Management of Early Progressive Corneal Ectasia Accelerated Crosslinking Principles Cosimo Mazzotta Frederik Raiskup Stefano Baiocchi Giuliano Scarcelli Marc D. Friedman Claudio Traversi 123 Management of Early Progressive Corneal Ectasia Cosimo Mazzotta • Frederik Raiskup Stefano Baiocchi • Giuliano Scarcelli Marc D. Friedman • Claudio Traversi Management of Early Progressive Corneal Ectasia Accelerated Crosslinking Principles Cosimo Mazzotta Frederik Raiskup Ophthalmology Speciality School Siena Department of Ophthalmology University and Siena Crosslinking Center Carl Gustav Carus University Siena Dresden Italy Germany Stefano Baiocchi Giuliano Scarcelli Ophthalmology Speciality School Department of Bioengineering Siena University University of Maryland Siena College Park, Maryland Italy USA Marc D. Friedman Claudio Traversi Avedro Ophthalmology Speciality School Waltham, Massachusetts Siena University USA Siena Italy ISBN 978-3-319-61136-5 ISBN 978-3-319-61137-2 (eBook) DOI 10.1007/978-3-319-61137-2 Library of Congress Control Number: 2017952041 © Springer International Publishing AG 2017 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland To Paola, Martina, Giulia and Lucia and to all Authors’ Families Preface For the last 10 years the advent of Riboflavin-UV-A-induced crosslinking (CXL) has drastically modified the natural history of Keratoconus and secondary corneal ectasia therapy. The number of corneal transplants for Keratoconus has notably reduced over a 30% drop in the last 5 years. Potentially correct and early use of CXL, at an early stage, can lead to its annulment in the next 5–10 years with notable savings for the health care system, of expenses for patients, and above all, radically improving patient quality of life which for years had been the “sword of Damocles” of surgery. This ambitious goal is possible if ophthalmologists pay ever more atten- tion to timely diagnosis and early treatment, especially in the paediatric age. Early identification of Keratoconus is the fundamental stage in this “ideal path”. The Scheimpflug cameras and new partial optical coherence light-based (OCT) tomog- raphers available in the clinical practice allow us to “surprise” the illness at its onset. One can, at this point, hypothesize a treatment that immediately stabilizes the pathological process, impeding its evolution, and most importantly stabilizing the cornea when the refractive defect is still modest and correctable, without difficulties with spectacles or contact lenses. Over 10 years have passed since the effective introduction of corneal CXL therapy, and the Dresden protocol remains the most important point of reference because it is the most studied and the most used, as well as the protocol with the most valued clinical results and longest follow-up. The fields of application have rapidly stretched from keratoconus to iatrogenic second- ary ectasias, especially post-Lasik, with excellent results and more recently extended to the treatment of therapy-resistant infectious keratitis. Nonetheless, the conven- tional CXL (C-CXL) protocol has shown some limits: the excessive duration (1 h), the need to remove the epithelium, post-operative pain, risk of infection, haze devel- opment (stromal wound healing complications), endothelial risks for thin corneas and long waiting lists. Recently, thanks to the principles articulated in the Bunsen- Roscoe law, accelerated crosslinking treatments (A-CXL) have emerged with the objective of shortening the procedure, maintaining efficiency. Some of these pro- posals are proving to be valid alternatives of the conventional CXL protocol, while other techniques such as super-fast A-CXL, trans-epithelial and iontophoresis- assisted CXL (I-CXL) have shown notable limits and are thus to be modified and evaluated in the long term, large number of cases and different age groups. Another challenging chapter is the attempt to combine treatments of improving the aberro- metric and refractive defect induced by Keratoconus. This is a dream for all patients vii viii Preface who are intolerant of contact lenses: stopping Keratoconus progression and simul- taneously improving the visual acuity without the necessity of resorting to corneal transplants. The so-called “Crosslinking plus” is already a reality for selected cases, reserved for patients with scarce visual acuity and intolerant to contact lenses, who are usually candidates for lamellar keratoplasty. The existence of clinical and instru- mental parameters permits these people to attempt a stabilizing approach associated with contemporary refractive empowerment or postponement before thinking about replacement surgery. The ball is rolling, but adjustments are necessary for patient ease and repetitive, satisfying results. Crosslinking is a therapy that has changed the story of Keratoconus all over the world, and it is in continuous evolution. Accelerated CXL procedures illustrated in the book will be the leading part of the future cross- linking revolution. Acknowledgements Special Thanks To Prof. Gian Marco Tosi, Head of the Ophthalmology Unit, Department of Medicine, Surgery and Neurosciences of Siena University, IT Prof. Ennio Polito, Head of the Post-Graduate Ophthalmology School of Siena University, IT and to Prof. Eberhard Spoerl, Ph.D., Dresden Technical University, GE Dr. Joshua N. Webb, Ph.D., University of Maryland, USA Dr. Robert Herber, Dresden Technical University, GE Dr. Janine Lenk, Dresden Technical University, GE Dr. Miguel Rechichi, M.D., Ph.D., Eye Center, Catanzaro, IT Dr. Mario Fruschelli, Ophthalmology Unit, Siena University, IT Dr. Maria Margherita De Santi, Dept. Human Pathology, Siena University, IT Dr. Pietro Rosetta, Humanitas University, Milan, IT *Dr. Yulia Litasova, Siena University, IT *Dr. Fiorella Fusco, Siena University, IT *Dr. Pierfrancesco Mellace, Siena University, IT *Dr. Simone Alex Bagaglia, Siena University, IT *Dr. Maria Eugenia Latronico, Siena University, IT *Dr. Gennaro Chimenti, Siena University, IT *Dr. Marco Capozzoli, Siena University, IT *Dr. Francesco Rana, Siena University, IT *Dr. Stefano Fazio, Siena University, IT *Dr. Tommaso Bacci, Siena University, IT *Dr. Francesco Martino, Siena University, IT *Dr. Giulia Esposti, Siena University, IT *Dr. Maria Sole Polito, Post-Graduate Ophthalmology School, Turin University, IT *Dr. Antonio Tarantello, Siena University, IT *Dr. Pietro Mittica, Siena University, IT *Dr. Giulia Cratocci, Siena University, IT +Dr. Giovanni Neri, Siena University, IT *Post-Graduate Ophthalmology School, Siena University, IT Mrs. Jennifer Berkeley for English editing of the Book ix Contents 1 Principles of Accelerated Corneal Collagen Cross-Linking . . . . . . . . . 1 1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 Corneal Structure and Ectasia Pathophysiology . . . . . . . . . . . . . . . . 1 1.2.1 Keratoconic Microstructure . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.2.2 Corneal Cross-Links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1.2.3 Standard Crosslinking and the “Dresden Protocol” . . . . . . . . 6 1.3 Accelerated Crosslinking, Photochemical Kinetic Principles . . . . . . 7 1.3.1 Laboratory Methods for Quantifying Crosslinking . . . . . . . . 8 1.3.2 Photochemical Kinetics of Corneal Crosslinking with Riboflavin and UVA Light . . . . . . . . . . . . . . . . . . . . . . . . 11 1.4 Clinical Correlation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 1.5 Accelerated Crosslinking Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 1.6 Accelerated Crosslinking Applications . . . . . . . . . . . . . . . . . . . . . . . . 25 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 2 Crosslinking Results and Literature Overview . . . . . . . . . . . . . . . . . . . . 33 2.1 Conventional Crosslinking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 2.1.1 The Standard “Dresden Protocol” . . . . . . . . . . . . . . . . . . . . . . 33 2.1.2 Medical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 2.1.3 Evidence of Progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 2.1.4 Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 2.1.5 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 2.1.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 2.2 T ransepithelial Crosslinking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 2.3 Accelerated Crosslinking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 2.3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 2.3.2 The 9 mW/cm2 Accelerated CXL . . . . . . . . . . . . . . . . . . . . . . 43 2.3.3 The 18 mW/cm2 Accelerated CXL . . . . . . . . . . . . . . . . . . . . . 45 2.3.4 The 30 mW/cm2 Accelerated CXL . . . . . . . . . . . . . . . . . . . . . 46 2.3.5 The 45 mW/cm2 Accelerated CXL . . . . . . . . . . . . . . . . . . . . . 49 2.3.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 2.4 Crosslinking for Paediatric Keratoconus: 10 Years-Follow-Up . . . . . . 50 2.4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 2.4.2 Demographic Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 xi xii Contents 2.4.3 Surgical Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 2.4.4 Clinical Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 2.4.5 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 2.4.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 3 Crosslinking Evidences In-Vitro and In-Vivo . . . . . . . . . . . . . . . . . . . . 63 3.1 H istology After Accelerated Cross-Linking (ACXL) . . . . . . . . . . . . 63 3.1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 3.1.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 3.1.3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 3.1.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 3.1.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 3.2 In Vivo Confocal Microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 3.2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 3.2.2 Stromal Healing After CXL . . . . . . . . . . . . . . . . . . . . . . . . . . 80 3.2.3 Epithelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 3.2.4 Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 3.2.5 Endothelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 3.2.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 3.3 Biomechanical Measurement: Brillouin Microscopy . . . . . . . . . . . . 87 3.3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 3.3.2 Measuring Corneal Biomechanics . . . . . . . . . . . . . . . . . . . . . 88 3.3.3 Brillouin Microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 3.3.4 Brillouin Microscopy to Assess CXL Mechanical Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 3.3.5 The Future of Brillouin Technology . . . . . . . . . . . . . . . . . . . 93 3.3.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 4 A ccelerated Crosslinking Protocols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 4.1 Dresden Accelerated CXL Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 4.2 Siena Crosslinking Center® Accelerated CXL Protocol . . . . . . . . . . 104 4.2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 4.2.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 4.2.3 Surgical Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 4.2.4 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 4.2.5 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 4.3 Transepithelial ACXL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 4.3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 4.3.2 Iontophoresis-CXL (I-CXL) . . . . . . . . . . . . . . . . . . . . . . . . . 112 4.4 Thin Corneas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 4.4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 4.4.2 Hypo-osmolar Riboflavin Solution . . . . . . . . . . . . . . . . . . . . 117 4.4.3 Transepithelial CXL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 4.4.4 Customized Pachymetry Guided Epithelial Debridement . . . 118