 7. Lafond G, Bazin R, Lajoie C. Bilateral severe keratoconus after laser in situ keratomileusis in a patient with forme fruste keratoconus. J Cataract Refract Surg 2001;27:1115– 18.
8. Chen D, Lam AKC. Intrasession and intersession repeatability of the Pentacam system on posterior corneal assessment in the normal human eye. J Cataract Refract Surg 2007;33:448–54. 9. Ciolino JB, Belin MW. Changes in the posterior cornea after laser in situ keratomileusis and photo refractive keratectomy. J Cataract Refract Surg 2006;32:1426–31. 10. Kim H, Joo CK. Measure of keratoconus progression using Orbscan II. J Refract Surg 2008;24:600-605. 11. Nilforoushan MR, Speaker M, Marmor M, et al. Comparative evaluation of refractive surgery candidates with placido topography, Orbscan II, Pentacam, and wavefront analysis. Cataract Refract Surg 2008;34:623– 31. 12. Wang Z, Chen J, Yang B. Posterior corneal surface topographic changes after laser in situ keratomileusis are related to residual corneal bed thickness. Ophthalmology 1999;106:406-09. 13. Karpecki PM. Bausch and Lomb Orbscan anterior segment analysis system. Wang M In: (Ed) Corneal topography in the wavefront era. Thoroare, USA:SLACK;2006:192-206. 14. Prisant O, Calderon N, Chastang P, et al. Reliability of pachymetric measurements using Orbscan after excimer refractive surgery. Ophthalmology 2003;110:511–15. 15. Matsuda J, Hieda O , Kinoshita S. Comparison of central corneal thickness measurements by Orbscan II and Pentacam after corneal refractive surgery. Jpn J Ophthalmol 2008;52:245–49. 16. Jain R, Dilraj G, Grewal SPS . Repeatability of corneal parameters with Pentacam after laser in situ keratomileusis. Indian J Ophthalmol 2007;55(5):341-47. 17. Belin MW, Khachikian SS, Arósio R. Keratoconus / Ectasia detection with the Oculus Pentacam: Belin/Ambrósio enhanced ectasia display. Highlights of ophthalmology 2007;55(6):5-12. 18. Maus M, Kröber S, Swardz T. Pentacam. In: Wang M. Corneal topography in the wavefront era. Thoroare, USA:SLACK;2006:281-93. 19. Holladay JT. Detecting forme fruste keratoconus with the Pentacam. Cataract and Refractive surgery today 2008;2:11-12. 20. Binder PS, Lindstrom RL, Stulting RD, et al. Keratoconus and corneal ectasia after LASIK. J Refract Surg 2005;21(6):749-52. 21. Buzard KA, Tuengler A, Febbraro JL. Treatment of mild to moderate keratoconus with laser in situ keratomileusis. J Cataract Refract Surg 1999;25:1600–09. 22. Ellis W. Radial keratotomy in a patient with keratoconus. J Cataract Refract Surg 1992;18:406–09. 23. Holland SP, Srivannaboon S, Reinstein DZ. Avoiding serious corneal complications of laser assisted in situ keratomileusis and photorefractive keratectomy. Ophthalmology 2000;107:640–52. 24. Rabinowitz YS. The genetics of keratoconus. Ophthalmol Clin N Am 2003;16:607-20.
AVOIDING KERATOCONUS IN PATIENTS UNDERGOING REFRACTIVE SURGERY
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INTRODUCTION
16
Keratoconus remains a common indication for corneal transplantation surgery. 1 Ectasia usually develops during adolescence and progresses slowly thereafter, with a minority of affected patients requiring corneal transplantation.2,3 The popularity of keratorefractive surgery and technological advances have contributed to an increased awareness of sub-clinical or forme fruste keratoconus. The fear of inducing, or of worsening pre-existing corneal ectasia by performing keratorefractive surgery has hastened our search for better diagnostic tools which detect subtle corneal abnormalities indicative of early ectasia. However, the diagnosis of forme fruste keratoconus remains particular difficulty. Corneal topography has become mandatory for all patients contemplating refractive surgery but in spite of improved software programmes it has not yet been perfected. A number of guidelines exist to help detect topographical evidence of ectasia but these alone are often insufficient to allow a definitive diagnosis to be made. Aberrometry records the higher order aberrations of the eye and has been found to have a role in the detection of corneal ectasia. 4-7 More specifically vertical coma is increased in both early (Figures 4.1A and B) and advanced (Figures 4.2A and B) ectasia.8,9 However, increased vertical coma in the presence of normal topography and low clinical suspicion is not diagnostic of ectasia and this finding should only be considered in addition to other factors and not as an isolated finding. More recently, new technology has been developed which records corneal hysteresis, a reflection of the corneal viscoelastic properties and is thought to provide an indication of its biomechanical integrity.10 The Reichert Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Buffalo NY, USA) can be used clinically to measure corneal hysteresis (CH) in addition to the corneal resistance factor (CRF) which reflects the overall resistance of the cornea. Kirwan et al examined both CH and CRF in normal eyes and eyes with forme fruste and advanced keratoconus.11 Both parameters were found to be significantly lower in eyes with advanced keratoconus compared with normal and forme fruste keratoconus (FFKC) eyes, while no difference was found between the latter two groups
when pachymetry matched. Due to significant overlap in both CH and CRF across all 3 groups, they concluded that this instrument was not useful as a single test in the detection of early ectasia. Laser in situ keratomileusis (LASIK) has been performed on more than 17 million people worldwide, but a dramatic increase in the reported incidence of keratoconus has not occurred.12 Binder reported 85 eyes with post LASIK ectasia.13 Faraj et al reported that 78% of patients with post LASIK have pre-existing forme fruste keratoconus, a preoperative central corneal thickness <500 µm or underwent treatment for high myopia with a residual stromal bed <250 µm. 14 More recently Randleman et al 15 established risk factors for the development of post LASIK ectasia which included those high-lighted by Faraj et al in addition to topographical abnormalities and young age at surgery. Other factors such as a history of eye rubbing, unstable refraction, a family history of ectatic eye disease and increased elasticity may also be predictive factors. Current practice involves performing corneal topography and aberrometry on all patients undergo LASIK or laser epithelial keratomileusis (LASEK). There is also a universal practise adopted by many ophthalmologists where a flap is not cut when the preoperative corneal thickness is <500μm. In many cases of post LASIK ectasia no apparent risk factors are evident. The question must be asked if the keratorefractive surgery was responsible for inducing the ectasia or if its development was inevitable whether or not the surgery had been performed. Wang et al reported a case of bilateral ectasia after unilateral LASIK in which ectasia appeared 20 months post operatively following a small amount of tissue removed in the LASIK eye. This was followed sometime later by the development of ectasia in the unoperated eye.16 A number of patients re-present some years following refractive surgery following redevelopment of myopia. In many, this is due to regression or myopic progression but myopic due to the development of keratoconus may also be the underlying cause. As mentioned above, in some patients analysis of the pre operative topography may show subtle signs of forme fruste keratoconus but in some the original topography is deemed to be entirely normal. Other factors must then be considered such as creation of an excessively
AVOIDING KERATOCONUS IN PATIENTS UNDERGOING REFRACTIVE SURGERY
Figure 4.1A: Corneal topography (Orbscan, Bausch and Lomb) showing evidence of forme fruste keratoconus
Figure 4.1B: Aberrometry (Zywave, Bausch and Lomb) from the same eye showing high level of 3rd order vertical (x-axis) coma
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
Figure 4.2A: Corneal topography (Orbscan, Bausch and Lomb) of eye with established keratoconus
Figure 4.2B: Aberrometry (Zywave, Bausch and Lomb) from the same eye showing high level of 3rd order vertical (x-axis) coma
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AVOIDING KERATOCONUS IN PATIENTS UNDERGOING REFRACTIVE SURGERY
thick flap at the time of surgery thus resulting in an excessively thin residual stromal bed. Greater reliability of newer keratomes and performance of intraoperative pachymetry should help avoid this problem. The development of anterior segment ocular coherence tomography (OCT), has made it possible to measure the thickness of the original flap and indeed the residual stromal bed in cases of post LASIK ectasia. In cases where these are found to be within acceptable limits, and in the absence of topographical abnormalities, it is likely that the keratorefractive surgery did not induce the ectasia and that the development of ectasia was inevitable. This serves to reinforce the fact that the pathogenesis of this keratoconus remains poorly understood. There are a number of morphological and functional differences between normal and keratoconic eyes and the paucity of cross-linking between collagen molecules is now the basis for crosslinking using riboflavin.17 The emphasis on diagnosis and treatment of keratoconus has gained huge momentum in recent times. Clearly in some cases with established disease corneal topography and aberrometry are diagnostic. It is that cohort of patients where suspicion of early form fruste disease arises, particularly those who wish to undergo refractive surgery that pose the main clinical dilemma. Undoubtedly the development of post LASIK ectasia is a serious matter and has medico-legal implications. It is clear that better diagnostic software that removes the uncertainty of diagnosis is required. Currently available topography machines, aberrometors and the ocular response analyzer while useful, still fall short of what is needed. Apart from this, certain criteria regarding patient selection and treatment should be adhered to in order to minimize risk. In particular large treatments in corneas with 500µ thickness should be avoided. There should be a move to cutting thin flaps and if there is any doubts particularly in patients with mild to moderate myopia LASEK should be the treatment of choice. Many surgeons perform intra-operative pachymetry and this is to be encouraged. A few of the newer technologies allow for the creation of flaps as thin as 80µm but as yet have no hard data on the efficacy of such flaps. Cross-linking is a new and innovative treatment for corneal ectasia.18 It could be a major advance if it
halts the progression of keratoconus and avoids or delays the need for corneal transplantation surgery. However, long-term data on the efficacy of crosslinking is required. Ng et al (personal communication), have applied cross-linking to the corneas of a number of patients with keratoconus and subsequently performed LASEK on these eyes. They report initial success and if this is the case it may be a new and exciting long-term innovative treatment. Forme fruste keratoconus and post LASIK ectasia strike fear in many refractive surgeons and the possible emergence of better diagnostic software and a possible non-invasive medical treatment would be a welcome new development. REFERENCES 1. Kang PC, Klintworth GK, Kim T, Carlson AN, Adelman R, Stinnett S, Afshari NA. Trands in the indications for penetrating keratoplasty, 1980-2001. Cornea 2005;24:801-03. 2. Tuft SJ, Moodaley LC, Gregory WM, Davison CR, Buckley RJ. Prognostic factors for the progression of keratoconus. Ophthalmology 1994;101:439-47. 3. Kennedy RH, Bourne WM, Dyer JA. A 48-year clinical and epidemiologic study of keratoconus. Am J Ophthalmol 1986;101:267-73. 4. Holland DR, Maeda N, Hannush SB, Riveroll LH, Green MT, Klyce SD, Wilson SE. Unilateral keratoconus. Incidence and quantitative topographic analysis. Ophthalmology 1997;104:1409-13. 5. Rao SN, Raviv T, Majmudar PA, Epstein RJ. Role of Orbscan 2 in screening keratoconus suspects before refractive corneal surgery. Ophthalmology 2002;109:1642-46. 6. Auffarth GU, Wang L, Volcker HE. Keratoconus evaluation using orbscan Topography System. J Cataract Refract Surg 2000;26:222-28. 7. Maguire LJ, Bourne WM. Corneal topography of early keratoconus. Am J Ophthalmol 1989;108:746-48. 8. Maeda N, Fujikado T, Kuroda T, Mihashi T, Hirohara Y, Nishida K, Watanabe H, Tano Y. Wavefront aberrations measured with Hartmann-Shack sensor in patients with keratoconus. Ophthalmology 2002;109:1996-2003. 9. Alio JL, Shabayek MH. Corneal higher order aberrations: A method to grade keratoconus. J Refract Surg 2006;22:539-45. 10. Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg 2005;31:156-62. 11. Kirwan C, O’Malley D, O’Keefe M. Corneal hysteresis and corneal resistance factor in Keratoectasia: Findings using the Reichert Ocular Response Analyzer. Ophthalmologica 2008;222:334-37.
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES 12. Condon PI. Will Keratectasia be a major complication for LASIK in the long-term? J Cataract Refract Surg 2006;32:2124-32. 13. Binder PS. Ectasia after laser in situ keratomileusis. J Cataract Refract Surg 2003;29:2419-29. 14. Faraj HG, Gatinel D, Chastang PJ, Hoang-Xuan T. Corneal ectasia after LASIK. J Cataract Refract Surg 2003;29:220. 15. Randleman J, Woodward M, Lynn M, Stulting RD. Risk assessment for ectasia after corneal refractive surgery. Ophthalmology 2008;115:37-50.
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16. Wang JC, Hufnagel TJ, Buxton DF. Bilateral keratectasia after unilateral laser in situ keratomileusis: A retrospective diagnosis of ectatic corneal disorder. J Cataract Refract Surg 2003;29:2015-18. 17. Wollensak J, Buddecke E. Biochemical Studies on human corneal proteoglycans – A comparison of normal and keratoconic eye. Graefes Arch Clin Exp Ophthalmol 1990;228:517-23. 18. Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue Exp Eye Res 1998;66:97-103.
CLINICAL SIGNIFICANCE OF COLLAGEN CORNEAL CROSS-LINKING IN POST-LASIK CORNEAL ECTASIA
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
POST-LASIK CORNEAL ECTASIA Corneal ectasia remains one of the most insidious complications after laser in situ keratomileusis (LASIK). Ectasia of the cornea is a progressive anterior shift of the cornea that is associated with central steepening and thinning, myopic shift, astigmatic changes and visual symptoms. Ectasia after LASIK is visionthreatening and is one of the most difficult complications to manage, requiring a penetrating keratoplasty in severe cases. Reported incidence of post-LASIK ectasia ranges from 0.12 to 0.66%. RISK FACTORS
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Currently recognized risk factors for the development of post-LASIK ectasia include high myopia, low residual stromal bed from excessive ablation or thick flap creation and preoperative topographic abnormalities, including forme fruste keratoconus and pellucid marginal corneal degeneration. Ectasia can also rarely occur in patients without identifiable risk factors. The current literature does not define a specific residual corneal thickness that would place an eye at risk for ectasia. By comparing the biomechanical properties of keratoconic corneas with normal corneas Andreassen et al. estimate that for the normal cornea, a residual stromal bed thickness less than 250 µm might produce a cornea with a tangential elastic modulus comparable to that of a keratoconic cornea. Barraquer suggests a 300 µm thickness of stress-bearing cornea. He also advised against lamellar surgery in corneas with less than 450 µm of total thickness and those with steep keratometry readings. In a literature review, Faraj et al. report that 78% of ectasia cases were forme fruste keratoconus or highly myopic eyes with an RSB less than 250 µm after LASIK and that 11% had an RSB greater than 250 µm but with a total corneal thickness less than 500 µm preoperatively. However, there have been reports of postoperative ectasia after a residual bed thickness over 250 µm is confirmed. Forme fruste keratoconus as defined by the Rabinowitz criteria is a risk factor for post-LASIK ectasia. Pellucid marginal corneal degeneration suspects are also at increased risk. Preoperative posterior float elevations greater than 40 mm may signify increased ectasia risk. It is wise to avoid LASIK
in patients with asymmetric inferior corneal steepening or asymmetric bowtie patterns with skewed steep radial axes above and below the horizontal meridian. THERAPEUTIC OPTIONS The two principal approaches to the management of corneal ectasia include restoration of vision by optical means to obviate irregular astigmatism, such as the use of rigid gas permeable contact lenses, and in more severe cases, restoration of tectonic integrity of the cornea by interventional means. In recent years, a variety of treatment modalities have emerged, and include methods to increase corneal rigidity, such as a novel collagen cross-linking approach, or the use of intrastromal implants, and recent techniques in central and peripheral lamellar keratoplasty. Current therapeutic options for iatrogenic keratectasia include: 1. Rigid contact lenses 2. Conductive keratoplasty 3. INTACS 4. Cross-link 5. Lamellar keratoplasty 6. Penetrating keratoplasty 7. Combination therapies. COLLAGEN CROSS-LINKING Cross-linking is a widespread method in the polymer industry to harden materials and also in bioengineering to stabilize tissue. Although various methods including glutaraldehyde cross-linking are in clinical use in other medical specialties, the method most extensively studied for corneal use is ultraviolet A (UV-A)/ riboflavin collagen cross-linking. This utilizes UV-A at 370 nm to activate riboflavin, generating reactive oxygen species that induce covalent bonds between collagen fibrils. In animal studies, collagen cross-linking by the combined riboflavin/UV-A treatment induced a significant increase in corneal rigidity by approximately 70%. In human, ultraviolet cross-linking treatment appears to be able to halt progression of corneal ectasia in keratoconus patients. SURGICAL TECHNIQUES After topical anesthesia, central corneal epithelium is removed within a 8 mm diameter. A 0.1% riboflavin solution (10 mg riboflavin-5-phosphate in 10 ml
CLINICAL SIGNIFICANCE OF COLLAGEN CORNEAL CROSS-LINKING IN POST-LASIK CORNEAL ECTASIA
dextran 20% solution) is applied every 5 min until the stroma was penetrated and aqueous is stained yellow. The irradiation is performed at working distance of a 10 cm for 30 min using a UVA double diode at 370 nm and an irradiance of 3mW/cm2 (equal to a dose of 5.4 J/cm 2 ). The required irradiance is controlled in each patient directly before the treatment to avoid a potentially dangerous UVA overdose. The parameters of the irradiation treatment must not be modified because of the risks for serious side effects. RESULTS Clinical Results The most important study about the use of cross-linking in iatrogenic keratectasia after LASIK came from Hafezi et al. In this case series, ultraviolet cross-linking treatment appears to be able to halt and even partially reverse iatrogenic corneal ectasia after LASIK with a follow-up of up to 25 months. In 90% of the eyes, BSCVA significantly increased, cylinder decreased. In all cases, researcher reported a reduction in the maximum K readings 12 months after cross-linking. 2 D or more difference between preoperative and postoperative K reading was present in 50% of the eyes treated. These results are comparable to that of cross-linking for corneal ectasia in keratoconus patients in which slight flattening of the cornea of up to 2D and 1.66 line increase in BSCVA were observed. Biomechanical Results Using a microcomputer-controlled biomaterial testing machine biomechanical stress–strain measurements showed an impressive increase in corneal rigidity of 71.9% in porcine and 328.9% in human corneas and Young’s modulus by the factor 1.8 in porcine and 4.5 in human corneas after cross-linking. COMBINED TREATMENTS Since collagen cross-linking alone does not normalize corneal curvature, attempts have been made to combine it with other surgical modalities. Chan et al. describe cross-linking treatment immediately after INTACS insertion, with a statistically significant greater mean change in cylinder (2.73D) and K steep (1.94D) compared with INTACS alone. While these results
appear promising, further studies evaluating safety, stability of effect and the effect of combination treatment with intrastromal implants are needed. In addition, combination of cross-linking technology with other modalities such as the various forms of lamellar keratoplasty may provide additional yields for ectasia patients. POTENTIAL COMPLICATIONS AND PREVENTIONS In early postoperative period, a temporary corneal haze similar to haze after photorefractive keratectomy can develop. This superficial haze disappeared only gradually despite intensive therapy. Histopathologic and confocal microscopic studies revealed that 300 mm deep stroma is depopulated of keratocytes after cross-linking therapy. Repopulation of this area takes up to 6 months. As long as the cornea treated has a minimum thickness of 400 mm the corneal endothelium will not experience damage, nor will deeper structures such as lens and retina. To prevent damage to the endothelium, the lens or the retina, safe clinical application of X-linking must respect the following criteria: 1. For diffusion of riboflavin throughout the corneal stroma, the epithelium should be removed. 2. Riboflavin solution should be applied for at least 5 minutes allowing riboflavin to permeate through the cornea before the UV irradiation (during the UV exposure, the riboflavin serves as both a photosensitizer and a UV blocker) 3. The UV irradiance must be homogenous and before each treatment, the desired irradiance of 3 mW/cm 2 should be controlled with a UVA meter. 4. Cornea must have a minimal central thickness above 400 mm to protect the endothelium. REFERENCES 1. Randleman JB. Post-laser in-situ keratomileusis ectasia: Current understanding and future directions. Curr Opin Ophthalmol 2006;17(4):406-12. Review. 2. Tan DT, Por YM. Current treatment options for corneal ectasia. Curr Opin Ophthalmol 2007;18(4):284-9. Review. 3. Spörl E, Huhle M, Kasper M, Seiler T. [Increased rigidity of the cornea caused by intrastromal cross-linking] Ophthalmologe 1997;94(12):902-6. German.
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES 4. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-ainduced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135(5):620-27. 5. Wollensak G, Iomdina E. Long-term biomechanical properties of rabbit cornea after photodynamic collagen crosslinking. Acta Ophthalmol 2008;11. [Epub ahead of print] 6. Hafezi F, Kanellopoulos J, Wiltfang R, Seiler T. Corneal collagen cross-linking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis. J Cataract Refract Surg 2007;33(12):2035-40. 7. Wollensak G. Cross-linking treatment of progressive keratoconus: New hope. Curr Opin Ophthalmol 2006;17(4):356-60.
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8. Chan CC, Sharma M, Wachler BS. Effect of inferiorsegment Intacs with and without C3-R on keratoconus. J Cataract Refract Surg 2007;33(1):75-80. 9. Mazzotta C, Balestrazzi A, Baiocchi S, Traversi C, Caporossi A. Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: In vivo confocal microscopic evaluation. Clin Experiment Ophthalmol 2007;35(6):580-82. 10. Wollensak G, Spoerl E, Wilsch M, Seiler T. Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment. Cornea 2004;23(1):43-49.
BIOPHYSICAL ASPECTS OF COLLAGEN, CORNEAL CROSS-LINKING COVERING DETAILS ABOUT UVA AND RIBOFLAVIN
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
RELEVANT ANATOMY The physical strength, constancy of shape and transparency are based on the anatomic and biochemical characteristics of the corneal stroma. Both the epithelium and the endothelium function to maintain corneal transparency.1 The corneal stroma consists of extracellular matrices, keratocytes (corneal fibroblasts) and nerve fibers. Cellular components occupy only 2 to 3% of the total volume of the stroma.2 The rest is occupied by various extracellular matrices mainly collagen and glycosaminoglycans.The collagens in the corneal stroma are primarily collagen type I with lesser amounts of the collagen type III, V and VI. Collagen are stiff fibrous molecules and one of the more abundant proteins throughout the body. Keratocytes synthesize a pro alpha chain of collagen Three molecules of pro alpha chain are hydroxylated, glycosylated and finally assembled to a procollagen triple helix structure. The characteristic feature of the collagen fibers in the corneal stroma is that they are extremely uniform and constant. This regular arrangement of collagen fibers in the stroma contributes to corneal transparency. The structural properties of the collagen frame work in the corneal stroma determine the biomechanical and optical properties of the tissue.3 BACKGROUND
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Keratoconus is a relatively frequent disease often affecting the young. The biomechanical resistance of the cornea in keratoconus patients is half the normal value. Treatment based on collagen cross-linking with the help of ultraviolet (UV) and the photosensitizer riboflavin has been introduced by Wolloensak.4 This treatment is aimed at the pathogenic cause of keratoconus and changes the intrinsic biomechanical properties of corneal collagen. The method of corneal cross-linking using riboflavin and UV-A is technically simple and less invasive than all other therapies proposed for Keratoconus, and unlike other miniinvasive methods, such as intrastromal rings (INTACS) and excimer laser surgery, which do not block keratectasia but merely treat the refractive effects of the diseases, it prevents and treats the underlying pathophysiological mechanism. Cross-linking is a common method in the polymer industry to harden materials and in bioengineering to
stabilize tissue. For example, chemical cross-linking with glutaraldehyde is used in the preparation of prosthetic heart valves and physical cross-linking by UV-A is often used in dentistry to harden filling materials. Similarly tissue specimens are preserved and hardened by glutaraldehyde or formaldehyde in pathology. Using UV-A at 370 nm and the photosensitizer riboflavin, the photosensitizer is excited into its triplet state generating so-called reactive oxygen(ROS) and to a much lesser degree superoxide anion radicals. The ROS can react further with various molecules including chemical covalent bonds bridging amino groups of collagen fibrils(type II photochemical reaction).5 The wavelength of 370 nm has been chosen because of an absorption peak of riboflavin at this wavelength. SURGICAL TECHNIQUE The treatment is conducted under sterile conditions in the operating room. The patient’s eye is anesthetized with topical anesthetic drops. The central 7 mm of the corneal epithelium are removed to allow better diffusion of riboflavin into the stroma. A 0.1% riboflavin solution (10 mg riboflavin-5-phosphate in 10 ml dextran 20% solution) is applied every 5 min starting 5 min before the irradiation. The irradiation is performed from a 1 cm distance for 30 min using a UVA double diode at 370 nm and an irradiance of 3 mW/cm2 (equal to a dose of 5.4J/cm2).The required irradiance is controlled in each patient directly before the treatment to avoid a potentially dangerous UVA overdose. STUDIES The first clinical study on the cross-linking treatment of keratoconus was performed by Wollensak.4 In this 3 year study, 22 patients with progressive keratoconus were treated with riboflavin and UVA. In all the treated eyes, the progression of keratoconus was stopped. In 16, there was a reversal and flattening of keratoconus by two diopters. In the follow-up 5 year study, 60 eyes could be included in the study. No patient had progression of keratoconus. Similar studies have shown stabilization of keratoconus. Caporossi et al showed a mean K reduction of 2.1+/ - 0.13 D in central 3.0 mm.6 Wittig- Silva C et al in a series of 66 eyes showed a progressive flattening of
BIOPHYSICAL ASPECTS OF COLLAGEN, CORNEAL CROSS-LINKING COVERING DETAILS ABOUT UVA AND RIBOFLAVIN
steepest simulated keratometer value over 12 months.7 Kanellopoulos AJ reported significant clinical improvement and apparent stability of more than one year following collagen cross-linking with sequential topography gradual PRK.8 Chan CC reported. Intacs with collagen cross-linking had a significantly greater reduction in cylinder than the Intacs only group.9 Studies have been conducted to see the biochemical effects, thermomechanical effects and confocal microscopy features. Using a microcomputer– controlled biomaterial testing machine, biomechanical stress-strain measurements showed an increase in corneal rigidity of 71.9% in porcine and 328.9% in human corneas and Young modulus by the factor 1.8 in porcine and 4.5 in human corneas. The cross-linking was maximal only in the anterior 300 microns. The greater biomechanical effect in human corneas is explained by the relatively larger portion of crosslinked stroma because of the lower corneal thickness of 550 microns in human corneas compared with 850 microns in porcine corneas.10 In thermomechanical experiments with porcine corneas, the maximal hydrothermal shrinkage temperature was found to be 70 degree C for the untreated controls , 75 degree C for the cornea cross linked with riboflavin and UV-A and 90 degree centigrade for cross linked with glutaraldehyde, demonstrating the dependence of the shrinkage temperature on the degree of cross-linking . The heat— dependent denaturation of non cross linked collagen could be demonstrated by the loss of birefringence in histological sections.11 Mazzota et al reported the ultrastructural analysis by Heidelberg retinal tomography II and in vivo confocal microscopy in humans.12 One month after the cross-linking therapy, the treated stroma was analyzed by in vivo confocal biomicroscopy at a depth of 80 to 90 microns. A reduction in the keratocyte number associated with a stromal edema (spongy or honeycomb like) was found. Subepithelial and anterior stromal nerve fibers were not found at this depth range. At 3 months, the presence of activated keratocytes, indicative of an initial repopulation of the anterior stroma was seen. However, it was not until the sixthmonth, that a dense cell population of activated keratocytes was observed, with regenerated nerve fibers and increased tissue density without edema.
One month after treatment, confocal analysis at a depth of 130 to 150 microns showed a refraction of keratocytes associated with stromal edema. After 3 months, the edema began to decrease together with an initial ketocyte repopulation and an increase in extracellular fibrillar matrix density. These findings were more accentuated at 6 months, when more activated nuclei and increased stromal density were observed. At this time, the edema had almost disappeared. At a depth of 170 to 180 microns, the edema was visible at 1 month in the intermediate stroma. It presented ghost nuclei in the fibrillar network, elongated nuclei and the absence of keratocytes. After 2 to 3 months, initial repopulation and reduced edema were evident, aided by the disappearance of the many hyperreflecting oval and elongated nuclei of keratocytic origin. The extracellular matrix had grown denser as the cell population had increased. This increase seemed compatible with a subclinical, microscopically detectable haze that did not seem to impair vision. The haze was greater in patients with more advanced keratoconus, and there were several dark Vogt microstriae. It was not detectable in patients with early-stage disease. At a depth of 270 to 300 microns, cell necrosis and stromal edema were evident at 1 month, with ghost cells or keratocyte apoptosis bodies in the fibrillar network. Intial signs of cell repopulation were observed at 3 months. Activated oval nuclei and elongated nuclei increased the reflectance of stroma at 3 and 6 months. The stromal depth of effective cross-linking depends on the concentration of riboflavin solution and the intensity of UV-A light.13 The cross-linking effect seems to localize anterior and collagen fiber diameter is significantly increased only in the anterior half of the stroma, because of the rapid decrease in UV-A irradiation across the corneal stroma as a result of riboflavin enhanced UV-A absorption.14 Kohlhass M et al showed significant stiffing of cornea only in the anterior 200 microns.15 Seiler T et al reported a demarcation line by slit lamp. 13 This line was seen in 14 of 16 patients at approximately 60% corneal depth. The line was identified by a thin slit and high illumination levels using a slit lamp that provide high levels of white light. In the corneal periphery, the line gradually adopts into
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
a conical shape because of the increasing total corneal thickness. The anterior localization of cross-linking treatment is a great advantage because in this way cytotoxic damage of the endothelium is avoided. Spoerl E reported increased resistence of cross linked cornea against enzymatic digestion supporting this new method in the treatment of corneal ulcers.16 In addition to keratoconus, the other group of patients in whom this treatment seems to work is corneal ectasia following LASIK.17,18 Anecdotal reports of UV cross-linking in the management of corneal edema and its use in the management of corneal ulcers have been presented, but these indications need careful evaluation. Risks and Side Effects UV light in general represents a potential danger to the human eye. UV-induced photochemical damage like sunburn or photokeratitis, both of which are caused, however, by UV-B light. In the cornea UV-B light (290-320nm) is mainly absorbed by the corneal epithelium. UV-B is also known to mutagenic causing for example, skin cancer. To avoid danger for the endothelium, lens or retina it is mandatory in each patient to perform preoperative pachymetry to exclude extended areas with less than 400 microns stromal thickness, and to check the UV-A irradiance exactly using a UV-A–meter. Stromal haze has been noted and it seems to correlate with the severity of keratoconus.19 Cross-linking treatment for keratoconus is a promising new method of treatment. The treatment is being offered to patients with documented progression of keratoconus. With more experience, prophylactic treatment may be possible at early stage. Additional refractive corrections may be considered if necessary. In long run, if keratoconus progression is found, a second cross-linking procedure may be the choice. REFERENCES
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1. Nishida T. Cornea in eds Krachmer JH, Mannis MJ, Holland EJ. Cornea . Fundamentals of cornea and external disease. Mosby publications 1997;12-3. 2. Otori T. Electolyte content of rabbit corneal stroma . Exp Eye Res 1967;6:356-7. 3. Daxer A, Misof K, Grabner B, Ettl A, Fratzi P. Collagen fibrils in the human corneal stroma:Structure and aging. Invest Ophthalmol Vis Sci 1998;39:644-48.
4. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet A-induced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-27. 5. Wollensak G. Cross-linking treatment of progressive keratoconus: new hope. Current Opinion In Ophthalmology 2006;17:356-60. 6. Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Parasurgical therapy for keratoconus by riboflavinultraviolet type A rays induced cross-linking of corneal collagen: preliminary refractive results in an Italian study. J Cataract Refract Surg 2007;33:1143-44. 7. Wittig–Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Lamoureux E, Lindsay RG, Sullivaran LJ, Snibson GR. A randomized controlled trial of corneal collage cross-linking in progressive keratoconus preliminary results. J Refract Surg, 2008;24:S720-25. 8. Kanellopoulos AJ,Binder PS.Collagen cross-linking (CCL) with sequential topography guided PRK a temporizing alternative for keratoconus to penetrating keratoplasty. Cornea 2007;26:891-95. 9. Chan CC, Sharma M, Wachler BS. Effects of inferior segment Intacs with and without C3R on keratoconus. J Cataract Refract Surg 2007;33:75-80. 10. Wollensak G, Spoerl E, Seiler T. Stress strain measurement of human and porcine corneas after riboflavin-ultraviolet A induced cross-linking J Cataract Refract Surg 2003;29:1780-85. 11. Spoerl E, Wollensak G, Dittert DD, Seiler T. Thermomechanical behaviour of collagen-cross-linked porcine cornea. Ophthalmologica 2004;218:136-40. 12. Mazzotta C, Balestrazzi A, Traversi C, Baiocchi S, Caporossi T, Tommasi C, Caporossi A. Treatment of progressive keratoconus by Riboflavin –UVA-induced cross-linking of corneal collagen. Ultra structural analysis by Heidelberg Retinal Tomograph II in vivo confocal microscopy in humans Cornea 2007;26;390-97. 13. Seiler T, Hafezi F. Corneal cross-linking induced stromal demarcation line. Cornea 2006;25:1057-59. 14. Wollensak G, Wilsh M, Spoerl E, Seiler T.Collagen fibre diameter in the rabbit cornea after collagen cross-linking by riboflavin UVA. Cornea 2004;23;503-7. 15. Kohlhass M, Spoerl E, Schilde T, Unger G , Wittig C, Pullinat LE. Biochemical evidence of the distribution of cross-linking in corneas treatment with riboflavin and ultraviolet A light. J Cataract Refract Surgery 2006;32:27983. 16. Spoerl E, Wollensak G, Seiler T. Increased resistance of cross linked cornea against enzymatic digestion. Curr Eye Res 2004;29:35-40. 17. Randleman JB. Post-laser-in-situ keratomileusis ectasia. Curr Opin Ophthalmol 2006;17:406-12. 18. Rabinowitz YS. Ectasia after laser in situ keratomileusis. Curr Opin Ophthalmol 2006;17:421-26. 19. Mazzota C, Blaestrazzi A, Baiochi S, Traversi C, Caporossi A. Stromal haze after combined riboflavin –UVA cornea collagen cross-linking in keratoconus: in vivo con focal microscopic evaluation: Clin Experiment Ophthalmol 2007;35:580-82.
THE IMPORTANCE OF EPITHELIAL DEBRIDEMENT FOR RIBOFLAVIN ABSORPTION PRIOR TO RIBOFLAVIN/ULTRAVIOLET-A
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
INTRODUCTION Keratoconus is the commonest corneal dystrophy affecting 1 in 2000 individuals. It is a degenerative, non-inflammatory disorder of the cornea, characterized by stromal thinning and resultant conical ectasia with associated irregular astigmatism and visual loss.1 It pathophysiology is poorly understood. It is thought to include biochemical, physical and genetic factors. However, no single proposed theory explains the various clinical features and it is likely that the development of keratoconus is the final common pathway for several different disorders. Whilst mild and sub-clinical cases may be corrected with spectacles and soft toric contact lenses, rigid contact lenses provide visual rehabilitation in the majority of cases. However, progressive disease often results in advanced ectasia with associated contact lens intolerance and corneal scarring, which in 10-25% of eyes necessitates surgical intervention usually in the form of corneal transplantation.2-5 In recent years a new therapeutic modality Riboflavin (vitamin B2)/ultraviolet A (UV-A) (370 nm) corneal collagen cross-linkage has been developed, which might be the first treatment available to stabilize the keratoconic process.6 In laboratory studies, it has been shown to increase the stress-strain measurements of corneal stromal tissue, increase its resistance to enzymatic digestion and thermal damage and reduce its hydration rate.7-11 It is thought to induce physical cross-linking of collagen via the lysyl oxidase pathway.12 Riboflavin is essential to this process and has the dual function of acting as a photosensitizer for the production of oxygen free radicals which induce the actual physical cross-linking of collagen12 as well as concentrating and absorbing the UV-A irradiation and preventing damage to deeper ocular structures such as the corneal endothelium, the lens and the retina.13-16 The technique has been shown to be safe with no loss of corneal transparency and no endothelial cell damage, provided the cornea is thicker than 400 μm, and no damage to deeper ocular structures.1316
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In an initial pre-clinical study, Spoerl et al demonstrated the need for complete central epithelial debridement by a lack of alteration in biomechanical properties of corneal tissue where the technique had been performed with the epithelium intact.16 On this
basis the epithelium was removed in the first published clinical studies prior to treatment. 14 Despite this recommendation a number of clinicians have elected to perform the technique with the epithelium intact in order to reduce the postoperative discomfort experienced by their patients.17 Some have advocated the use of multiple applications of the topical anesthetic tetracaine 1% in an attempt to loosen the epithelial tight junctions.17 Others have advocated limited full-thickness epithelial debridement in a gridlike pattern, with islands of intact epithelium to facilitate more rapid postoperative epithelial healing (Professor D. Reinstein, personal communication). In order to investigate the importance of epithelial removal for facilitating the entry of riboflavin into the corneal stroma, we have measured the light transmission spectra of porcine corneas after riboflavin eyedrop administration using spectrophotometry following either complete epithelial debridement, superficial epithelial trauma or no epithelial trauma with the pre- and perioperative administration of topical tetracaine 1%.18 We have also investigated techniques to assist the entry of riboflavin into the stroma by either loosening the epithelial tight junctions with application of Alcohol solution 20% for 40 seconds or by removing the epithelium in a grid pattern rather than complete debridement.19 These measurements have been compared with untreated control corneas and the absorption spectrum of the riboflavin solution itself. We have also examined the effects of the cross-linkage treatment on light transmission by exposing a number of corneas to UVA irradiation in combination with riboflavin eyedrops. METHODOLOGY OF OUR STUDIES18,19 One hundred and twenty-five porcine eyes were transported on ice from a local abattoir within 24 hours of death. A visual examination of each specimen for the presence of corneal scarring or opacity resulted in 13 eyes being excluded from the study. The remaining 112 eyes were stored overnight in a sealed bag at 4°C. From these 45 eyes were selected at random for inclusion in the study and divided into the following treatment groups: 1. Controls: The central epithelium (10.00 mm in diameter) was completely removed from 5 corneas using a scalpel blade; the epithelium was left intact on a further 4 corneas.
THE IMPORTANCE OF EPITHELIAL DEBRIDEMENT FOR RIBOFLAVIN ABSORPTION PRIOR TO RIBOFLAVIN/ULTRAVIOLET-A
2. Riboflavin only (superficial epithelium trauma, basal epithelium intact): Following scraping of the superficial epithelium over the central cornea for 10-15 seconds with a scalpel blade and using visual inspection to ensure the basal layers were still intact, riboflavin 0.1% drops (10mg riboflavin-5-phosphate in a 10 ml dextran T-500 20%) were applied to the anterior surface of 6 corneas at 5-minute intervals for 30-minutes. 3. Riboflavin plus UV-A (superficial epithelium trauma, basal epithelium intact): Following superficial epithelial trauma (as described above), riboflavin 0.1% drops were applied to 6 corneas. After waiting for 5-minutes the corneas were exposed to a 3 mW/cm2 dose of UV-A (370 nm) at a distance of 1cm from the anterior surface of the cornea. The cross-linking treatment lasted 30minutes during which time further riboflavin 0.1% eye drops were applied at 5-minute intervals. 4. Tetracaine plus Riboflavin (no epithelial trauma): Topical tetracaine 1% and riboflavin 0.1% eye drops (10 mg riboflavin-5-phosphate in a 10 ml dextran T-500 20%) were administered to the intact, non-traumatized anterior corneal surface of 6 corneas at 5-minute intervals over a 35minute period, in order to simulate 5 minute preoperative and 30-minute operative time periods. 5. Tetracaine and Riboflavin eyedrops plus UV-A (no epithelial trauma): Tetracaine 1% and riboflavin 0.1% eyedrops were applied to 6 corneas with an intact non-traumatized epithelium. After waiting for 5 minutes the corneas were exposed to a 3 mW/cm2 dose of UV-A (370 nm) at a distance of 1cm from the anterior surface of the cornea. The cross-linking treatment lasted 30 minutes during which time further riboflavin and tetracaine drops were applied at 5-minute intervals. 6. Riboflavin only (epithelium completely removed): Following complete de-bridement of a central 10 mm area of corneal epithelium with a scalpel blade, riboflavin 0.1% drops were applied at 5-minute intervals for 30-minutes in 6 eyes. 7. Riboflavin plus UV-A (epithelium completely removed) (Figure 7.1): Following complete removal of the central epithelium, riboflavin 0.1% drops were applied to the exposed stromal
Figure 7.1: A cornea with complete central epithelial debridement following UV-A/riboflavin treatment. A homogeneous area of yellow discoloration can be seen beneath the area of full-thickness epithelial trauma (black arrow). At the corneal periphery under areas of intact epithelium there is no yellow discolouration (white arrow)
surface. After waiting for 5-minutes the corneas were exposed to a 3mW/cm2 dose of UV-A (370 nm) at a distance of 1cm from the anterior surface of the cornea. The cross-linking treatment lasted 30-minutes during which time riboflavin drops were applied at 5-minute intervals. 8. Alcohol group: In 6 eyes, 20% alcohol solution was applied to the central corneal epithelium with a 9.00 mm laser epithelial keratomileusis (LASEK) well for 40 seconds. Following alcohol administration no attempt was made to remove the epithelium. Riboflavin eyedrops were then administered to the anterior corneal surface. After waiting for 5-minutes the corneas were exposed to a 3mW/cm 2 dose of UV-A (370 nm) at a distance of 1cm from the anterior surface of the cornea. The exposure time was 30-minutes during which time further riboflavin drops were applied at 5-minute intervals. 9. Grid pattern epithelial debridement (Figure 7.2): Following a grid pattern full thickness epithelial trauma of the central cornea, at least 7 ° 7 mm in size and with 30 to 40 separate abrasions placed within this area, riboflavin drops were applied to 6 eyes. After waiting for 5-minutes the corneas were exposed to a 3 mW/cm2 dose of UV-A (370 nm) at a distance of 1cm from the anterior surface of the cornea. The cross-linking treatment lasted 30-minutes during which time riboflavin drops were applied at 5-minute intervals.
31
MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
spectrum for each sample was normalized against a baseline transmission spectrum of the chamber filled with silicon oil. A further transmission spectrum over the same wavelength range (400-700 nm) was obtained for riboflavin 0.1% solution (10 mg riboflavin-5phosphate in a 10 ml dextran T-500 20%) alone. Student t-tests were used to compare transmission values. Results with p<0.05 were considered statistically significant. RESULTS FROM OUR STUDIES18-19
Figure 7.2: A cornea with grid pattern epithelial trauma following UV-A/riboflavin treatment with application of Riboflavin 5 minutes pre-treatment and every 5 minutes during 30 minutes of ultraviolet light exposure. Although areas of yellow discolouration (black arrow) in a grid pattern can be seen beneath the areas of full-thickness epithelial trauma, there is lack of homogeneous absorption
32
Immediately following treatment each cornea with a 3 mm scleral rim was dissected from the globe and placed into a specially designed sample holder. The natural curvature of the cornea was maintained by clamping the scleral rim within the sample holder and injecting silicon oil (Dow Corning 200/5cS, BDH Laboratory Supplies, Poole, UK) into the chamber behind it. Silicon oil was also injected into the front chamber of the holder so as to maintain a uniform refractive index and reduce light scatter.20 The sample holder was then positioned into the spectrophotometer (PYE Unicam, SP8-100 UV/VIS) in such a way that light passed through the center of the cornea in the anterior-posterior direction. The optics of the unit and the aperture were set to give a slit of (no larger than) 1 ° 1mm on the surface of the cornea, i.e. at the point where the center of the cell lies, and it was ensured that the cell lay such in the path length that the beam was always incident on the center. A transmission spectrum was measured for each cornea at 10 nm intervals within the range of 400 to 700 nm. Although this spectrum is within the visible spectrum, it is outside the treatment wavelength of 350 to 380 nm. However, it does include one of the peak absorption spectra of Riboflavin at 400 to 490 nm and is therefore relevant to detect changes in light transmission due to stromal absorption of Riboflavin. Using the method detailed by Kostyuk and colleagues, 20 the transmission
Removal of the epithelium had no significant affect on the transmission spectra of control corneas. In each case, a gradual increase in light transmission occurred between 400 and 700 nm. Based on this finding, the spectra of all control corneas (with or without epithelium) were averaged for comparison with the various study groups. Figures 7.3A to C show the average transmission spectra of control corneas, corneas treated with riboflavin only and corneas treated with riboflavin plus UV-A. The standard error bars associated with each spectrum are the result of variations in the hydration of corneas within treatment groups. The transmission spectrum of corneas with superficial epithelial trauma (but with basal epithelium intact) treated with either riboflavin alone or with riboflavin and UV-A, did not differ from each other or from that of the control corneas (Figure 7.3A). Similarly, the transmission spectrum of corneas with no epithelial trauma treated with either riboflavin and tetracaine alone or with riboflavin, tetracaine and UVA, did not differ from each other or from that of the control corneas (Figure 7.3B). Complete removal of the epithelium prior to either riboflavin-only or riboflavin plus UV-A treatment did however result in a dramatic reduction in light transmission between 400 and 510 nm (P<0.01) (Figure 7.3C). At 450 nm light transmission was on average 32% lower in riboflavintreated corneas that had experienced complete epithelial removal compared to the untreated control corneas. This dip in light transmission may be attributed to the presence of riboflavin within the tissue which absorbs light between 400-510 nm (Figure 7.4). The light transmission spectrum of corneas with a fully removed epithelium treated with riboflavin plus UVA did not differ from those treated with riboflavin alone (Figure 7.3C).
THE IMPORTANCE OF EPITHELIAL DEBRIDEMENT FOR RIBOFLAVIN ABSORPTION PRIOR TO RIBOFLAVIN/ULTRAVIOLET-A
Figure 7.3: (A) Average light transmission spectra of 9 untreated porcine corneas (Δ), 6 riboflavin-only treated corneas with superficial epithelial trauma (Δ) and 6 riboflavin plus UV-A treated corneas with superficial epithelial trauma (Δ). S.E. bars are shown. (B) Average light transmission spectra of 9 untreated porcine corneas (Δ), 6 riboflavin and tetracaine treated corneas with an intact epithelium (Δ) and 6 riboflavin and tetracaine plus UV-A treated corneas with an intact epithelium (Δ). SE bars are shown. (C) Average light transmission spectra of 9 untreated porcine corneas (Δ), 6 riboflavin-only treated corneas with epithelium completely removed (Δ) and 6 riboflavin plus UV-A treated corneas with epithelium completely removed (Δ), SE bars are shown
33
MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
Figure 7.4: Light transmission spectrum of riboflavin solution
The transmission spectrum of corneas following application of 20% Alcohol solution applied for 40 seconds and treated with riboflavin and UV-A (Figure 7.5, red diamonds) were similar to controls (Figure 7.5, yellow diamonds), with no significant differences between the groups for wavelengths between 400 nm and 510nm, corresponding to one of the absorption peaks of riboflavin (Figure 7.4). The transmission spectrum of corneas with grid pattern epithelial trauma treated with riboflavin and UV-A (Figure 7.5, green diamonds) showed a dip in transmission between 400490 nm (p<0.03) compared to controls, which may be attributed to the presence of riboflavin in the stroma. This dip in transmission was less than that seen in the complete epithelial debridement group (Figure 7.5, blue diamonds), with significant differences between these two groups between 400nm and 490nm (p<0.001). This is very likely to be attributable to increased stromal uptake of riboflavin in the presence of complete epithelial debridement. Figure 7.2 shows a cornea with grid pattern epithelial trauma following UV-A/riboflavin treatment, although areas of yellow discoloration in a grid pattern can be seen beneath the areas of full-thickness epithelial trauma, there is lack of homogeneous absorption compared to full epithelial debridement as seen in Figure 7.1. DISCUSSION
34
Riboflavin/UV-A corneal collagen crosslinkage is the first therapeutic modality that may halt the progression
of the ectatic process in keratoconus and postkeratorefractive surgery ectasia.6 Riboflavin is a key component of the photochemical cross-linking treatment as it increases corneal absorption of UV-A to approximately 95%8 and thereby protects the deeper ocular structures especially the endothelium from UVA damage.13-16 Published clinical and laboratory studies of corneal collagen crosslinkage therapy have generally advocated the complete removal of the epithelium to allow adequate penetration of the riboflavin into the corneal stroma.6-16,21,22 However, in an attempt to reduce the early postoperative discomfort experienced by the patient (caused as a result of epithelial removal), some clinicians have elected to perform the procedure with the epithelium intact.17 They postulate that topical anesthetic drops can loosen epithelial tight junctions allowing penetration of riboflavin into the corneal stroma. In our studies we used spectrophotometry to investigate the importance of complete epithelial debridement by assessing the ability of riboflavin to penetrate the stroma of corneas treated with topical anesthetic eyedrops (tetracaine 1%), after superficial epithelial trauma (in which the basal epithelium remained intact), following a 20% Alcohol solution applied for 40 seconds, after a grid pattern fullthickness epithelial debridement and compared them to corneas in which the central 10 mm of epithelium had been completely debrided.
THE IMPORTANCE OF EPITHELIAL DEBRIDEMENT FOR RIBOFLAVIN ABSORPTION PRIOR TO RIBOFLAVIN/ULTRAVIOLET-A
Figure 7.5: Transmission spectra of porcine corneas: controls (yellow diamonds), 20% alcohol (red diamonds), grid pattern epithelial debridement (green diamonds) and complete epithelial debridement (blue diamonds)
Our results have shown that in the immediate postoperative period, the light transmission spectrum of fully de-epithelialized porcine corneas treated with riboflavin eyedrops is altered by the presence of riboflavin within the stroma (Figure 7.1) and the subsequent exposure of the cornea to UV-A light does not produce any further changes to the transmission spectrum. It is of note that riboflavin is an decomposes in the presence of light at wavelengths below 500 nm, so that any acute changes in light transmission due to riboflavin absorption will be short-lived and in the clinical setting the yellow discoloration of the cornea due to riboflavin, which is clearly visible following the treatment has cleared 24 hours later.14 The normality compared to controls of the transmission spectra of corneas which underwent superficial epithelial trauma but had an intact basal epithelium, clearly suggests the need to remove all epithelial cell layers prior to treatment to permit stromal penetration of riboflavin (Figure 7.3A). Similarly, the concomitant use of repeated tetracaine 1% eyedrops over the 35-minute treatment period did not appear in our study to allow stromal penetration of riboflavin through an intact corneal epithelium even18 (Figure 7.3B). It appears that the presence of an intact basal
epithelial layer acts as an effective barrier to riboflavin absorption by the corneal stroma and that this barrier is not sufficiently altered either by superficial epithelial trauma or repeated tetracaine eyedrop administration. Similarly, with 20% Alcohol solution applied for 40 seconds we found no differences in transmission spectra between 400 nm and 510 nm compared to non-treated control corneas (Figure 7.5). Once again, this suggests that the usage of an application of 20% alcohol in the presence of an intact epithelium is not sufficient to allow adequate riboflavin penetration into the corneal stromal and correspondingly alter its normal light transmission spectrum. A grid pattern of full thickness epithelial debridement did appear to allow some riboflavin stromal penetration, indicated by a significant dip in the transmission spectrum between 400 nm and 490 nm compared to controls (Figure 7.5). This dip in transmission, however, was significantly less compared to that seen after complete central epithelial removal (Figure 7.5). This suggests that whilst partial fullthickness epithelial debridement does allow riboflavin stromal absorption it is less than with complete removal. Indeed examination of the corneas immediately following treatment revealed that whilst
35
MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
36
riboflavin had penetrated the stroma immediately beneath the areas of epithelial debridement the areas beneath intact epithelium had not been stained yellow with the uptake of riboflavin being heterogeneous (Figure 7.2). This is in contrast to corneas where the epithelium had been completeley removed where yellow discolouration was homogeneous (Figure 7.1). It was only with complete central epithelial debridement that we found consistent changes in the light transmission spectra of our treated corneas which suggested significant riboflavin stromal uptake. Such considerations are very important as failure to achieve adequate stromal absorption of riboflavin is likely to limit the crosslinkage process.12,14,15 Indeed, recent studies investigating immunofluorescent changes following cross-linking treatment with riboflavin and UV-A also indicate the need to remove the epithelium prior to treatment.23 It is of note, however, that although inadequate stromal absorption of riboflavin will undoubtedly result in increased UV irradiance of the endothelium, lens and retina at energy levels of 3mW/ cm2 toxic levels will not be reached.12-16 Our study results are in contrast to the clinical results of Chan17 and Pinelli (Eyeworld 2007, May, 34-36) who performed the crosslinkage procedure with the epithelium intact and advocate the use of tetracaine 1% to loosen the epithelial tight junctions. Chan et al reported a possible an additive effect, in terms of reduction in refractive cylinder, steep and average keratometry values and lower-upper keratometry ratios, with corneal collagen crosslinkage following inferior intacs insertion compared to inferior intacs insertion alone in keratoconic eyes.17 However, such results must be interpreted with respect to the nonrandomized, retrospective nature of their study and that keratoconus is a heterogeneous condition in which accurate, repeatable refractive, keratometric and topographic measurements may be difficult to obtain. In addition, crosslinkage treatment was performed in their patients immediately following intra-stroma ring segment insertion and it may be that epithelial trauma associated with the procedure (both mechanical and due to exposure), together with the deep stromal incision required for ring segment insertion may have facilitated corneal stromal riboflavin absorption. Pinelli in a non-peer reviewed article, documented similar outcomes following riboflavin/UV-A crosslinkage treatment with and without epithelial removal. Similar
to Chan et al.15 they reported fluorescence in the anterior chamber which they attributed to riboflavin penetration although direct measurements were not made. Whilst such findings are of interest we do not believe they give direct evidence that riboflavin can be significantly absorbed into the corneal stroma without removal of all layers of the corneal epithelium prior to topical administration and they are not supported by the spectrophotometric measurements in this study and the recent findings of others.23 Such considerations are important as failure to achieve adequate stromal absorption of riboflavin is likely to limit the crosslinkage process.12,16 It is important to note, however, that spectrophotometic analysis does not provide direct assessment of stromal riboflavin stromal uptake and whilst the absence of any significant alteration of light transmission spectra suggests limited riboflavin absorption it does not preclude small amounts of riboflavin uptake. Further studies directly measuring stromal riboflavin levels are indicated. It may also be of interest to investigate the UV range from 350 to 380 nm where the treatment wavelength is situated, although our analysis of the visible spectrum does include one of the peak absorption spectra of Riboflavin at 400 to 490 nm. It is also important to remember that in eyes with advanced keratoconus the basal epithelial layer is often broken and may behave differently in terms of its barrier functions in comparison to a normal healthy cornea,24 although this procedure is typically only performed on eyes with mild to moderate keratoconus with central pachymetric thicknesses of 400μm or greater in which the basal layer is usually intact. CONCLUSION Complete removal of the corneal epithelium is an essential component of riboflavin/UV-A crosslinkage therapy as superficial epithelial trauma, tetracaine administration and 20% alcohol application for 40 seconds alone is not sufficient to permit the penetration of riboflavin into the corneal stroma. Whilst partial grid-pattern epithelial removal does allow some riboflavin penetration, uptake is limited and nonhomogeneous unlike full-thickness complete central epithelial debridement. Such considerations are important as failure to achieve adequate stromal absorption of riboflavin may impair the efficacy of the cross-linkage process.
THE IMPORTANCE OF EPITHELIAL DEBRIDEMENT FOR RIBOFLAVIN ABSORPTION PRIOR TO RIBOFLAVIN/ULTRAVIOLET-A
REFERENCES 1. Krachmer JH, Feder RS, Belin MW. Keratoconus and related non-inflammatory corneal thinning disorders. Surv Ophthalmol 1984;28:293-322. 2. Javadi MA, Motlagh BF, Jafarinasab MR, Rabbanikhah Z, Anissian A, Souri H, Yazdani S. Outcomes of penetrating keratoplasty in keratoconus. Cornea 2005;24(8):941-46. 3. Reeves SW, Stinnett S, Adelman RA, Afshari NA. Risk factors for progression to penetrating keratoplasty in patients with keratoconus. Am J Ophthalmol 2005;140(4):607-11. 4. Mamalis N, Anderson CW, Kreisler KR, Lundergan MK, Olson RJ. Changing trends in the indications for penetrating keratoplasty. Arch Ophthalmol 1992;110(10):1409-11. 5. Al-Yousef N, Marvrikakis I, Mavrikakis E, Daya SM. Penetrating keratoplasty: indications over a 10-year period. Br J Ophthalmol 2004;88(8):998-1001. 6 Wollensak G. Cross-linking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006;17(4):356-60. 7. Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine cornea after riboflavin/ultraviolet-A-induced cross-linking. J Cataract Refract Surg. 2003;29:1780-85. 8. Spoerl E, Schreiber J, Hellmund K, Seiler T, Knuschke P.. Untersuchungen zur Verfestigung der Hornhaut am Kaninchen. Ophthalmologe 2000;97:203-06. 9. Spoerl E, Wollensak G, Seiler T. Increased resistance of cross linked cornea against enzymatic digestion. Curr Eye Res 2004;29:35-40. 10. Spoerl E, Wollensak G, Dittert DD, Seiler T. Thermomechanical behaviour of collagen crosslinked porcine cornea. Ophthalmologica 2004;218:136-40. 11. Wollensak G, Aurich H, Pham DT, Wirbelauer C. Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A. J Cataract Refract Surg 2007;33(3):516-21. 12. Andley U. Photo-oxidative stress. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology, vol. 1, Philadelphia: WB Saunders 1992;575-90.
13. Wollensak G, Spoerl E, Wilsch M, Seiler T. Endothelial cell damage after riboflavin-ultraviolet-A-treatment in the rabbit. J Cataract Refract Surg 2003;29:1786-90. 14. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-Ainduced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-27. 15. Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA-riboflavin cross-linking of the cornea. Cornea 2007;26:385-89. 16. Spoerl E, Huhle M, Seiler T. Induction of crosslinks in corneal tissue. Exp Eye Res 1998;66:97-103. 17. Chan CK, Sharma M, Boxer-Walcher BS. Effect of inferiorsegment intacs with and without C3-R on keratoconus. J Cataract Refract Surg 2007;33:75-80. 18. Hayes S, O°Brart DP, Lamdin LS, Doutch J, Samaras K, Meek KM, Marshall J. An investigation into the importance of complete epithelial debridement prior to Riboflavin/ Ultraviolet A (UVA) corneal collagen cross-linkage therapy. J Cat Ref Surg 2008;34:557-61. 19. Samaras K, O°Brart DPS, Doutch J, Hayes S, Marshall J, Meek K. Effect of Epithelial Retention and Removal on Riboflavin Absorption in Porcine Corneas. J Ref Surg 2008 (in press). 20. Kostyuk O, Navolina O, Mubard TM, et al. Transparency of the bovine corneal stroma at physiological hydration and its dependence on concentration of ambient ion. Journal of Physiology 2002;543:633-42. 21. Wollensak G, Wilsch M, Spoerl E, Seiler T. Collagen fiber diameter in the rabbit cornea after collagen-cross-linking. Cornea 2004;23:503-7. 22. Kohlhaas M, Spoerl E, Schilde T. Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light. J Cataract Refract Surg 2006;32(2):279-83. 23. Bottos KM, Dreyfuss JL, Regatieri, Lima-Filho AA, Schor P, Nader HB, Chamon W. Immunofluorescence confocal microscopy of porcine corneas following collagen crosslinking treatment with riboflavin and ultraviolet A. J Refract Surg 2008;24:S715-9. 24. Hollingsworth JG, Bonshek RE, Efron N. Correlation of the appearance of keratoconic cornea in vivo by confocal microscopy and in vivo by light microscopy. Cornea 2005;24:397-405.
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38
INDICATIONS AND CONTRAINDICATIONS: TRADITIONAL TECHNIQUE VS TRANSEPITHELIAL TECHNIQUE
INTRODUCTION The term cross-linking indicates a medical intervention; it was originally used in specialties such as dentistry and orthopedics. Theo Seiler, MD, PhD, of Switzerland, was the first to suggest applying this principle to ophthalmology, more specifically cross-linking corneal collagen fibers. After researching this idea, Professor Seiler and his colleagues studied the use of riboflavin (vitamin B2) and UVA irradiation, noting that the combination induced a strengthening of the corneal stroma. This effect was obtained by creating new bonds between the collagen fibers—where unstable riboflavin molecules produced these bonds after irradiation with UVA. This early research proved an effective treatment for keratoconus; however, one problem was standardizing the main parameters of the treatment, including riboflavin concentration and penetration, UV fluence, and time of exposure. This standardization was necessary to render the treatment safe and effective. PRESENT The corneal collagen cross-linking, or C3-R, treatment initially required epithelial debridement to improve riboflavin penetration in the stroma; however, now the treatment may be performed with or without deepithelialization. There are different opinions regarding epithelial debridement, but we must remember that most complications of the procedure (infections, slow healing, subepithelial haze) arise from de-epithelialization. Epithelial healing in keratoconic corneas is indeed much slower than in healthy corneas, and may take several weeks after C3-R in some eyes (personal observation). Some surgeons argue that leaving the epithelium on the stroma is less efficacious because it slows the penetration of the riboflavin on the stroma; however, our experiences demonstrate the opposite. Recently, Pinelli et al used fluoroscopy to observe the absorption of riboflavin in the absence of epithelial debridement (Figure 8.1). Riboflavin 0.1% was applied to the cornea via a saturated Merocel sponge and left on the eye for 5 minutes before the start of UVA light administration. We repeated riboflavin applications every 3 minutes. After 6 minutes, the riboflavin penetrated under the epithelium; after 14 minutes, it penetrated the middle of the stroma; and after 30 minutes, we observes its full diffusion. Our research
demonstrated that during C3-R treatments, leaving the epithelium in tact does not significantly limit the penetration of the riboflavin. PERSONAL EXPERIENCE Observing via fluoroscopy the riboflavin absorption without epithelial removal, we noticed that the epithelium does not restrict significantly the riboflavin penetration. Riboflavin 0.1% (PriaLight®, PriaVision, Menlo Park, CA, USA) was applied on the cornea via a saturated Merocel sponge for 5 minutes before the start of UVA light administration. The riboflavin is then applied every 3 minutes during the whole procedure. After 6 minutes the riboflavin penetrates under the epithelium; after 14 minutes it penetrates in the middle stroma and after 30 minutes we can observe its full diffusion (Fig. 8.1). On this basis, we conducted a comparative study to evaluate the difference between C3-R with and without disepithelialization on patients affected by keratoconus. Each group (group A and group B) was composed of five patients each. The A group was disepithelialization treated monocularly with C3-R without disepithelization; the B group was treated monocularly with C3-R with disepithelization. Before the treatment, all patients had an assessment of uncorrected visual acuity (UCVA), best spectaclecorrected visual acuity (BSCVA), manifest refraction spherical equivalent (MRSE), bio-microscope evaluation (corneal and lens transparency), intraocular pressure (IOP), corneal computerized topographic examination (Eyesys), linear scan optical tomography (Orbscan II), endothelial cell count and ultrasound pachimetry, and a satisfaction questionnaire was also administrated in order to monitor the level of satisfaction reached by the two different groups. All examinations were repeated at six and nine months after C3-R treatment. Exclusion criteria included pachimetry thinner than 400 µm and aphakic eye. Each eye was treated with proparacaine 0.5% for < 30 minutes before exposure (i.e. approximately two drops every 5 minutes). Riboflavin was then applied on the cornea for < 25 minutes before irradiation and was then activated by a 30-minute exposure to the
39
MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
Figure 8.1: The penetration of riboflavin under the epithelium
UV-A light (i.e. 370 nm fluence at 3 mW/cm 2 ). Riboflavin solution was reapplied on the cornea every 3 minutes during the UV-A irradiation. RESULTS
40
Before the treatment, UCVA ranged from 0.1 to 0.3, BSCVA from 0.4 to 0.7, medium K value ranged from 45 to 49 D, and corneal thickness from 432 to 463 microns At six and nine months postoperatively there were not significant differences in the analyzed parameters between the disepithelialized group and the non disepithelialized one. Mean K decreased, SE decreased, RMS error decreased, gained lines in UCVA and BSCVA, pachimetry increased and no endothelial cells loss were observed in both groups (FIG. 8.2). The only remarkable difference regarded discomfort evaluation and satisfaction questionnaire. The de-epithelialized group showed demarcation lines in the stroma (probably due to migration of keratocytes), that not necessarily represent a sign of cross-linking. According to our R and D department, signs of linking have to be demonstrated through direct and indirect analysis (direct: confocal microscopy and/
Figure 8.2: Comparative postoperative results
or electronic microscopy; indirect through the study of the molecular properties of collagen). The non-deepithelized group showed transparent cornea without any stromal abnormality (Figures 8.3 and 8.4).
INDICATIONS AND CONTRAINDICATIONS: TRADITIONAL TECHNIQUE VS TRANSEPITHELIAL TECHNIQUE
Figure 8.3:
Figure 8.4:
41
MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
Figure 8.5: Changes of central curvature after corneal collagen cross-linking without deepithelialization at tangential videokeratography. Top center: preoperative. Top right: 1 week after treatment, showing initial improvement. Bottom center: 3 weeks after treatment, further improvement. Bottom left: differential map, showing a cone flattening of 4 diopters
42
The postop. therapy for the first group needed topical steroids for two weeks, while the second group of patients only needed artificial tears for one week. At the Second International Corneal Cross-linking Congress 2006, in Zurich, Switzerland, Pinelli et al reported results and characteristics of our C3-R treatment protocol2: • No epithelial debridement; • Two drops of proparacaine 0.5% every 5 minutes for 15 minutes; • A 5-minute presoak with riboflavin solution (0.1% riboflavin-5-phosphate and dextran); • Up to 30 minutes of exposure to UV-A light (370 nm fluence at 3mW/cm2) to the central 7 mm of the cornea (with the speculum in place); • UV-A light combined with reapplication of riboflavin solution every 3 minutes. The penetration of riboflavin through intact epithelium can be enhanced by substances increasing its permeability, such as ethylenediaminetetraacetic acid (EDTA)3 and topical gentamicin. Dr Leccisotti is currently pre-treating for 3 hours with these 3 components, all included in a standard topical
gentamicin industrial preparation (Ribomicin eyedrops, Farmigea, Italy), then by topical anesthetic (oxybuprocaine) for 30 minutes, before instilling riboflavin and irradiating with UV-A. His results at 6 months are encouraging, with BCVA unchanged in 21 eyes, improved in 11 eyes, worsened in 1 eye by 1 Snellen line. Mean BCVA improvement, in decimals, is 0.15. Mean curvature improvement is 1.3 diopters (Figure 8.5). Endothelial safety was tested by specular microscopy, and cell density was unchanged at 1 month and 6 months. This is reassuring, and shows that UV-A penetration is (as expected) under the threshold of endothelial damage. Pinelli et al have a patented a riboflavin formula (0,1% plus tensioactive) which is at the present time under investigation on rabbits eyes. Dr Leccisotti and Dr Pinelli truly believe that in the near future the transepithelial procedure will be a new frontier of the treatment for keratoconus; the methods, epi-off and epi-on, can consist of different options for different cases. In the history of refractive surgery similar phenomenon are now routine for everybody (first step with PRK and then LASIK) and
INDICATIONS AND CONTRAINDICATIONS: TRADITIONAL TECHNIQUE VS TRANSEPITHELIAL TECHNIQUE
there is the firm belief that these two approaches to the cure of the keratoconus disease can cohabit in the near future. FUTURE Although ophthalmologists are still debating whether to remove or keep the epithelium in tact before C3-R treatment, we prefer to avoid de-epithelialization and its associated discomfort, especially until a scientific method or new technology in vivo will demonstrate the opposite. In our opinion, the C3-R treatment of the future will be a less invasive, painless technique that does not require de-epithelialization. A bilateral option may also be psychologically easier and more accepted by
our patients. Thus far, C3-R treatments are effective, and results and follow-up are very encouraging. The numerous studies on C3-R and its impending CE mark demonstrate its safety. REFERENCES 1. Pinelli R, “Corneal collagen cross-linking with riboflavin (C3-R) treatment opens new frontiers for keratoconus and corneal ectasia”, Eyeworld, May 2007;34-40. 2. Pinelli R. “The Italian Refractive Surgery Society (SICR) results using C3-R”, paper presented at the Second International Congress of Corneal Cross-linking (CCL), Zurich, 2006. 3. Nakamura T, et al. Electrophysiological characterization of tight junctional pathway of rabbit cornea treated with ophthalmic ingredients. Biol Pharm Bull 2007;30:236064.
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CONSIDERATIONS ON ENDOTHELIAL SAFETY IN UV-A—CROSS-LINKING TREATMENT
ABSTRACT Purpose Using the absorption coefficient of 53 cm-1, established in riboflavin soaked porcine corneas, it can be calculated that, using UVA 365 nm at 3.0 mW/cm2, the cytotoxic endothelial threshold is reached in corneas thinner than 400 µm. We have measured the absorption coefficient in postmortem human corneas after instilling riboflavin. Setting Department of Ophthalmology, University Hospital Antwerp, Antwerp University Methods Corneal thickness was measured in 9 pairs of human donor eyes, using Pentacam Scheimpflug and ultrasound pachymetry. In one eye of each donor the epithelium was manually removed over an 8 mm zone; in the fellow eye the epithelium was left intact. In both eyes, riboflavin 0.1% in dextran 20% was instilled on the intact globe for 20 minutes. After this period the corneas were rinsed and a corneoscleral disc was trephined. The transmission of the central part of the cornea was measured in transillumination, using the UV light source and the UV detector of the cross-linking device. Results The average corneal thickness measured was 658.5 ± 51.5 µm after epithelial removal, and 758.3 ± 98.8 µm without epithelial removal. The average transmittance after instillation of riboflavin for 20 minutes was 12.89 ± 4.10% with epithelial abrasion and 28.52 ± 4.39% without (p<0.05). The resultant average absorption coefficient is 32 ± 5 cm-1 when the epithelium is removed, and 17 ± 2 cm-1 when it is left intact (p<0.05). These results show that the amount of riboflavin taken up by the cornea is much higher when the epithelium is removed. These findings may be relevant in the discussion on the necessity to remove the epithelium for corneal cross-linking. Conclusion The absorption coefficient (53 cm-1) established for porcine corneal strips soaked in riboflavin, is not reflecting the clinical situation. Using human donor globes, we established an absorption coefficient of 32 cm-1 implying a minimal corneal thickness of at least 490 µm to ensure endothelial safety.
INTRODUCTION Corneal collagen cross-linking (C3R) by means of ultraviolet-A (UV-A) light and riboflavin (vitamin B2)
is a technique developed by Wollensak and Seiler that consists in creating extra cross links in the corneal stroma to increase the rigidity of the corneal tissue. The excitation of the photosensitizer riboflavin by UVA irradiation with a wavelength of 365 nm leads to the formation of free radicals that induce new chemical bonds between collagen fibers. Stress-strain measurements of porcine and human corneas have shown that corneas become significantly more stiff after treatment. 1 Preliminary clinical reports show that C3-R is a promising technique to stop the progression of keratoconus. The proposed treatment protocol uses UV-A 365 nm at 3.0 mW/cm 2 for 30 minutes, corresponding to a total dose of 5.4 J/cm².2 Concern may persist relating to the safety of the cross-linking treatment for the endothelium. In rabbits, Wollensak et al. showed a cytotoxic effect of C3-R treatment on corneal endothelium at an endothelial UVA dose of 0.36 mW/cm2 for 30 minutes, that is a dose of 0.65 J/cm².3 Using the absorption coefficient of 53 cm-1 that was found in earlier experiments with porcine corneas4, it can be calculated that in corneas thinner than 400 µm, the cytotoxic endothelial UV-A irradiance of 0.36 mW/cm 2 is reached using the standard surface irradiance of 3.0 mW/cm 2 . 3 The authors conclude that pachymetry should be routinely performed before C3-R treatment to exclude thin corneas and to avoid endothelial damage. Wollensak refers to two publications when quoting the absorption coefficient of the cornea saturated with riboflavin as 53cm-1.3,5 In one experiment riboflavin treated porcine corneas were used without clear specifications on how the measurements were performed. 4 The second reference is on “UV absorbance of the human cornea in the 240 to 400 nm range” by Kolozsvari6, in which the absorbance of fresh postmortem human corneas is studied without the use of riboflavin. A later report by Spoerl refers to an absorption coefficient of 70 cm -1 in human riboflavin treated corneas without specification of the method of measurement (unpublished data).7 In this article we propose to measure the absorption coefficient of riboflavin-saturated human corneas for UV-A light with a wavelength of 365 nm, in order to estimate the accuracy of the previously reported values. An exact determination of the absorption coefficient is essential to calculate the critical damage threshold of the corneal endothelium.
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
We also want to investigate whether riboflavin can penetrate into the cornea if the epithelium is left intact. In the standard treatment protocol it is obligatory to remove the corneal epithelium to allow for diffusion of the riboflavin into the stroma. Nevertheless, Pinelli and others report similar clinical results in C3-R treatment without removal of the epithelium.8 He suggests that the pretreatment use of topical anesthetics might allow for the penetration of riboflavin through the epithelium. MATERIALS AND METHODS Materials Donor eyes were obtained from the Ocular Tissue Bank of the University Hospital Antwerp; they were discarded for use as donor tissue because of medical contraindications. Riboflavin-5-phosphat 0.5% (G. Streuli and Co AG, Uznach, Switzerland) was diluted with a dextran T-500 20% solution in NaCl 0.9% to obtain a riboflavin 0,1% solution as used for clinical C3-R. The corneal transmittance was measured by placing the excised cornea between the UV-source and the UV-detector of the cross-linking device, used for the clinical treatments (both provided by IROC AG, Zürich, Switzerland), as demonstrated in Figure 9.1. Methods 1. Measurement of the absorption coefficient of the cornea, with and without epithelium after riboflavin solution instillation. Eighteen eyes of 9 donors were used to calculate the absorption coefficient of the cornea for UVA light with a wavelength of 365 nm and to investigate the influence of epithelial removal.
46
Figure 9.1: Set-up of the transmittance measurements
a. Measurement of postmortem corneal thickness. All 18 eyes of the 9 donors were used to calculate the average postmortem corneal thickness. The thickness of the donor corneas before and after epithelium removal was measured using Scheimpflug imaging (Pentacam, Oculus GmbH, Wetzlar) and/or ultrasound pachymetry. b. Measurement of corneal transmittance. In one eye of each pair (alternatively right or left) the epithelium was manually removed using a blunt spatula over about an 8 mm diameter zone under the microscope. The fellow eye was used as a control and its epithelium was left intact. In both eyes, riboflavin 0.1% in dextran 20% was instilled on the intact globe for 20 minutes, 1 drop every 30 seconds to compensate for the fact that the drops run off the globe. At the end of 20 minutes the corneas were rinsed, gently wiped with a compress and a corneoscleral disc was trephined. The transmission of the central part of the cornea was measured in transillumination. 2. Influence of prolonged riboflavin 0.1% soaking or instillation on the absorption coefficient of the cornea, with and without epithelium. In 2 pairs of the corneoscleral discs of the first experiment, additional measurements were made in order to establish whether it is possible to increase riboflavin uptake and increase UVabsorption by soaking the corneas or prolonging the instillation time. a. Soaking experiments: Two corneas from one donor from the first experiment, one cornea with intact epithelium and one without epithelium, were soaked in riboflavin for an extra 20 minutes. A transmittance measurement was made every 5 minutes. These tests enabled us to determine a curve of riboflavin absorption by the cornea. b. Prolonged instillation experiments. Two corneas from another donor, one with its epithelium intact and one with its epithelium removed, received extra drops on the anterior surface of the cornea. The transmittance was measured 40, 45, 55 and 65 minutes after the initial start of the instillation of drops.
CONSIDERATIONS ON ENDOTHELIAL SAFETY IN UV-A—CROSS-LINKING TREATMENT
c. Increase of riboflavin absorption by the cornea with respect to time: In hindsight we thought it would be interesting to have a complete analysis of the corneal riboflavin saturation through soaking to establish the steady-state value of the absorption coefficient: two extra corneoscleral discs, one with and one without epithelium, were soaked in riboflavin. Every 5 minutes, the corneas were rinsed, the surface gently wiped and the transmittance was measured. d. Effect of riboflavin concentration on the absorption coefficient: In a final effort to obtain a higher value for the absorption coefficient, we removed the epithelium from 2 donor eyes and instilled undiluted riboflavin 0.5% (Streuli Gmbh) for 20 minutes. After instillation, the corneas were rinsed and gently wiped and the corneoscleral discs trephined. Based on the transmittance measurements of the central cornea the absorption coefficient can then be calculated. 3. Influence of proparacaine on riboflavin penetration of corneas with intact epithelium: Two eyes from the same donor were used to calculate the absorption coefficient of the cornea at 365 nm, in order to investigate the influence of proparacaine 0.5% eyedrops on riboflavin corneal penetration. For this experiment, we have followed the protocol as described in the communication of Pinelli. In both eyes, the epithelium was left intact. In one eye, proparacaine drops were instilled for 15 minutes, 2 drops every 5 minutes. In an oral communication at the 3rd Cross-linking Conference (December 2008, Zürich) Pinelli described a presoaking time with riboflavin of 5 minutes. We presoaked both eyeballs in riboflavin 0.1% solution even longer, for 10 minutes. At the end of the 10 minutes, the corneas were rinsed, gently wiped with a compress and a corneoscleral disc was trephined. The transmission of the central part of the cornea was measured in transillumination.
removal of the epithelium, and 758.3 ± 98.8 µm without epithelium removal. 1-b. The average transmittance after instillation of riboflavin for 20 minutes was 12.89 ± 4.10% with epithelial abrasion and 28.52 ± 4.39% without. A χ²-test shows that there is a significant difference between the transmittance of the cornea with or without epithelium abrasion (p<0.05). The absorption coefficient can then be calculated taking into account the measured corneal thickness for the donor eyes using the LambertBeer formula:
T=
I In(T) = e — μχ ⇔ μ = — where I0 χ
T is transmittance, I is transmitted light intensity and I 0 is the incident light intensity, x is the thickness of the cornea, µ is the absorption coefficient, e indicates the exponential function and ln is the neperian logarithm (the inverse function of an exponential). The resulting average absorption coefficient is 32 ± 5 cm-1 when epithelium is removed, and 17 ± 2 cm -1 when it is left intact. The average absorption coefficients are statistically different (p<0.05): the amount of absorbed riboflavin by the cornea is then much higher when the epithelium is removed. Both corneas in Figure 9.2 have been instilled with riboflavin for 20 minutes. The right hand cornea shows the staining by the riboflavin in the zone where the epithelium has been removed; the distinction between the part saturated by riboflavin and the rest of the cornea can easily be seen. The cornea on the left is the one without
RESULTS 1-a. The average corneal thickness measured with the Scheimpflug technique was 658.5 ± 51.5 µm after
Figure 9.2: Photograph of the corneoscleral disks of both eyes of the same donor after instillation of riboflavin drops; the epithelium is intact in the left cornea
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
Figure 9.3: Change of the absorption coefficient of corneas, with and without epithelium removal, in the course of time, instilled with or soaked in 0.1 % riboflavin solution
48
epithelial removal; riboflavin seems not to have penetrated into the stroma through the intact epithelium. 2. We tried to establish whether it would be possible to increase UV absorption by corneas with and without intact epithelium by soaking the corneas or increasing the instillation time. a. Soaking experiments Measurement of transmittance was continued every 5 minutes from 20’ (moment of trephination) to 40 minutes after initiation of instillation. The corneas were soaked in riboflavin 0.1% from 20 minutes to 40 minutes. The absorption coefficients systematically increase throughout this experiment. b. Prolonged instillation measurements The corneal transmittance was measured from 20 (time point of trephination), and after 40, 45, 55 and 65 minutes after initiation of instillation. Instillation of riboflavin 0.1% was uninterruptedly continued. The absorption coefficient shows a slight increase which does not seem to be relevant. The data presented in Figure 9.3: both corneas without epithelium have a higher initial absorption coefficient, reflecting the uptake of riboflavin. Extra- instillation does not change
the absorption coefficient in a relevant way, suggesting that prolonging the duration of instillation for the clinical treatment is not useful. Soaking on the other hand does increase the absorption coefficient, but this is not clinically applicable. It shows that the endothelial layer with its gap junction allows extra uptake of riboflavin into the cornea. c. Increase of riboflavin absorption by the cornea with respect to time. We were curious to know the absorption coefficient for a cornea maximally saturated with riboflavin, through soaking of fresh corneoscleral discs in riboflavin 0,1% for a total period of 45 minutes, one with the epithelium removed, both soaked in riboflavin solution from time point 0. The results are available in Figure 9.4. In these two eyes a steady-state is reached after 30 minutes with absorption coefficients leveling off between 30 and 35 cm -1 which indicates that the absorption coefficient of 32 cm -1 , found in our first experiment after 20 minutes of instillation reflects a riboflavin saturated cornea. d. Effect of the riboflavin concentration on the absorption coefficient. The absorption coefficient of the cornea without epithelium and instilled with riboflavin 0.5% was 71 cm-1.
CONSIDERATIONS ON ENDOTHELIAL SAFETY IN UV-A—CROSS-LINKING TREATMENT
Figure 9.4: Change of the absorption coefficient of corneas, with and without epithelium removal, in the course of time, soaked for 40 minutes in 0.1 % riboflavin solution
3. The transmittance of the corneas with and without proparacaine instillation was respectively 27.8% and 26.4%. The calculated absorption coefficients were then respectively: 18 cm-1 and 19 cm -1 respectively with and without proparacaine. These results are in the range of the absorption coefficient of corneas with intact epithelium. DISCUSSION In the first experiment we have determined that the absorption coefficient of human postmortem corneas, instilled with riboflavin 0,1% in dextran for 20’ – as applied in the standard C3R-treatment protocol – amounts to 32 ± 5 cm-1 with the epithelium removed, and to 17 ± 2 cm-1 when the epithelium is left intact. Prolonging the instillation time as in the second experiment, did not lead to an increased absorption coefficient; soaking corneas, allowing the riboflavin to enter through the endothelium, amounted to an absorption coefficient around 35 cm-1. To limit the postmortem corneal edema and the resulting increase in corneal thickness which could be responsible for a falsely low value of the absorption coefficient, we have limited to less than 24 hours the interval between the donor’s decease and enucleation/ preparation time as much as possible. In animal eyes the experiments can be performed immediately after
death, but for logistical reasons postmortem times in animals often run up to several hours as well. We may have used a normal corneal thickness of 520 µm in the calculations because the bulk of the absorption occurs in the anterior part of the cornea; even then the absorption coefficients would be 40 cm -1 for epithelium off and 21 cm-1 for epithelium on, which is still well below the quoted values of 53 cm-1 for porcine corneas4 and 70 cm-1 for human corneas.7 If the absorption coefficient of the cornea for UVA 365 nm is 53 cm-1, the minimal corneal thickness for safe C3R-treatment must be 400 µm as recommended by Spoerl7 and Wollensak3,10, using the Lambert-Beer equation. This absorption coefficient was obtained using strips of porcine corneal tissue, soaked in riboflavin.4 If however the absorption coefficient is 32 ± 5 cm-1, as we have calculated in human corneas (with epithelium removed), the cornea should have a thickness of 660 µm to be safe for the endothelium (from 490 to 848 µm). The treatment of keratoconic eyes according to the clinical protocol using UVA 365 nm with 3 mW/cm2 irradiance, could therefore reach the critical threshold for damage of the endothelial cells. In the clinical experience and in confocal microscopy examinations11 however, until now there have been no reports on endothelial damage. Either the human endothelial cells are more resistant to UVA irradiation than their animal counterparts (the damage thresholds have been determined in rabbit corneas3
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
and on porcine endothelial cell cultures10), or more extensive and prolonged studies of the human endothelium in clinical trials are necessary to show a possible detrimental effect in the longer term. Based on our third experiment some conclusions can also be made on the necessity of epithelial abrasion to allow penetration of riboflavin in the cornea. The transmittance for UVA of the human cornea as quoted in other studies was 25%6 to 30%.9 We confirmed this number in the first group of eyes, instilled with riboflavin for 20 minutes, and in which the epithelium was left intact, thereby (indirectly) demonstrating that riboflavin does not enter the cornea if the epithelium is not removed. In our experiment with instillation of proparacaine before soaking the cornea with the riboflavin solution, the absorption coefficient remained unchanged, suggesting that the epithelial barrier for penetration of riboflavin remained intact. With regard to the safety of the endothelium, the treatment as proposed by Pinelli is not risky for the patient cornea.8 Wollensak established that the cytotoxic UV-A irradiance level of the corneal endothelium in absence of riboflavin is about 10 times lower than when the riboflavin (acting as a photosensitizer) is present. On porcine endothelial cells he found a UV-A damage threshold of 4 mW/cm² for 30 minutes.10 Further basic and clinical research is mandatory to fine-tune the safety threshold of corneal cross-linking with riboflavin for the human endothelial cells. ACKNOWLEDGEMENTS We would like to thank Nezahat Bostan, laboratory technician of the Antwerp University Hospital cornea
50
bank, for enabling this research with her supportive help and Rudi Leysen, our medical photographer, for the images of the corneas. REFERENCES 1. Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking. J Cataract Refract Surg 2003;29:1780-85. 2. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-Ainduced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-27. 3. Wollensak G, Spoerl E, Wilsch M, et al. Endothelial cell damage after riboflavin-ultraviolet-A treatment in the rabbit. J Cataract Refract Surg 2003;29:1786-90. 4. Spoerl E, Schreiber J, Hellmund K, et al. Untersuchungen zur Verfestigung der Hornhaut am Kaninchen. Ophthalmologe 2000;97:203-06. 5. Wollensak G, Spoerl E, Wilsch M, et al. Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment. Cornea 2004;23:43-49. 6. Kolozsvari L, Nogradi A, Hopp B, et al. UV absorbance of the human cornea in the 240- to 400-nm range. Invest Ophthalmol Vis Sci 2002;43:2165-68. 7. Spoerl E, Mrochen M, Sliney D, et al. Safety of UVAriboflavin cross-linking of the cornea. Cornea 2007;26:385-89. 8. Pinelli R. Corneal collagen cross-linking with riboflavin: Results at six months follow-up in 20 eyes. Free paper, XXIV Congress of the ESCRS, 2006. 9. Boettner EA, Wolter JR. Transmission of the ocular media. Investigative Ophthalmology 1962;1:776-81. 10. Wollensak G, Spoerl E, Reber F, et al. Corneal endothelial cytotoxicity of riboflavin/UVA treatment in vitro. Ophthalmic Res. 2003;35:324-28. 11. Mazzotta C, Traversi C, Baiocchi S, et al. Conservative treatment of keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: qualitative investigation. Eur J Ophthalmol 2006;16:530-35.
CORNEAL COLLAGEN CROSS-LINKING WITH RIBOFLAVIN AND ULTRAVIOLET-A LIGHT: STEP BY STEP TECHNIQUE
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
INTRODUCTION Corneal collagen cross-linking with riboflavin is a new method to increase the biomechanical stability of the cornea by inducing additional cross-links between or within collagen fibers using UV-A light and riboflavin as photomediators. The procedure is variously known as CXL, CCL, and C3-R. It was developed from 1993 to 1997 by Prof. Theo Seiler and Prof. Eberhard Spoerl at the University of Dresden, Germany. The first patients were treated in 1998. Clinical trials are continuing, but the treatment is seeing increasing adoption by the ophthalmological community, and has shown success in treating early cases of keratoconus, pellucid marginal degeneration, iatrogenic keratectasia after refractive lamellar surgery, and corneal melting that is unresponsive to conventional therapy.
Figure 10.1A: Parallel corneal layers
Figure 10.1B: Collagen cross-linking
TECHNIQUE BACKGROUND
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Photo-polymerization using UV-A light was found to be the most promising technique to achieve cross-links in connective tissue. Photo-polymerization is activated by means of a non-toxic and soluble photo-mediator (riboflavin/dextran solution) and a wavelength (UV-A) which is absorbed strongly enough to protect deeper layers of the eye. In this technique, riboflavin (vitamin B2) has two important functions: it absorbs UV-A radiation and acts as a photo-sensitizer for the generation of reactive oxygen species (singlet oxygen). In combination with UV-A light, riboflavin forms radicals that cause the cross-linking. This process leads to physical crosslinking of the corneal collagen fibers. (Figures 10.1A and 10.1B) show the parallel corneal layers (white) and the collagen cross-linking (red) which increases after treatment. UV-A light with riboflavin therapy has been shown to increase corneal rigidity by 71.9% in porcine corneas and by 328.9% in human corneas. Corneas cross-linked with riboflavin and UV-A rays require a higher temperature for hydrothermal shrinkage and show a greater resistance to collagenase digestion, particularly in the anterior stroma. In human cadaver corneas, corneal stiffness increased by a factor of 4.5 after cross-linking with UV-A radiation and riboflavin solution, as reported by Prof. Eberhard Spoerl (Figure 10.2).
Figure 10.2: Cross-linked (top) and untreated (below) strips from the same cornea (Courtesy of Prof. Spoerl)
RIBOFLAVIN AND ULTRAVIOLET A LIGHT Riboflavin, also known as Vitamin B2, is a naturally occurring photosensitizer. It is the precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), two coenzymes that are crucial for the metabolism of carbohydrates, fats and proteins into energy. Riboflavin is an essential constituent of all living cells. It is water soluble and only a trace amount is found in the human body. The deleterious effects of ultraviolet light on ocular structures have been well documented. With the use of riboflavin as a photosensitizing agent, however, there is an ultraviolet-A transmission rate of only approximately 7% across the cornea, thus limiting
CORNEAL COLLAGEN CROSS-LINKING WITH RIBOFLAVIN AND ULTRAVIOLET-A LIGHT: STEP BY STEP TECHNIQUE
ultraviolet-A irradiance of the lens and retina. Nevertheless, concern remains about ultraviolet-A cytotoxicity to the corneal endothelium. In rabbits, the cytotoxic level for corneal endothelial damage induced by ultraviolet-A light was 0.36 mW/cm². Using the aforementioned surgical technique, this level could be reached in corneas with a central thickness of less than 400 µm, so it is imperative that surgeons measure corneal pachymetry preoperatively to ascertain that at least this threshold is met. The lens receives 0.65 J/cm² of UV-A irradiance, which is far less than the amount needed to produce cataract (70 J/cm²). As for retinal damage, research with rhesus monkeys has shown a threshold level of 81 mW/cm², which, again, is not achieved with a standard treatment. PREPARATION OF 0.1% RIBOFLAVIN SOLUTION • Dissolve Dextran T500 in physiological salt solution to achieve a 20% Dextran T500 solution. • Dilute Riboflavin-5-phosphate 0.5% with Dextran solution to achieve a 0.1% Riboflavin solution (Ratio of mixture: 1 part of Riboflavin-5-phosphate 0.5% – 4 parts of Dextran T500 20%). • Protect the solution from light, and use it within 24 hours.
Figure 10.3: After removal of the corneal epithelium riboflavin/dextran solution is instilled for 20-30 minutes (Courtesy of Prof. Theo Seiler)
STEP BY STEP TECHNIQUE 1. The procedure is typically performed under sterile conditions in the operating room. The patient is premedicated with two drops of topical anesthetics 2-5 minutes before surgery. A wire eyelid speculum is placed for exposure. 2. The corneal epithelium is removed (fully or partially, in uniform pattern), by mechanical scraping over the central 8-9 μm of the cornea with a blunt spatula to allow for better diffusion of the riboflavin (riboflavin molecule is too large to penetrate intact epithelium). 3. The photosensitizer, 0.1% riboflavin solution (10 mg of riboflavin-5-phosphate in 10 mL of dextran-T-500 20% solution) is applied to the deepithelialized cornea every 3 minutes for approximately 20-30 minutes (Figure 10.3). 4. Using a slit-lamp inspection with blue light, the surgeon may ensure that riboflavin has reached the anterior chamber (Figure 10.4). UV-A light
Figure 10.4: Slit-lamp check of the riboflavin penetration. The anterior chamber has to be slightly yellow (Courtesy of Prof.Theo Seiler)
exposure should only be initiated after a clear fluorescence is observed in the anterior chamber. If you are not sure about saturation of the stroma, continue to drop riboflavin/dextran solution until yellow flare in the anterior chamber is noted.
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5. Measure corneal thickness at thinnest point after 30 min of riboflavin application. If under 400 µm, use hypotonic riboflavin solution without dextran (310.7 mOsm/l) to enforce swelling of the cornea. Apply 2 drops every 30 seconds until corneal thickness is at least 400 µm. 6. As an additional safety feature, the output energy intensity can be checked prior to each treatment using the UV light meter that is delivered with the system (Figure 10.5). 7. The irradiating source is placed 5 cm from the cornea’s center and applied for 30 minutes (Figure 10.6). The 370 nm wavelength allows approximately 93% of UV light to be absorbed into the cornea, thus, there is no risk for damage to the lens and retina. The UVA light interacts with the riboflavin, producing reactive oxygen molecules that cause the formation of chemical bonds between and within the corneal collagen fibrils, making them stiffer. 8. During irradiation treatment, a drop of riboflavin solution is applied every 5 minutes to sustain the necessary concentration of riboflavin and prevent desiccation of the cornea (Figure 10.7). 9. The surgeon keeps the cornea moist with a drop of balanced salt solution every 2 minutes. 10. At the conclusion of the procedure, the patient receives topical antibiotic and a bandage contact lens is applied for 72 hours or until corneal reepithelization is complete. This is followed by application of fluorometholone 0.1% eyedrops twice daily for 6 weeks. If necessary, artificial tears are prescribed.
Figure 10.5: Intensity check prior to each treatment
Figure 10.6: UV-A illumination of the cornea (Courtesy of Prof.Theo Seiler)
SAFETY
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Corneal cross-linking is considered to be a safe procedure, provided the recommended safeguards are observed. 1. A clinically used UV source should ensure a perfect homogenous irradiance. Hot spots may cause local damages of endothelium cells especially in thin corneas. 2. The irradiated area of the cornea must be limited to 8 μm. Only the cornea is irradiated. Sclera, goblet cells and limbus are not treated. 3. The following treatment parameters are chosen to reach a strong cross-linking effect and to avoid damages of the adjacent tissues:
Figure 10.7: During UV-A irradiation, a drop of riboflavin solution is applied every 5 minutes (Courtesy of Prof.Theo Seiler)
CORNEAL COLLAGEN CROSS-LINKING WITH RIBOFLAVIN AND ULTRAVIOLET-A LIGHT: STEP BY STEP TECHNIQUE
• Wavelength: 370 nm • Irradiance: 3mW/cm2 (Dose: 5.4 J/cm2) • Irradiation time: 30 minutes. 4. To avoid high absorption of UVA in the cornea: • Remove the diffusion barrier (epithelium). • Minimum corneal thickness has to be 400 μm after removal of the epithelium. • Concentration of riboflavin must be 0.1%. • Diffusion time of riboflavin has to be 20-30 min.
5.
6.
7.
8.
MORE RESEARCH REQUIRED We believe that collagen cross-linking might become a standard treatment for progressive keratoconus. Longterm studies must exclude serious late complications and confirm the durability of the stiffening effect. Currently available published data, unpublished data, and personal observations by current international investigators make a convincing argument that collagen cross-linking is significantly safer than corneal transplantation. In the current situation, there are not yet enough data available to establish a list of indications and contraindications. A potential clinical acceptance of the procedure requires the results of prospective controlled studies that are currently underway. In the future, we may be able to further improve vision by combining the cross-linking procedure with procedures such as intracorneal ring implantation, orthokeratology, topography-guided photorefractive keratectomy, and conductive keratoplasty, an area that is under clinical research. Other possibilities which are under investigation include stabilizing cornea after radial keratotomy, and treating corneal edema and bullous keratopathy. REFERENCES 1. Seiler T, Spoerl E, Huhle M, Kamouna A. Conservative therapy of keratoconus by enhancement of collagen crosslinks. Invest Ophthalmol Vis Sci 1996;37:S1017. 2. Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res 1998;66:97-103. 3. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-Ainduced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-27. 4. Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine corneas after
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riboflavin-ultraviolet-A-induced cross-linking. J Cataract Refract Surg 2003;29:1780-5. Spoerl E, Wollensak G, Seiler T. Increased resistance of cross-linked cornea against enzymatic digestion. Curr Eye Res 2004;29:35-40. Wollensak G, Wilsch M, Spoerl E, Seiler T. Collagen fiber diameter in the rabbit cornea after collagen cross-linking by riboflavin/UVA. Cornea 2004;23(5):503-507. Wollensak G, Spoerl E, Reber F, Seiler T. Keratocyte cytotoxicity of riboflavin/UVA-treatment in vitro. Eye 2004;18(7):718-22. Pinelli, R. C3-Riboflavin for the treatment of keratoconus. J Cataract and Refractive Surgery Today Europe 2006;1:4950. Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Parasurgical therapy for keratoconus by riboflavinultraviolet type A rays induced cross-linking of corneal collagen: preliminary refractive results in an Italian study. J Cataract Refract Surg 2006;32:837-45. Wollensak G. Cross-linking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006;17:356-60. Kohlhaas M, Spoerl E, Schilde T, Unger G, Wittig C, Pillunat LE. Biomechanical evidence of the distribution of crosslinks in corneas treated with riboflavin and ultraviolet A light. J Cataract Refract Surg 2006;32:279-83. Mazzotta C, Traversi C, Baiocchi S, Sergio P, Caporossi T, Caporossi A. Conservative treatment of keratoconus by riboflavin-uva-induced cross-linking of corneal collagen: qualitative investigation. Eur J Ophthalmol 2006;16:5305. Hafezi F, Kanellopoulos J, Wiltfang R, Seiler T. Corneal collagen cross-linking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis.. J Cataract Refract Surg 2007;33(12):2035-40. Hafezi F, Iseli HP. Pregnancy-related exacerbation of iatrogenic keratectasia despite corneal collagen crosslinking. J Cataract Refract Surg 2008;34(7):1219-21. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen cross-linking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008;34(5):796-891. Kohnen T. Riboflavin-UVA corneal collagen cross-linking as an evolving surgical procedure for progressive ophthalmic tissue diseases. J Cataract Refract Surg 2008;34(4):527. Mencucci R, Mazzotta C, Rossi F, Ponchietti C, Pini R, Baiocchi S, Caporossi A, Menchini U. Riboflavin and ultraviolet A collagen cross-linking: in vivo thermographic analysis of the corneal surface. J Cataract Refract Surg. 2007;33(6):1005-08. Daxer A, Misof K, Grabner B, Ettl A, Fratzl P. Collagen fibrils in the human corneal stroma:Structure and aging. Invest. Ophthalmol. Vis Sci 1998;39(3):644-48.
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ADVANCES IN CORNEOPLASTIQUETM: ART OF LASER VISION SURGERY
INTRODUCTION The individual or combined use of amniotic membranes, glue, lamellar cornea, synthetics, i.e. INTACS, etc. and finally the Excimer laser as a sculpting tool towards an effort to perfect vision is what I wish to introduce as a new trend and possibly a superCorneoplastique™. specialty in eye care— Corneoplastique™ Simply put, the ocular surface inclusive of the cornea (irrespective of the causative incident, i.e. LASIK complications/infection/trauma/previous surgery) is prepared by any one or a combination of the above techniques in single or multiple stages to prepare for the final fine tuning using the Excimer laser towards a visual goal where early rehabilitation and aesthetic outcomes are a welcome association with promising uncorrected visual acuity (Gulani AC, Corneoplastique™ Advanced Corneal Surgery Course. SASCRS-Durban, South Africa; Aug 2005). This is in contrast to the more extensive standard surgical techniques like penetrating keratoplasties, etc. where in most cases the final unaided visual outcome despite a long rehabilitation period is less than optimal. Synergistically though, these standard surgeries, due to their proven track record can always serve as a backup plan in selection of any of the above mentioned techniques. Corneoplastique™ includes all forms of laser vision surgery itself: LASIK and various variants of laser vision surgery are performed on the cornea cornea. It is important that refractive surgeons recognize the importance of the ART of Laser Vision Surgeries by understanding the cornea and the whole spectrum of corneal surgery. I remind LASIK surgeons that besides T echnique T” is of equal, if not more and Technology, the third “T Tissue” (in this case; Cornea). importance and that is “T Corneal surgical experience and knowledge will in all probability enhance the ability of a laser vision Surgeon to better select the candidacy of their patients, prevent complications and also prepare them to react in an efficient manner towards any inadequate/ unforeseen outcomes. Similarly, these advanced corneal techniques can be used to even prepare patients who have had corneal problems like, corneal scars, pterygiums, previous surgeries like cataract surgery/corneal transplants/ radial keratotomy, etc. to make them suitable for laser vision surgery in a therapeutic mode towards a visual goal.
This ART of blending the full spectrum of ocular surface and corneal surgery in a therapeutic approach either before (To prepare the cornea) or after laser vision surgery (to repair the cornea) is the core function of this possible new superspecialty. This ability to Prepare the cornea for laser vision surgery and to Repair the cornea from laser vision surgery using these techniques will raise the confidence of refractive surgeons and patients alike. Indications for Corneoplastique Corneoplastique™ would be the following : 1. Corneal scars (from previous surgeries / trauma / healed corneal ulcers / infections) 2. Pterygiums (advanced/ recurrent) 3. Previous surgeries (cataract surgery / corneal transplants / radial keratotomy, etc.) 4. Lasik and laser vision surgery complications 5. Corneal degenerations / dystrophies. The art of blending the whole spectrum of surface ocular and corneal surgery using these topical, brief, aesthetic, and visually promising techniques either singly or in combinations shall raise the bar on making all surface surgeries visually focused. CORNEOPLASTIQUE™ IN ACTION What I want more surgeons to do is use less terminology and more logic. “When I look at a complication it does not matter to me what surgery was done or what laser was used. I look at it as, here’s a cornea; what does it have? Does it have a scar, irregular astigmatism, is it thin, de-centered ablation, etc.? and approach that problem accordingly”. Using my recently introduced 5S system (Gulani AC. 5S Classification System: ASCRS, California, March 2006) we can devise a plan to heal/repair the cornea appropriately and finally fine tune using the Excimer Laser (VISX Star S4 Santa Clara, CA). My goal all the time is unaided 20/20. The 5Ss stand for shape, sight, scar, site and strength. This 5S system is an expansion of a three-level corneal classification system I devised several years ago (Flow chart 11.1).1 The three-level system was based on the tissue components involved in the LASIK surgery, and I assigned LASIK corneal complications to Level I (corneal section), Level II (interface) or Level III (ablation bed). This helped identify and treat a range of corneal problems.
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES Flow chart 11.1: Gulani “5S” classification system
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Similarly, the 5S system addresses questions about the cornea’s state in order to customize a treatment plan. It does not give importance to the technology used or the causative pathology itself.2 Here are its components: 1. S ight. Is the patient correctable to 20/20 with glasses and/or hard contact lenses? 2. Site. Is the involvement central or peripheral? 3. Scar. Is the cornea clear or scarred? 4. Strength. Is the cornea thin/ectatic (Keratoconus) or thick (Epikeratophakia/Bullous keratopathy)? 5. Shape. Is the cornea myopic (Steep), Hyperopic (Flat) or Astigmatic (Regular/Irregular)? This 5S system allows you to understand, allocate and plan a corrective approach in addition to your knowledge of not only LASIK but lamellar corneal surgery in general (LASIK is lamellar surgery, hence any preparation or repair of the cornea for LASIK shall usually involve a lamellar approach). Surgeons must be familiar with the wide spectrum of advanced surgical options available to provide the most appropriate way to deal with a problem (Gulani AC, Corneoplastique™: Art of Vision Surgery (Abstract). ISOPT, Berlin, Germany, March 2006). The knowledge of optics, anatomy, physiology and the combination of these unchanged concepts can only be strengthened with advancing technology. For an example on how this concept works, let’s take two cases and make a surgical plan: 1. Patient with LASIK ectasia: Here the patient’s cornea basically has a problem with three of the 5Ss, i.e. Strength, Shape and Sight.
Stage I: Sutureless Lamellar Keratoplasty (Provides the Strength)—Remember to use a donor cap that is THICKER (Two reasons: remember the fact that the donor will deturgese and also that you will have more cornea to sculpt with the Excimer Laser at a later stage). Stage II: Excimer Laser ASA (provides Shape and therewith S ight) 2. Now lets take a patient with an opposite problem. Aphakic Epikeratophakia with decentered, scarred epi-lenticle. Ss (It is Here the cornea has a problem with all 5S Strength), SScarred, central Site affected thicker (S with poor Shape and Sight) Scar and Strength Stage I: Remove the epi-lenticle (S are addressed) Sight is addressed) Stage II: Secondary IOL (S If needed further Stage III. Excimer laser to fine tune the Shape and further improve Sight. Having personal experience with the full spectrum of vision corrective surgeries including presbyopic multifocal lenses like ReStor, Phakic Implants like the anterior, posterior and iris-supported IOLs, INTACS, etc. we can use these concepts universally to plan through the anterior chamber and cornea for final unaided vision. New technology corneal surgical lasers, i.e. Intralase, Da Vinci, Femtec and Carl Zeiss are moving in this direction and I see them as an integral part of my Corneoplastique™ concept. I could be planning a posterior lamellar transplant – DLEK/DSAEK (My technique is called Key Hole Transplant) ReStor IOL, INTACS, Wavefront Lasik,
ADVANCES IN CORNEOPLASTIQUETM: ART OF LASER VISION SURGERY
Figure 11.1: Radial Keratotomy, Astigmatic Keratotomy, Hexagonal Keratotomy and previous Corneal Transplant. In all of these cases the S factor affected was Shape so the only treatment needed was excimer laser vision surgery for unaided emmetropia
Amniotic resurfacing, etc.; it does not matter as long as the sequence and stages of surgery make sense for a final outcome- Unaided emmetropia emmetropia. Also, at any stage we can always fall back on any of the traditional surgeries which will always be a backup for these patients, i.e. PKP, etc. What we realize with the above examples and many more (Figures 11.1 to 11.7) is that we need to plan each stage with preparation for the next; also if the patient is already very happy at any intermediary stageStop. The patient and their satisfaction is what we are addressing not a topography chart. In summary, practically any ocular situation (status post-cataract surgery, glaucoma surgery, retinal surgery, corneal transplant, trauma, chemical burns, etc.) provided it has visual potential and no ongoing or uncontrolled visually debilitating pathology can be addressed to achieve its best unaided visual capacity. It is also very important to note here that the 20/20
we aim for in such cases is not the same as in a virgin LASIK case where we are not pleased with 20/20 and constantly strive to achieve 20/15 and 20/10. The 20/20 in these cases is qualitatively low (Gulani AC, Ginsberg A., Quality of Vision and Optec 5000, March 2006). These are patients with poor/distorted vision and becoming functional even with 20/40 (as refractive surgeons we must always talk in terms of unaided vision) is an ecstatic, life-changing outcome. Especially if you consider that these techniques are all brief/topical/ aesthetically pleasing and therefore a fond memory for the patients. As long as there is no intraocular pathology or disease, i.e. retinal / neurological / uncontrolled glaucoma, etc.; there is no reason why we cannot stage towards a perfected visual outcome. The ability to help patients with refractive surgical complications/ previous surgeries/chemical burns/trauma/ etc. towards 20/20 vision is no longer out of reach in aspirations or outcomes.
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Figure 11.2: In cases of Keratoconus, besides Shape the factor affected could also be Strength. When the corneal thickness is still above 350 microns we can put synthetic inserts like INTACS. Assymetric, On-Axis INTACS for Keratoconus and PMD
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Figure 11.3: Conditions wherein the Amniotic graft was used to correct ocular surface problems and also extended to heal the corneal defects associated with them (i.e. Extensive pterygium with central corneal involvement). Thus correcting the Site, Sight, Strength and Scar. This was followed by excimer laser ablation for achieving the desired Shape for unaided emmetropia
ADVANCES IN CORNEOPLASTIQUETM: ART OF LASER VISION SURGERY
Figure 11.4: These are cases of anterior supraBowman scars. The Sight and Strength being good, we can peel these scars under the excimer laser followed by simultaneous refractive ablation leading to correction of Scar (Unclear Cornea), Shape (Ammetropia) and Site (Central)
Figure 11.5: Patient who had Aphakic d e c e n t e r e d Epikeratophakia nearly two decades ago with best corrected 20/20 vision. Stage I: Removal of her epiLenticle (Correction of Site, Scar, Shape and Strength). This was followed by placement of secondary IOL (Sight) to uncorrected vision 20/25
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Figure 11.6: Posteior corneal transplant (DSEK, DSAEK , KeyHole) for a case of Pseudophakic Bullous keratopathy. We have thus corrected the Site, Scar, Strength and Sight. This was followed by excimer laser surgery to correct the Shape
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Figure 11.7: Various forms of lamellar corneal repairs to build the cornea in preparation for the final S(Shape) with the excimer laser. These repairs could be anterior lamellar (Sutureless or sutured) or posterior (Sutureless-Key Hole) transplants
ADVANCES IN CORNEOPLASTIQUETM: ART OF LASER VISION SURGERY
I use the Pentacam in my practice routinely (Gulani AC, Pentacam in Full Spectrum Refractive Surgery: Advanced Corneal Topography Course- AAO, Las Vegas 2006) and find it to be an essential tool towards a synergistic planned approach towards achieving emmetropia. This coupled with imaging techniques (ReSeevit Software and CSO imaging systems) provides intricate details for surgical planning. With numerous refractive surgical modalities available today (refs 3 and 4) and also the new combinations of surgeries that we are seeing in their infancy (Cataract surgery post-LASIK, etc.) I believe diagnostic technologies will need surgeons to guide them through the waters of innovation as our
understanding and demands have surely increased and so have patient expectations. REFERENCES 1. Gulani AC. “Lasik Corneal Complications: A New Stratified Classification”. Ophthalmology 1999;106:1457-58. 2. Gulani AC. “A New Concept for Refractive Surgery: Corneoplastique”. Ophthalmology Management 2006;57-63. 3. Gulani AC, Wang M. Future of Corneal Topography. Textbook of Corneal Topography in the Wavefront Era. Slack Inc 2006;26:303-04. 4. Gulani AC, L Probst. “ CONS of PRESBYOPIC LASIK”. In: LASIK: Advances, Controversies and Custom. Slack Inc (2004) 32B;367-69.
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APPLICATIONS OF COLLAGEN CORNEAL CROSS-LINKING
INTRODUCTION Keratoconus is a non inflammatory, degenerative disease that compromises the structural integrity of the collagen matrix within the corneal stroma. The development of a localized, cone shaped ectasia that is accompanied by thinning of the stroma in the area of the cone is the hallmark of this condition. The stromal thinning and loss of Bowman’s layer are associated with increased degradative enzyme activities and a decline in the enzyme inhibitors. Keratoconic corneas have decreased total protein and sulphated proteoglycan levels, decreased collagen cross-linking and a variable total collagen content (Fig. 12.1). 60% of the keratoconic corneas have apoptotic stromal keratocytes compared to normals and signs of increased oxidative damage that further lead to decreased cell function and cell death. The keratoconic corneas have unevenly distributed stromal lamellae that insert transversely into the Bowman’s layer. This can lead to corneal lamellar slippage and stretching, another possible hypothesis.
radical byproducts of metabolism in a young cornea and the lower cross-linking explains the increased incidence of keratoconus in the young population. However, the young diabetics escape this hypothesis because of the glucose related glycation that accelerates cross-linking in diabetic corneas. Collagen cross-linking is a new non invasive procedure for keratoconus described by Woolensak et al which strengthens the weak cornea. With the help of ultraviolet light (UV-A) and photosensitizer riboflavin (0.1%), the collagen cross-linking is increased. Thus the basic pathology of keratoconus is addressed with changes in the intrinsic biochemical properties of the corneal collagen. MECHANISM OF C3-R TREATMENT Application of 0.1% of riboflavin on the cornea along with penetration for approximately 250µ and irradiation of riboflavin molecules through UV-A (at 370 nm) leads to loss of internal chemical balance of riboflavin molecules producing oxygen free radicals. This makes the riboflavin molecule unstable and it regains stability by cross-linking with collagen fibrils. Cross-linking is brought about by bridging amino groups of collagen fibrils (Fig. 12.2).
Figure 12.1: Schematic of abnormalities associated with keratoconus corneas
BASIC SCIENCE BEHIND C3-R TREATMENT The biomechanical strength of the cornea in keratoconus is considerably reduced. Progression of keratoconus slows with age because of the reduction in free radicals generated in the cornea and/or increased cross-linking that naturally occurs with age. The increased free
Figure 12.2: Mechanism of action in C3-R treatment
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Figure 12.3: Preoperative topography prior to C3-R treatment
Collagen cross-linking results in an increased intra and inter fibrillar covalent bonds by photo sensitized oxidation and cause biomechanical stabilization of the cornea. A significant increase of 328.9% in the biomechanical rigidity of human corneas has been documented. APPLICATIONS C3-R treatment by enhancing the collagen crosslinking has gained enormous appeal in the treatment of early and moderately advanced progressive keratoconus (Figs 12.3 and 12.4). However patients with advanced cone/ectasia, those with significant stromal scarring, corneal thickness of less than 400µ at the thinnest point and a poor BCVA with contact lenses are poor candidates for a C3-R treatment as a rehabilitation option. C3R AND POSTLASIK ECTASIA
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C3-R treatment is again a viable option in post lasik ectasia which hitherto had the only option of a custom
designed contact lenses or a corneal transplant in advanced stages. The dictum of 400µ in the thinnest point of the cornea could be a limiting feature in post lasik ectasia. The process of swelling the cornea to 400µ and then harnessing C3-R treatment is the way to proceed. 0.1% riboflavin (in 20% dextran) is applied for the first ½ hour. Pachymetry is measured and in situations where the corneal thickness falls short of 400µ, 0.5% riboflavin drops (diluted in BSS in 1:4 proportion) is used every 5 seconds, thus swelling the cornea to the optimal 400µ limit. The hypo-osmolar solution should be applied deligently every 5 seconds as the cornea deswells if the drop application is done in a slower fashion. Again one should not swell a keratoconic cornea greater than 80µ as these eyes have a different swelling behavior. C3-R WITH INTACS Intacs enable targeted flattening of the cornea. However it does not address the underlying structural problem which is weakened collagen. It appears intuitive to combine C3-R with intacs in patients with keratoconus
APPLICATIONS OF COLLAGEN CORNEAL CROSS-LINKING
Figure 12.4: Postoperative topography following C3-R treatment
to derive the maximal advantage. There are several possible explanations for the increased effect of intacs with the addition of cross-linking. It could be a simple additive measure to flatten the cornea. It is also reasonable to postulate that C3-R treatment following intacs causes pooling of riboflavin in the area of intac segment with resultant increased cross linkage. The increased biomechanical effect of C3-R clubbed with Intacs enhances the pattern and distribution of collagen changes. Further on, the increased collagen diameter of the newly synthesized collagen has a further pulling effect on the cone, a consequent potentiated flattening. C3-R ENHANCED PRK IN KERATOCONIC EYES This is another area of increased interest. Surface ablation is definitely accepted to result in lesser biomechanical stress than Lasik. Hence the pretreatment option of C3-R followed by PRK a couple of months later is a possible detour in these eyes, may be a window period of better visual acuity till the eventual corneal transplant.
C3-R FOR PROGRESSIVE HYPEROPIC FOLLOWING RK Continued uncontrolled flattening with increasing hyperopia is noticed occasionally in post RK eyes. C3R treatment improves cross-linking and tightens the RK incisions and leads to a more stable cornea, halting progressive flattening and hyperopia. C3-R TREATMENT IN PELLUCID MARGINAL DEGENERATION Collagen cross-linking has shown favorable outcomes in eyes with pellucid marginal degeneration. However a larger 11 mm should be exposed as of against the usual 9 mm advocated. A merocoel protection ring is adviced to protect the limbal stem cells and an eccentric corneal light exposure is advised. PREGNANCY AND ESTROGEN Estrogen receptors are present in human corneas. Increased estrogen levels during pregnancy has been
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found to reduce the biomechanical stability of the cornea with increasing K values to ectasia. Collagen cross-linking, if performed, is noticed to bring about a regression of K values.
The proposed mechanism is that cross-linking increases the cornea’s resistance to digestive enzymes such as collagenases which are a part of the inflammatory melting process.
C3-R AND PSEUDOPHAKIC BULLOUS KERATOPATHY
INFECTIOUS CORNEAL ULCERS AND C3-R
These eyes need to be initially treated with glycerol to deswell the cornea. Once the thickness of cornea drops to 400µ, C3-R treatment could be performed optimally.
Small study groups have treated recalcitrant infectious corneal ulcers with slowly improved resolution and epithelial healing.
C3-R AND IOP VALUES
CONCLUSIONS
False high IOP values are noted in cross linked eyes as the cornea tends to become stiffer and harder.
C3-R treatment has gained universal acceptance and brings in hope and better realization of vision in this section of the population, the keratoconic eyes.
CORNEAL MELTS AND C3-R Successful use of cross-linking is reported in literature for corneal melts. A lower surface irradiation (2.5 mw/ cm²) is suggested to compensate for a thinner cornea.
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REFERENCES 1. Textbook on “Modern Management of Keratoconus” Brian S Boxer Wachler MD, Shawn Jalali MD, Colin CK Chan MD (Eds): 1st Edition 2008;7(3):76-91.
CROSS-LINKING PLUS TOPOGRAPHY-GUIDED PRK FOR POST-LASIK ECTASIA MANAGEMENT
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INTRODUCTION
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LASIK SURGERY has become a medical phenomenon throughout the world over the last 20 years. It all started in the laboratories of the University of Krete in Greece and under the direction of Ioannis Pallikaris, MD in 1988. It was the natural evolution of the boom in automated lamellar surgery that was popularized in South America that same decade and the introduction of cornea shaping by the excimer laser. It has become one of the most common procedures humans undergo worldwide, and for sure, the most common elective procedure that medicine offers today. Throughout the years there have been several lessons in LASIK that have been learned by refractive surgeons. One of those has been the limitation to the amount of laser ablation that the human cornea can withhold, before changing its biomechanical properties. Post-LASIK ectasia has been recognized as a serious complication from the early years of LASIK development. 1 Throughout this time several safety “paradigms” have been arbitrarily communicated through meetings and publications establishing the safety margin for residual stroma bed. Even today procedures performed years ago may complicate and develop ectasia. In most cases a very small residual stromal bed is usually the isolated contributing factor along with irregular cornea topography pre-operatively suggesting forme fruste keratoconus.2 It remains though quite a challenge to explain why some “uneventful” procedures that had perfect pre-op topography and well documented “enough” residual stromal bed thickness may develop keratectasia. As a cornea surgeon I have had the opportunity to treat several patients with this dreaded complication in the past. The initial treatment in the 90’s was penetrating keratoplasty when the ectasia could not be rehabilitated with RGP contact lenses.3 In the early 2000’s INTACS became a potential option. I have personally have not had a good clinical results with INTACS in regard to their stability in ecstatic corneas.4 In 2002 I became involved with collagen cross-linking with the use of UVA irradiation and topical riboflavin after I became familiar with the work of Seiler Wollensak and Spoel in Dresden and Zurich with this application.5-8 This is the case report of the first patient I encountered:9
A 29-year old patient that had underwent uniocular LASIK for the correction of myopic astigmatism 3 years ago. His initial UCVA was 20/80 and his BSCVA was 20/20 with a refraction of –2.00 –175 ’ 85. Three months post-LASIK he began experiencing regression with myopia and astigmatism to the point of UCVA 20/200 and BSCVA 20/80 with –3.50 –2.00 ’ 120. Based on irregular topography and the loss in BSCVA, the treating physician soon recognized that a mechanism of ectasia had begun. Because this was not functionally correctable with spectacles or contact lenses, the decision was made to implant intracorneal ring segments for the management of this complication. Unfortunately, the patient’s UCVA remained 20/200 and BSCVA 20/100. The treating surgeon recommended cornea transplantation as the next step. My initial evaluation of the patient was made 11 months post-LASIK and 3 months after intracorneal ring implantation. Corneal thickness by Orbscan (Bausch and Lomb, Rochester, NY) and ultrasound pachymetry was 410 μm at the thinnest point, and the endothelial cell count was 2,750 cells per μm2 (Noncon Robo; Konan Medical, Hyogo, Japan). OPTIONS FOR TREATMENT We have had poor long-term outcomes with intracorneal ring segments in post-LASIK ectasia4, a fact which we discussed with the patient. We discussed the benefits and risks of corneal transplant, as well as combined ultraviolet radiation and riboflavin treatment in order to achieve collagen cross-linking and biomechanical stabilization of the corneal ectasia. We then obtained patient consent to remove the failed intracorneal ring segments. Itreated his cornea with a single application of UV-A radiation at 3 mW/cm2 for 30 minutes (KeraCure; Priavision, Menlo Parl, Ca) combined with 0.1% riboflavin ophthalmic solution. This treatment was performed after removing the corneal epithelium with 20% ETOH placed on the surface for 30 seconds. The riboflavin solution was applied for about 2 minutes in order to soak the stromal bed and protect the iris, crystalline lens and retina from UV irradiation. One drop every 2 minutes was applied during the 30 minutes of irradiation. A bandage contact lens was placed on the cornea for 5 days, and the patients was treated with topical ofloxacin 1% (Ocuflox; Allergan, Irvine, Ca) and prednisolone acetate 1% (Predforte, Allergan) four times a day for
CROSS-LINKING PLUS TOPOGRAPHY-GUIDED PRK FOR POST-LASIK ECTASIA MANAGEMENT
10 days. The bandage contact lens was removed at day 4, following complete reepithelialization. IMPROVEMENT IN VISUAL ACUITY At 3 months, the patient’s UCVA improved from 20/ 400 to 20/70 and his BSCVA improved from 20/200 to 20/40. The refraction changed from –4.50 –4.50 ’ 120 to –4.50 –4.00 ’ 115, and corneal topography changed as seen in (Figure 13.1B). The stability of these parameters and the corneal topography between months 1 and 3 of this treatment, encouraged us to proceed with topography-guided PRK. We sought to reduce the irregular astigmatism and attempt to provide the patient with visual acuity not requiring spectacle or soft contact lens correction. Because the patient’s corneal thickness was 410 μm, we were able to treat his full spectacle correction using the Allegretto Wave excimer laser (Wavelight, Erlangen Germany) topography-guided customized ablation treatment (TCAT) software. After placing 20% dilution of ETOH on the corneal surface for 30 seconds and subsequent epithelium removal, I performed laser treatment. A bandage contact lens was placed for 5 days and the patient was treated again with ofloxacin and prednisolone four times a day for 10 days. The bandage contact lens was removed at day 4, following complete re-epithelialization. One month after topographyguided treatment, the patient’s UCVA was 20/20- and BSCVA was 20/20 with a refraction of +0.50 –5.0 ’ 160. The corneal endothelium count has remained stable at 2,700 cells per μm2. The patient complained of night vision symptoms of halos and ghosting. The patient is now at 34 months postoperative and enjoys UCVA of 20/20 with some mild night vision problems and corneal topography as shown in (Figure 13.1). One can also appreciate the difference map between pre and post topography-guided treatment in Figure 13.1D, as well as the actual ablation profile that was used for the treatment. TREATMENT OF IATROGENIC KERATECTASIA Different techniques have been suggested for the treatment of iatrogenic keratectasia without satisfactory outcomes either biomechanically or visually, with the patient’s journey most frequently ending with pentrating conreal graft. Reports of the use of riboflavin/
UV-A corneal cross-linking have been shown to slow down keratoconus and progressive iatrogenic ectasia. During the past 3years, we have had extensive experience with customized topography-guided excimer ablations which we have presented and reported.10,11 This customized approach can, in our opinion, address the extreme cornea irregularity that these cases may have and enhance visual rehabilitation. This was the first report of post-LASIK ectasia treatment using a combination of UVA collagen cross-linking to stabilize the corneal biomechanics, followed by surface excimer laser ablation for visual rehabilitation. Remarkable corneal stabilization, together with full visual rehabilitation, leads us to believe that this approach may have a wider application in the near future. Considering the tremendous burden on the patient in everyday life, as well as the medical-legal issues involved in such a complication of elective excimer laser refractive surgery as iatrogenic keratectasia, we feel that the combined procedure discussed here is now a valuable alternative to therapeutic cornea transplantation and should be considered in any case that enables the application of this treatment. It is though in my opinion necessary for the clinician to take special consideration in treating these cases. By no means can the excimer laser be considered an instrument for emmetropia in these patients in a fashion similar to routine LASIK and/or PRK refractive cases. The treatment should be directed towards “ normalizing” the cornea surface and allowing for improvement of BSCVA. There is an obvious danger in thinning these corneas to much by giving in to the “temptation” to correct the refractive error. This was the initial desire of these patients anyway. Having no previous work to relay on, I arbitrarily took a conservative approach to the matter and limited the refractive laser treatment to the minimum and never to allow removal of over 50 microns the thinnest cornea. Several cases followed this success story over the last 5 years. We have presented a case series at the AAO annual meetings in 2005 and 2006. A Similar Example Follows (Figures 13.2A to E) A 28-year-old male physician underwent LASIK in November 2002. For -5.50 -1.50 ’ 015 (20/20) OD and -4.25 -1.25 ’ 0168 (20/20) OS. Four months following surgery, the uncorrected vision was 20/25
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Figure 13.1: This display of topographies depicts the following: (1) The cornea topography of this case when first seen by the authors with central cornea ectasia and mid-periphery flattening as an effect of the INTACS that were present. At this point BSCVA was 20/200 (2) The cornea topography here is 2 months following the removal of INTACS and 1 month following UVA collagen cross-linking. The central steepening is still present and the effect of the INTACS removal is appreciated compared to the previous image mostly at the mid-periphery, that appears steeper now. At this point BSCVA was 20/200 (3) The lower row image in the center is an estimated cornea topographic ablation pattern as a laser treatment plan of the topographyguided procedure that took place in the case. It is notable that this ablation pattern is highly irregular with “deeper” ablation plan just inferiorly and right to the center, that matches though the central cornea irregularity in the previous topographies. (4) The cornea topography here is 6 months following topography-guided PRK. The central cornea appears more regular and much flatter. At this point BSCVA and UCVA is 20/20 (5) The lower row image on the left is a comparison map. This map depicts the difference of subtracting the cornea topography 4 (final result) from the cornea topography 1 (original state of this complication when encountered by us). The difference resembles impressively the topography-guided ablation pattern (next image to the right) demonstrating effectively the specificity of this treatment in reducing the pathogenic cornea irregularity, which we theorize that contributed in the drastic improvement of BSCVA
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in both eyes. The manifest refraction was +0.25 -1.25 ’ 090 (20/20) OD and was +0.25 -0.25 ’ 110 (20/15) OS but the topography suggested the early development of ectasia . At this time, the keratometry readings were 38.75/39.25 ’ 22 (OD) and 38.50/ 39.00x162 (OS) and the pachymetry readings were 375 microns (OD) and 407 microns (OS).
The patient returned on February 21, 2005, with an uncorrected vision of 20/40 in the right eye and 20/20 in the left eye. A manifest refraction in the affected right eye of -0.75 -3.50 ’ 091 (20/30), and +0.75 -0.50 X0128 (20/20) OS. The topography at this point suggested the presence of ectasia only in the right eye 2a and Orbscan 2c.
CROSS-LINKING PLUS TOPOGRAPHY-GUIDED PRK FOR POST-LASIK ECTASIA MANAGEMENT
Figure 13.2A
Figure 13.2B
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Figure 13.2C
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Figure 13.2D
CROSS-LINKING PLUS TOPOGRAPHY-GUIDED PRK FOR POST-LASIK ECTASIA MANAGEMENT
Figure 13.2E Figures 13.2A to E: A 28-year-old male physician underwent LASIK in November 2002. for -5.50 -1.50 X015 (20/20) OD and -4.25 -1.25 X0168 (20/20) OS. Four months following surgery, the uncorrected vision was 20/25 in both eyes. The manifest refraction was +0.25 -1.25 X090 (20/20) OD and was +0.25 -0.25 X110 (20/15) OS but the topography suggested the early development of ectasia . At this time, the keratometry readings were 38.75/39.25X22 (OD) and 38.50/39.00x162 (OS) and the pachymetry readings were 375 microns (OD) and 407 microns (OS). The patient returned on February 21, 2005, with an uncorrected vision of 20/40 in the right eye and 20/20 in the left eye. A manifest refraction in the affected right eye of -0.75 3.50 X091 (20/30), and +0.75 -0.50 X0128 (20/20) OS. The topography at this point suggested the presence of ectasia only in the right eye 2a and Orbscan 2c. Two years following UVA collagen cross-linking with refractive error of -2.00 -3.00 X0170 (20/30). the uncorrected vision in the affected right eye was 20/30, with a manifest refraction of -1.50 -1.75 X073 (20/20). The Orbscan at this point is 2d and the comparison 2b and 2e of pre and post UVACCL appearance of the posterior cornea elevation is self explanatory
MINIMAL CORNEAL THICKNESS Special emphasis must be taken to ensure minimal corneal thickness preoperatively because of potential cytotoxic effects of UVA on corneal endothelial cells. Previous experimental studies in rabbit corneas have investigated dose-dependent cytotoxicity to the corneal endothelium. surface irradiance according to the protocol described herein, may not be used in corneas thinner than 350 μm. This mimimal thickness should also be respected in human corneas. The laser treatment must
be applied with caution because more rigid corneas may have a different ablation depth-per-pulse than the untreated one. Indeed, it appears to result in overcorrections when these corneas are treated with excimer laser versus a normal PRK or LASIK procedure. For this reason, our recommendation is to use 75- 80% of the measured sphere and cylinder as a correction parameter when planning the ablation with T-CAT software. Larger comparative studies and longer followup is necessary in order to validate the long-term efficacy of this combined treatment with UV/riboflavin
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followed by topography-guided excimer laser treatment.10 The refractive and topographic stability of more than 3 years, however, appears to validate this minimally invasive treatment of iatrogenic keratectasia and leads us to believe that it may have an even wider application in the near future. We have utilized this modality in idiopathic keratoconus cases as well with similar results.11 As a cornea surgeon I do feel that UVA CCL may be the single most important introduction in cornea surgery and keratoconus and cornea ectasias in general over the last 25 years. If our initial clinical experience holds true I the future follow up it may be able to significantly minimize the necessity for cornea transplantation in ectatic cornea disorders. Can LASIK “ regressions” be a form of ectasia? I would like to present another case to you: Six years ago, a 34-year-old female underwent LASIK for -11.00 D of myopia (Figs 13.3A to 3C). During the procedure a Moria M2 (Moria; Antony, France) microkeratome was used to create a 125-μm flap (calculated with subtraction pachymetry) and an Allegretto 200 Hz laser (Wavelight; Erlangen, Germany), with a planned 6-μm optical zone, was used to conserve tissue. Total treatment centrally was planned to 130 μm. The residual cornea bed measured 320 μm. For 5 years after the surgery, the patient was satisfied, and plano, with 20/20 visual acuity. The patient now presents 20/40 UCVA and 20/20 BSCVA, with eyes measuring -1.50 D and -0.75 D. No ectasia is evident on the topography and Oculus Pentacam (Oculus Optikgerate GmbH, Wetzlar, Germany). The patient’s preoperative measurements: Central cornea thickness is approximately 460 μm. I have relatively extensive experience in cases like this, as I have seen many patients treated for high myopia in the past. None of my cases have developed any corneal I have seen this type of LASIK regression many times in the past and have addressed the problem several different ways. In some cases, I have re-lifted the flap to do an additional enhancement, after measuring the flap thickness intraoperatively in order to avoid significantly reducing the postenhancement residual stromal bed. (Since 2000, I have tried to adhere to the guideline of 270 μm for residual stroma following LASIK). Another potential method of treatment for this patient would be to perform a customized retreatment with asphericity adjustment
as an additive (Wavelight 400 Hz Allegretto Wave EyeQ laser; Wavelight Laser Technologie AG, Erlangen, Germany). I would include a treatmentgoal of -0.50 D for the Q value (asphericity), in ordertoreduce spherical aberrations that are typically induced during the correction of high myopes. The hope is that the post-enhancement Q value would be less positive. Through past experience, we have learned that correction of -10.00 D shifts the 30o asphericity of the cornea from an average -0.30 D to ± 2, therefore inducing significant spherical aberrations. In the case of this patient, I chose not to use either of the previously mentioned options. Considering that the cornea was stable, I pulled from my experience with UVA collagen cross-linking as a means to rehabilitate ectatic corneas after LASIK. I proposed that the patient was experiencing a late biomechanical shift of the thinned cornea. The patient and I discussed the option of crosslinking the cornea and then enhancement, if necessary. I determined that performing an enhancement first may not be successful if the refraction continued to regress in the future. We therefore decided to proceed with collagen cross-linking with the PriaVision device (PriaVision, Menlo Park, California) for 30 minutes in conjunction with 1% riboflavin solution applied every 2 minutes to the surface of the deepithelialized cornea. Initially the patient was unsatisfied and experienced pain and discomfort for the first 10 days while the epithelium healed. That changed at 1-month followup, however, when we discovered her UCVA was back to 20/20 and her refractive error was -0.25 D. In the end, our patient achieved a VA of 20/15. I would therefore use this case to confirm previous reports on the biomechanical changes of the cornea following LASIK, and establish a significant biomechanical effect of the UVA cornea cross-linking to the operated cornea—with a change in the posterior cornea contour centrally and paracentrally (Figure 13.3C). This is a comparison map of the posterior cornea surface by the Wavelight Oculyzer (Pentacam). The first map on the left is the pre-UVA CCL posterior cornea surface devoid of any signs of ectasia. The middle map is the same posterior surface one month following UVA CCL. It is evident that there has been been a flattening change, more evident in the difference map on the right, The mid-periphery of the posterior cornea shows a “flattening” effect confirming the biomechanical change in this cornea following the collagen cross-
CROSS-LINKING PLUS TOPOGRAPHY-GUIDED PRK FOR POST-LASIK ECTASIA MANAGEMENT
Figure 13.3A
Figure 13.3B
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Figure 13.2C Figures 13.3A to C: (a) is the 2000 pre-op Orbscan of the right eye; (b) is the 2006 post-op pentacam of the same treated eye; (c) 1 month post-UVA CCL pentacam images of the same cornea that establish a significant biomechanical effect of the UVA CCL to the operated cornea with a change in the posterior cornea contour centrally and paracentrally
linking. This effect appears to have corrected the late regression of -1 Diopter. I believe this case shows that any surprise regressions noted—even years—after LASIK could be biomechanical changes of the cornea, and could be treated by this minimally invasive alternative. Figure 13.4 decribe a similar case: These are Pentacam comparison maps of a 27 y/o female that underwent LASIK for -10 OU 5 years ago
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She had an enhancement fro -1.00 OU 3 years ago and deteriorated again to -1.5D Instead of enhancement she underwent UVA CCL and the refraction regression reversed to plano. The pentacam comparison of pre and post UVA CCL for the sagittal curvature front (Fig. 13.4A) and posterior cornea elevation (Fig. 13.4B) shows the biomechanical change of cross-linking that produced the regression reversal.
CROSS-LINKING PLUS TOPOGRAPHY-GUIDED PRK FOR POST-LASIK ECTASIA MANAGEMENT
Figure 13.4A
Figures 13.4A and B: These are Pentacam comparison maps of a 27 y/o female that underwent LASIK for -10 OU 5 years ago. She had an enhancement fro -1.00 OU 3 years ago and deteriorated again to -1.5D Instead of enhancement she underwent UVA CCL and the refraction regression reversed to plano. The pentacam comparison of pre and post UVA CCL for the sagittal curvature front (Figure 13.4a) and posterior cornea elevation (Figure 13.4b) shows the biomechanical change of cross-linking that produced the regression reversal Figure 13.4B
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REFERENCES 1. Binder, PS. Ectasia after laser in situ keratomileusis. J Cataract Refract Surg 2003;29:2419-29. 2. Randleman JB, Russell B, Ward MA, Thompson KP, Stulting RD. Risk factors and prognosis for corneal ectasia after LASIK.Ophthalmology 2003;110(2):267-75. 3. Klein SR, Epstein RJ, Randleman JB, Stulting RD. Corneal ectasia after laser in situ keratomileusis in patients without apparent preoperative risk factors. Cornea 2006;25(4):388-403. 4. Kanellopoulos A, PeL Perry H, Donnenfeld E. Modified Intracorneal Ring Segment Implantations (Intacs) for the Management of Moderate to Advanced Keratoconus: efficacy and Complications. Cornea 2006;25:29-33. 5. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet -ainduced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-27. 6. Seiler, T, Hafezi F. Corneal cross-linking-induced stromal demarcation line. Cornea 2006;25:1057-59.
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7. Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res 1998;66:97-103. 8. Hafezi F, Mrochen M, Jankov M, Hopeler T, Wiltfang R, Kanellopoulos A, Seiler T. Corneal collagen cross-linking with riboflavin/UVA for the treatment of induced kerectasia after laser in situ keratomileusis 2007. 9. Kanellopoulos A. Management of post-LASIK ectasia with UVA collagen cross-linking followed by customized topography-guided PRK - an efficient approach to avoid corneal transplantation. Letter-to-the-editor in press Ophthalmology 2007. 10. Kanellopoulos AJ. Topography-guided Custom retreatments in 27 symptomatic eyes. J Refract Surg 2005;21:S513-18. 11. Kanellopoulos AJ, Pe L. Wavefront-guided Enhancements using the Wavelight Excimer Laser in Symptomatic Eyes Previously Treated with LASIK. J Refract Surg 2006;22:34549. 12. Kanellopoulos AJ , Binder PS. Collagen cross-linking (CCL) with Sequential topography-guided PRK. A temporizing alternative to penetrating keratoplasty. J of Cornea –in press
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INTRODUCTION The major causes of irregular astigmatism are corneal stromal degenerations (such as keratoconus and pellucid marginal degeneration) and post laser assisted in situ keratomileusis (Lasik) corneal ectasia. Keratoconus and pellucid marginal degeneration are bilateral, non-inflammatory diseases characterized by progressive corneal thinning and steepening, whereas ectasia is a serious postoperative late complication after refractive surgery.1,2 The treatment consists of spectacles, rigid contact lenses, intrastromal corneal ring segments (ICRS),3-29 corneal collagen cross-linking (CCL) with Riboflavin and Ultraviolet-A (UV-A)30-41 and when these treatment options are no longer effective, penetrating keratoplasty (PK). 42 Expectations are limited, and consequences may be unpredictable, anatomically and functionally.1 INTRACORNEAL RING SEGMENTS’ AND IRREGULAR ASTIGMATISM
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Intracorneal Ring Segments’ (Intacs, Addition Technology, Fremont, California, USA) are originally designed to correct low myopia.4 Refractive adjustment is achieved by flattening the central corneal curvature while maintaining clarity in the central optical zone. It is a removable and tissue-saving technique. Several studies have demonstrated the efficacy and the reversibility of ICRS in correcting myopia,4-6 but further reports revealed that ICRS are also suitable for keratoconic3,4,7-12,16-29 or post Lasik ectatic13-15 eyes since they increase corneal topographic regularity and patients’ uncorrected visual acuity (UCVA). There are different types of ICRS, depending on their curvature, width, and zone of implantation all of them made of arc-like polymethyl methacrylate (PMMA). Intacs inserts have a crescent-shaped arc length of 150 degrees. Their inner diameter is 6.8 mm and the outer diameter is 8.1 mm, with a thickness which ranges from 0.25 to 0.45 mm in 0.05 increments. Last generation Intacs SK have an arc length of 150’, a width of 1.3 mm and are packaged in two thicknesses: 0.40 and 0.45 mm. The segment profile has an elliptical, edgeless shape providing a diffractive design to achieve reduced halo, glare and increased quality of vision at the 6.0 mm optical zone.
KeraRings (Mediphacos, Belo Horizonte, Brazil) are newly developed segments that are characterized by a triangular cross-section that induces a prismatic effect on the cornea. Their apical diameter is 5 mm and the flat basis width is 0.6 mm with variable thickness (0.15to 0.30-mm with 0.5-mm steps) and arc lengths (90 degrees, 160 degrees, and 210 degrees). The optical zone provided by KeraRing segments is 5.0 mm in diameter. Tunnel creation for segment implantation can be made manually using mechanical devices. This step of the procedure correlated with a number of possible complications such as epithelial defects, perforation, infectious keratitis, shallow or uneven or asymmetric segment placement, corneal stromal edema around the incision, extension of the incision toward the central visual axis or the limbus, and persistent incisional gaping.16-18 Alternatively, channel creation can be carried out with a femtosecond laser because it can deliver energy accurately to a precise depth in a programmed way making the procedure for many surgeons much safer, quicker and simplier.19-23 Clinical Outcomes Colin et al24 in 2001 reported their one year followup after Intacs implantation in 10 patients with keratoconus. Spherical equivalent error and refractive astigmatism were reduced. At one year follow-up, uncorrected visual acuity (UCVA; approximately 20/ 50) was significantly better than pre-operative best spectacle corrected visual acuity (BSCVA approximately 20/200). Average BSCVA was improved by approximately two lines compared with baseline measurements. Topographic corneal shape was improved for all subjects. In 2003, Siganos et al3 presented a prospective study of 33 keratoconic eyes treated with Intacs (mean follow-up 11.3 months). The mean UCVA and BSCVA improved significantly. Of 33 eyes, four eyes loss 1 to 2 lines of BSCVA, whereas 25 eyes experienced 1 to 6-line gain. Segments’ removed from 4 eyes and one eye underwent successful PKP. In 2005, Hellstedt et al25 assessed the outcomes of 50 keratoconic eyes treated with Intacs. Both UCVA and BSCVA improved throughout follow-up. Visual functioning index improved from 61.6 ± 21.1 to 80.8 ± 22.5. The mean change in corneal astigmatism was 2.9 ± 2.9 D at 6 months follow-up.
INTACS AND CORNEAL COLLAGEN CROSS-LINKING WITH RIBOFLAVIN AND ULTRAVIOLET-A
Alio et al26 presented in 2005 a prospective study of 26 keratoconic eyes divided in two groups based on their topographic findings. At one year, spherical equivalent error, mean keratometric values and refractive astigmatism were reduced significantly in both groups. In group 1, the mean UCVA improved from 20/100 to 20/32, whereas the mean BSCVA improved from 20/50 to 20/32. In group 2, the mean UCVA improved from 20/400 to 20/63, whereas the mean BSCVA improved from 20/50 to 20/32. The European study 11 published in 2006 documented a prospective study of Intacs for the management of keratoconus in 57 eyes. At 6-month evaluation, 78% of patients showed improvement of two lines or more in UCVA (p < 0.001). BSVCA of 20/ 40 or better improved from 53% of patients preoperatively to 74% of patients (p < 0.033). Manifest refraction spherical equivalent improved to 3.1 ± 2.5 D ( p < 0.001) compared with the preoperative examination. Keratometry decreased a mean of -4.3 ± 2.8 D from the preoperative readings (p < 0.002). Kymionis et al9 reported a long term retrospective series of 17 keratoconic eyes treated with Intacs. After 5 years spherical equivalent error was statistically significant reduced compared with the preoperative measurements, while UCVA, BSCVA improved in most patients. In 2006, Ertan et al22 presented the outcomes of Intacs implantation using the femptosecond laser in a retrospective study of 118 eyes with keratoconus. At the end of the first postoperative year, 81.3% of eyes had improved UCVA and 73.7% had improved BSCVA. The mean keratometry decreased from 51.56 to 47.66 D and the mean spherical equivalent decreased from -7.57 to 3.72 D. Rabinowitz et al12 pulished in 2006 a comparative study of Intacs insertion in keratoconic eyes using femptosecond laser or a mechanical spreader for tunnel creation. Both groups demonstrated significant reduction in average keratometry, spherical equivalent, refraction, UCVA, BSCVA, surface irregularity index and surface asymmetry index. Differences between groups were not statistical significant. Kymionis et al15 reported in 2006 the long term follow-up (5 years) of Intacs for the management of post Lasik corneal ectasia in a retrospective study. At 5 years, the spherical equivalent error was reduced with
statistical significance. Pre-Intacs UCVA was 20/100 or worse in all eyes, whereas, at the last follow-up examination, six out of eight eyes had UCVA 20/40 or better. Two eyes (25%) maintained the pre-Intacs BSCVA, while the rest experienced a gain of one or two lines. Alio et al,29 presented a prospective noncomparative case series to evaluate the potential of using Intacs to correct posterior ectasia LASIK. All cases showed marked improvement after segment implantation. Postoperatively, there was a reduction in the magnitude of the posterior and anterior corneal surface steepening, an increase in the topographical regularity index and a significantly enlargement of the optical zone. In 2005, Mularoni et al28 evaluated the use of Intacs for the treatment of pellucid marginal degeneration in eight patients. At 12-month follow-up UCVA improved in all eyes and six eyes (75%) had a BSCVA of at least 20/25. CORNEAL COLLAGEN CROSS-LINKING AND IRREGULAR ASTIGMATISM The original idea was conceived at Dresden Technical University in the 1990s.31 The basic observation was the fact that young patients with diabetes almost never have keratoconus, because of the natural cross-linking effect of glucose, which increases corneal resistance in this patients. 32-34 The clinical indications for collagen cross-linking are melting processes of the cornea and corneal thinning disorders such as keratoconus, pellucid marginal degeneration, and iatrogenic keratectasia after Lasik. The technique of corneal collagen cross-linking consists in the photopolymerization of the stromal fibers by the radical formation effect of a photosensitizing substance (riboflavin) and UV light from a solid-state UVA source.31 Histopathological ex vivo studies revealed an increase in the diameter of the collagen fibers to a depth of 300 μm, greater resistance to enzyme breakdown (anticollagenase effect), apoptosis of keratocytes in the anterior and intermediate stroma and gradual repopulation by deep keratocytes.35 The formation of chemical bonds between the collagen fibrils accompanied by increasing collagen fibers diameter induces the biomechanical stability of
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corneal collagen. 36 Wollensak et al reported an increase of 328.9% in corneal rigidity in human corneas after cross-linking. The stiffening of the corneal collagen flattens the corneal apex which produces a total eye dioptric power reduction. This phenomenon can partially explain the improvement in patients’ uncorrected visual acuity. Changes in the best spectacle-corrected visual acuity are mainly related to the improvement in corneal symmetry demonstrated overall by the early coma reduction in the anterior corneal surface. The main complication after corneal cross-linking is endothelial cell damage.37 Additionally there have been published cases of DLK38 in post CCL patient with ketatectasia after Lasik and herpetic keratitis with iritis39 in a post CCL keratoconic patient. Clinical Outcomes
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In 2003, Wollensak et al30 presented the results of twenty-three eyes of 22 patients with moderate or advanced progressive keratoconus after corneal crosslinking. Mean patients’ follow-up time of 23.2 ± 12.9 months (range 3 to 47 months). In all treated eyes, the progression of keratoconus was at least halted. In 16 eyes (70%) regression with a reduction of the maximal keratometry readings by 2.01 D and of the refractive error by 1.14 D was found. Visual acuity improved slightly in 15 eyes (65%). Wollensak et al36 reported in 2006 the three and 5-year follow-up examination of patients that participated in the first clinical study to evaluate corneal collagen cross-linking with riboflavin and Ultraviolet-A in keratoconic patients. In all 60 eyes the progression of keratoconus was at least stopped. In 31 eyes there also was a slight reversal and flattening of the keratoconus by up to 2.87 D. Best corrected visual acuity improved slightly by 1.4 Snellen lines. Kohlaas et al40 published in 2005 a case report of post-Lasik ectasia treated with corneal cross-linking. Due to the stiffening of anterior part of the corneal, the progression of keratectasia was prevented. Refraction and corneal topography have been stabile for eighteen months. In 2007, Hafezi et al41 presented the outcomes of rivoflavine and UVA corneal cross-linking in ten patients (10 eyes) with post Lasik ectasia. In all cases keratectasia was arrested and / or partially reversed, while BSCVA was improved in 9 eyes.
Given the fact that collagen turnover is 2 to 3 years, more long term studies are essential to determine whether corneal cross-linking with riboflavin and UVA have a long standing or a transient clinical effect. INTACS COMBINED WITH CORNEAL COLLAGEN CROSS-LINKING AND IRREGULAR ASTIGMATISM Intracorneal Ring Segments’ implantation and Corneal Collagen Cross-linking with Riboflavin and UltravioletA as we described are minimally invasive techniques for the treatment of irregular astigmatism. Since ICRS insertion re-shapes the cornea and CCL inhibits or slows the progression of irregular astigmatism, a logical solution would be to combine the two treatment methods in order to synergize their effect (Fig. 14.1). Chan et al29 studied the combination of Intacs with corneal collagen cross-linking with Riboflavin (C3-R) in 2007, in a retrospective, nonrandomized, comparative cases series comprising of 12 eyes of nine patients who had inferior segment Intacs placement without C3-R (Intacs only group) and 13 eyes of 12 patients who had inferior segment Intacs implantation and afterwards C3-R (Intacs with C3-R group). Intacs with C3-R had a significantly greater reduction in cylinder than the Intacs-only group (p < 0.05). Steep
Figure 14.1: Kerrarings implantation followed by UV-X in a keratoconic eye
INTACS AND CORNEAL COLLAGEN CROSS-LINKING WITH RIBOFLAVIN AND ULTRAVIOLET-A
and average keratometry were reduced significantly more in the Intacs with C3-R group (p < 0.05). But which is the right treatment sequence? A pretreatment with ICRS would significantly re-shape the cornea by flattening and regularizing it, which would be followed by CCL in order stabilize the cornea in this newly achieved state. Alternatively, the CCL procedure could be done first, followed by a reshaping procedure. Segments’ implantation in a “soft” cornea is expected to have a greater flattening effect, than ICRS insertion in a stiff cornea. Therefore, it looks logical to perform first the ICRS placement and afterwards to “freeze” corneal stroma with CCL. Preliminary, unpublished data of a prospective study [keratoconic eyes that underwent both treatments (ICRS and CCL) with different sequence] seems to support this theoretical approach. CONCLUSION Intracorneal ring segments and corneal collagen crosslinking with Riboflavin and Ultraviolet-A seems to have a synergic effect as treatments for irregular astigmatism. Implantation of ICRS followed by corneal collagen cross-linking with Riboflavin and UltravioletA possibly have greater keratoconus improvements than\CCL procedure followed by ICRS placement. More, large, comparative studies are needed in order to verify or reject these preliminary results. REFERENCES 1. Kennedy RH, Bourne WM, Dyer JA. A 48-year clinical and epidemiologic study of keratoconus. Am J Ophthalmol 1986;101:267-73. 2. Haw WW, Manche EE. Iatrogenic kearectasia after a deep primary keratotomy during laser in situ keratomileusis. Am J Ophthalmol 2001;132:920-1. 3. Siganos CS, Kymionis GD, Kartakis N, et al. Management of keratoconus with Intacs. Am J Ophthalmol 2003;135:64-70. 4. Schanzlin DJ, Asbell PA, Burris TE, et al. The intrastromal corneal ring segments’. Phase II results for correction of myopia. Ophthalmology 1997;104:1067-78. 5. Fleming JF, Lovisolo CF. Intrastromal corneal ring segments in a patient with previous laser in situ keratomileusis. J Refract Surg 2000;16:365-7. 6. Lovisolo CF, Fleming JF, Pesando PM. Intrastromal corneal ring segments. Fabiano Edotore, Canelli, Italy, 2002.
7. Colin J, Cochener B, Savary G, et al. Correcting keratoconus with intracorneal rings. J Cataract Refract Surg 2000;26:1117-22. 8. Colin J, Malet FJ. Intacs for the correction of keratoconus: Two-year follow-up. J Cataract Refract Surg 2007;33:6974. 9. Kymionis GD, Siganos CS, Tsiklis NS, et al. Long-term follow-up of Intacs in keratoconus. Am J Ophthalmol 2007;143:236-44. 10. Kanellopoulos AJ, Pe LH, Perry HD, Donnenfeld ED. Modified intracorneal ring segment implantations (INTACS) for the management of moderate to advanced keratoconus: efficacy and complications. Cornea 2006;25:29-33. 11. Colin J. European clinical evaluation: use of Intacs for the treatment of keratoconus. J Cataract Refract Surg 2006;32:747-55. 12. Rabinowitz YS, Li X, Ignacio TS, et al. INTACS inserts using the femtosecond laser compared to the mechanical spreader in the treatment of keratoconus. J Refract Surg 2006;22:764-71. 13. Sharma M, Boxer Wachler BS. Comparison of singlesegment and double-segment Intacs for keratoconus and post-LASIK ectasia. Am J Ophthalmol 2006;141:891-5. 14. Kymionis GD, Siganos CS, Kounis G, et al. Management of post-LASIK corneal ectasia with Intacs inserts: one-year results. Arch Ophthalmol 2003;121:322-26. 15. Kymionis GD, Tsiklis NS, Pallikaris AI, et al. Long-term follow-up of Intacs for post-LASIK corneal ectasia. Ophthalmology 2006;113:1909-17. 16. Boxer Wachler BS, Christie JP, Chandra NS, et al. Intacs for keratoconus. Ophthalmology 2003;110:1031-40. 17. Ruckhofer J, Stoiber J, Alzner E, Grabner G. One year results of European multicenter study of intrastromal corneal ring segments. Part 2: complications, visual symptoms, and patient satisfaction; the Multicenter European Corneal Correction Assessment Study Group. J Cataract Refract Surg 2001;27:287-96. 18. Siganos D, Ferrara P, Chatzinikolas K, et al. Ferrara intrastromal corneal rings for the correction of keratoconus. J Cataract Refract Surg 2002;28:1947-51. 19. Kwitko S, Severo NS. Ferrara intracorneal ring segments for keratoconus. J Cataract Refract Surg 2004;30:812-20. 20. Rabinowitz YS, Li X, Ignacio TS, Maguen E. INTACS inserts using the femtosecond laser compared to the mechanical spreader in the treatment of keratoconus. J Refract Surg 2006;22:764-71. 21. Sugar A. Ultrafast (femtosecond) laser refractive surgery. Curr Opin Ophthalmol 2002;13:246-49. 22. Ertan A, Kamburoglu G, Bahadir M. Intacs insertion with the femtosecond laser for the management of keratoconus: one-year results. J Cataract Refract Surg 2006;32:2039-42. 23. Ertan A, Bahadir M. Topography-guided vertical implantation of Intacs using a femtosecond laser for the treatment of keratoconus. J Cataract Refract Surg 2007;33:148-51.
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES 24. Colin J, Cochener B, Savary G, et al. Intacs inserts for treating keratoconus. One-year results. Ophthalmology 2001;108:1409-14. 25. Hellstedt T, Makela J, Uusitalo R, et al. Treating keratoconus with INTACS corneal ring segments. J Refract Surg 2005;21:236-46. 26. Alio JL, Artola A, Hassanein A, et al. One or 2 Intacs segments for the correction of keratoconus. J Cataract Refract Surg 2005;31:943-53. 27. Alio J, Salem T, Artola A, Osman A. Intracorneal rings to correct corneal ectasia after laser in situ keratomileusis. J Cataract Refract Surg 2002;28:1568-74. 28. Mularoni A, Torreggiani A, Di Biase A, et al. Conservative treatment of early and moderate pellucid marginal degeneration: a new refractive approach with intracorneal rings. Ophthalmology 2005;112:660-66. 29. Chan CC, Sharma M, Wachler BS. Effect of inferior-segment Intacs with and without C3-R on keratoconus. J Cataract Refract Surg 2007;33:75-80. 30. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-ainduced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-27. 31. Spoerl E, Huhle M, Seiler Th. Induction of cross-links in corneal tissue. Exp Eye Res 1998;66:97-103. 32. Hadley JC, Meek KM, Malik NS. The effect of glycation on charge distribution and swelling behavior of corneal and scleral collagen. Invest Opthalmol Vis Sci 1996;37:1010. 33. Sady C, Hosrof K, Nagaraj RH. Advanced Maillard reaction and cross-linking of corneal collagen in diabetes. Biochem Biophys Res Commun 1995;214:793-97.
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34. Zhao HR, Nagaraj RH, Abraham EC. The role of D- and e amino groups in the glycation-mediated cross-linking of γB-cristallin. J Biol Chem 1997;272:14465-69. 35. Wollensak G, Spoerl E, Wilsh M, et al. Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment. Cornea 2004;23:43-49. 36. Wollensak G. Cross-linking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006;17:356-60. 37. Spoerl E, Mrochen M, Sliney D, et al. Safety of UVA– Riboflavin Cross-linking of the Cornea. Cornea 2007;26:385-89. 38. Kymionis DG, Bouzoukis DI, Diakonis VF, et al. Diffuse lamellar keratitis after corneal cross-linking in a patient with post-laser in situ keratomileusis corneal ectasia Cataract Refract Surg 2007;33:2135-37. 39. Kymionis DG, Portaliou DM, Bouzoukis DI, et al. Herpetic keratitis with iritis after corneal cross-linking with riboflavin and ultraviolet A for keratoconus J Cataract Refract Surg 2007;33:1982-84. 40. Kohlhaas M, Spoerl E, Speck A, et al. Eine neue behandlung der keratektasie nach LASIK durch kollagenvernetzung mit riboflavin/UVAlicht. Klin Monatsbl Augenheilkd. 2005;222:430-36. 41. Hafezi F, Kanellopoulos J, Wiltfang R, Seiler T. Corneal collagen cross-linking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis. J Cataract Refract Surg 2007;33:2035-40. 42. Frost NA, Wu J, Lai TF, Coster DJ. A review of randomized controlled trials of penetrating keratoplasty techniques. Ophthalmology 2006;113:942-49.
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INTRODUCTION Keratoconus is a non-infiammatory cone-like ectasia of the cornea, which is usually bilateral and progress over time, with consequent central or paracentral thinning of the stroma and irregular astigmatism (Fig. 15.1). The relevance of keratoconus in the general population seems to be relatively high, with approximately 1 in 20001, even if the diffusion of new diagnostic means will permit to find prevalence rates certainly greater. In nearly all cases both eyes are affected, at least from a topographic point of view. The cause of keratoconus is unknown, but it seems that enzymatic changes in corneal epithelium, such as decrease of the levels of the inhibitors of proteolytic ezymes and an increase of the lysosomal enzymes can be involved in the cornea degradation. At the beginning, glasses are sufficient to correct myopia and astigmatism still regular or slightly irregular; successively, in cases of high astigmatism, it becomes necessary to apply hard contact lenses. Epikeratoplasty is efficacious in patients which do not endure contact lenses and which do not show a significant central corneal opacity, but, due to its visual outcomes not perfect, it was dropped. Intracorneal rings also can be an option2, but all these described techniques unfortunately only correct
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Figure 15.1: Keratoconus
refractive errors and do not treat the cause underlying the corneal ectasia and, therefore, they do not permit to stop the progression of keratoconus. In 1996 3 , some theoretical studies started investigating more deeply the underlying causes of keratoconus and the possible parasurgical techniques to stop its progression. In all patients affected by keratoconus a reduced degree of cross-links in the corneal collagen fibers has been observed; that is, the aim of those studies was firstly to determine how to increase those cross-links to obtain an improved mechanical stability of the cornea and increase the resistance against enzymatic degradation. CORNEAL COLLAGEN NETWORKS Collagen is a structural protein organized in fibers. Those fibers are responsible of limiting the tissue deformation and preventing mechanical brakes. The collagen fibers are chemically stable and have high mechanical properties. Inside the connective tissue, fibroblasts synthetize tropocollagen molecules, the base blocks of collagen fibers. Those molecules have a typical weight of 300 kDa, a length of 280 nm with an average diameter of 1.5 nm. The molecule is composed by 3 helicoidal chains (alpha-chains) interlaced each other like a rope (Figure 15.2).
Figure 15.2: Collagen triple helicoidal chain
TRANSEPITHELIAL CROSS-LINKING FOR THE TREATMENT OF KERATOCONUS: CONCEPTS
The factors of stabilization of those collagen molecules are related to the interactions between the 3 helics and are due to Hydrogen links, Ionic links and intra-chain reticulations (cross-links). Tre stroma, composed mainly by collagen lamellae, gives to cornea 90% of its thickness. Between the lamellae keratocites can proliferate, migrate and turn into their activate state. Integrity of corneal epithelium for the switch of keratocites (resting cells) in fibroblasts (active cells) is very important. Cheratansulphate type I is the most important mucopolysaccaride present in corneal stroma: it plays an important tole for the orientation of collagen mashes and lamellae (corneal clarity, tensile strength) and for corneal hydration (corneal edema). PHOTOCHEMICAL CROSS-LINKING There are many different possibilities of cross-linking:4 • Lysyl oxidase (LOX) cross-links collagen enzymatically • Transglutaminase (12h, pH=3) • Sugar aldehydes (diabetes – Advanced Glycation Endproducts AGEs) • Chemical cross-linking (glutaraldehyde, formaldehyde, DPPA) • Photochemical cross-linking (UV, ionizating radiation) The interaction between organic tissues and radiation depends on the type of radiation used. The ionizing radiation has enough energy to turn out electrons from the atoms of the tissues. Other types of radiation, i.e. UV radiation, have not enough energy to turn out electrons but to make them jump to higher energy levels (exciting radiation). In the human biologic tissues, water molecule is present at a rate of 70 to 90% so it is clearly the main target of radiation. During the water radiolysis process, the energy applied to water molecules ionizes them and generate free radicals molecules. Free radicals are continuously produced in tissues and quickly inactivated by chemical or enzymatic transformation. In the eye, ascorbic acid absorbs UV radiation (at cornea, lens and vitreous body districts); it is a cofactor of several enzymes, the best known of which are prlyne hydroxylase, enymes involved in byosinthesis of collagen. In vitreous body, after cataract surgery (absence of glutathione), ascorbic acid (in ascorbate
form) absorbs UV not stopped by lens, resulting in the formation of free radicals, disaggregation of hyaluronic acid and increase an cross-linking of collagen fiber networks. RIBOFLAVIN-UV-A TREATMENT A photo sensitizer is a substance which is activated by the absorpion of light at a given wavelight and which can induce free radical reactions in its activate form. This substance can amplify light radiation effect on biologic tissues. The basic mechanism of the photochemical treatment of keratoconus is to use Riboflavin as a photo sensitizer and apply on it UV irradiation at a determined wavelength to induce free radicals reactions and increase this way the cross-links in the collagen fibers. Riboflavin has a high UV absorption between 360 and 450 nm; due its additional shielding all structures behind the corneal stroma, including corneal endothelium, anterior chamber, iris, lens and retina, are exposed to a residual UV radiant exposure less Than 1J/cm2 (in accordance with safety guidelines). The UV source is typically a group of 3 to 5 Light Emitting Diodes producing a radiation of 370 nm wavelength and 3 mW/cm2 intensity (Figure 15.3). The cross-linking effect is obtained in three steps (Figure 15.4). CORNEAL EPITHELIUM Remove or not remove the epithelium is a matter of a therapeutic range of the X-linking with riboflavin technique. The goal of the treatment is to obtain
Figure 15.3: UVA source (Courtesy of Peschke GmbH)
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Figure 15.4: Photochemical induction of cross-links
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mechanical X-linking of collagen fiber networks of the corneal stroma without side effects (edema, demarcation lines in the anterior stroma of the cornea, phlogosis, etc). The widespread technique of cross-linking is based on a central abrasion (with a diameter of 8 mm). This abrasion is made because the epithelium is believed to be a barrier to the correct diffusion of riboflavin so a possible factor of decreased effectiveness of the treatment. What has been observed during the different studies5,6 is that free radicals mediated by the riboflavin irradiated with UV light can create cell damage. Keratocytes showed (in both laboratory and clinical studies in epithelium-removed eyes) cells death up to a 350 nm depth. After 6 months the area is repopulated by keratocites which, differently from corneal endothelium, can reproduce. To preserve the endothelium a minimum corneal thickness of 400 nm should be assured. The barrier-effect produced by the riboflavin, present at the level of the tear film and of the corneal epithelium, is one of the qualifying aspects of the transepithelial technique. Actually, this aspect makes the technique safer as far as the endothelial damage is concerned, especially in the thin corneas (400 microns), because most of the
radiating energy emitted for the treatment, is blocked before entering the superficial layers of the corneal stroma. Moreover, a part of the energy reaches the superficial corneal stroma, where is located the riboflavin, even if in a small quantity, and then to produce free radicals and cross-links between the collagen fibers. The news in this treatment is represented by the possibility of realizing cross-linking keeping the epithelium unaltered. This natural barrier protect the cornea but it is not an impermeable stratus: it is an osmotic membrane through which the riboflavin can penetrate to the cornea. Of course, the riboflavin itself cannot penetrate easily so the question is, at this stage, about the real effectiveness of the treatment, compared with the traditional one. If we combine the riboflavin drops with a tense-active substance, we can have a more efficient penetration to the cornea. This substance acts as a vector for riboflavin, with a double effect: reaching the cornea and filling the epithelium, contributing so far to its strengthening (Figure 15.5). The advantages of this particular technique is that all the macroscopic side effects related to the epithelium-removal technique are not present: no pain, no stromal edema (due to the abrasion) and, more important, the possibility to treat both eyes in the same session (85% of patients has bilateral keratoconus, so the treatment is in most cases necessary in both eyes). Even if we assume that the riboflavin cannot penetrate efficiently the epithelium, we think that as the photo sensitizer is distributed homogeneously on
Figure 15.5: Patient eye under C3-R treatment
TRANSEPITHELIAL CROSS-LINKING FOR THE TREATMENT OF KERATOCONUS: CONCEPTS
the treated eye, we can at least obtain an increased rigidity of the corneal epithelium, thus a decreased instability in visual acuity of the patient. Remove or not remove the epithelium is a matter of a therapeutic range of the X-Linking with riboflavin technique. The goal of the treatment is to obtain mechanical X-Linking of collagen fiber networks of the corneal stroma without side effects (edema, demarcation lines in the anterior stroma of the cornea, phlogosis, etc) The real question is about the effectiveness of the treatment, as the safety issues are not a worry of this technique: keeping the epithelium unalterated mean reducing most of the side effects of the treatment (included the death rate of keratocites and the number of endothelial cells). We continue our studies in this way because we believe that the epithelium removal
is something that could be avoided in the treatment and transepithelial technique will become the standard in Cross-linking treatments. REFERENCES 1. Rabinowitz YS. Keratoconus – Surv Ophthalmol 1998. 2. Colin J, et al. Correcting keratoconus with intracorneal rings, JCRS 2000. 3. Seiler T, Spoerl E, et al. Conservative therapy of keratoconus by enhancement of collagen cross-links, 1996. 4. Spierl E. Physical background of the riboflavin/UV crosslinking of the cornea. World Vision Surgery Symposium 2007. 5. Wollensak, Spoerl, et al. Keratocyte apoptosis after collagen cross-linking using riboflavin/UVA treatment 2004. 6. Spoerl E. Seiler T, et al. Safety of UVA-Riboflavin Crosslinking of the Cornea. Cornea 2007.
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CORNEAL COLLAGEN CROSS-LINKING IN KERATOCONUS
INTRODUCTION
Effect on Collagenase Resistance
Keratoconus is an ectatic, progressive, noninflammatory disease of the cornea. Reported estimates of the prevalence of keratoconus vary between 50 and 230 per 100 000. In keratoconus, there are normalsized collagen fibers; however, the number of collagen lamellae are abnormally low. The collagen lamellae are released from their interlamellar attachments or from their attachment to Bowman’s layer and become free to slide. The treatment options for keratoconus include glasses, contact lenses, collagen cross-linking, intrastromal ring segments and corneal transplantation.1 Corneal collagen cross-linking is performed by using UV-A at 370 nm and the photosensitizer riboflavin, stiffening the collagen matrix of the cornea.2 Cross-linking treatment is the first and only therapeutic option that has changed the natural course of keratoconus by stopping progression.3
Cross-linking causes increased resistance against collagenase digestion in porcine eyes. This effect is stronger in the anterior part of the cornea. This resistance to collagenase may play an important role in keratoconus since collagenase activity is increased in keratoconus. In tear samples of keratoconus patients, collagenase metabolites are 2.5 times higher than normals.7
EFFECTS OF CROSS-LINKING ON CORNEAL STROMA
Effects on Hydration Behavior
Biomechanical Effects Tensile strength of cornea is decreased in keratoconus. Biomechanical stress-strain measurements in human corneas showed an increase in corneal rigidity of 328.9% and an increase in Young’s modulus by the factor of 4.5 after cross-linking. The cross-linking effect is maximal in the anterior 300 μm of the cornea.4 Thermomechanical Effects The maximal hydrothermal shrinkage temperature was found to be 75’C for cross-linked porcine corneas and 70’C for untreated controls. This effect is more pronounced on the anterior stroma of the cornea.5 Morphological Effects Collagen fiber diameter was increased by 12.2% in the anterior stroma and by 4.6% in the posterior stroma in rabbit eyes. This is because of the induced crosslinks, pushing the collagen polypeptide chains apart, resulting in increased intermolecular spacing. Increase in collagen fiber diameter and corneal rigidity due to collagen cross-linking is also observed in diabetes mellitus and aging.6
Biochemical Effects In the gel electrophoresis of cross-linked porcine corneas, there was an additional intense polymer band in the stacking gel that was resistant to mercaptoethanol, heat, and pepsin treatment. This polymer band complies well with the morphologic correlate of an increased fiber diameter after crosslinking treatment. Its chemical stability supports hopes of a long-term effect of the new treatment.8
Cross-linked porcine eyes were examined by biomicroscopy, optical coherence tomography (OCT) and light microscopy. Less edema was found in the anterior stroma, confirming prior findings that the cross-linking effect is strongest in the anterior half of the stroma. Cross-linked cornea did not induce a specific signal on OCT, and OCT is therefore not suited for clinical controls of the cross-linking effect.9 EFFECTS OF CROSS-LINKING ON KERATOCYTES Cross-linking caused keratocyte apoptosis on anterior stroma in rabbit eyes. Keratocyte apoptosis is sometimes reflected clinically by a transient mild corneal edema.10 HRT II in vivo confocal microscopy in human eyes with keratoconus also proved rarefaction of keratocytes in the anterior and intermediate stroma associated with stromal edema (spongy or honeycomb-like) immediately after treatment. Three months after the operation, keratocyte repopulation and disappearance of edema was observed. Six months after the operation, keratocyte repopulation was complete.11 Keratocyte apoptosis is not only observed after cross-linking but also in corneal abrasions, Herpes, PRK, LASIK, epikeratophakia and keratoconus.10
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Indications in Keratoconus • Progressive disease (usually age <~35-40 years). Contraindications in Keratoconus Pachymetric thinnest point <400 μm Severe dry eye Pregnancy or nursing Dark microstriae in reticular pattern in confocal microscopy (because of the risk of postoperative corneal haze) • Biomicroscopically evident Vogt striae • Herpes keratitis (since UV can activate herpes).
• • • •
The Surgical Procedure
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Radiation output should be checked before each treatment with a UV light meter. Ingestion of an oral analgesic 1 hour before surgery is recommended. Below, is the step by step corneal cross-linking procedure in keratoconus: • Instill topical anesthetic and antibiotic drops in the conjunctival sac. • Prepare and drape the eye in the usual fashion. Insert a lid speculum. • Remove the epithelium totally (Figure 16.1A) or partially (Figure 16.1B) with a Kuhnt type corneal scarifier. • Instill isotonic riboflavin %0.1 (Medio-cross, Kronen-Apotheke, Kiel) every 2 minutes for 30 minutes, i.e. 15 drops. • Check the corneal penetration of riboflavin with a slit lamp using the blue light. To proceed, the yellow colored riboflavin should exist in the anterior chamber. Otherwise, continue instillation of riboflavin until the anterior chamber gets yellow. • Check corneal thickness with ultrasonic pachymetry. It should be at least 400 μm thick to proceed. Otherwise, instill hypotonic riboflavin 0.1% (Vitamin B2, Kronen Apotheke, Kiel) every 10-15 seconds until the cornea is swelled enough. • Start UVA radiation by UV-X TM (IROC AG, Switzerland) at a distance of 5 cm from the apex of the cornea. By adjusting the aperture, radiate only the unepithelialized cornea, avoid radiating the limbal stem cells (Figure 16.2). • During the application of UVA radiation for 30 minutes, continue to instill isotonic riboflavin 0.1% every 2 minutes.
Figure 16.1A: Complete epithelial removal
Figure 16.1B: Partial epithelial removal
• When the 30 minutes of radiation treatment is over, wash the cornea thoroughly with BSS. • Instill an antibiotic drop and put a bandage lens on the cornea. Follow-up Postoperatively, cycloplegic, antibiotic, antiinflammatory and artificial tear drops are prescribed as well as an oral analgesic. Topical steroid is started after the bandage lens is taken off at 3 to 5 days postoperatively and then tapered in 3 weeks. An oral analgesic may be taken as needed.
CORNEAL COLLAGEN CROSS-LINKING IN KERATOCONUS
Figure 16.2: UVA radiation with riboflavin 0.1%
One month after cross-linking treatment, contact lens use could be started. The durability of the stiffening effect is unknown. Because the collagen turnover in the cornea is estimated to be between 2 to 3 years, a repeat treatment may become necessary in the long run. 3,11 CLINICAL RESULTS The first clinical results of collagen cross-linking in keratoconus were reported by a research group from Dresden University in 2003. In this study, 23 eyes of 22 patients with keratoconus were included and only one eye of each patient was treated except one case that was treated bilaterally. The follow-up period was from 3 to 47 (23.2 ± 12.9) months. The BCVA improved in 65% of the patients by an average of 1.26 lines. The refractive correction improved by an average of 1.14D. In 70% of the patients, maximum K was flattened by an average of 2.01 D. K value remained stable in 5 patients and in 1 patient, an increase of 0.28 D was present. In 22% of the fellow control eyes, however, maximum K value increased by an average of 1.48D.3 The same research group later published their longterm results in 2008 on 153 eyes of 111 patients. The minimal follow-up time was 12 months and the maximum follow-up time was 7.5 years. Keratectasia significantly decreased in the 1st year by 2.29 D, in the 2nd year by 3.27 D, and in the 3rd year by 4.34 D. Visual acuity improved significantly in at least one
line or remained stable (i.e., no line loss) in the 1st year in 48.9% and 23.8%, respectively; in the 2nd year in 50.7% and 29.6%, respectively; and in the 3rd year in 60.6% and 36.4%, respectively. No severe side effects were observed. Three patients showed continuous progression of keratoconus and received cross-linking treatment again.12 Wiitig-Silva C et al reported the preliminary results of a randomized, controlled trial enrolling 66 eyes of 49 patients with documented progression of keratoconus. Interim analysis of treated eyes showed a flattening of the steepest simulated keratometry value (K-max) by an average of 0.74 diopters (D) at 3 months, 0.92 D at 6 months, and 1.45 D at 12 months. A trend toward improvement in best spectacle-corrected visual acuity was also observed. In the control eyes, mean Kmax steepened by 0.60 D after 3 months, by 0.60 D after 6 months, and by 1.28 D after 12 months. Best spectacle-corrected visual acuity decreased by logMAR 0.003 (P = .883) over 3 months, 0.056 (P = .092) over 6 months, and 0.12 (P = .036) over 12 months. No statistically significant changes were found for spherical equivalent or endothelial cell density. These results suggest stabilization of cross-linked eyes.13 Cross-linking has also been effective following inferior-segment INTACS implantation. The addition of collagen cross-linking to the INTACS procedure resulted in greater reduction in cylinder, steep and average keratometry and lower-upper ratio in corneal topography than INTACS insertion alone.14 Since cross-linking stabilized keratoconus, the idea of treating the refractive error with PRK after crosslinking evolved. One year after cross-linking treatment, PRK was performed in one eye of a keratoconus case and an UCVA of 20/20 was achieved. This refractive result remained stable during a follow-up period of 18 months.15 RISKS AND SIDE EFFECTS The harmful effects of UV light to the eye such as photokeratitis is well-known. This photochemical damage is caused, however, by UV-B-light. Corneal epithelium mainly absorbs UV-B (290-320 nm) in photokeratitis.2 In cross-linking treatment, a small peak-like sector of the UV-A spectrum (370 nm) is used. By the help of photosensitizer riboflavin, UV-A absorption in the
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cornea is increased, resulting in a UV-A transmission of only 7% across the cornea.2 In rabbit eyes, the cytotoxicity threshold for corneal endothelial cells is 0.36 mW/cm’. By using standard surface UVA dose of 3 mW/cm2, this cytotoxic level could only be reached if the cornea is thinner than 400 μm. Therefore, in thinner corneas, irradiation should not be performed because of the cytotoxic risk to the endothelium.16,17 The cataractogenic dose of UV-A is 70 J/cm2. With the current treatment parameters, the lens only receives 0.65 J/cm2 which is far below the cataractogeneous level. In addition, lens damage is usually induced by UV-B light which has a higher energy because of a shorter wavelength than UV-A.3 The retinal damage with complete loss of photoreceptor layer in rhesus monkeys was reported at a UVA dose of 81 mW/cm2 which is not reached with the standard treatment protocol.2 In the early clinical studies of cross-linking, no side effects other than transient corneal edema and foreign body sensation which lasts 24-48 hours were reported. No persistent epithelial defect of the cornea, endotheliopathy, cataract and glaucoma were observed. However in 2007, corneal haze after collagen linking was reported by various authors. In one case report, corneal haze after cross-linking treatment for keratoconus disappeared only gradually despite intensive topical anti-inflammatory therapy.18 In a clinical study, haze that is not effecting vision was developed in 2 of 5 eyes with grade 3 keratoconus (according to Krumeich keratoconus clinical staging). No haze was observed in grade I or II eyes. In vivo confocal microscopy of the eyes that developed haze revealed reticular hyporeflective microstriae preoperatively. The authors suggested that the detection of reticular hypo-reflective microstriae by in vivo confocal analysis could represent a relative contraindication to perform cross-linking.19 The effect of cross-linking treatment on epithelium and subepithelial/stromal nerve plexus was studied by in vivo HRT II confocal microscopy in humans. The epithelium reached regular morphology and density in 5 days. Disappearance of subepithelial stromal nerve fibers was observed in the central irradiated area where, 1 month after the operation, initial reinnervation was observed. Six months after the operation, the anterior subepithelial stroma recolonized by nerve fibers with restoration of corneal sensitivity.20
Corneal melting on a case with severe atopic disease and keratoconus following cross-linking and deep anterior lamellar keratoplasty (DALK) due to subclinical infection with Herpes simplex virus (HSV) was reported. Penetrating keratoplasty and intensive antiviral and immunosuppressive medical treatment were necessary to control that infection.21 REFERENCES 1. Feder RS, Kshettry P. Noninflammatory ectatic disorders. In: Krachmer JH, Mannis MJ, Holland EJ, (Eds): Cornea, China, Elsevier Mosby 2005;955-74. 2. Wollensak G. Cross-linking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006;17(4):356-60. 3. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-ainduced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135(5):620-27. 4. Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet—A induced cross-linking. J Cat Refract Surg 2003;29(9):1780-85. 5. Spoerl E, Wollensak G, Dittert DD, Seiler T. Thermomechanical behavior of collagen-cross-linked porcine cornea. Ophthalmologica 2004;218(2):136-40. 6. Wollensak G, Wilsch M, Spoerl E, Seiler T. Collagen fiber diameter in the rabbit cornea after collagen cross-linking by riboflavin/UVA. Cornea 2004;23(5):503-07. 7. Spoerl E, Wollensak G, Seiler T. Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res 2004;29(1):35-40. 8. Wollensak G, Redl B. Gel electrophoretic analysis of corneal collagen after photodynamic cross-linking treatment. Cornea 2008;27(3):353-56. 9. Wollensak G, Aurich H, Pham DT, Wirbelauer C. Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A. J Cataract Refract Surg 2007;33(3):516-21. 10. Wollensak G, Spoerl E, Wilsch M, Seiler T. Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment. Cornea 2004;23(1):43-49. 11. Mazzotta C, Balestrazzi A, Traversi C, Baiocchi S, Caporossi T, Tommasi C, Caporossi A. Treatment of progressive keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: ultrastructural analysis by Heidelberg Retinal Tomograph II in vivo confocal microscopy in humans. Cornea 2007;26(4):390-97. 12. Hoyer A, Raiskup-Wolf F, Spoerl E, Pillunat LE. Collagen cross-linking with riboflavin and UVA light in keratoconus–results from Dresden. Ophthalmologe 2008;e-pub ahead of print). 13. Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg 2008;24(7):720-25.
CORNEAL COLLAGEN CROSS-LINKING IN KERATOCONUS 14. Chan CC, Sharma M, Wachler BS. Effect of inferior-segment Intacs with and without C3-R on keratoconus. J Cataract Refract Surg 2007;33(1):75-80. 15. Kanellopoulos AJ, Bindr PS. Collagen cross-linking (CCL) with sequential topography-guided PRK: a temporizing alternative for keratoconus to penetrating keratoplasty. Cornea 2007;26(7):891-95. 16. Wollensak G, Spoerl E, Wilsch M, Seiler T. Endothelial cell damage after riboflavin-ultraviolet-A treatment in the rabbit. J Cat Refract Surg 2003;29(9):1786-90. 17. Wollensak G, Spoerl E, Reber F, Pillunat L, Funk R. Corneal endothelial cytotoxicity of riboflavin/UVA treatment in vitro. Ophthalmic Res 2003;35(6):324-28. 18. Herrmann CI, Hammer T, Duncker GI. Haze formation (corneal scarring) after cross-linking therapy in keratoconus. Ophthalmologe 2007; [Epub ahead of print]
19. Mazzotta C, Balestrazzi A, Baiocchi S, Traversi C, Caporossi A. Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation. Clin Experiment Ophthalmol 2007;35(6):580-82. 20. Mazzotta C; Traversi C, Baiocchi S, Sergio P, Caporossi T, Caporossi A. Conservative treatment of keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: qualitative investigation. Eur J Ophthalmol 2006;16(4):530-35. 21. Eberwein P, Auw-Hadrich C, Bimbaum F, Maier PC, Reinhard T. Corneal melting after cross-linking and deep lamellar keratoplasty in a keratoconus patient. Klin Monatsbl Augenheilk 2008;225(1):96-98.
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CORNEAL COLLAGEN CROSS-LINKING WITH RIBOFLAVIN (C3-R) COMBINED WITH INTRASTROMAL RING SEGMENT IMPLANTATION
INTRODUCTION Since the 18th century’s first description of keratoconus,1,2 the ophthalmic community has long been searching for a method to stop the potentially devastating progression of the most common, naturally occurring, non-inflammatory ectatic corneal disorder. Generally bilateral, most often asymmetrical, keratoconus is characterized by ongoing stromal thinning and anterior bulging of both corneal surfaces, with the apex of the cone-shaped change located paracentrally and inferiorly.3-5 The resulting conicoid geometry of the corneal surface gives rise to unstable, irregular myopic astigmatism and asymmetrical high order aberrations,6 which can be adequately corrected by spectacles and soft contact lenses only in early stages. In mid-advanced phases, quality of vision and quality of life improvements have been usually considered as secondary aims, obtainable in the minority of cases, unless a corneal transplantation is performed, the last option to restore corneal architecture and improve eyesight.7-12 Until a genetic cure will be available, the only conservative weapon against mid-advanced keratoconus in the classic eye care armamentarium has been the rigid gas-permeable (RGP) contact lens (CL) wear, still the mainstay of the optical management of the disorder.13 The observation of some reshaping effect (a sort of “good” warpage) induced by hard CL wear on the surfaces of the cornea corneal molding (corneal molding) 14-17 led to the common misconception that these lenses may play a therapeutic role in arresting the evolution of the disease. Unfortunately, this statement turned out not to be true; instead, it is now clear that inadequacy of tear exchange and/or apical clearance may cause hypoxic damage and scarring of the apex of the cone, thus accelerating the way to the keratoplasty.18-23 More recently, the diffusion of reversed geometry overnight wear of CLs to temporarily correct slight myopic errors (modern orthokeratology) 24-26 added a contribution to the knowledge on the plasticity of the cornea and the remodelling effect induced by a rigid contact lens was based on a more standardized approach. Eye care providers are now aware of the high sensitivity of the keratoconic cornea to be moulded, so that even a slight rubbing may alter the corneal topography,27 thus influencing its surface regularity indices and visual performance. In virgin keratoconus eyes, overnight
corneal molding (Figure 17.1) is rarely applied because of the major inconvenience of effect’s duration that is too short for practical reason. Actually, even the nicest reshaping does not last longer than 3 hours after the CL wear is suspended, and uncorrected visual acuity rapidly falls under 20/40, considered the threshold to comfortably perform regular daily activities. A 10-year experience on intrastromal corneal ring (ICR) segments (INTACS, KeraRing, Ferrara Ring) implantation in keratoconus has shown that the surgical placement of PMMA inserts into the deep stroma of ectatic corneas is a safe procedure. It has the potential to recover a more physiological position (in front of the pupil and close to the visual axis) of the displaced apex of the cone and to reduce the values of irregular astigmatism, therefore improving both unaided and best spectacle-corrected visual acuity. Postoperatively, all the indices of topographic regularity (semimeridian profile, corneal uniformity…) improve with lower power variance and minimal change of asphericity. Better contact lens fitting and tolerance28-30 have been frequently observed (Figures 17.2A to D). For unknown reasons, yet to be studied, we anecdotally observed that the corneal surface reshaping obtained with the wear of a customized reversed geometry contact lens lasts longer (in some cases even two to three days) in keratoconic eyes already implanted with intrastromal ring segments. In the last 5 years, therefore, the combination of ICR (mainly Ferrara Ring, INTACS are utilized in less than 10% of cases) and custom designed RGP CL overnight corneal molding performed not earlier than one month after surgery has been our procedure of choice in the management of progressive keratoconus. The recent introduction of the C3-R (Corneal Collagen Cross-linking with Riboflavin) Riboflavin), a minimally invasive para-surgical technique that induces a photopolymerization of the altered stromal collagen fibers64-66 by the combined action of a photosensitising substance (riboflavin, vitamin B2) and ultraviolet A light exposure emitted at 370 nm from a suitable source (Figures 17.3A to D) has shown the ability to safely increase of at least three times the corneal rigidity by strengthening the collagen stromal structure, thus stabilizing ectatic corneal disorders31-37 and inducing a moderate improvement of corneal surface irregularity and visual acuity over time.
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Figure 17.1: The Wood light fluorescein images immediately after reverse-geometry RGP lens fitting in a stage II KC eye (a) and two hours later (b). After RGP corneal molding, tangential topography (d) and corneal aberrometry elevation map (f) show a more uniform pattern. Pre-molding tangential and corneal elevation wavefront maps are shown in c and e, respectively. A significant decrease of all high order aberrations is evident in f
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Due to the corneal sub-edema, small changes of aided and unaided visual vision were observed during early recovery. Moderate improvements started from the third month. Two and three-year data showed a significant reduction of the spherical equivalent and of the mean K-reading detected topographically (about 2.00 D), as well as a positive change of the topographic indices of corneal morphology and symmetry, with a reduction in lower order (myopic astigmatism) and higher order aberrations (coma in particular), which may explain the improvement in uncorrected and bestspectacle-corrected visual acuity. Patients often describe a better quality of vision with less ghosting, glare and starbursting around light sources at night, despite an almost unchanged corneal topography. The optical and visual performances improvement seems to be related to an increased corneal symmetry induced by a restored corneal rigidity after collagen shrinkage.56-59 The knowledge on the combination of C3-R and ICR is very limited; after C3-R, a complete apoptotic damage of keratocytes and mild inflammatory reaction
occur. Cell loss is completely repaired by keratocyte repopulation by six weeks, when cytoarchitecture of the cornea seemed back to normal;34 it is therefore considered advisable to perform ICR implantation not earlier than six months post-C3-R for safety reasons. Before these data were available, however, we implanted ten eyes six months after C3-R and twelve eyes immediately before C3-R. In all patients, we found no specific complication but a significant reduction of the expected reshaping effect of the corneal surface. Instead, C3-R application after ICR surgery (from three months to years) has shown to augment the positive effect of ICR segment surgery in all cases (Carlo Lovisolo, unpublished data). PURPOSE, METHODS AND MATERIALS To determine whether a triple procedure, i.e. the addition of C3-R to our standard approach (ICR surgery plus corneal molding) may be more effective to treat keratoconus, we performed a retrospective nonrandomized comparative case series study.
CORNEAL COLLAGEN CROSS-LINKING WITH RIBOFLAVIN (C3-R) COMBINED WITH INTRASTROMAL RING SEGMENT IMPLANTATION
Figures 17.2A to D: KeraRing (Ferrara Ring) PMMA segments (A) have 160° of arc, 5.0 mm optical zone (B) and a triangular shape (C). The tangential topography difference map (D) shows the average expected outcome (anterior surface steepens over the segment bodies, then a progressive flattening occurs) after implantation of one infratemporal Ferrara ring segment in a stage II keratoconus
The outcomes of 18 eyes (10 patients), who received KeraRing (Ferrara Ring) implantation plus overnight corneal molding with customized CLs (Group A) were compared to the results observed in 15 eyes (12 patients), who had KeraRing (Ferrara Ring) surgery combined to overnight corneal molding and a C3-R treatment (Group B). All the selected eyes had stage II or stage III keratoconus according to the Ferrara-Amsler classification,28 i.e. they showed a best-spectaclecorrected visual acuity (BSCVA) lower than 20/50, with evident distortion of the keratometric mires, mean central K-readings from 48.0 to 58.0 D, biomicroscopic signs of altered corneal profile like the Vogt’s striae and a significant thinning at the cone apex, with minimal corneal pachymetry readings higher than 400 μm and were intolerant to conventional CL wear. Phase 1: Intrastromal Ring Segment Insertion was performed as the first procedure. After corneal marking
was completed with a gentian violet inked instrument under topical anesthesia, suction was applied and a 0.9 mm long, 70% of pachymetry reading deep incision, connected to two intrastromal tunnels of 5 mm of diameter (5.4 mm and 6.4 mm of internal and external diameter, respectively) were created with the femtosecond laser (IntraLase Fs Laser, Advanced Medical Optics, Inc., Santa Ana, CA, USA). The incision was placed on the coma axis as identified by the CSO videokeratographer (Firenze, Italy) (Figures 17.4A and B). LINK TO THE VIDEO The choice of segment thickness and symmetrical or asymmetrical combination was made on the basis of the KC type and stage, the degree of coma, astigmatism and corneal irregularity, on the basis of the Lovisolo nomograms. 28 After vancomycin rinsing of the
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Figures 17.3A to D: Surgical table prepared for C3-R (A) and two phases of UV-A light irradiation under 0.1% riboflavin-5-phosphate and dextran solution application (B, C) of the VEGA CBM X-LinkerTM (CSO, Firenze, Italy) (D)
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Figures 17.4A and B: As the most effective correction occurs when the ring segments are positioned on the coma direction, a corneal aberrometry-based software is utilized to choose the site of incision, which is usually positioned on the coma axis (A), instead than on the steepest topographic meridian. In the example shown in (B), the topographic steep axis was 7°, while the coma axis was 49°. The video shows the tunnel creation by the Femtosecond laser (IntraLase, AMO)
CORNEAL COLLAGEN CROSS-LINKING WITH RIBOFLAVIN (C3-R) COMBINED WITH INTRASTROMAL RING SEGMENT IMPLANTATION
Figures 17.6A and B: Wood light fluorescein patterns of oldgeneration conventional RGP CL (A) and modern four-zone reverse-geometry lens (B)
Figures 17.5A to D: Site of incision and segment placement positions are marked (A). As an alternative to the femtolaser, the incision cut, the pocketing and the channelization may be performed manually (B,C,D) with appropriate instrumentation
channels was made, the plastic ring segments were positioned. Incision borders were gently hydrated and left sutureless in all cases. A 65% hydration, 8.7-mm base curve soft bandage contact lens was applied. Then a regimen of antibiotic-steroid combination plus an aggressive use of lubricant drops was recommended (Figures 17.5A to D). Phase 2: Overnight CL corneal molding was initiated 40 days post-ICR procedure. The molding lens induces a temporary change of the shape of the cornea, taking advantage from corneal plasticity, the epithelial layer’s one in particular. While conventional CLs are designed to cause little or no effect on the corneal shape, these lenses are designed to intentionally flatten the cornea in a controlled way, to bring the eye into correct focus to compensate for the refractive error. 25,26 While traditional CL designs have secondary and peripheral curves flatter than the central curve of the lens, the lenses utilized for corneal molding have one or more peripheral curves steeper than the optical zone’s curvature (“reverse-geometry CLs”)42-44 (Figures 17.6A and B). The radius of curvature of the back optical zone is always custom-designed to determine the shape the
cornea will assume after the molding, thus the amount of refractive error to be corrected (spherical or spherotorical). The lift of peripheral curves over the cornea around the optical zone creates a tear reservoir. In the reverse zone, joining of the optical with the alignment zone, there are one or more curves steeper than the back optical zone. The alignment zone is the bearing zone of the lens; it gives stability to the lens and keeps it centered; its curvature is flatter than the reverse zone, but steeper than the optical zone. The peripheral zone, flatter than the alignment zone, allows the lens edge to lift from the cornea, to achieve an adequate tear turnover under the lens. This tear exchange is necessary to get in new tear liquid to oxygenate the cornea, and to get out the debris and metabolic residuals formed under the lens. The controlled pressure by the edge lift minimizes the risk of corneal insults and helps the CL removal by mean of lid tension. When the lens is on the eye, the patient can see clearly, like with a conventional fitting. After the sleeping hours and CL removal when the patients wake up, the cornea retains its modified shape for a certain amount of time, and the patient continues to see well, even without the lens. This treatment is reversible and, if the patient stops wearing the lenses completely, the topographic and refractive condition of the eye will regress to the pre-treatment level.38 The overnight use has the obvious advantage of reducing the interference with the environmental factors (dust, wind, conditioned air, sports) that can give trouble during the day; in addition, the pressure of closed lids improves the rapidity of corneal molding. Since the lids are closed during overnight wear and tear circulation behind the lens is reduced by the inactivation of the blink pump, high oxygen permeable materials are necessary to provide sufficient oxygenation to the
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Figures 17.7A to C: Slit lamp Wood light ideal fluorescein patterns of a custom designed reverse-geometry lens fitted with the purpose of corneal molding in a virgin keratoconus eye (A), in an eye implanted with a superior INTACS ring segment (B). Side view of case b is shown in (C). Two videos of the latter and another case are available with the link
cornea. 39,40 The lens material (siloxy-fluoromethacrylate Dk 100, Boston XO, hexafocon-A) has shown to induce minimal edematous swelling of the stroma. Moreover, the morning lens removal allows for a rapid recovery,41 as well as proper cleansing and elimination of debris and waste products. The fitting procedure requires a perfect centration that is critical for the efficacy of the mold but not easy to obtain. The movement observed after each blink must be higher than 0.2 mm and lower than 1.0 mm, always inferior to a conventional RGP-CL fitting. The ideal fluorescein pattern shows an image with concentric rings: the dark center (minimal apical clearance, some times minimal touches) corresponds to the bulging conicoid area to be molded; the surrounding green area, a variable thickness tear reservoir (depending on the intended corrective effect, between 30 and 80 microns). A midperipheral dark ring (the alignment zone) with a minimal clearance, sometimes a slight touch and a thin green ring (the edge lift, 80 to 100 micron) follow (Figures 17.7A to C). The transition between the different zones should be blended and smooth. After the first adaptation, there should be no air bubbles, indicating an excessive lift in the tear reservoir zone. LINK TO THE VIDEO
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Dealing with safety of corneal molding, we observed some cases of grade 1 fluorescein staining of the epithelium, which disappeared in the evening, but no significant corneal infiltrates or ulcers or other adverse events. Minimal or no changes were observed in the
central thickness of the cornea, as measured with an ultrasound pachymeter (Allergan Humphrey 850, Carl Zeiss Meditec). Confocal microscopy (Confoscan 3000, NIDEK, Japan) showed no measurable changes in the endothelium, sub-basal nerve plexus or in the anterior, intermediate and deep stroma (overall density and activation of keratocytes were not modified) while the basal layer of the epithelium showed larger and less regular cells after the molding (Figure 17.8). A slight increase in reflectivity of the matrix was observed and can be explained by a mild increase of corneal glycosaminoglycans production, that is a reversible phenomenon probably due to an aspecific reaction of an already altered corneal parenchyma (mild cellular edema due to hypoxia and/or mechanical effects).45-55 To try to explain the biomechanical working mechanism (the negligible flattening observed in the central cornea was counterintuitive), we hypothesize the role of mid-peripheral forces induced by the displacement of the epithelium that results from a proper compression by the CL alignment zone. This hypothesis certainly deserves further confirmation to accurately explain the achieved regularization of both corneal surfaces. Phase 3 (for Group B only): Corneal Collagen Cross-linking with Riboflavin (C3-R) was performed after 3 months of CL corneal molding. Immediately after CL removal, 30 minutes of Ultraviolet A exposure (5.4 J/cm2 at 370 nm) with the VEGA CBM X-LinkerTM (CSO, Firenze, Italy)63 were applied to the central cornea (after a minimum diameter of 7 mm of epithelial
CORNEAL COLLAGEN CROSS-LINKING WITH RIBOFLAVIN (C3-R) COMBINED WITH INTRASTROMAL RING SEGMENT IMPLANTATION
Figure 17.8: Confocal microscopy images (Confoscan 3000, NIDEK, Japan) of different corneal layers (epithelium, anterior, mid and posterior stroma, endothelium) pre (bottom lines) and post-CL (upper lines) corneal molding
debridement). 0.1% riboflavin-5-phosphate and dextran solution (RicrolinTM, SOOFT, Montegiorgio, AP, Italy) was applied every 3 minutes. A 65% hydration, 8.7-mm base curve soft bandage contact lens was applied. Then a regimen of antibiotic-steroid combination plus an aggressive use of lubricant drops was recommended for a month. Overnight CL wear was stopped for 1 month, and then reinitiated. Outcome measurement data (uncorrected and spectacle best corrected visual acuities, refraction, videokeratographic average simulated keratometry and indices of corneal regularity, including coma aberration (CSO topographer, Firenze, Italy), corneal epithelial thickness as measured with VHF echography (Artemis 2, Ultralink, St. Petersburg, FLA, USA) were collected at baseline and at the overall 6-month gate. RESULTS Since there is a potential for further change overtime, as it has been showed to occur after C3-R alone, the reported results must be considered preliminary. Both groups showed statistically significant improvement of all parameters. The mean outcome of group B (intrastromal corneal ring segments + CL molding with C3-R) had a significantly greater reduction in cylinder and sim-K and improvement of the corneal surface regularity indices than group A
(intrastromal corneal ring segments + CL molding without C3-R) (Table 17.1). UCVA and BSCVA significantly improved in both groups. In Group A, all eyes showed reversibility to the pre-molding conditions (both functional and morphological) after CL wear suspension; in Group B, however, 9 eyes (60%) did not return to visual acuity baseline levels, although similar topographic regression was observed. In this phase of knowledge, this phenomenon is unexplainable. A possible factor might be due to the remodelling of the epithelium that thins over the top of the regions corresponding to the segments and thickens in the flattest zones (Figures 17.9A to D).67 Two anecdotal examples of outcome after the triple procedure (group B) are showed in Figures 17.11 and 17.12. Table 17.1: Summary of postoperative change (at 6 month gate)
Change in values UCVA (log MAR)
ICR+C3-R+CLM
ICR+C3-R
P value
0.89 ± 0.72
0.79 ± 0.62
0.5
BSCVA (log MAR)
0.31 ± 0.28
0.29 ± 0.27
0.6
Sphere
3.33 ± 2.61
2.26 ± 2.44
0.07*
Cylinder
2.70 ± 1.18
1.44 ± 1.87
0.02*
Av. Sim-K
3.33 ± 2.01
1.89 ± 1.97
0.03*
Lower-Upper 18.69 ± 13.17 Ratio (Fig. 17.10)
8.61 ± 11.21
0.03*
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Figures 17.9A to D: Very high frequency echography (Artemis 2, Ultralink) images (A,B) and epithelial thickness map (C) of a keratoconic cornea implanted with a single 5.0-mm, 250 µm Ferrara Ring segment in the lower cornea (D) show the compensating behaviur of the epithelium. The thickest points of the epithelium are closer to the ring area, where the corneal surface shows the maximum flattening effect; the thinnest points are above the segments, where maximum steepening is obtained by the implants’ physical presence. After C3-R, this compensating factor is enhanced
Figures 17.10A and B: In keratoconus, lower/upper ratio (the dividing dotted line is put on the steep meridian, as shown in b, instead than on the horizontal axis, as shown in a) seems a more sensitive index than the conventional inferior/superior ratio
Figures 17.11A to D: Videokeratographies of stage II KC preoperatively (A), 3 years after intrastromal corneal ring segment surgery; UCVA was 20/100, BSCVA: 20/25- with -4.00 sph -3.75 cyl (B). 3 months after CL molding on ICR, 48 hours after CL removal, UCVA was 20/20 (C); 30 days after C3-R and CL removal. UCVA was 20/80; BSCVA was 20/25 with -1.75 sph -2.00 cyl (D)
Figures 17.12A to D: Videokeratographies of stage II KC preoperatively (A), 1 year after intrastromal corneal ring segment surgery; UCVA was 20/200, BSCVA: 20/40 with -6.00 sph -2.25 cyl (B). 6 months after CL molding on ICR, 24 hours after CL removal, UCVA was 20/25 (C); 50 days after C3-R and CL removal. UCVA was 20/80; BSCVA was 20/30 with -3.00 sph -1.25 cyl (D)
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DISCUSSION AND CONCLUSION Keratoconus is the most frequent reason for corneal transplantation surgery in the western world. It usually affects young patients, generally leading to significant visual handicap. According to the literature, its incidence is continuously growing, up to 1 out of a thousand, thanks to the recent diagnostic advancements (corneal topography in particular). Despite the longstanding interest of the ophthalmic community and the involvement of international organizations in education and clinical research, the exact etiopathology of keratoconus remains obscure,60,61 as well as its prognosis and cure. Examples of inheritance coupled with a higher incidence in closed ethnic communities provide circumstantial evidence that both genetic and environmental factors may be involved. However, neither inheritance mechanisms nor transmission patterns have been elucidated and keratoconus appearance is sporadic in most situations, leaving no pharmacologic or genetic way to prevent its evolution to advanced stages. Evolution is unpredictable. Some patients experience a slow progression for years; others record a rapid escalation in 6-12 months, followed by a process of stabilization with very small changes for the rest of their life. Some are diagnosed only late in life, i.e. after the age of 40, when the condition seldom worsens. About 20% of patients are destined to surgery, mostly penetrating keratoplasty (PKP)62, although the cornea does not show significant opacities (apical scarring) in the vast majority of cases. In our opinion, the decision to entirely replace a transparent cornea in a young patient, as is the case for the average keratoconus patient, must be made carefully. Among the decisive factors, the degree of achievable visual performance and the patient’s life-style play a central role. For some people, a BCVA of 20/30 may be insufficient, though it is judged satisfactory by most patients. The chance of being successful with PKP is high (grafts achieve good results in about 95% of cases, the percentage ranging from 85 to 99% in literature). However, the risk of sight-threatening postoperative complications (from 1 to 10 cases out of 100) must be considered. Functional recovery following corneal transplantation is usually long, often lasting more than one year. The sutures are generally removed at 18 months and the patient might be compelled to use steroids for months. During
this period there is a risk of microbial keratitis and traumatic wound dehiscence. Initially the donor cornea is swollen and often, during the healing process, it remains thicker than the remaining host tissue. Most of patients are between 20 and 35 years of age with a long life expectancy. Considering that Optisolpreserved and cultured donor corneas lose on average 50% of endothelial cells in the first year and graft cell loss continues overtime, a 20-year-old patient will face a limited duration of the graft vitality. The peripheral ring of the recipient cornea remains at all times a potential source of recurrence, as statistical data show a general trend towards an increase in astigmatism overtime. Immunologically-mediated graft rejection, endothelial failure and high post-PKP ammetropia are not uncommon. Even in uneventful surgeries, with timely suture removal or adjustment, it is common for the edge of the graft to be a little raised or tilted in comparison with the surrounding tissue. For this reason, the graft is usually steeper than the host cornea, inducing various degrees of myopia and regular or irregular astigmatism. Only about 40% of eyes have less than three diopters of astigmatism. At least 25% of cases show more than 5.00 diopters of astigmatism and around 30% have cylinder between 3.00 and 5.00 D. This percentage increases over time - at ten years of follow-up, more than 30% of patients show more than 5 diopters, more than 40% have between 3.00 and 5.00 D. In fact, about 60% of transplant recipients require RGP contact lens wear or additional surgeries like LASIK, PRK-PTK, relaxing or wedge incisions to correct post-PKP refractive error. If a contact lens is needed, it may take up to one year to fit the lens, considering that it is better to wait until the sutures are removed. Also, the prescription may vary for several months after surgery. It is our feeling that a well informed patient is generally reluctant to undergo PKP, while surgeons should consider it as the last resort. Both should be very interested in more conservative alternatives, capable of delaying the need for a graft. Among the different options available, the combination of intrastromal corneal ring segment implantation plus overnight contact lens corneal moulding has demonstrated excellent safety and efficacy rates. Corneal collagen cross-linking with riboflavin may be associated (the “triple procedure”) to further enhance
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and stabilize the postoperative improvements of visual performances. REFERENCES
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1. Rebus Sci Nat Med 1752;1(part 3):531-38. 2. Scarpa A. Trattato delle Principali Malattie degli Occhi. Napoli: Tipografia Palma, 1825. 3. Amsler M. Keratocone Classique et Keratocone Fruste. Arguments Unitaires Ophthalmologica 1946;111:96-101. 4. Lovisolo CF, Fleming JF, Pesando PM. Intrastromal Corneal Ring Segments Chapter 6 2002. Fabiano Ed. Canelli (AT) Italy. 5. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol 1984;28:293-322. 6. Abugova TD, Shapiro ESh, Korniushina TA, et al. Optical aberrations of the eye in keratoconus Vestn Oftalmol. 1985;101:36-9. 7. Belin MW, Fowler WC, Chambers WA. Keratoconus. evaluation of recent trends in the surgical and nonsurgical correction of keratoconus. Ophthalmology 1988;95:3359. 8. Crews MJ, Driebe WT, Jr, Stern GA. The Clinical management of keratoconus: a 6 year retrospective study. Clao J 1994;20:194-97. 9. Lass JH, Lembach RG, Park SB, et al. Clinical management of keratoconus. A multicenter analysis. Ophthalmology 1990;97:433-45. 10. Lawless M, Coster DJ, Phillips AJ, et al. Keratoconus: diagnosis and management. Aust and NZ J Ophth 1989; 17:33-60. 11. Mandell R. Contemporary management of keratoconus. ICLC 1997;24:43-58. 12. Smiddy WE, Hamburg TR, Kracher GP, et al. Keratoconus: Contact lens or keratoplasty? Ophthalmology 1988; 95:487-92. 13. McMonnies CW. The biomechanics of keratoconus and rigid contact lenses. Eye Contact Lens 2005;31:80-92. 14. Klyce SD, Ochsner RD. Method for quantitative evaluation of corneal shape changes by contact lens molding Curr Eye Res 1985;4:727-29. 15. Andreassen TT, Simonsen AH, Oxlund H. Biomechanical properties of keratoconus and normal corneas. Exp Eye Res Oct 1980;31:435-41. 16. Briceno-Garbi EA. Variations in corneal curvature and refractive error in CAB gas-permeable contact lens wearers. J Am Optom Assoc 1984;55. 17. Iskeleli G, Oral AY, Celikkol L. Changes in corneal radius and thickness in response to extended wear of rigid gas permeable contact lens. Clao J 1996;22:133-35. 18. Brightbill F, Stainer G. Previous hard contact lens wear in keratoconus. Cont Int Lens Med J 1979;5:43-47. 19. Gasset AR, Houde WL, Garua-Berngochea M. Hard contact lens wear as an environmental risk in keratoconus. Am J Ophthalmol 1978;85:339-41.
20. Hartstein J. Keratoconus that developed in patients wearing corneal contact lenses-report of four cases. Arch Ophthalmol 1968; 80:345-46. 21. Korb DR, Finnemore VM, Herman JP. Apical changes and scarring in keratoconus as related to contact lens fitting techniques. J Am Optom Assoc 1982;53:199-205. 22. Macsai MS, Varley GA, Krachmer JH. Development of keratoconus after contact lens wear. Arch Ophthalmol 1990;108:534-38. 23. Tufts SJ, Moodaley LC, Gregory WM, et al. Prognostic factors for the progression of keratoconus. Ophthalmology 1994;101:439-47. 24. Swarbrick HA. Orthokeratology (corneal refractive therapy): what is it and how does it work? Eye Contact Lens 2004;30:181-85. 25. Matsubara M, Kamei Y, Takeda S, et al: Histologic and histochemical changes in rabbit cornea produced by an orthokeratology lens. Eye Contact Lens 2004;30:198-206. 26. Choo J, Caroline P, Harlin D. How does the cornea change under corneal reshaping contact lenses? Eye Contact Lens 2004;30:211-3;218. 27. Mansour AM, Haddad RS. Corneal topography after ocular rubbing cornea 2002;21:756-58. 28. Lovisolo CF, Fleming JF, Pesando PM. Intrastromal corneal ring segments 2002. Fabiano Ed. Canelli (AT) Italy. 29. Lovisolo CF, Fleming JF. Intracorneal ring segments for iatrogenic keratectasia after laser in situ keratomileusis or photorefractive keratectomy. J Refract Surg 2002;18:53541. 30. Siganos D, Ferrara P, Chatzinikolas K, et al. Ferrara intrastromal corneal rings for the correction of keratoconus J Cataract Refract Surg 2002;28:1947-51. 31. Cannon DJ, Foster CSl. Collagen Cross-linking in Keratoconus. Invest Ophthalmol Vis Sci 1978;17:63-65. 32. Wollensak G. Cross-linking treatment of progressive keratoconus: New Hope. Curr Opin Ophthalmol 2006;17:356-60. 33. Raiskup-Wolf F, Hoyer A, Spoerl E, et al. Collagen crosslinking with riboflavin and ultraviolet—A light in keratoconus: long-term results. J Cataract Refract Surg 2008;34:796-801. 34. Spoerl E, Mrochen M, Sliney D, et al. Safety of UVAriboflavin cross-linking of the cornea. Cornea 2007;26:385-89. 35. Wollensak G, Iomdina E, Dittert DD, et al. Wound healing in the rabbit cornea after corneal collagen cross-linking with riboflavin and UVA. Cornea 2007;26:600-5. 36. Mazzotta C, Balestrazzi A, Traversi C, et al. Treatment of progressive keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: ultrastructural analysis by Heidelberg Retinal Tomograph II in vivo confocal microscopy in humans. Cornea 2007;26:390-97. 37. Spoerl E, Seiler T. Techniques for Stiffening the Cornea. J Refract Surg 1999;15:711-13. 38. Soni PS, Nguyen TT, Bonanno JA. Overnight orthokeratology: refractive and corneal recovery after discontinuation of reverse-geometry lenses. Eye Contact Lens 2004;30:254-62; discussion 263-4.
CORNEAL COLLAGEN CROSS-LINKING WITH RIBOFLAVIN (C3-R) COMBINED WITH INTRASTROMAL RING SEGMENT IMPLANTATION 39. Holden B, Mertz G. Critical oxygen level to avoid corneal edema for daily and extended wear contact lenses. Invest Ophthalmol 1984:63. 40. Swabrick H, Holden B. Extended wear lenses. In: Phillips A, Speedwell L, editors. Contact Lenses: ButterworthHeinemann 1997:494-6. 41. Holden B, Sweeny D, La Hood D, et al. Corneal deswelling following overnight wear of rigid and hydrogel contact lenses. Current Eye Res 1988;7:49-53. 42. Wlodyga R, Bryla C. Corneal molding: the easy way. Contact Lens Spectrum 1989;4:58-62. 43. Calossi A. Metodo di personalizzazione di una lente per il trattamento della miopia. IT Patent BO2002A000595, 2002. 44. Calossi A. A new customized esa-curve reverse geometry lens design for overnight orthokeratology. Paper presented at the 33’ European Contact Lens Society of Ophthalmologists Congress Venezia (Italy) 2003. 45. Brown D, Chwa MM, Opbroek A, et al. Keratoconus corneas: Increased gelatinolytic activity appears after modification of inhibitors. Curr Eye Res 1993;12:571-81. 46. Bureau J, Fabre EJ, Hecquet C, et al. Modification of prostaglandin E2 and collagen synthesis in keratoconus fibroblasts, Associated with an increase of interleukin 1 Alpha Receptor Number. Comptes Rendus de I’Academie des Sciences 1993; 316:425-30. 47. Critchfield JW, Calandra AJ, Nesburn AB, et al. Keratoconus: I Biochemical Studies. Exp Eye Res 1988;46:953-63. 48. Fabre EJ, Bureau J, Pouliquen Y, et al. Binding Sites for Human Interleukin 1 Alpha, Gamma Interferon and Tumor Necrosis Factor on Cultured Fibroblasts of Normal Cornea and Keratoconus. Curr Eye Res 1991;10:585-92. 49. Halainen A, Salo T, Forsius H, et al. Increase in Type I and Type IV Collagenolytic Activity in Primary Cultures of Keratoconus Cornea. Eur J Clin Invest 1986;16:78-84. 50. Kao WW, Vergnes JP, Ebert J, et al. Increased Collagenase and Gelatinase Activities in Keratoconus. Biochem Biophys Res Commun 1982; 107:929-36. 51. Kenney MC, Burgeson RE, Butkowski RJ, et al. Abnormalities of the Extracellular Matrix in Keratoconus corneas. Cornea 1997;16:345-51.
52. Oxlund H, Simonsen AH. Biochemical Studies of Normal and Keratoconus Corneas. Acta Ophthalmol 1985; 63:666-69. 53. Radner W, Zehetmayer M, Skorpik C, et al. Altered Organization of Collagen in the Apex of Keratoconus Corneas. Ophthalmic Res 1998;30:327-32. 54. Rehany U, Lahav M, Shoshan S. Collagenolytic activity in keratoconus. Ann Ophthalmol 1982;14:751-54. 55. Tsuchiya S, Tanaka M, Konomi H, et al. Distribution of Specific Collagen Types and Fibronectin in Normal and Keratoconus Corneas. Jpn J Ophthalmol 1986;30:14-31. 56. Edmund C. Corneal elasticity and ocular rigidity in normal and keratoconic eyes. Acta Ophthalmol 1988;66:13440. 57. Foster CS, Yamamoto GK. Rigidity in Keratoconus. Am J Ophthalmol 1978;86:802-6. 58. Edmund C. Assessment of an elastic model in the pathogenesis of keratoconus. Acta Ophthalmol 1987;65:545-50. 59. Wang H, Prendiville PL, McDonnell PJ, et al. An ultrasonic technique for the measurement of the elastic moduli of human cornea. J Biomech. 1996;29:1633-36. 60. Hall KGC. A Comprehensive Study of Keratoconus. Brit J Physio Opt 1963;20:215-56. 61. Karseras AG, Ruben M. Aetiology of Keratoconus. Brit J Ophth 1976;60:522-25. 62. Paglen PG, Fine M, Abbott RL, et al. The Prognosis for Keratoplasty in keratoconus. Ophthalmology 1982;89:651-54. 63. Lembares A, Hu XH, Kalmus GW. Absorption Spectra of Corneas in the Far Ultraviolet Region. Invest Ophthalmol Vis Sci 1997;38:1283-87. 64. Kaas-Hansen M. The Histopathological Changes of Keratoconus. Acta Ophthalmol 1993;71:411-14. 65. Teng CC. Electron Microscopy Study of the Pathology of Keratoconus. Part I. Am J Ophthalmol 1963;55:18-47. 66. Pataa C, Joyon L, Roucher Fl. Ultrastructure of Keratoconus. Arch Ophtalmol Rev Gen Ophtalmol 1970;30:403-17. 67. Reinstein DZ, Silverman RH, Coleman DJ. High-frequency ultrasound measurement of the thickness of the Corneal epithelium. Refract Corneal Surg 1993;9:385-87.
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INTACS EFFECT ON KERATOCONIC EYES Keratoconus is a corneal ectatic disease that is characterized by non-inflammatory progressive thinning of the paracentral and/or inferior corneal stroma. It is with progressive deformation of the cornea, in the form of irregular astigmatism, which may lead to a significant decrease in visual acuity. Although keratoconus is almost always bilateral, asymmetry between eyes is frequently observed.1,2 Intracorneal ring segments (ICRS), which was first proposed by Fleming and Reynolds3 for the correction of low degrees of myopia, have been recently investigated to correct ectatic corneal diseases. The effect of intracorneal ring segments on the soft corneal keratoconic tissue is much greater than that on normal corneas in case of myopia. The aim from implanting ICRS is not to treat or eliminate the existing disease or should not be considered as a traditional refractive surgical procedure. However, ICRS is a surgical alternative aiming to decrease the astigmatism and corneal abnormality, and thus to increase the visual acuity to acceptable limits as a way to at least delay the need of corneal grafting.4,5 According to the postulates of Barraquer and Blavatskaya, intracorneal ring acts as tissue addition leading to a flattening in the cornea periphery. The diameter of the ring is proportionally inverse to the flattening intensity thus, the smaller the diameter, the more tissue added (ring thickness) with the higher myopic correction.6 In 1987, intrastromal rings introduced as synthetic intracorneal implants for the correction of various degrees of myopia. An elastic modulus, or modulus of elasticity, is the mathematical description of an object or substance’s tendency to be deformed elastically (i.e. nonpermanently) when a force is applied to it. In keratoconus, the corneal elastic modulus is reduced due to pathology in the corneal stroma.7,8 From a biomechanical perspective, the resistance to deformation is reduced in relation with the reduction of the elastic modulus that leads to increased strain and protrusion in the cornea. The consequence is increased curvature and corneal thinning, the hallmarks of keratoconus. Since stress is defined as applied force divided by cross-sectional area, stress focally increases in the zone of corneal thinning
Figure 18.1: A uniform corneal thickness (TOP) produces a uniform stress distribution. A nonuniform corneal thickness (BOTTOM) produces a stress concentration in the thinnest region
(Figure 18.1). 9 The placement of intracorneal ring segments generates both an immediate response that interrupts the biomechanical disease progression in keratoconus, and a time-dependent biomechanical response that allows subsequent improvement of vision over 6 months.10 The immediate response governed by the elastic properties and the long-term response is by viscoelastic properties.9 Intracorneal ring placement results in a reduction of astigmatism and improved visual acuity.5,10 This is accomplished by shortening the path length of the portion of the collagen lamellae which are central to the segments. Redistribution of corneal curvature leads to a redistribution of corneal stress, interrupting the biomechanical cycle of keratoconus disease progression and in some cases (Figure 18.2).9 CROSS-LINKING EFFECT IN EYES WITH INTACS The structural properties of collagen framework in the corneal stroma determine the biomechanical and optical properties of tissue. Optimal corneal optics requires a smooth, regular surface with a healthy tear film and epithelium. The regular arrangement of stromal cells and macromolecules is necessary for a clear vision. The lattice arrangement of collagen fibrils embedded in the
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Figure 18.2: The red biomechanical cycle reflects disease progression in keratoconus. The blue biomechanical cycle reflects the impact of INTACS placement. Once the segments are inserted, the curvature is decreased centrally, including the region of the cone. As curvature is decreased in this region, the stress is redistributed, and the decompensatory biomechanical cycle of keratoconus is broken
112
extracellular matrix acts as a diffraction grating to reduce light scattering by means of destructive interference. Scattering is greater anteriorly, resulting in a higher refractive index that decreases from 1.401 at the epithelium to 1.380 in the stroma and 1.373 posteriorly. In normal collagen regulation we can see clear, because size of lattice elements is smaller than the wavelength of the visible light.11 In keratoconic corneas include loss of arangement of fibrils in the anterior stroma, decrease in the number of collagen lamellae, separation of collagen bundles.12,13 For the first time, a new treatment based on collagen crosslinking (CXL) has been introduced by Wollensak. 14,15 This new treatment is aimed at the pathogenic cause of keratoconus and changes intrinsic biomechanical properties of corneal collagen. This treatment creates additional chemical bonds inside the corneal stroma by means of a photopolymerization in the anterior stroma while minimizing exposure to the surrounding structures of the eye.16 CXL is a widespread method in the polymer industry to harden materials and also in bioengineering to stabilize tissue. For example, chemical CXL with glutaraldehyde is used in the preparation of prosthetic heart valves and physical CXL by UVA is often used in dentistry to harden filling materials. 15,17 Tissue
specimens are preserved and hardened by glutaraldehyde or formaldehyde in pathology using same method. The photosensitizer is excited into its triplet state generating so-called reactive oxygen species (ROS) being mainly singlet oxygen and to a much lesser degree superoxide anion radicals using UVA at 370 nm and the photosensitizer riboflavin. The reactive oxygen species can react further with various molecules inducing chemical covalent bonds bridging amino groups of collagen fibrils (type II photochemical reaction). The wavelength of 370 nm was chosen because of an absorption peak of riboflavin at this wavelength.18 A significant challenge in drug delivery is the local administration of drugs to the eye.19,20 To be effective, most drugs must penetrate across the eye’s tissue barriers (e.g. cornea, sclera and conjunctiva) to reach therapeutic targets within the globe. Often, these tissues present the rate limiting step to effective delivery. Thus, the ability to predict rates of drug transport across ocular tissues would be a powerful tool in the development of new drugs and drug delivery strategies.20 Epithelium and Cornea Permeability A number of centers around the world are now performing CXL treatment with removal of epithelium as first described by the authors. The cornea contains three primary layers, which are stacked sequentially from the outer to inner surface: epithelium, stroma, and endothelium. In the human eye, the epithelium contains 5-7 layers of cells each connected by tight junctions, which is expected to provide a large barrier to anything but small lipophilic compounds. In normal eyes, the stroma is a thick fibrous, largely acellular tissue composed mostly of water, which should not provide a lipophilic barrier. Finally, the endothelium is a monolayer of cells with large intercellular junctions, which should present a leaky lipophilic barrier. The resistance to transport across the whole cornea can be thought of as a sum of resistances to transport across each of the individual corneal layers, where the resistance to transport (R) is the inverse of permeability (P): R cornea: R epithelium + R stroma + R endothelium Using this “sum of resistances” approaches allows us to determine which layers of the cornea provide
TRANSEPITHELIAL CROSS-LINKING TREATMENT IN EYES WITH INTACS
rate-limiting barriers by comparing the permeability of full cornea to the permeability of cornea with one or more of its layers removed. For example, if the permeability of full cornea was found to be smaller than that of de-epithelialized cornea, it would suggest that the epithelium presents a significant barrier to transport. In contrast, if the permeability of full cornea was found to be equal to that the epithelium does not present a significant barrier to transport. When the stromal layer of cornea isolated, its permeability shows no apparent dependence on molecular radius as expected for its anatomical structure. Because whole cornea and corneal stroma have such different permeability properties, it at first appears that the stroma is not a rate-limiting barrier within the cornea. Permeability of just the endothelial layer of cornea displays a strong dependence on both distribution coefficient and molecular size. This indicates that both the lipophilic pathway across cells and the hydrophilic pathway between cells are important. To determine if endothelium is a rate-limiting step for transport across the full cornea, the permeability of endothelium can be compared to that of the cornea. For molecules with same distribution coefficient, endothelial permeability is generally larger than that of cornea, which indicates that the endothelium is more permeable and, thus, not a rate-limiting barrier. Neither stroma nor endothelium is uniquely rate-limiting but each can play a role in limiting transport of small, lipophilic compounds. By process of elimination, this leaves the epithelium as the dominant barrier in the cornea. Almost no permeability data exist in the literature for corneal epithelium alone. If we accept that epithelium dominates cornea’s barrier properties, it still remains unclear which of the other layers (stroma, endothelium) is the second most important barrier.20 Non-removal of epithelium has considerable benefits in terms of postoperative pain and more rapid healing. Some complications have been reported in the literature after CXL treatment with removal epithelium such as herpetic keratitis with iritis. 21 Chemically epithelial distriubtion can be created instead of removal of epithelium. Figures 18.3 and 18.4 show confocal biomicroscopic views of normal epithelium and change after 20% alcohol application. In Figure 18.4, there is no intact epithelial membrane and we are expecting no tight junctions. The intact
Figure 18.3: Confocal microscopic view of normal epithelium (Courtesy of Kaufman H)
Figure 18.4: Corneal epithelium after 20% alcohol application for 25 sec (Courtesy of Kaufman H)
epithelium is a barrier that slows the absorption of riboflavin (molecular weight 376,37 g/mol) into the cornea so it penetrates slowly and incompletely. For that reason chemically disturbed epithelium (20% alcohol) or debrided epithelium removes diffusion barrier for riboflavin molecule and speeds saturation of the corneal stromal tissue.20,22 An important point to remember is that while riboflavin reduces UV penetration by absorbing it, the absorption then results in the very reaction which causes cytotoxic reaction. Infact the presence of riboflavin makes the cornea 10 times more UV sensitive. It would be ideal if the riboflavin penetration could be limited to the first 300 micron of the cornea as this would limit the photochemical reaction to this level and thus ensure protection of the endothelium.23
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
Our experience showed us only alcohol application without epithelium removal, prove riboflavin penetration more. Under sterile conditions 20% alcohol is applied for 25 seconds similar with LASEK procedure. Initially 0.5% proparacaine and 2% pilocarpine eyedrops are administered every 2 minutes and 5 minutes, respectively for 30 minutes; for anesthesia, miosis in order to minimize exposure of the lens and decrease photosensitivity. Then, riboflavin drops (0.1% riboflavin-5-phosphate and 20% dextran) are administered every 3 minutes, for 30 minutes. Penetration of riboflavin to the corneal stroma and anterior chamber was confirmed by slit-lamp examination. Then, collagen CXL procedure is performed by exposing the central 7.0 mm cornea to UV-A light (3.0 mW/cm2, at 370 nm), for 30 minutes, This is combined with continued topical application of riboflavin solution (0.1% riboflavin-5-phosphate and dextran) every 3 minutes, without removal of epithelium (Figures 18.5A and B); similar to the technique described by Chan et al.24 Intact epithelium led to less patient discomfort after procedure. After treatment, artificial tears are used for a few days. In this study25 twenty-five eyes of 17 patients had INTACS implantation and then underwent collagen CXL between June 2007 and December 2007. Initial and follow-up examinations, surgical procedures were performed. Collagen CXL was performed 3,98 ± 5,7
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Figures 18.5A and B: Pretreatment pentacam view (3A), after riboflavin installation (3B)
months after the INTACS implantation. The inclusion criteria were bilateral keratoconus without corneal scarring, contact lens intolerance, corneal thickness greater than 400 µm and endothelial cell count more than 3000/mm2. All patients were examined initially, 3 months after INTACS implantation, and 2 months after collagen CXL for uncorrected and best corrected visual acuity (UCVA and BCVA) using Standard Snellen chart. Corneal topography was performed using Pentacam (Oculus Opticgerate GMBH). We retrospectively obtained the data from before INTACS implantation, after INTACS just prior to crosslinking (1st visit; mean time interval: 3,98 ± 5,7 months) and at 2 months after cross-linking (2nd visit; mean time interval : 2,67 ± 2,67 months). Results were compared from before INTACS to after INTACS and from after INTACS/before cross-linking to after crosslinking. Surgical Technique INTACS were inserted to 70% depth of cornea in all eyes using Intralase (Intralase Corporation, Irvine CA). Peripheral pachymetry was performed in all cases to ensure sufficient corneal thickness and placement of INTACS to the appropriate depth. The pulse duration was 600 femtoseconds, with the inner to outer diameter of the INTACS tunnel set from 6.7mm to 8.2 mm. Spot size was 1 micron and the energy was 6 microjoules. INTACS segments were implanted inferiorly and superiorly based on patients’ preoperative spherical equivalent and the location of the cone. A thicker segment was placed inferiorly, and a thinner segment was placed superiorly to preferentially flatten the inferior cornea in eyes with asymmetric cone. All eyes underwent CXL procedure 3,98 ± 5,7 months after INTACS insertion (supplies obtained from Peschke Meditrade GmbH). Initially 0.5% proparacaine and 2% pilocarpine eye drops were administered every 2 minutes and 5 minutes, respectively for 30 minutes; for anesthesia, miosis in order to minimize exposure of the lens and decrease photosensitivity. Then, riboflavin drops (0.1% riboflavin-5-phosphate and 20% dextran) were administered every 3 minutes, for 30 minutes. Penetration of riboflavin to the corneal stroma and anterior chamber was confirmed by slit-lamp examination. Then, collagen CXL procedure was performed by exposing the central 7.0 mm cornea to UV-A light (3.0 mW/cm2, at 370 nm), for 30 minutes,
TRANSEPITHELIAL CROSS-LINKING TREATMENT IN EYES WITH INTACS
This was combined with continued topical application of riboflavin solution (0.1% riboflavin-5-phosphate and dextran) every 3 minutes, without removal of epithelium; similar to the technique described by Chan et al.24 Intact epithelium led to less patient discomfort after procedure. After treatment, artificial tears were used for a few days. Statistical Analysis Preoperative data were compared with data obtained 3,98 months after INTACS implantation and the latter was compared with data obtained 2,67 months after CXL. Paired sample T test was used to compare the parameters (UCVA, BCVA, spherical and cylinder values, steepest K value, mean-K value). RESULTS The mean-age of the patients was 25,14 ± 7,11 (range:16-39). Preoperative mean UCVA and BCVA were 1.61 ±1.23 (range: 0,1-4) and 4.18 ±2.09 (range:0,2-8) snellen lines respectively. Mean preoperative K values, spherical and cylindrical values were 49.9D ± 4.59 D (range: 40-58 D) ; -3.89 ±4.89 D (range: -12- 0) and -3.74 ± 1.90 D (range: -8- (-1)), respectively. After INTACS treatment, mean UCVA and BCVA were 3,58 ± 2,29 D (range: 0,5-10) and 6,54 ±2.02 D (range:2-10) respectively. Mean preoperative K values, spherical and cylindrical values were 47.60 D ± 3.68
D (range: 39,4 - 54,8 D) ; -1,90 ± 2,87 D (range: -3(-6)) and -3.52 ± 1.65 D (range: -1- (-8)), respectively. After cross-linking, mean UCVA and BCVA were 4.80 ± 2.00 D (range: 1-10); 7.27 ± 2.02 D (range:3-10) respectively and mean K, spherical and cylindrical values were 47.46 ± 3.54 D (range:40-54), 1,68 ± 2.18 D (range:-5-(2)) and -3.11 ±2.32 D (range: -6 – (3)), respectively. The preoperative, post-operative 1st visit (3,98 months after INTACS implantation) and post-operative 2nd visit (2,67 months after collagen CXL) parameters are shown in Table 18.1. The mean follow-up was 3.98 months after INTACS and 2.67 months after CXL. INTACS treatment was significantly effective on each parameter except the cylinder values. There was improvement in UCVA, BCVA, manifest refraction, steepest K value, mean-K values after CXL treatment; however it reached significance only for UCVA, BCVA and spherical values (p<0.05). The mean changes in visual acuity, manifest refraction, and keratometry from before INTACS to ≅ 4 months after INTACS summarized in Table 18.2. The post-INTACS values served as the baseline for the CXL to ≅ 2 months after CXL are also presented INTACS alone resulted in an ≅ 2-line improvement in UCVA and BCVA. After CXL, an additional line of UCVA and BCVA was gained. The gain in BCVA was significant; whereas, the gain in UCVA was not. INTACS alone resulted in decrease in myopia with a 2 D decrease in sphere and nearly 0,5 D decrease in cylinder. CXL
Table 18.1: INTACS compared to CCL/INTACS
Parameter
Preoperative (Mean±SD)
Post-INTACS (1st visit)† (Mean±SD)
P*
Post-INTACS/ CCL(2nd visit)† (Mean±SD)
P**
UCVA (Snellen)
1.61±1.23
3.58±2.29
0.05>
4.80±2.0
0.05>
BCVA(Snellen)
4.18±2.09
6.54±2.02
0.05>
7.27±2.02
0.05>
Spherical refraction (D)
-3.89±4.89
-1.90±2.87
0.05>
-1.68±2.18
0.05>
Cylindrical refraction (D)
-3.74±1.90
-3.52±1.65
0.05<
-3.11±2.32
0.05<
Mean keratometry (D) Steepest Keratometry (D)
49.9±4.59 51.58±4.69
47.6±3.68 49.93±4.13
0.05> 0.05>
47.46±3.54 49.53±3.71
0.05< 0.05<
† Data obtained 3 months after INTACS implantation ‡ Data obtained 2 months after collagen cross-linking * Paired samples t-test of comparison between preoperative data and 1st visit ** Paired samples t-test of comparison between 1st visit data and 2nd visit data UCVA: Uncorrected visual acuity BCVA: Best corrected visual acuity
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES Table 18.2: Change in parameters after INTACS implantation and after CCL
Parameter
Change Between PostINTACS†- PreINTACS (Mean±SD)
Change Between PostCCL‡- PostINTACS† (Mean±SD)
P*
UCVA (Snellen)
1.90±2.04
1.22±0.84
>0.05
BCVA(Snellen)
2.02±1.53
0.77±1.60
<0.05
Spherical refraction (D)
2.08±3.96
0.50±0.98
>0.05
Cylindrical refraction (D)
0.48±0.95
0.15±1.48
>0.05
Mean keratometry (D)
-2.22±2.33
-0.35±1.12
<0.05
Steepest Keratometry (D)
-1.28±2.49
-0.76±1.26
>0.05
† Data obtained 3 months after INTACS implantation ‡ Data obtained 2 months after collagen cross-linking * Paired samples t-test of comparison between change in parameters UCVA: Uncorrected visual acuity BCVA: Best corrected visual acuity
resulted in another 0,50 D improvement in sphere and only a small (0,15 D) decrease in cylinder. Neither of these changes were significant. INTACS alone achieved a mean 2,22 D flattening of mean K values and -1,28 D flattening of the K steep values. Additional flattening of the keratometric values was observed after CXL, with mean K values decreasing significantly by an average of 0,35 D and K steep decreasing by 0,76 D (Figs 18.6 to 18.8). CONCLUSION
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There are many reports in keratoconus treatment using INTACS (6-9,23-26). We reported , the mean UCVA and BCVA increased significantly to 3.29 ± 2.64 (Snellen lines) and 6.02 ± 2.70 (Snellen lines) respectively after INTACS implantation. In this study, the mean K reading was 51.56 ± 5.22 D at the preoperative examination. At 1-year after implantation, the mean keratometry reading had decreased to 47.66 ± 4.30 D.26 The first clinical study on the CXL treatment of keratoconus was performed by Wollensak.14 This new treatment is aimed at the pathogenic cause of keratoconus and changes intrinsic properties of corneal collagen. In this 3-year study, 22 patients with progressive keratoconus were treated with riboflavin and UVA. CXL had a favorable effect on all treated eyes. In 16 eyes (72%) , there was also a slight reversal and flattening of keratoconus by two diopters. Best corrected visual acuity improved slightly in 15 eyes
(68%). According to the results of CXL treatment, regression of the disease was achieved in 70% of eyes, with a reduction of the maximal keratometry readings by 2.01 D and of the refractive error by 1.14 D.14 In our study, UCVA improved by 1.2 lines and mean K value decreased by 0.35 D, 2 months after CXL treatment. Caporossi et al, 27 showed a mean K reduction of 2,1 D which is more than our result when we compare only CXL treatment change. Braun et al.22 reported stabilization of keratoconus in all 22 patients and 27 eyes, and regression by 2 D in 12 eyes (44%) after CXL treatment. In our study, when CXL was performed after INTACS implantation, UCVA improved by 1,2 lines and mean-K value decreased by 0,35 D, 2 months after CXL treatment. Pre-operative mean UCVA increased from 1.61 lines to 4.8 lines; and mean K value decreased from 49.8 D to 47.2 D after INTACS / CXL. Our improvement in refractive and topographic results with INTACS and CXL are not as favorable as those reported with CXL treatment alone. Chan et al, 24 reported the first study about combined treatment INTACS and CXL. They showed that the combination of CXL with INTACS led to better results than INTACS insertion alone, as proved by greater reductions in manifest refraction, steep K and average K. In their study, mean changes in UCVA, BCVA, sphere and mean-K values were 6.5 lines, 1 lines, 0.12 D and 1.34 D respectively after INTACS with CXL; and 9.5 lines, 1 line, 0.25 D and 0.21 D respectively after only INTACS treatment. They concluded that this might be the result of
TRANSEPITHELIAL CROSS-LINKING TREATMENT IN EYES WITH INTACS
Figure 18.6: Change in BCVA and UCVA after INTACS and Cross-linking treatment. These bars show participation of each treatment method to total treatment efficiency
Figure 18.7: Change in mean-K and steepest-K value after INTACS and CXL treatment
Figure 18.8: Change in spheric and cylindric values after INTACS and CXL treatment
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biomechanical coupling from local collagen changes around the segments. CXL with the epithelium removed versus transepithelial treatment is another controversial issue. Applied riboflavin must diffuse into the cornea stroma for treatment efficiency. The intact epithelium is barrier that slows the absorbtion of riboflavin into the cornea so it penetrates slowly and incompletely. 27 CXL treatment without removing epithelium causes inadequate penetration of riboflavin and therefore enhances ultraviolet (UV) penetration and results in possible cell damage. Pinelli et al reported their 6 months’ CXL results and found comparable outcomes without removal of epithelium in terms of changes in keratometry, vision and endothelial cell count ( The Italian Refractive Surgery Society results using C3R, 2nd International Congress on CXL, Zurich 2006). Sharma and Boxer Wachler also reported similiar results after CXL without removing epithelium.(Corneal collagen CXL with riboflavin for corneal stabilization. American Academy of Ophthalmology Annual meeting October 2005). Riboflavin absorbs UV and reduces penetration; the absorption then causes cytotoxic reaction. Riboflavin sensitizes the cornea to UV, by ten times. It would have been ideal, if the riboflavin penetration could be limited to the first 300 microns of the cornea, to spare the endothelium. Limited penetration of riboflavin in superior part of cornea, in eyes with intact epithelium may be actually safer in UV-A application. Podskochy et al, 29 showed increased keratocyte damage with ultraviolet light when the epithelium was removed. This study reported that epithelium may play a significant role in absorbing UV-A and thus protect cornea and deeper structures from damage. In our study, treating keratoconus with INTACS followed by CXL resulted in more regular topography with visual improvement. There was significant improvement in UCVA and BCVA values after CXL. On the other hand, mean-K values and BCVA were statistically better after initial INTACS treatment. In our hands, CXL treatment after INTACS was not as effective on mean-K values and on manifest refraction as compared to previous studies.24 On the other hand, other studies showed INTACS combined with CXL is a more effective strategy than CXL alone or INTACS alone in respect to UCVA, BCVA30.
Recently Chan et al (Chan C, Hodge C, Sutton G. Collagen CXL with INTACS, WOC , Hong-Kong, 2008) compared outcomes of same day CXL and INTACS, INTACS alone and CXL 6 months after INTACS treatment. They showed that there was significant difference among 3 groups and same day CXL and INTACS treatment had better results. In advanced cases of keratoconus, CXL may be considered after INTACS implantation as to provide slight improvement in refractive and visual results with possible stabilisation effect and without significant adverse consequences. This study is limited by the number of patients and short term follow-up; further controlled studies with longer follow-up are needed. REFERENCES 1. Rabinowitz YS, Nesburn AB, McDonnell PJ. Videokeratography of the fellow eye in unilateral keratoconus. Ophthalmology 1993;100:181-86. 2. Li X, Rabinowitz YS, Rasheed K, Yang H. Longitudinal study of the normal eyes in unilateral keratoconus. Ophthalmology 2004;111(3):440-46. 3. Colin J, Cochner B, Savary G, et al. Correcting keratoconus with intracorneal rings. J Cataract Refract Surg 2000;26:1117-22. 4. Alio JL, Shabayek MH. Intracorneal ring segments (INTACS) for keratoconus correction: long term follow-up. J Cataract Refract Surg 2006;32:978-85. 5. Barraquer JI. Modification of refraction by means of intracorneal inclusion. Int Ophthalmol Clin 1966;6:5378. 6. Fleming JR, Reynolds Al, Kilmer L. The intrastromal corneal ring-two cases in rabbits. J Refract Surg 1987;3:227-32. 7. Andreassen TT, Simonsen AH, Oxlund H. Biomechanical properties of keratoconus and normal corneas. Exp Eye Res 1980;31:435-41. 8. Nash IS, Greene PR, Foster CS. Comparison of mechanical properties of keratoconus and normal corneas. Exp Eye Res 1982;35:413-24. 9. Roberts C. Biomechanics of INTACS in keratoconus. Intracorneal Ring Segments and Alternative Treatments for Corneal Ectatic Diseases. ed. Colin J, Ertan A Kudret Göz Yayýnlarý, Ankara 2007;159-66. 10. Ertan A, J. Colin. “Intracorneal rings for keratoconus and keratectasia,” J. Cataract Refract Surg 2007;33:1303-14. 11. Jester JV, Moller-Pedersen T, Huang J, et al. The cellular basis of corneal transparency evidence for “corneal cristallins”. J Cell Sci 1999;112:613-22. 12. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol 1984:28:293-322.
TRANSEPITHELIAL CROSS-LINKING TREATMENT IN EYES WITH INTACS 13. Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998:42:217-319. 14. Wollensak G, Spoerl E, Seiler T. Riboflavin ultraviolet – A – induced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-27. 15. Wollensak G, Sporl E, Seiler T. Treatment of keratoconus by collagen Cross-lýnkýng. Ophthalmology 2003;100:4449. 16. Wollensak G. Cross-lýnkýng treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006;17(4):356-60. 17. Sung H-W, Chang W-H, Ma C-Y, Lee M-H. Crosslýnkýng of biological tissues using genipin and/or carbodiimide. J Biomed Mater Res 2003;64A:427-38. 18. Krishna CM, Uppuluri S, Riesz P, et al. A study of the photodynamic efficiencies of some eye lens constituents. Photochem Photobiol 1991;54:51-58. 19. Lang JC. Ocular drug delivery: Conventional ocular formulations. Adv Drug Deliv Rev 1995;16;39. 20. Prausnitz MR, Noonan JS. Permeability of cornea, sclera and conjunctiva: a literature analysis for drug delivery to the eye. J Pharm Sci 1998;87(12):1479-88. 21. Kymionis GD, Portaliou DM, Bouzoukis DI, et al. Herpetic keratitis with iritis after corneal Cross-lýnkýng with riboflavin and ultraviolet A for keratoconus. J Cataract Refract Surg 2007;33:1982-84. 22. Spoerl E, Mrochen M, Sliney D, et al. Safety of UVARiboflavin Cross-linking of the Cornea. Cornea 2007;26:385-89.
23. Colin CKC, Wachler BSB. Corneal Collagen Cross-lýnkýng with Riboflavin and UVA. Intracorneal Ring Segments and Alternative Treatments for Corneal Ectatic Diseases. ed. Colin J, Ertan A, Kudret Göz Yayýnlarý, Ankara 2007;16787. 24. Chan CKC, Sharma M, Wachler BSB. Effect of inferiorsegment INTACS with and without C3-R on keratoconus. J Cataract Refract Surg 2007;33:75-80. 25. Ertan A, Karacal H, Kamburoglu G. Refractive and Topographic Results of Transepithelial Cross-linking Treatment in Eyes with INTACS. Cornea (in press). 26. Ertan A, Kamburoðlu G, Bahadýr M. INTACS insertion with the femtosecond laser for the management of keratoconus: One-year results. J Cataract Refract Surg 2006;32:2039-42. 27. Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Parasurgical therapy for keratoconus by riboflavinultraviolet type A rays induced cross-linking of corneal collagen. Preliminary refractive results in an Italian study. J Cataract Refract Surg 2006;32:837-45. 28. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol 1984:28:293-322. 29. Podsckochy A, Gan L, Fagerholm P. Apoptosis in UVexposed rabbit corneas. Cornea 2000;19(1):99-103. 30. Wollensak G, Wilsch M, Spoerl E, Seiler T. Collagen fiber diameter in the rabbit cornea after collagen Cross-linking by riboflavin/UVA. Cornea 2004;23(5):503-507.
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RE-SHAPING KERATOCONUS: LASER PRK FOLLOWED BY CORNEAL CROSS-LINKING
INTRODUCTION Keratoconus is a bilateral, noninflammatory corneal disorder that leads to inferior paracentral corneal thinning, inferior corneal steepening, and irregular astigmatism.1 Although the etiology remains uncertain 14% of cases are associated with a genetic predisposition. Keratoconic patients could present with complaints of decreased vision, glare, photophbia, and monocular diplopia. External clinical signs of keratoconus include Munson’s sign (protrusion of inferior lid on down gaze) and Rizutti’s sign (conical reflection on the nasal cornea when light is shone temporally). Slit lamp presentations of keratoconus include inferior paracentral corneal thinning, presence of an ectatic cone within the area of corneal thinning, inferior corneal steepening,Vogt striae (vertical stress lines in the posterior stroma), and a Fleischer ring (iron deposits in the basal layer of the corneal basal epithelium), linear scars can also be seen as result of breaks in Bowman’s layer. Breaks in Descemet’s membrane can lead to stromal edema and corneal hydrops with intrastromal clefts and vascularization. Resolution of corneal hydrops can lead to corneal scarring. Patients with Keratoconus also have scissoring on retinoscopy and the presence of Charleaux oil droplet reflex, a bright reflex from conical apex surrounded by a dark circular shadow produced by the corneal ectasia. There are various methods for grading of keratoconus worldwide. The KISA%, created by Rabinowitz provides an algorithm to quantify results from computerized videokeratoscopy to classify whether a patient has keratoconus.2 McMahon and colleagues and the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) have proposed a method called keratoconus severity score (KSS) for grading of the severity of kerraoconus.3 New Pentacam Technology (Oculus Inc.) provides parameters that can be further correlated and associated with related anatomy for a more descript diagnostic acumen along with a keratoconus detection software based on relative indices.4-5 In this chapter, I shall introduce my classification system that is used in my practice to apply Excimer Laser in a surface ablative (ASA/ PRK) mode for keratoconus and related ectatic disorders.6-7
GULANI CLASSIFICATION SYSTEM FOR LASER SURGERY IN KERATOCONUS Laser as Primary Treatment (In this subset, the patient is informed that we can strive for vision directly with the laser keeping the surgical interventions noted in Level II as back up plan to be applied in single or combined approaches to address any complication induced or progression of cone if needed) Class I Clear Cornea Class II Scarred Cornea Laser as Staged Secondary Treatment Class I Following corneal surgery: a. INTACS b. Lamellar Keratoplasty c. Penetrating Keratoplasty d. C3-R cross-linking e. Conductive Keratoplasty Class II Following intraocular surgery: a. Phakic Implant 1. Anterior 2. Posterior b. Cataract surgery with lens Implant 1. Monofocal 2. Toric 3. Presbyopia-corrective Each case of keratoconus is unique. From their appearance to their topographies and even their refractions, optical effects and aberrations. Over years of numerous clinical and surgical encounters, I found one thing consistent in all of them- “Irregular Astigmatism.” Since I am a firm believer in logic and clinical sense over market-hyped terminologies, I decided to personally approach every case of keratoconus as an asymmetric, high irregular astigmatism associated with other refractive errors ie. Myopia, hyperopia and or presbyopia.8-9
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Lets first understand why we can or even should use Excimer Laser in a case of proven Keratoconus: Patients with Keratoconus are frustrated with their vision and resultant life style (especially when they have exhausted their options with glasses and contact lenses). Once they have passed the stage of such nonsurgical options, they are facing surgery to rehabilitate their vision.
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Among surgical options presented in the current times: 1. Corneal transplant (invasive surgery with long term adverse impact including life style restriction and also little ability to bring patients to uncorrected 20/20 vision). 2. INTACS: Excellent, reversible, less invasive surgery (may even delay or avoid transplant in many cases), but unpredictable in most cases and majority of cases shall need contact lenses and or glasses after the surgery to help patients see. Given that these patients in most cases are otherwise healthy young adults at the prime of their professional and personal stage in life, we must look at them as people rather than as an eyeball with a book diagnosis. We must therefore want to provide them the best vision they are capable of and that too without dependence on glasses and contact lenses if possible. Remembering again that they are at their most productive stages of their life and just like our refractive patients must be encouraged to lead a visually independent life. Here, we need to balance our desire to provide an enhanced lifestyle with our honest intention to keep safety for these patients utmost in our minds. If selecting a choice of INTACS for these patients since compared to a corneal transplant it is less invasive and more promising visually, we are doing the right thing and explaining to patients that they will come close to 20/40 and also that they shall need contact lenses and or glasses. This is a fair choice for someone who despite a hard contact lens trial does not see better than 20/40 preoperatively. But what about the keratoconic patient who has passed the non-surgical option (CLs and glasses) stage and yet sees 20/20 best corrected? In such cases, how are we justified in doing an approved procedure like INTACS (since we have to do something now that this patient cannot function with contact lenses or glasses) to make their vision
worse ie.20/40 from their preoperative potential of 20/20?
This is where I find a place for the Excimer Laser. Using the Excimer Laser in a surface mode (no LASIK in any case or any flap cutting) we can address the Keratoconus as what I call “Astigmatism gone wild” to “Tame” it to a shape resulting in excellent unaided vision. Yes, theoretically the Excimer Laser will remove tissue and so accelerate the Keratoconus but we also delivering 20/20 unaided vision (remember this 20/ 20 may not ever match the 20/20 of our simple Lasik cases but coming to unaided 20/20 from legal blindness for a Keratoconus patient is visibly, sheer ecstacy) to these very affected patients for the first time in their life. Here is the discussion with the patient: This is an option because you do meet the criteria for Laser surgery. If after laser surgery (no one can guarantee the duration that this will last) your vision does drop from 20/20 to 20/40 or worse either by natural progression or by the Laser surgery that you had then you fit the criteria for INTACS surgery. Again, keeping in synch with my corneoplastique concepts, all of the mentioned surgeries available out there can always be used a back up. The patient never loses candidacy for them. This discussion underscores the honest desire to help keratoconic patients lead a productive life of visual freedom knowing that there are back up plans in place. Also with the application of Collagen Cross-linking (C3-R) , we may be able to arrest these keratoconic corneas after Laser Surgery in the final shape created to prevent progression in the future. So keeping the above discussion in mind lets see how to apply these concepts in everyday practice. I have used technologies including Pentacam anterior segment analyzer, multiple types of corneal topographers, wavefront technologies, Optec6500 and Visual simulators that zero in on cases that are obvious. Nevertheless, the Keratometer, Refractive retinoscopy and hard contact lens trial are a very important adjunct forming the mainstay of detection, grading and treatment selection.10-11 Simply put, if we start approaching every keratoconus as a form irregular astigmatism, we can apply the methodology of thought process and surgical
RE-SHAPING KERATOCONUS: LASER PRK FOLLOWED BY CORNEAL CROSS-LINKING
planning towards excellent visual outcomes. The corneal surface can be recontoured with an excimer laser in cases of keratoconus. This approach of correcting corneal architecture and finally shaping the contour with an Excimer Laser falls under the realm of my concept of Corneoplastique™.12-15 Numerous studies in scientific literature have investigated the use of laser treatment for keratoconus to give patients better and more comfortable vision with and without glasses or soft contact lenses. In these studies, the authors hope to avoid or delay the need for corneal transplant in keratoconus eyes, giving these patients better vision with and without glasses or soft contact lenses. 16 Further more, it was found that Excimer laser surgery can improve vision and the ability to wear contact lenses, and does not interfere with subsequent corneal transplantation surgery. 17 The downside to PRK is that it is not a standard treatment for keratoconus. Rather, it is controversial because the procedure thins out the cornea. In keratoconus, the cornea is already thin and unstable and additional tissue removal can cause further progressive distortion. However, the Excimer laser may have potential therapeutic benefit in removing certain corneal scars. Some studies suggest that PRK may have a role in very mild and stable sub clinical keratoconus. Regardless, Excimer treatment in these instances is done selectively on a case-by-case basis. I have successfully treated all types of keratoconus (the grade of severity does not matter as much as the parameters listed below) with surface laser vision surgery (ASA/PRK) by simply approaching them as a case of assymteric irregular astigmatism. We have devised a set of criteria for Excimer Laser PRK surgery for Keratoconus.
Gulani- Nordan criteria for Laser PRK in Keratoconus: • Patient is symptomatic with poor visual acuity and double vision or glare and cannot tolerate contact lenses (meaning the options of gasses or contact lenses has run out for any number of reasons). • Clinical examination and signs suggesting corneal shape irregularity. • Best corrected visual acuity of 20/30-20 (even if with hard contact lens trial). Best corrected vision below 20/40 would indicate INTACS. • Refraction is stable (with review of prior documented exams).
• Astigmatism Higher than Myopia/ Hyperopia preferred. • Corneal thickness is more than 400 μm in the thinnest part and also after laser shall be preferably not less than 350. • Corneal scar even if present is less than the anterior one third in depth.18 • Patient ‘s understanding that using the Excimer laser is an “off-label” use and that if for some reason (due to laser or natural progression) if their keratoconus worsens then they would be candidates for INTACS/ LK/ PKP in that order of decreasing selection. If these criteria are met, I design a plan to correct this corneal shape and surface irregularity with the Excimer laser. Even though I have treated practically every grade and combination of keratoconus with or without associated surgeries in stages or previously done elsewhere, in this chapter I shall limit myself to a discussion for primary laser PRK on Keratoconus and briefly mention the spectrum of Laser applications in combination approaches for the full spectrum of Keratoconus surgical care. DISCUSSION AND RESULTS All the cases were confirmed Keratoconus with present day criteria inclusive of topography and we did not differentiate treatment based on stage. Rather, we used my consistent approach based on visual potential and corneoplastique approach along with the classification system. In this study we included 14eyes of 10 patients (9 males and 5 females) ranging in age from 20-66 years old with follow-up ranging from 6 months to 3 years. Each of these patients underwent Surface Excimer Lasr (PRK / ASA) using standard protocol. No variance from my PRK technique was used in any of these cases.19 Following a normal PRK postoperative course, 13 out of 14 eyes achieved uncorrected vision of 20/ 20, one of the fourteen eyes achieved uncorrected vision of 20/40 (which was her best corrected vision preoperatively due to amblyopia) and 6 eyes of the 13 eyes at 20/20 achieved uncorrected vision of 20/15 (Figs 19.1 and 19.2A and B). The point I want to stress here is that the postoperative evaluation of success of this treatment is
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Figure 19.1: Laser PRK for Keratoconus (preop and postop topographies with Differential map). Post op vision Unaided 20/15
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based entirely on the uncorrected visual acuity and subjective response of the patient. Patients were asked to grade the vision compared to before laser surgery on the grade of 1 to 10 (10 being the best). All the patients treated with this approach placed a subjective evaluation grade of 10 or more. All of the patients stated that they had no complaints at night and all of them noted that their vision at night was improved compared to best corrected vision preoperatively. In all cases, Excimer Laser ablation resulted in postoperative corneas no thinner than 350 microns, which is enough to rehabilitate the cornea or perform any other corneal surgery in the future ie INTACS (Figs 19.3A and B). One can also treat patients previously operated with INTACS to correct residual astigmatism with laser vision surgery in the PRK mode. Lets analyze this concept. The fact that the Keratoconus or corneal ectasia has been stabilized by the INTACS (acting as braces) allows us to shape the
cornea just a little more (of course contact lenses and glasses are the non-interventional options here) since astigmatism removes the least amount of tissue when ablated with the Excimer Laser. Also since the inner optic zone for Intacs is 7mm - 7.2mm, the laser ablation zone can be extended to 6.5mm without eroding the superior roof of the INTACS (Figs 19.4A and B). INTACS is an excellent way to correct or minimize the ectasia but since it is an inaccurate surgery (even though most patients do well, we cannot predict who will do well, how well and by when); I reserve it for patients with Keratoconus who are best corrected to 20/40 or less (Gulani AC. INTACS : A Refractive Surgery to Prepare and Repair. INTACS Round Table. ASCRS, May 2007) Surgical techniques other than Penetrating Keratoplasty have been suggested for management of keratoconus with variable success besides Laser surface ablation,20-23 intrastromal rings,24-26 intraocular lens,27 keratotomies, 28 and lamellar keratoplasty. 29-30 Collagen cross-linking of the cornea has also been
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Figure 19.2A: Laser PRK for Pellucid Marginal Degeneration Patient (preop and postop topographies with differential map). Post op vision Unaided 20/15
Figure 19.2B: Differential map of same patient
introduced to halt the progression of ectasia in keratoconus.31-32 C3-R® (COLLAGEN CROSS-LINKING) Wollensak et al33 is credited with the seminal study that showed that corneal cross-linking (exposure to UV-A light at 3.0 mW/cm2 and riboflavin 0.1% for 30 minutes) was able to stop progressive keratoconus in all 23 eyes of 22 eyes. The patients ranged in age from 13 to 58 with the average age 34.7 ± 11.9 years. Steep keratometry values reduced from 2.01 diopters was also seen in 70% of eyes with a refractive correction of 1.14 diopters. Over an average follow-up time of 23 months, no scarring in cornea, no lens opacities
(i.e. no cataracts), and no endothelial cell loss were seen. Intraocular pressure did not change postoperatively. Five year follow-up results to the 3 year study have been published in Wollensak’s review of crosslinking.34 In 150 eyes treated so far, 60 have 5 year follow-up and no progression of keratoconus has been seen in any of these patients. In 31 eyes (52%), a reduction in keratometry of 2.87 diopters was seen with best-spectacle corrected visual acuity (BSCVA) improving by 1.4 lines in these eyes. Other clinical studies in the United States, Italy, Brazil, and England have been smaller with shorter follow up, but are consistent with the above cited studies in terms of efficacy and high safety profile.
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Figure 19.3A: Laser PRK for Keratoconus (preop and postop topographies). Post op vision Unaided 20/15
Figure 19.3B: Differential map of same patient
We observed that the corneal topography changes post-treatment indicated preferential flattening over the cone. Targeted flattening consistently occurs over the steepest part of the cone with less flattening on less steep areas. Corneal coupling occurs in many patients after C3-R®, which is similar to, but less consistent than single segment Intacs® placement. With C3-R®, if the cone is located inferiorly, than flattening can occur inferiorly and superior steepening may occur as well. This coupling effect (flattening below and steepening above) results in better corneal symmetry and BSCVA afterwards. There have been individual case reports of dramatic improvement in BSCVA
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without impressive changes in topography. These observations may be explained by the optical regularization of the cornea resulting from crosslinking. It is worth noting that 99% primary keratoconus and keratoectasia (LASIK-induced ectasia) patients treated to date have been stabilized after a one-time C3-R® procedure. There have been some patients with very aggressive forms of ectasia that required a second C3-R® treatment to achieve stabilization. It almost seems too good to be true, but the results from multiple ophthalmologists around the world are remarkably consistent.
RE-SHAPING KERATOCONUS: LASER PRK FOLLOWED BY CORNEAL CROSS-LINKING
Figure 19.4A: Laser post INTACS Clinical picture
Figure 19.4B: Differential topography map of Laser post INTACS, same patient with vision unaided 20/25
BOXER WACHLER 10 STEP C3-R® PROTOCOL Treatments may be performed unilaterally or bilaterally at the same time if C3-R® is indicated for both eyes. If one eye is to be treated, the fellow eye is taped closed and covered. We performed the procedure per our
protocol described below. Although somewhat laborintensive to perform (application of riboflavin solution every 3 minutes for a total of 30 minutes), this is the necessary means to achieve the desired effect for patients. 1. The UVA device is periodically calibrated with a UVA meter to ensure that the irradiation is 3.0 mW/cm2 ± 0.3. 2. Topical anesthesia is administered. Tetracaine 0.5% works well as it loosens the epithelial cell tight junctions to facilitate penetration of riboflavin into the stroma with intact epithelium. 3. Two surgical spear-type sponges are made “soppy wet”: one sponge with 0.1% riboflavin solution and the sponge with Tetracaine. 4. Tetracaine is applied to the eye which is then closed for 5 minutes to allow preliminary superficial riboflavin absorption (“pre-soaking”). Note: when a procedure is not being performed, the bottle of riboflavin solution is stored in a refrigerator as it is prudent to avoid unnecessary external light exposure. 4. A speculum is inserted to expose the eye and the patient is instructed to look at the center of the lights. 5. The UVA light is positioned on the cornea at the proper distance from the eyes. The working distance varies according to the device used. The irradiation is performed for 30 minutes. 6. The “soppy wet” sponge soaked with riboflavin is wiped on the cornea every three minutes. The “soppy wet” sponge soaked with Tetracaine is applied every 10 minutes for patient comfort. 7. After 30 minutes, the device is turned off and the speculum is removed. 8. Artificial tears are applied and the patient asked to keep eyes closed for 5 minutes to allow lubrication of the corneal surface. 9. The patient is advised to spend to rest of the day keeping his or her eyes closed. 10. Patients are given valium (or other benzodiazepine) to promote sleeping when arrival at home or the hotel room for out of town patients. A dilute bottle of anesthetic drops is given to the patient that can be used every 20 minutes as needed. Often these drops are not used by patients because recovery is typically comfortable. This bottle should be discarded after two days because there are no significant amounts of preservatives.
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Patients can expect some mild foreign body sensation for the remainder of the day. Pain does not occur with the epithelium-on technique, which is our technique (see below for more details on this technique compared to epithelium-off). On the next day exam after C3-R ® with epithelium-on, slit lamp biomicroscopy of the cornea appears completely normal or rarely may reveal a few areas of scattered punctate epitheliopathy. Mild foreign body sensation or grittiness may be present on the first day that will resolve in a day or two. Patients may be examined again at 3 months and again at 1 year. On occasion, patients may be examined at a more frequent basis. If C3-R® is being performed with epithelial removal, initially a 7 mm corneal abrasion is created first after topical anesthetic is given. The procedure is then performed as described above. At the end of the procedure, a bandage contact lens is placed for 3-7 days while the epithelium heals. Analgesic medication is necessary as patients often experience pain during these days of epithelial healing. The wide spectrums of applications are only limited by our logic and imagination. I also want to point out
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that by logic, I do mean responsible thinking and knowledge of anatomy, optics and physiology in selecting the most appropriate surgery or surgeries and keeping in mind that they be synergistic towards a visual goal.35 Approaching the cornea of a patient as an asymmetric high irregular astigmatism and by applying simple inclusion criteria we are not only clear in our head about the treatment as a refractive surgeon but we are helping patients to understand that keratoconus is an approachable condition despite its progressive nature with surgical options at every stage to help the patient live a continued, productive life. Applying our classification system we can therefore address practically all presentations of Keratoconus. For example in cases outlined above the Excimer Laser can be used as a primary surgery for Keratoconus on clear corneas (Class I ) or scarred corneas ( Class II). In some cases we may need to build the cornea in strength, scar removal and tissue replacement ie. Lamellar Keratoplasty (Fig. 19.5) or Penetrating Keratoplasty (Fig. 19.6) and then present for Excimer laser surgery (Classification system Class I) or in specific
Figure 19.5: Lamellar keratoplasty to strengthen a case of very thin keratoconic cornea (222 microns) and also to decrease keratometry by nearly 20 D). This case is now ready for Laser PRK for residual refractive error to achieve excellent unaided vision
RE-SHAPING KERATOCONUS: LASER PRK FOLLOWED BY CORNEAL CROSS-LINKING
Figure 19.6: Penetrating Keratoplasty for a case of Keratoconus with very thin and full thickness scarred cornea as Stage I, followed by Laser PRK to unaided 20/20 vision. Topography picture post Laser PRK
cases we can prepare in a cataractous age population to customize their cataract surgery in manipulating the optics intra ocularly (i.e. Toric IOL) and then addressing the final refractive residual error on the cornea (Class IIb) (Fig. 19.7). C3-R®, A MANDATED STAGE II FOLLOWING THE RESHAPING OF KERATOCONUS? I can envision a future wherein a keratoconic cornea once brought to its desired shape by the Excimer Laser in a PRK / ASA mode, INTACS or Conductive keratoplasty or even after corneal building procedures like Lamellar Keratoplasty followed by Excimer PRK/ ASA can then undergo C3-R treatment for cross-linking into a more stable and long lasting effect. The use and indications for C3-R® will only expand as we use it not only for primary treatments but also for solidifying modified shapes as a secondary mandated procedure. For example, applying C3R®,
Figure 19.7: Toric IOL was performed in this elderly male as Stage I to correct high myopia, cataract and high astigmatism.in this case followed by Laser PRK for residual astigmatism to unaided 20/20 vision. Differential Map picture
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Figure 19.8: Conductive Keratoplasty was performed in this patient followed by C3R cross-linking
can also be done on a keratoconic cornea treated previously with conductive keratoplasty (Class II e) (Fig. 19.8). Studies are needed for long term impact to make Stage II C3-R® a future mainstream application. These very principles follow the concepts that have been brought together under my concepts of Corneoplastique™ wherein topical, brief, elegant, aesthetically pleasing, least invasive surgeries are used singly or in stages towards a goal of unaided emmetropia. Corneoplastique prepares for the final fine tuning using the Excimer Laser towards a visual goal where early rehabilitation and aesthetic outcomes are essential, with promising uncorrected visual acuity.36-41 REFERENCES
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1. Krachmer JH, Feder RS, Belin MW. Keratoconus and related noninflammetory corneal thinning disorders.Surv Ophthalmol 1984;28(4):293-322. 2. Rabinowitz YS, Rasheed K. KISA% index:a quantitative videokeratography algorithm embodying minimal topographic criteria for diagnosing keratoconus.J Cataract Refract Surgg 1999;25(10);1327-35.
3. McMohan TT, et al. A new method for grading the severity of keratoconus: the Keratoconus Severity Score (KSS). Cornea 2006;25(7):794-800. 4. Gulani AC, Holladay J, Belin M, Ahmed I. Future Technologies in LASIK- Pentacam Advanced Diagnostic for Laser Vision Surgery. In Experts Review of Ophthalmology 2008- London (in Press). 5. Gulani AC. “ Pentacam Technology in Lasik”- Corneal Refractive Surgery in Video Atlas of Ophthalmic Surgery. XVII. 2008;(2). 6. Gulani A C. Pentacam Technology in Full Spectrum of Refractive Surgery: KMSG International Conference, Madrid, Spain. June 2006. 7. Gulani A C. Pentacam - Basics and Advanced Course: Proceedings of Florida State of Ophthalmology Conference. Naples, Florida. Aug 2006. 8. Gulani AC. Corneoplastique™ Advanced Corneal Surgery Course. SASCRS- Durban, South Africa; Aug 2005. 9. Gulani AC. Corneoplastique™: art of Vision Surgery (abstract) ISOPT, Berlin, Germany March 2006. 10. Nordan LT. Keratoconus: Diagnosis and Treatment. Arch Ophthalmol 1996;114(2):135-41. 11. Nordan LT. Keratoconus and Lasik: Ambiguiuty has no place in Keratorefractive surgery: Cataract and Refractive Surgery today 2006. 12. Gulani AC. Corneoplastique™. Techniques in Ophthalmology 2007;5(1):11-20.
RE-SHAPING KERATOCONUS: LASER PRK FOLLOWED BY CORNEAL CROSS-LINKING 13. Gulani AC. “A New Concept for Refractive Surgery: Corneoplastique” Ophthalmology Management 2006;5763. 14. Gulani AC. Corneoplastique: Art of Vision Surgery (Abstract). Journal of American Society of Laser Medicine and Surgery 2007;19:40. 15. Gulani AC. “Corneoplastique” Video Journal of Cataract and Refractive Surgery. Vol XXII. Issue 2006;3. 16. Excimer laser photorefractive keratectomy for treatment of keratoconus . J Mortensen, A Ohrström J Refract Corneal Surg (Vol. 10, Issue 3:368-72. 17. Appiotti A, Gualdi M Treatment of keratoconus with laser in situ keratomileusis, photorefractive keratectomy, and radial keratotomy. J Refract Surg 15:S240-2. 18. Gulani AC. Combined corneal scar excision, PRK surgery seeks unaided emmetropia. Ocular Surgery News. Cornea and External disease section, June 2008. 19. Gulani AC. Excimer Laser PRK: Refractive Surgery to the Rescue. In Textbook- Mastering Advanced Surface Ablation Techniques. J P Publishers 2007;26:246-48. 20. Buzard KA, Tuengler A, Febbraro JL. Treatment of mild to moderate keratoconus with laser in situ keratomileusis. J Cataract Refract Surg 1999;25:1600-1609. 21. Kasparova EA, Kasparov AA. Six-year experience with excimer laser surgery for primary keratoconus in Russia. J Refract Surg 2003;19(suppl):250-54. 22. Mortensen J, Carlsson K, Ohrstrom A. Excimer laser surgery for keratoconus. J Cataract Refract Surg 1998;24:893-98. 23. Cochener B, Le Floch G, Volant A, Colin J. Le laser Excimer peut-il tenir une place dans le traitement du keratocone? [Could the laser excimer have a place in the treatment of keratoconus?]. J Fr Ophtalmol 1997;20:758-66. 24. Colin J, Cochener B, Savary G, Malet F. Correcting keratoconus with intracorneal rings. J Cataract Refract Surg 2000;26:1117–22. 25. Siganos D, Ferrara P, Chatzinikolas K, et al. Ferrara intrastromal corneal rings for correction of keratoconus. J Cataract Refract Surg 2002;28:1947-51. 26. Alio JL, Artola A, Ruiz-Moreno JM, et al. Changes in keratoconic corneas after intracorneal ring segment explantation and reimplantation. Ophthalmology 2004;111:747–51. 27. Sauder G, Jonas JB. Treatment of keratoconus by toric foldable intraocular lenses. Eur J Ophthalmol 2003;13:577-79.
28. Bowman CB, Thompson KP, Stulting RD. Refractive keratotomy in keratoconus suspects. J Refract Surg 1995;11:202-6. 29. Busin M, Zambianchi L, Arffa RC. Microkeratome-assisted lamellar keratoplasty for the surgical treatment of keratoconus. Ophthalmology 2005;112:987-97. 30. Watson SL, Ramsay A, Dart JK, et al. Comparison of deep lamellar keratoplasty and penetrating keratoplasty in patients with keratoconus. Ophthalmology 2004;111:1676-82. 31. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A induced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-7. 32. Mazzotta C,Balestrazzi A,Traversi C,et al. Treatment of progressive keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: ultrastructural analysis by Heidelberg Retinal Tomograph II in vivo confocal microscopy in humans.Cornea 2007;26940:390-97. 33. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-Ainduced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-27. 34. Wollensak G. Cross-linking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006;17:356-60. Review. 35. Gulani AC. Principles of Surgical Treatment of Irregular Astigmatism in Unstable Corneas. TextBook of Irregular Astigmatism . Diagnosis and Treatment . Thorofare , NJ: SLACK Incorporated 2007;251-61. 36. Mertens E, Gulani AC, Karpecki P. The Orbscan Technology. In Textbook- Mastering Techinques of LASIK, EPILASIK and LASEK. Techniques and Technology. J.P. Publishers 2007;98:310-20. 37. Gulani AC, McDonald M, Majmudar P, Koch D, Packer M, Waltz K. “Meeting the challenge of Post-RK patients”Review of Ophthalmology 2007; IV(10):49-54. 38. Mertens E, Gulani AC. Post – Lasik corneal ectasia: In Textbook- Mastering the Techniques of Customized Lasik. J P Publishers 2007;31:284-93. 39. Gulani AC, Alio J, et al. “Abnormal Preoperative Topography in Refractive Surgery Complications: Cataract and Refractive Surgery Today Journal 2007;7(2)37-42. 40. Gulani AC. “How to put logic into action after Lasik”Review of Ophthalmology 2006;XIII(9):60-64. 41. Gulani AC, Wang M. Future of Corneal Topography. Textbook of Corneal Topography in the Wavefront Era. Slack Inc 2006;26:303-304 Slack Inc.
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CROSS-LINKING IN KERATOCONUS: ADVANTAGES AND DISADVANTAGES
INTRODUCTION The management of keratoconus begins with spectacle correction. Once glasses fail to provide adequate visual function, contact lens fitting is required. Corneal collagen cross-linking stiffens the collagen matrix and stops the progression of keratoconus. Contact lens intolerant patients with clear central corneas may benefit from intracorneal ring segment insertion. Penetrating keratoplasty or lamellar keratoplasty is recommended for advanced cases.1 The advantages and disadvantages of cross-linking treatment for keratoconus are discussed in this chapter. One of the major advantages of cross-linking is that it prevents progression progression. No treatment modality other than cross-linking could convert progressive disease to forme fruste of keratoconus.2 Even after corneal transplantation, recurrence of keratoconus could occur.1 Collagen cross-linking is a simple procedure to perform. The learning curve for collagen cross-linking is much less significant than the learning curve for corneal transplantation or corneal intrastromal ring segment implantation. short. The rehabilitation period after cross-linking is short Postoperatively, the epithelium is healed completely in 3 to 5 days, and a contact lens could be worn in a month. After penetrating keratoplasty however, it takes almost a year to visually rehabilitate the eye.1 Collagen cross-linking is an extraocular procedure with no serious complications complications. However, corneal transplantation could have serious risks such as graft rejection, infection and glaucoma.1 Intrastromal ring segment implantation also has significant side effects such as infectious keratitis, loss of BSCVA, anterior chamber perforation during initial surgery, and anterior segment perforation during exchange.3 There are however a number of disadvantages to collagen cross-linking. The durability of the stiffening effect is unknown unknown. Because the collagen turnover in the cornea is estimated to be between 2 to 3 years, a repeat treatment may become necessary in the long run. 2,4 Cross-linking treatment cannot be performed if the cornea is less than 400 μ m . Therefore, it is not
suitable for advanced keratoconus. For advanced keratoconus patients who cannot be fitted with a contact lens, corneal transplantation is still the only option for treatment.5,6 Cross-linking has some mild complications such as haze. In one case report, corneal haze after crosslinking treatment for keratoconus disappeared only gradually despite intensive topical anti-inflammatory therapy.7 In a clinical study, haze that is not effecting vision was developed in 2 of 5 eyes with grade 3 keratoconus (according to Krumeich keratoconus clinical staging). No haze was observed in grade I or II eyes.8 Overall, however, the advantages of collagen crosslinking far outweigh the disadvantages in the treatment of progressive keratoconus. REFERENCES 1. Feder RS, Kshettry P. Noninflammatory ecstatic disorders. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea, China 2005, Elsevier Mosby 955-74. 2. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-ainduced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135(5):620-27. 3. Rapuano CJ, Sugar A, Koch DD, Agapitos PJ, Culbertson WW, de Luise VP, Huand D, Varley GA. Intrastromal corneal ring segments for low myopia. A report by the American Academy of Ophthalmology. Ophthalmology 2001;108:1922-28. 4. Mazzotta C, Balestrazzi A, Traversi C, Baiocchi S, Caporossi T, Tommasi C, Caporossi A. Treatment of progressive keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: Ultrastructural analysis by Heidelberg Retinal Tomograph II in vivo confocal microscopy in humans. Cornea 2007;26(4):390-97. 5. Wollensak G, Spoerl E, Wilsch M, Seiler T. Endothelial cell damage after riboflavin-ultraviolet-A treatment in the rabbit. J Cat Refract Surg 2003;29(9):1786-90. 6. Wollensak G, Spoerl E, Reber F, Pillunat L, Funk R. Corneal endothelial cytotoxicity of riboflavin/UVA treatment in vitro. Ophthalmic Res 2003;35(6):324-28. 7. Herrmann CI, Hammer T, Duncker GI. Haze formation (corneal scarring) after cross-linking therapy in keratoconus. Ophthalmology 2007; [Epub ahead of print] 8. Mazzotta C, Balestrazzi A, Baiocchi S, Traversi C, Caporossi A. Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation. Clin Experiment Ophthalmol 2007;35(6):580-82.
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INTRODUCTION Emerging therapeutic corneal procedures such as ultraviolet collagen cross-linking are showing promise as possible adjunctive therapies to more familiar corneal reshaping techniques such as intracorneal segments for the treatment of keratoconus and LASIK ectasia. We have begun calling these procedures corneoplastics. Corneoplastics are a group of techniques, most of them coming from refractive corneal surgery, that try to modify the corneal shape with a therapeutic purpose, and they are quickly emerging as the next frontier in corneal therapies. We are creating a new environment for the treatment of diseases that were untreatable before. Corneoplastic techniques allow surgeons to model the structure of the cornea without having to resort to invasive techniques such as penetrating keratoplasty or lamellar grafting. We are in a moment in which corneoplastic techniques are modeling techniques that can be used in different ways in order to create better corneal optics, to create better corneal topography, to improve the optical performance of the cornea for refractive purposes (Fig. 21.1). The first ophthalmologist to use the term corneoplastics was most likely Arun C Gulani, MD, from Jacksonville, Fla. Now, this concept is spreading abroad, becoming a new worldwide subspeciality allied to refractive and corneal surgery.1 COMBINING NEW AND OLD TECHNIQUES Corneoplastic techniques can be broken down into biomechanical methods such as intracorneal segments
Figure 21.1: Corneoplastics concept
Figure 21.2: Corneoplastic techniques
or incisional techniques, elastic methods including ultraviolet collagen cross-linking and conductive keratoplasty (CK) and mixed methods such as excimer laser ablations or intracorneal lenses (Fig. 21.2). Some of these methods are already well-known in their efficacy. Intracorneal segments, for example, are currently the best corneoplastic option for treating corneal pathologies such as keratoconus and LASIK ectasia. On the other hand, one of the most promising new approaches for managing keratoconus and LASIK ectasia is collagen cross-linking, or C3-R, in which riboflavin is applied to the cornea (usually after epithelial removal) followed by about 30 minutes of UV light irradiation. This causes new bonds to form between adjacent collagen molecules in the cornea, increasing corneal rigidity as much as three or four times. In several recent studies this has not only stopped the progression of keratoconus, but has caused some degree of reversal and improved visual acuity in many eyes.2,3. The procedure is not yet approved by the US Food and Drug Administration, but has received the CE mark in Europe. By combining this method with intracorneal segments, the efficacy of the implants can be enhanced beyond their current capabilities (Fig. 21.3). Intracorneal segments have been used for keratoconus for more than 7 years, and these cases are more or less stable. Of course some of them were not ideal cases in the beginning. Although they did improve, some of them were followed by a residual increase in the corneal steepness because the keratoconus was advanced and was not stopped
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end, it is possible that few patients will require penetrating keratoplasty. But, if we can delay a penetrating keratoplasty in a keratoconus patient for one or two decades, this could be consider the main objective for corneoplastics; because the risks of corneoplastic procedures such as intracorneal rings and cross-linking are so minimal when we compare to related risks of penetrating keratoplasty. UNFINISHED BUSINESS
Figure 21.3: Combined corneoplastic technique: Corneal scrapping followed by riboflavin instillation for cross-linking, 4 months after keraring implantation
completely by the ring. At this moment the combination of UV cross-linking to these cases is adding rigidity and strength to the cornea, and stopping this process that was slowed after the rings in some cases. The ideal result of combining these procedures would be to avoid procedures such as corneal grafts. You can never guarantee the outcome of a corneal grafting technique, and moreover, keratoconus may relapse on a corneal graft. This is the state of the art at this moment in the treatment of keratoconus, but it is far from ideal, far from being defined as a solution in young patients, because keratoconus may relapse in them. The most desirable situation is to find an alternative to corneal grafting. It is important to notice that at the
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While these techniques are showing promise, there is much to be learned and modified. For example, while researchers are eagerly anticipating the various applications of UV collagen cross-linking, they are also aware that UV light is toxic to the ocular structures, making it necessary to explore alternative energy options. We can anticipate in the future other sources of energy will be substituted for UV light and will not be as potentially harmful. In addition, the biomechanical qualities of the cornea pose challenges to the accurate application of combined techniques. Understanding the behavior of corneal tissue following corneoplastic procedures is complicated by its intricate structure. By the present time one of the structures of the eye which can be damage by UV light are the limbal steam cells, protecting them using a limbal shield is recommended. We use a cellulose sponge ring over the limbus to protect the steam cells during UV light exposure (Fig. 21.4). When is the best time to approach for combine cross-linking and intracorneal rings and for keratoconus? At the Instituto Oftalmológico Novavision in Mexico City we have been doing the manual technique for
Figure 21.4: Cellulose sponge ring protecting steam cells during UV exposure
CORNEOPLASTICS USING CORNEAL COLLAGEN CROSS-LINKING AND INTRACORNEAL RINGS OF KERATOCONUS AND LASIK ECTASIA
intracorneal rings implantation (either Intacs or Keraring) for 8 years, and for the last 5 years we use IntraLase femtoseconds technology to carve the channels for intracorneal rings implantation to treat keratoconus and LASIK ectasia. Since the beginning we noticed that this combination femoseconds laser and keraring provide us an excellent corneoplastic procedure, because we achieved better topographic and refractive results than expected. In fact, today we consider this combination as a partial refractive procedure for such irregular corneas. Controversies arise at this point. When we need to cross-link, if we end with good topographic and refractive result? Few surgeons prefer to cross-link first and then proceed with rings implantation, others use simultaneous cross-linking and corneal ring implantation during the same day, and some surgeons like myself we rather to wait 3 to 4 months after intracorneal ring implantation for cross-linking. I consider this adjunctive procedure especially for two indications: First in the case of residual myopic refractive error after femtoseconds laser and
intracorneal ring implantation, and second when we face to an unstable cornea after intracornreal ring implantation. At the present time, our preferred technique for cross-linking after intracorneal rings is to use excimer laser for a 40 microns of PTK at 7 mm of optical zone, followed first by 20 minutes of riboflavin instillation, one drop each 2 minutes, and second 20 minutes of UV light exposure using riboflavin installation each 2 minutes. The best approach for corneoplastics philosophy in keratoconus is to consider first intracorneal rings to remodel heavely irregular corneas like in the case of Pellucid Marginal Degeneration, and second crosslinking after to improve stability. It is vital to recognize that important mechanical remodeling is only feasible with intracorneal rings, because reduction of corneal central power is only 2 diopters at 24 months after cross-linking, besides, crosslinking itself, is not capable of improving irregular topography in the case of Pellucid Marginal Degeneration. An example of mechanical remodeling with intracorneal rings is presented, followed by crosslinking (Fig. 21.5).
Figure 21.5: Corneoplastics using combine technique for pellucid marginal degeneration: Only one inferior Keraring segment followed by crosslinking. Orbscan dual map axial topography map shows three principles of corneoplasics: Improving optics, topography and refraction
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Figure 21.6: Case example treating ectasia with topo-guided PRK and cross-linking pentacam treatment plan and differential map
COMBINING TREATMENTS EXPERIENCES Given the early success of the C3-R treatment, researchers in the United States and around the world are investigating the effectiveness of combining it with other existing approaches. Wachler compared C3-R with Intacs to Intacs alone as a treatment for keratoconus. 4 They found that you can get an augmented effect by combining the treatments. They first placed the intacs, and then applied the riboflavin treatment. The intacs with C3-R group showed significantly greater flattening in K-steep and K-average than in the Intacs-only group, as well as significantly greater reduction in manifest cylinder. However, the changes in BCVA and UCVA were not statistically significantly different between the two groups.4,5
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CROSS-LINKING AND PRK One of the most promising uses of the C3-R procedure is in combination with a modified version of PRK. In about 200 of the 300 cases Kanellopoulos has used the cross-linking technique followed some months after by PRK, using the WaveLight topography-guided laser platform to normalize the shape of the cornea.6 This procedure combines a myopic PRK over the apex of the cone with a segment of hyperopic PRK at the opposite side of the cornea (Fig. 21.6). The combination flattens the ectatic part of the cornea and steepens the part of the cornea that’s very flat. As a result, you’re removing very little tissue but making the cornea smoother. Kanellopoulos notes that this type of PRK is a specialized intervention because treating the refractive
CORNEOPLASTICS USING CORNEAL COLLAGEN CROSS-LINKING AND INTRACORNEAL RINGS OF KERATOCONUS AND LASIK ECTASIA
error isn’t necessarily the goal. The goal is to normalize the cornea as much as possible to increase BSCVA. BSCVA increases if you decrease the amount of irregular astigmatism. So the number one treatment target is cylinder, and to improve the irregular astigmatism and the number two target is correcting some of the sphere. More importantly, that eye does not need a cornea transplant. Some surgeons might argue that this could be done using wavefront-guided technology. In mild cases of ectasia that’s true. However, a wavefront-guided system will try to ablate tissue until it’s all equal, so it removes three times as much. Tissue reserve is a big issue in ectasia cases. Kanellopoulos has manifested, one surprising effect of the cross-linking treatment is that corneal tissue reacts differently to laser ablation, which is an issue if the cornea is cross-linked before ablation. In cross-linked corneas consistently get more refractive result than expected. He hasn’t yet found a formula to compensate for the difference. As we know, keratoconus requires very irregular ablations. However, undercorrecting by 25 percent is recommended to play it safe. Once it
was clear that this sequential approach of cross-linking first followed by PRK 6 months after, it has been safe and effective combination, now the procedures can be taken simultaneously the very same day. REFERENCES 1. Alio J. Corneoplastics emerging as the newer frontier in corneal therapies. Ocular Surgery News Europe/AsiaPacific Edition. 2007. 2. Wollensak G. Cross-linking treatment of progressive keratoconus: New Hope. Curr Opin Ophthalmol 2006;17:4:356-60. 3. Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Para surgical therapy for keratoconus by riboflavinultraviolet type A rays induced cross-linking of corneal collagen: Preliminary refractive results in an Italian study. J Cataract Refract Surg 2006;32:5:837-45. 4. Chan CCK, Sharma M, Boxer Wachler BS. The effect of inferior segment Intacs with and without corneal collagen cross-linking with riboflavin (C3-R) on keratoconus. J Cataract Refract Surg 2007;33:75-80. 5. Kent C. Update: Managing and predicting ectasia. Review Ophthalmology 2007;14. 6. Kanellopoulos. Perfecting Cross-linking with PRK. IntraLase users meeting. ASCRS Chicago 2008.
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COLLAGEN CORNEAL CROSS-LINKING DIFFERENT TECHNIQUES
INTRODUCTION A number of new technologies are becoming available to cornea and refractive surgeons for the treatment of corneal irregularities such as keratoconus and postLASIK Keratectasia and irregular astigmatism.The new approaches involve corneoplastics procedures to remodel the cornea through mechanical techniques (intracorneal rings), biochemical techniques (crosslinking), and mixed methods (laser ablation). Corneal collagen cross-linking represents a new therapeutic option for delaying or halting keratoectasia in progressive keratoconus and post-LASIK ectasia. The basic technique was developed in Dresden in 1998 by Wollensak, Spoerl and Seiler, however, it was not until 2003 that the first clinical trial data in 22 first patients was published by the same authors.1 Collagen cross-linking described by Seiler might halt and even slightly reverse the progression of keratoconus.The aim of this technique is to strengthen lamellar fibers, thereby restoring the cornea’s structural integrity. The aim of the present chapter is to describe the different techniques for cornea collagen cross-linking that have been described: • Original Seiler cross-linking technique • Caporossi cross-linking technique • Kanellopoulos IntraLase cross-linking technique • Sánchez-León modified post-LASIK ectasia crosslinking technique • PTK cross-linking technique • Simultaneous topo-guided PRK and cross-linking Keratoconus is a condition in which the tensile strength of the cornea’s lamellar fibers diminish to about half of their normal values, causing the cornea to assume a conical shape with an off-centre apex, and resulting in irregular astigmatism. The condition generally first appears when a patient is between 10 and 20 years of age. In most cases the deformation of the cornea progresses up to a certain point and then stops as mysteriously as it began.When this occurs, the condition is called forme fruste keratoconus. However, in the case of “frank” keratoconus the condition becomes progressively worse for several decades, perhaps even for the lifetime of the patient, although the progression slows over time. Topography studies suggest that forme fruste keratoconus has an incidence of about 5:1000, while progressive keratoconus has an incidence of about 1- 2:1000. With
collagen cross-linking it may be possible to transform the progressive form of keratoconus into the more benign, forme fruste keratoconus. SEILER CROSS-LINKING TECHNIQUE Collagen cross-linking stiffens collagen by creating new chemical bonds between collagen molecules. It occurs naturally as a consequence of ageing and diabetes. In fact, type 1 diabetes provides complete protection against keratoconus. 2 After experimenting with several techniques to induce collagen cross-linking in human corneal tissue, Seiler and his associates decided that the application of riboflavin (vitamin B2) combined with UV radiation offered the most favorable safety/efficacy ratio. In that technique the ultraviolet light causes riboflavin to release oxygen radicals, which in turn create new crosslinking bonds between lamellar fibers and within the collagen molecules. Seiler’s procedure involves the scraping of the epithelium from the central 9.0 mm of the cornea, the application of riboflavin in 20% dextrane, and irradiation of the area with 3mW/cm2 of ultraviolet light at a wavelength of 365 nm for 30 minutes (Figure 22.1). Based on animal experiments and early clinical experience they found that these parameters happened to be the best combination for an optimal stiffening (1.5-fold) and maximal safety. Moreover, in vitro und in vivo-experiments showed that with the current parameters there was no apoptosis of endothelial cells if the corneal thickness was at least 400 microns. CLINICAL TRIAL CONFIRMS EFFICACY OF COLLAGEN CROSS-LINKING Clinical results so far suggest that not only does the collagen cross-linking achieved in this way halt the
Figure 22.1: Seiler cross-linking original technique
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progression of keratoconus, but it also causes keratoconic corneas to assume a more normal shape with consequent improvements in visual acuity. In a study involving 26 eyes of 25 keratoconus patients who underwent the cross-linking treatment, corneal topography showed progression halted in every case after a follow-up of one to five years (mean 2.4 years). In addition, maximal K-readings decreased by a mean of 1.38 D (p<0.01) and were significantly reduced in 65% of the cases. Furthermore, visual acuity improved by a mean of 1.3 lines (p< 0.01). Today, it is possible by medical and therapeutic means to transform keratoconus into the forme fruste state.3 CAPOROSSI CROSS-LINKING TECHNIQUE SIENA EYE CROSS PROJECT The technique of Riboflavin UV-A collagen crosslinking 4,5 involves the photo-polymerization of corneal collagen by increasing chemical inter- and intra-helical bond formation. This mechanism of molecular cross-linking allows the cornea to build strength and a resistance to ectasia. The mechanism of hardening and thickening the cornea is mediated by a photodynamic reaction between the photosensitizer Riboflavin 0.1 % / Dextrane 20% solution (Ricrolin; Sooft, Italy) and low-dose UV-A irradiation (3 mW/ cm2 ) with a total exposure time of 30 minutes. The release of reactive oxygen species (ROS) during the reaction stimulates covalent bond formation between collagen fibers. At the University of Siena, the UV-A irradiation is delivered by a solid state UV-A illuminator named CBM. (Caporossi-Baiocchi-Mazzotta) X-Linker VEGA, which is CE-marked.5,8
circular illumination spot and the biggest and most constant in its diameter. In order to do this, they increased the cross-linkable area to 11 mm, by using an illuminator made of a five UV-A LED array (37010), mounted on a heat sink system in the source head of the equipment and powered by a stabilized circuit to provide an energy equal to a safe and efficient value (5.4 J/cm2 , thus 3.0 mW/cm2 as power density). A second goal of the project was to increase the working distance up to 1.5-1.8 cm to operate more efficiently on the cornea. A further goal was to achieve a sharper focus and improved adjustment control of the UV-A spot. This particular feature was obtained by inserting two low-power red laser sources into the optical head, thus not interfering with the “therapeutic” wavelength, as aiming-beam function.8 To achieve direct control of the whole procedure and of the focusing function, they inserted a microcolor-camera into the center of the UV-A array to show, in real-time mode, the correct aiming-beam alignment so that we could control the correct centering of the irradiated area. The “live” picture is shown on an LCD monitor mounted on the control unit of the equipment8 (Figure 22.2). This particular visual-control feature plays a very important role in maintaining constant UV-A irradiation. This is particularly important because a
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The only difference on the illuminators between the Siena project and the Dresden original technology was in the energy stabilizing system (CM controller). The new illuminator was designed to obtain a timely, homogeneous irradiation, thus avoiding the emission peak and energy decrease related to battery pack systems. In 2005 the “CBM X linker” was created (Caporossi-Baiocchi-Mazzotta cross-linker),6,8 and the aim of this new technology was to obtain the most
Figure 22.2: The “live” picture is shown on the LCD monitor, mounted on the control unit of the new CBM-VEGA. The monitor also shows the elapsed time and the current step of the procedure
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±1 mm defocus can diminish the energy provided to the corneal tissue by 8-10%. A 0.2 mm decentration can cause the same decrease in energy, while a 0.5 mm increase in decentration is associated with a 20% decrease in the energy that reaches the corneal apex. The monitor displays important information for the surgeon during the procedure, such as the current stage of the operation, device calibration, staining phase with related timer from 10 to 30 minutes, and elapsed treatment time for each five-minute step (steps one to six). Finally, a new feature is the camera-coaxial fixation point, which makes ocular alignment fixation easier for the patient. THE RESULTS Since 2004, 44 eyes were treated, each affected by growing keratoconus, clinically and instrumentally reported. The mean age of patients was 23.2 years of age (between 14 and 42 years). All patients in this Eye Cross Study were treated in accordance with the Siena Eye Cross protocol (Dresden modified) with crosslinking Riboflavin UV-A.5-7 Patients were followed up to 24 months postoperatively. Temporary haze was observed in a few cases (15%; four within the first three months, one case after six months), however, this disappeared after one month of therapy with preservative-free topical steroids. The most common side effect reported during the first postoperative month was temporary corneal edema (15 days/three months), which disappeared progressively after steroid and topical NSAID administration. No delayed re-epithelialization or endothelial damage was apparent during the 24-month follow-up period, and there were no incidences of keratoconus worsening in any of the treated eyes during follow-up. An average decrease in K-reading of around 1.5 D was observed. The average, top-line results achieved in the 44 eyes of the Siena Eye Cross Study are shown in Table 22.1 22.1. On the whole, all eyes demonstrated refractive stability 24 months after treatment, without any clinical or instrumental signs of the disease returning.
Table 22.1: Data collected after 24 months from 44 eyes treated in accordance with the Siena Eye Cross protocol (Dresden modified) with cross-linking Riboflavin UV-A
Parameter
24-month follow-up (average result)
K topographic value
Reduction of >2D
UCVA
Improvement of 2.7 Snellen lines
BSCVA
Improvement of 1.9 Snellen lines
Symmetry
Improvement > 70%
Aberrations
Significant reduction in comatic aberrations
collagen fibers if we remove or not remove the epithelium. Some researches are in favor of leaving the epithelium intact in order to achieve a faster visual rehabilitation and diminish of the symptoms. Kanellopoulos has promoted a new technique especially designed for an early disease or forme fruste keratoconus, using the IntraLase femtoseconds laser to create a corneal pocket at 100 microns depth, and only 5’ of side cut, then instilling a one-time, onedose amount of 0.1% riboflavin in that pocket. With these technique we would be able to cross-link the cornea selectively, 60 microns above the pocket and 200 microns below without having to remove the corneal epithelium Figures 22.3A to D. Kanellopoulos’ team has been experimenting with cutting down the amount of time needed for the procedure. They are experimenting with delivering the same energy in a shorter amount of time by doubling the fluence. They have found that 7 milliwatts per square centimeter may be a reasonable means of cutting down on the treatment time, going from 30 minutes to 15 with the same total irradiance of about 5.5 joules.9 METHODS • 10 keratoconic cornea were cross-linked utilizing • 7mW ’ 15 minutes UVA irradiation of 370 nm wavelength (5.2 joules) • Intracorneal 0.1% riboflavin instillation assisted by a 100 micron in depth and 7 mm in diameter pocket created with the IntraLase femtoseconds laser (5 degree side cut).
KANELLOPOULOS INTRALASE CROSSLINKING TECHNIQUE
RESULTS
There is an international controversy about if the procedure will induce cross-linking of the corneal
• The biomechanic effect compared favorably to previously published techniques
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Figures 22.3A to D: Kanellopoulos IntraLase cross-linking technique 100 microns, 7 mm OZ IntraLase pocket is created (A). Intra-stromal pocket dissection (B). Riboflavin is injected at the intra-stromal (C). UV light exposure (D)
• Keratometry reduced by 1.7D and spherical equivalent reduced by 1.5 D. • The procedure was minimally uncomfortable in all patients. • No endothelial cell change • Follow-up 8-4 months (average 7 months). SANCHEZ-LEÓN MODIFIED TECHNIQUE FOR LASIK ECTASIA
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We have decided to treat some patients with Lasik ectasia leaving the epithelium intact for a fast visual recovery and to reduce the symptoms. We consider using some of the steps suggested by Kanellopoulos IntraLase cross-linking technique. The procedure consist in identify the Lasik flap edge, followed by gently 10’ opening using a Sinsky hook. Then an IntraLase Lasik spatula (Rehin, inc.) is used to create an intra-stromal pocket, leaving the rest of the margin of the flap intact. The 0.1% Riboflavin is instilled direct in to the stromal space. A ring of weck cell sponge is
used in order to protect the limbal steam cells. Finally the UV- cross-linking light is used for 30 minutes Figures 22.4. We have observed that this technique produces similar biomechanical benefit and minimal discomfort for the patients. We present a dual Orbscan map post Lasik ectasia case to show the benefit of this technique, with intact epithelium. The postoperative axial topography map shows some improvement and a reduction of 0.5 Dt of central corneal power is noticed also, at 3 months follow-up Figure 22.5. PTK CROSS-LINKING TECHNIQUE Just recently our group have been attempted to remove the epithelium using the excimer laser PTK mode. The laser is programmed to treat 40 microns and 7 mm of optical zone. We think this approach may be recommended in order to promote a smother epithelial regeneration and particularly helpful in those cases with previous radial keratotomy. As we know many cases with previous incisional corneal techniques suffer
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Figures 22.4A to D: Sánchez-León modified post-LASIK ectasia cross-linking technique. Epithelium remains intact to promote fast visual recovery. Pocket dissection is performed under the flap (A). Riboflavin is injected at the intra-stromal space (B). A weck cell material shield is used to protect the limbal area (C). UV light exposure (D)
Figure 22.5: Cross-linking after LASIK ectasia. Postoperative axial topography map shows some improvement and a reduction of 0.5 Dt of central corneal power also, at 3 months follow-up
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of unstable cornea, and they can benefit of a crosslinking procedure, so scraping the epithelium can open the unhealed corneal wounds and affect our final result.10 SIMULTANEOUS TOPO-GUIDED PRK AND CROSS-LINKING This subject is covered at the end of the Corneoplastics using corneal collagen cross-linking and intracorneal rings for keratoconus and lasik ectasia chapter. While the time progress we have observed that the original corneal collagen cross-linking therapeutic option delay or halt keratoectasia in progressive keratoconus and post-LASIK ectasia. Latest attempts leaving an intact epithelium, have been tough in order to fast visual rehabilitation and reducing the symptoms. These techniques seems to offer same biomechanical benefits. REFERENCES 1. Kunath GS, Manifest H. Diabetes and keratoconus: a retrospective case-control study. Graefes Arch Clin Exp Ophthalmol. 2000;238(10):822-25. 2. Seiler T. New Approaches for Corneal Remodeling for Refractive Surgery. ESCRS Symposium Report. Eurotimes. 2005.
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3. Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Parasurgical therapy for keratoconus by riboflavinultraviolet type A rays induced cross-linking of corneal collagen: preliminary refractive results in an Italian study. J Cataract Refract Surg 2006;32(5):837-45. 4. Mazzotta C, Traversi C, Baiocchi S, Sergio P, Caporossi T, Caporossi A. Conservative treatment of keratoconus by riboflavin-uva-induced cross-linking of corneal collagen: qualitative investigation. Eur J Ophthalmol 2006; 16(4):530-35. 5. C Mazzotta, et al. Treatment of progressive keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: ultrastructural analysis by Heidelberg Retinal Tomography II in vivo confocal microscopy in humans. Cornea 2007;26(4):390-97. 6. R Mencucci, C Mazzotta, et al. Riboflavin and ultraviolet A collagen cross-linking: in vivo thermographic analysis of the corneal surface. J. Cataract Refract. Surg. 2007;33(6):1005-8. 7. A Caporossi, S Baiocchi, C Mazzotta. La Voce AICCER, 2006;4. 8. Kanellopoulos Wollensak, E Spoerl, T Seiler. Riboflavin/ ultraviolet-a-induced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-27. 9. Seiler T, Huhle Keratoconus: at a crossroads. EyeWorld 2008. 10. Walcher B. Cross-linking may halt hyperopia progression after corneal refractive procedures. Ocular Surgery News US Edition 2006;1.
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INTRODUCTION The development of corneal ectasia is a wellrecognized complication of LASIK and amongst other contributory factors, unrecognized preoperative forme fruste keratoconus is also an important one. Patients with this disorder are poor candidates for refractive surgery because of the possibility of exacerbating keratectasia. It is known that posterior corneal elevation is an early presenting sign in keratoconus and hence it is imperative to evaluate posterior corneal curvature (PCC) in every LASIK candidate. TOPOGRAPHY Topography is valuable for preoperative ophthalmic examination of LASIK candidates. Three-dimensional imaging allows surgeons to look at corneal thickness, as well as the corneal anterior and posterior surface and it can also predict the shape of the cornea after LASIK surgery. Topographic analysis using three dimensional slit scan system allows us to predict which candidates would do well with LASIK and also confers the ability to screen for subtle configurations which may be a contraindication to LASIK. ORBSCAN
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The Orbscan (Bausch and Lomb) corneal topography system uses a scanning optical slit scan which makes it fundamentally different from the corneal topography that analyzes the reflected images from the anterior corneal surface. The high-resolution video camera captures 40 light slits at 45 degrees angle projected through the cornea similarly as seen during slit lamp examination. The slits are projected on to the anterior segment of the eye: the anterior cornea, the posterior cornea, the anterior iris and anterior lens. The data collected from these four surfaces are used to create a topographic map. Each surface point from the diffusely reflected slit beams that over-lap in the central 5-mm zone is independently triangulated to x, y, and z coordinates, providing three-dimensional data. This technique provides more information about the anterior segment of the eye, such as anterior and posterior corneal curvature, elevation maps of the anterior and posterior corneal surface and corneal
thickness. It has an acquisition time of 4 seconds.1 This improves the diagnostic accuracy. It also has passive eye-tracker from frame to frame and 43 frames are taken to ensure accuracy. It is easy to interpret and has good repeatability. PRIMARY POSTERIOR CORNEAL ELEVATION The diagnosis of frank keratoconus is a clinical one. Early diagnosis of forme fruste can be difficult on clinical examination alone. Orbscan has become a useful tool for evaluating the disease, and with its advent, abnormalities in posterior corneal surface topography have been identified in keratoconus. Posterior corneal surface data is problematic because it is not a direct measure and there is little published information on normal values for each age group. In the patient with increased posterior corneal elevation in the absence of other changes, it is unknown whether this finding represents a manifestation of early keratoconus. The decision to proceed with refractive surgery is therefore more difficult. Posterior Corneal Topography One should always use the Orbscan system to evaluate potential LASIK candidates preoperatively to rule out primary posterior corneal elevations. Eyes are screened using quad maps with the normal band (NB) filter turned on. Four maps include (a) anterior corneal elevation: NB = ± 25 µ of best-fit sphere. (b) posterior corneal elvevation : NB = ± 25 µ of best fit sphere. (c) Keratometric mean curvature: NB = 40 to 48 D (d) Corneal thickness (pachymetry): NB = 500 to 600 µ. Map features within normal band are colored green. This effectively filters out variations falling within the normal band. When abnormalities are seen on normal band quad map screening, a standard scale quad map should be examined. For those cases with posterior corneal elevation, three-dimensional views of posterior corneal elevation can also be generated. In all eyes with posterior corneal elevation, the following parameters are generated (a) radii of anterior and posterior curvature of the cornea, (b) posterior best fit sphere, (c) difference between the corneal pachymetry value in 7 mm zone and thinnest pachymetry value of the cornea.
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Figure 23.1: Showing general quad map of an eye with primary posterior corneal elevation. Notice the red areas seen in the top right picture showing the primary posterior corneal elevation
Preexisting Posterior Corneal Abnormalities Figures 23.1 to 23.6 show the various topographic features of an eye with primary posterior corneal elevation detected during pre-LASIK assessment. In Figure 23.1 (general quad map) upper left corner map is the anterior float, upper right corner map is posterior float, lower left corner is keratometric map while the lower right is the pachymetry map showing a difference of 100 µm between the thickest pachymetry value in 7 mm zone of cornea and thinnest pachymetry value. In Figure 23.2, normal band scale map of anterior surface shows “with the rule astigmatism” in an otherwise normal anterior surface (shown in green), the posterior float shows significant elevation inferotemporally. In Figure 23.2 only the abnormal areas are shown in red for ease in detection. Figure 23.3 is three-dimensional representation of the maps in Figure 23.2. Figure 23.4 shows threedimensional representation of anterior corneal surface with reference sphere. Figure 23.5 shows threedimensional representation of posterior corneal surface
showing a significant posterior corneal elevation. Figure 23.6 shows amount of elevation (color coded) of the posterior corneal surface in microns (50 µm). In the light of the fact that keratoconus may have posterior corneal elevation as the earliest manifestation, preoperative analysis of posterior corneal curvature to detect a posterior corneal bulge is important to avoid post LASIK keratectasia. The rate of progression of posterior corneal elevation to frank keratoconus is unknown. It is also difficult to specify that exact amount of posterior corneal elevation beyond which it may be unsafe to carry out LASIK. Atypical elevation in the posterior corneal map more than 45 µm should alert us against a post LASIK surprise. Orbscan provides reliable, reproducible data of the posterior corneal surface and all LASIK candidates must be evaluated by this method preoperatively to detect an “ early keratoconus”. Elevation is not measured directly by Placido based topographers, but certain assumptions allow the construction of elevation maps. Elevation of a point
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Figure 23.2: Showing quad map with normal band scale filter on in the same eye as in Figure
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Figure 23.3: Showing three-dimensional normal band scale map. In the top right note the red areas which shows the elevation on the posterior cornea. The anterior cornea is normal
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Figure 23.4: Showing three-dimensional anterior float. Notice it is normal
Figure 23.5: Showing three-dimensional posterior float. Notice in this there is marked elevation as seen in the red areas
on the corneal surface displays the height of the point on the corneal surface relative to a spherical reference surface. Reference surface is chosen to be a sphere. Best mathematical approximation of the actual corneal surface called best-fit sphere is calculated. One of the criteria for defining forme fruste keratoconus is a posterior best fit sphere of > 55.0 D. Ratio of radii of anterior to posterior curvature of cornea > 1.21 and < 1.27 has been considered as a keratoconus suspect . Average pachymetry difference between thickest and the thinnest point on the cornea in the 7 mm zone should normally be less than 100 µm.
Agarwal Criteria to Diagnose Primary Posterior Corneal Elevation 1. Ratio of the Radii of anterior and posterior curvature of the cornea should be more than 1.2. In Figure 23.2 note the radii of the anterior curvature is 7.86 mm and the radii of the posterior curvature is 6.02 mm. The ratio is 1.3. 2. Posterior best fit sphere should be more than 52 D. In Figure 23.2 note the posterior best fit sphere is 56.1 D. 3. Difference between the thickest and thinnest corneal pachymetry value in the 7 mm zone should be more than 100 microns. The thickest
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Figure 23.6: Showing three-dimensional posterior corneal elevation measured in microns
pachymetry value as seen in Figure 23.2 is 651 microns and the thinnest value is 409 microns. The difference is 242 microns. 4. The thinnest point on the cornea should correspond with the highest point of elevation of the posterior corneal surface. The thinnest point as seen in Figure 23.2 bottom right picture is seen as a cross. This point or cursor corresponds to the same cross or cursor in Figure 23.2 top right picture which indicates the highest point of elevation on the posterior cornea. 5. Elevation of the posterior corneal surface should be more than 45 microns above the posterior best fit sphere. In Figure 23.2 you will notice it is 0.062 mm or 62 microns. IATROGENIC KERATECTASIA
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Iatrogenic keratectasia may be seen in some patients following ablative refractive surgery (Figs 23.7 and 23.8). The anterior cornea is composed of alternating collagen fibrils and has a more complicated interwoven structure than the deeper stroma and it acts as the major
stress-bearing layer. The flap used for LASIK is made in this layer and thus results in a weakening of that strongest layer of the cornea which contributes maximum to the biomechanical stability of the cornea. The residual bed thickness (RBT) of the cornea is the crucial factor contributing to the biomechanical stability of the cornea after LASIK. The flap as such does not contribute much after its repositioning to the stromal bed. This is easily seen by the fact that the flap can be easily lifted up even up to 1 year after treatment. The decreased RBT as well as the lamellar cut in the cornea both contribute to the decreased biomechanical stability of the cornea. A reduction in the RBT results in a long term increase in the surface parallel stress on the cornea. The intraocular pressure (IOP) can cause further forward bowing and thinning of a structurally compromised cornea. Inadvertent excessive eye rubbing, prone position sleeping, and the normal wear and tear of the cornea may also play a role. The RBT should not be less than 250 mm to avoid subsequent iatrogenic keratectasias.2–4 Reoperations should be undertaken very carefully in corneas
POSTERIOR CORNEAL CHANGES IN REFRACTIVE SURGERY
Figure 23.7: Shows a patient with iatrogenic keratectasia after lasik. Note the upper right hand corner pictures showing the posterior float has thinning and this is also seen in the bottom right picture in which pachymetry reading is 329
Figure 23.8: Shows the same patient with iatrogenic keratectasia after lasik in a 3 D pattern. Notice the ectasia seen clearly in the bottom right picture
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with RBT less than 300 mm. Increasing myopia after every operation is known as “dandelion keratectasia”. The ablation diameter also plays a very important role in LASIK. Postoperative optical distortions are more common with diameters less than 5.5 mm. Use of larger ablation diameters implies a lesser RBT postoperatively. Considering the formula: Ablation depth [ mm] = 1/3 . (diameter [mm])2 x (intended correction diopters [D])), 4,5 it becomes clear that to preserve a sufficient bed thickness, the range of myopic correction is limited and the upper limit of possible myopic correction may be around 12 D.6 Detection of a mild keratectasia requires knowledge about the posterior curvature of the cornea. Posterior corneal surface topographic changes after LASIK are known. Increased negative keratometric diopters and oblate asphericity of the PCC, which correlate significantly with the intended correction are common after LASIK leading to mild keratectasia.6,7 This change in posterior power and the risk of keratectasia was more significant with a RBT of 250 µm or less.8 The difference in the refractive indices results in a 0.2 D difference at the back surface of the cornea becoming equivalent to a 2.0 D change in the front surface of the cornea. 6 Increase in posterior power and asphericity also correlates with the difference between the intended and achieved correction 3 months after LASIK. This is because factors like drying of the stromal bed may result in an ablation depth more than that intended.6 Reinstein et al predict that the standard deviation of uncertainty in predicting the RBT preoperatively is around 30 µm. [Invest Ophthalmol Vis Sci 40 (Suppl):S403, 1999]. Age, attempted correction, the optical zone diameter and the flap thickness are other parameters that have to be considered to avoid post LASIK ectasia.9,10 The flap thickness may not be uniform throughout its length. In studies by Seitz et al, it has been shown that the Moris Model One microkeratome and the Supratome cut deeper towards the hinge, whereas the Automated Corneal Shaper and the Hansatome create flaps that are thinner towards the hinge. Thus, accordingly, the area of corneal ectasia may not be in the center but paracentral, especially if it is also associated with decentered ablation. Flap thickness has also been found to vary considerably, even upto 40 µm, under similar conditions and this may also result in a lesser RBT than intended.11-17
It is known that corneal ectasias and keratoconus have posterior corneal elevation as the earliest manifestation.18 The precise course of progression of posterior corneal elevation to frank keratoconus is not known. Hence it is necessary to study the posterior corneal surface preoperatively in all LASIK candidates. EFFECT OF POSTERIOR CORNEAL CHANGE ON IOL CALCULATION IOL power calculation in post-LASIK eyes is different because of the inaccuracy of keratometry, change in anterior and posterior corneal curvatures, altered relation between the two and change in the standardized index of refraction of the cornea. Irregular astigmatism induced by the procedure, decentered ablations and central islands also add to the problem. Routine keratometry is not accurate in these patients. Corneal refractive surgery changes the asphericity of the cornea and also produces a wide range of powers in the central 5 mm zone of the cornea. LASIK makes the cornea of a myope more oblate so that keratometry values may be taken from the more peripheral steeper area of the cornea, which results in calculation of a lower than required IOL power resulting in a hyperopic “surprise”. Hyperopic LASIK makes the cornea more prolate, thus resulting in a myopic “surprise” post-cataract surgery. Post-PRK or LASIK, the relation between the anterior and posterior corneal surface changes. The relative thickness of the various corneal layers, each having a different refractive index also changes and there is a change in the curvature of the posterior corneal surface. All these result in the standardized refractive index of 1.3375 no longer being accurate in these eyes. At present there is no keratometry, which can accurately measure the anterior and posterior curvatures of the cornea. The Orbscan also makes mathematical assumptions of the posterior surface rather than direct measurements. This is important in the LASIK patient because the procedure alters the relation between the anterior and posterior surfaces of the cornea as well as changes the curvature of the posterior cornea. Thus direct measurements such as manual and automated keratometry and topography are inherently inaccurate in these patients. The corneal power is
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therefore calculated by the calculation method, the contact lens overrefraction method and by the CVK method. The flattest K reading obtained by any method is taken for IOL power calculation (the steepest K is taken for hyperopes who had undergone LASIK). One can still aim for -1.00 D of myopia rather than emmetropia to allow for any error, which is almost always in the hyperopic direction in case of pre-LASIK myopes. Also, a third or fourth generation IOL calculating formula should be used for such patients. REFERENCES 1. Fedor P, Kaufman S Corneal topography and imaging. eMedicine Journal 2001;2:6. 2. Seiler T, Koufala K, Richter G. Iatrogenic keratectasia after laser in situ keratomileusis. J Refract Surg 1998;14(3):31217. 3. Seiler T, Quurke A W. Iatrogenic keratectasia after laser in situ keratomileusis in a case of Forme Fruste keratoconus. J Refract Surg 1998;24(7):1007-09. 4. Probost LE, Machat JJ. Mathematics of laser in situ keratomileusis for high myopia. J Cataract refract Surg 1998;24. 5. Mc Donnell PJ. Excimer laser corneal surgery: new strategies and old enemies (review). Invest Ophthalmol Vis Sci 1995;36;4-8. 6. Seitz B, Torres F, Langenbucher A, et al. Posterior corneal curvature changes after myopic laser in situ keratomileusis. Ophthalmology 2001;108(4):666-72. 7. Geggel HS, Talley AR. Delayed onset keratectasia following laser in situ keratomileusis. J Cataract Refract Surg 1999;25(4):582-86.
8. Wang Z, Chen J, Yang B. Posterior corneal surface topographic changes after laser in situ keratomileusis are related to residual corneal bed thickness. Ophthalmology 1999;106(2):406-09. 9. Pallikaris IG, Kymionis GD, Astyrakakis NI. Corneal ectasia induced by laser in situ keratomileusis. J Cataract Refract Surg 2001;27(11):1796-802. 10. Argento C, Cosentino M J, Tytium A, et al. Corneal ectasia after laser in situ keratomileusis. J Cataract Refract Surg 2001;27(9):1440-48. 11. Binder PS, Moore M. Lambert RW et al. Comparison of two microkeratome systems. J refract Surg 1997;13;14253. 12. Hofmann RF, Bechara SJ. An independent evaluation of second generation suction microkeratomes. Refract Corneal Surg 1992;8:348-54. 13. Schuler A, Jessen K, Hoffmann F. accuracy of the microkeratome keratectomies in pig eyes. Invest Ophthalmol Vis Sci 1990;31:2022-30. 14. Behrens A, Seitz B, Langenbucher A, et al. Evaluation of corneal flap dimensions and cut quality using a manually guided microkeratome (published erratum appears in J Refract Surg 1999;15:400). J Refract Surg 1999;15:11823. 15. Behrens A, Seitz B, Langenbucher A, et al. Evaluation of corneal flap dimensions and cut quality using the Automated Corneal Shaper microkeratome. J Refract Surg 2000;16:83-89. 16. BehrensA, Langenbucher A, Kus MM, et al. Experimental evaluation of two current generation automated microkeratomes: The Hansatome® and the Supratome®. Am J Ophthalmol 2000;129:59-67. 17. Jacobs BJ, Deutsch TA, Rubenstein JB. Reproducibility of corneal flap thickness in LASIK. Ophthalmic Surg Lasers 1999;30:350-53. 18. McDermott G K Topography’s benefits for LASIK. Review of Ophthalmology. Editorial 9:03 issue.
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COMPLICATIONS WITH THE USE OF COLLAGEN CROSS-LINKING
We have employed collagen cross-linking with the last six years in the treatment of ectasia after refractive surgery such as LASIK and PRK as well as the treatment of primary keratoconus with relative success. In our center, we have now treated over 800 cases of primary keratoconus and/or ectasia following refractive surgery and in over 500 cases we combined the cross-linking treatment with the use of partial topography-guided PRK procedure in order to facilitate visual rehabilitation. Complications have been very seldom with our technique and they go as follows: We have experimented in the laboratory with the use of different riboflavin solution concentrations and different levels of energy and we have found that by doubling the concentration of riboflavin one can enhance as it has been described literature CCL by tenfold and create opaque patches in the cornea that will present significantly cross linked tissue. We have not encountered this combination clinically even in our more recent studies in using high fluence UV light at the level of 7 mW and the level 15 mW. In all cases performed that it remains a potential complication and one has to be careful to calibrate the distance that UV light sources place from the level of the cornea as well as the fluence of the light source are for each case to avoid over exposure and potential toxic levels of UV light that could create significant cornea opacities. Second group of potential complication is infection. We have seen some such complications that are very rare and 750 cases that we have treated we have encountered only one infection that was cured within few days with the use of topical 45 vancomycin solution and it is attributed to either contamination of the surgical field during the removal of epithelium and/ or the contamination of riboflavin drops. Therefore, our technique is advised we have changed our technique of the epithelium removal and utilizing excimer laser episcrape looking into seriously advantage of the no touch technique of the cornea epithelium and the reduction of the possibility of transferring pathogens up to the cornea surface and to the stroma with the CCL process. Obviously, single use packaging for the riboflavin solution is essential in order to avoid contamination, from patient to patient, through the riboflavin solution. The infection though since lot of these patients remain
with a bandage lens for the several days remains an important potential complication and it had been some reports in literature and some that I am unfamiliar with personal complications that mandate significant antibiotic prophylaxis and striae technique for the procedure whatsoever. Third group of complications is potential endothelial toxicity from high levels of free oxygen radical information at the endothelial level and this can potentially happen with high fluence of riboflavin, with high concentration of riboflavin at the endothelial level, higher fluence of UV light and thinner cornea than expected. It has been reported by the zero group in the past, and it has been recommended by that group that cornea is thinner than 400 microns thinnest/total cornea thickness to use hypotonic riboflavin solution in order to induce some cornea edema, and for the cornea to reach thickness over 400 microns and avoid this potential complication. In overall experience, we have used riboflavin solution created by Priavision that is likely hypotonic at 350 millios small and 0.1% riboflavin sodium phosphate concentration and we have not encountered even in corneas with total cornea thickness of 350 microns any endothelial toxicity. We have encountered though in almost 1000 cases that we have treated so far, a couple cases that had transit cornea edema by interestingly enough did not drop the endothelium cell count when measured at 6 month interval. The endothelium toxicity remains a significant fact to be considered and mandate caution as we had published in the past along with the original basic science work done on CCL. Last combination treatments of using a partial PRK after CCL or a combination with CCL brings a new group of potential complication such as persistence epithelium defects by these two treatments are combined, especially when mitomycin is used to avoid cornea scarring. Permanent cornea scarring that we encountered more in cases that we treated with PRK after the cross-linking procedure, we reduce this complication significantly when the two treatments were combined, partial topography-guided PRK first and then collagen cross-linking , but potential scaring from cross-linking alone or from the combination treatment of cross-linking simultaneously with refractive procedure or later time treated with refractive
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MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES
procedure remains a potential complication since we have light poud of care sight at 300 microns depth with the CCL procedure which will generate has been shown in basic signs and treatments as well in within 3 months after the procedure. This would mean that if one patient with crosslinking underwent a PRK procedure six months after the original CCL procedure, freshly we populate cure sight might be activated in higher scaring may be anticipated. This is definitely being our experience in we presented in several AAO meetings and press currently. So basically, a collagen cross-linking although minimally invasive for the rest of the eye pauses the potential risk of cornea infection, thus mandating proper active treatment and sterile technique as well as good control of the surgical environment and the sterility of the riboflavin solution. The potential over or under cross-linking, the potential of endothelium toxicity, from free oxygen radicals reaching the level of the cornea endothelium and creating a permanent cornea endothelium damage as well as potentional
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scaring when perform a lower combined with partial PRK. Last potential complications that I have not mentioned is the potential of regeneration of ectasia following cross-linking, it had been some reports and this happening in otherwise stable patients that had become pregnant, so pregnancy may pause a high risk for ectasia in cornea even after collagen cross-linking and there had been some anecdotal reports of ectasia resulting after a cornea has been stabilized with collagen cross-linking and then treated with a PRK procedure. This would make sense if the PRK procedure removed significant amount of tissue and creating a significant biomechanical change in the cornea producing more vulnerable situation for ectasia. The benefits though from this procedure are far away the potential risks and when used with caution I think we reward patients and clinicians are like as it has in our clinical practice by reducing significant in the number of penetrating keratoplasty utilized for visual rehabilitation with keratoconus and cornea ectasias.
Index A Advances in corneoplastique™ 56 Applications of collagen corneal crosslinking 64 applications 66 basic science behind C3-R treatment 65 C3-R and IOP values 68 C3-R and post-LASIK ectasia 66 C3-R and pseudophakic bullous keratopathy 68 C3-R enhanced PRK in keratoconic eyes 67 C3-R for progressive hyperopic following RK 67 C3-R treatment in pellucid marginal degeneration 67 C3-R with INTACS 66 corneal melts and C3-R 68 infectious corneal ulcers and C3-R 68 mechanism of C3-R treatment 65 pregnancy and estrogen 67 Avoiding keratoconus in patients undergoing refractive surgery 15
B Biophysical aspects of collagen corneal cross-linking 25 relevant anatomy 26 risk and side effects 28 studies 26 surgical techniques 26 treatment 28
C C3-R combined with intrastromal ring segment implantation and overnight contact lens molding in keratoconus 98 link to the video 101 purpose, methods and materials 100 results 105
C3-R® (Collagen cross-linking) 125 Collagen corneal cross-linking in postLASIK corneal ectasia 21 collagen cross-linking 22 combined treatments 23 post-LASIK corneal ectasia 22 potential complications and preventions 23 results 23 biomechanical results 23 clinical results 23 risk factors 22 surgical techniques 22 therapeutic options 22 Collagen corneal cross-linking techniques 140 Caporossi cross-linking technique Siena eye cross project 142 efficacy of collagen cross-linking 141 results 143 Seiler cross-linking techniques 141 Complications with the use of collagen cross-linking 156 Considerations on endothelial safety in UV-A–cross-linking treatment 44 materials and methods 46 Corneal biomechanical properties 5 terminology 6 corneal hysteresis 6 corneal resistance factor 6 Corneal biomechanical properties in normal, keratoconic eyes and post-LASIK eyes 7 Corneal collagen cross-liking in keratoconus 92 clinical results 95 effects of cross-linking on corneal stroma 93 biochemical effects 93 biomechanical effects 93 effect on collagenase resistance 93 effects on hydration behavior 93 morphological effects 93 thermomechanical effects 93
effects of cross-linking on keratocytes 93 contraindications in keratoconus 94 follow-up 94 indications in keratoconus 94 surgical procedure 94 risks and side effects 95 Corneal collagen cross-linking (C3-R) 1 exclusion criteria 3 future prospects 4 indications for C3-R treatment 3 parameters for C3-R treatment 3 physiology 2 postoperative follow-up 4 preoperative work up for C3-R treatment 3 steps of C3-R technique 3 Corneal collagen cross-linking and irregular astigmatism 83 clinical outcomes 84 Corneal collagen cross-linking with riboflavin and ultraviolet a light 51 preparation of 0.1% riboflavin solution 53 riboflavin and ultraviolet a light 52 safety 54 step by step technique 53 technique background 52 Corneal ectasia 9 assessment 10 orbscan 10 pentacam 11 risk factors 13 Corneoplastics using corneal collagen cross-linking and intracorneal rings 134 combining new and old techniques 135 combining treatments experiences 138 cross-linking and PRK 138 unfinished business 136 Corneoplastique™ in action 57 Cross-linking effect in eyes with INTACS 111
MASTERING CORNEAL COLLAGEN CROSS-LINKING TECHNIQUES Cross-linking in keratoconus 132 advantages 133 complications 133 disadvantages 133 Cross-linking plus topography-guided PRK for post-LASIK ectasia management 69 options for treatment 70
E Effect of posterior corneal change on IOL calculation 154 Epithelium and cornea permeability 112 statistical analysis 115 surgical technique 114
G Grid pattern epithelial debridement 31 Gulani classification system for laser surgery in keratoconus 121 laser as primary treatment 121 laser as secondary treatment 121
I Iatrogenic keratectasia 152 Importance of epithelial debridement for riboflavin absorption 29 methodology 30 results 32 Improvement in visual acuity 71 INTACS combined with corneal collagen cross-linking and irregular astigmatism 84 INTACS effect on keratoconic eyes 111
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Intracorneal ring segments and irregular astigmatism 82 clinical outcomes 82
K Kanellopoulos intralase cross-linking technique 143 methods 143 results 143 Keratoconus progression 28
M Minimal corneal thickness 75
R Riboflavin and their mechanism of action on the cornea 25 Riboflavin plus UV-A 31
S Sanchez-León modified technique for LASIK ectasia 144 Siena eye cross project 142 Simultaneous topo-guided PRK and cross-linking 146 Spectrophotometry in porcine corneas 29 Spheric and cylindric values 117
T O Ocular response analyzer ORA 6
P Posterior corneal changes in refractive surgery 147 orbscan 148 primary posterior corneal elevation 148 Agarwal criteria to diagnose primary posterior corneal elevation 151 posterior corneal topography 148 preexisting posterior corneal abnormalities 149 topography 148 Prophylactic treatment 28 PTK cross-linking technique 144
Tetracaine plus riboflavin 31 Traditional technique vs transepithelial technique 38 contraindications 39 indications 39 personal experience 39 results 40 Transepithelial cross-liking for the treatment of keratoconus 87 corneal collagen networks 88 corneal epithelium 89 photochemical cross-linking 89 riboflavin-UV-A treatment 89 Transepithelial cross-linking treatment in eyes with INTACS 110 Treatment of iatrogenic keratectasia 71
U Unaided emmetropia 58
