VetBooks.ir VetBooks.ir VetBooks.ir Advances In The Canine Cranial Cruciate Ligament VetBooks.ir VetBooks.ir Advances In The Canine Cranial Cruciate Ligament Second Edition Edited by Peter Muir BVSc, MVetClinStud, PhD, Diplomate ACVS, ECVS VetBooks.ir This edition first published 2018 © 2018 ACVS Foundation This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. Edition History 1st Edition © 2010 ACVS Foundation; 2nd Edition © 2018 ACVS Foundation All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Peter Muir to be identified as the author of the editorial material in this work has been asserted in accordance with law. Registered Office John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA Editorial Office 111 River Street, Hoboken, NJ 07030, USA For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. 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Library of Congress Cataloging-in-Publication Data Names: Muir, Peter, BVSc, editor. | American College of Veterinary Surgeons. Foundation, issuing body. Title: Advances in the canine cranial cruciate ligament / edited by Peter Muir. Description: Second edition. | Hoboken, NJ : Wiley ; [United States] : American College of Veterinary Surgeons Foundation, 2018. | Includes bibliographical references and index. | Identifiers: LCCN 2017026733 (print) | LCCN 2017027885 (ebook) | ISBN 9781119261735 (pdf) | ISBN 9781119261742 (epub) | ISBN 9781119261711 (cloth) Subjects: | MESH: Dog Diseases–surgery | Anterior Cruciate Ligament | Dogs–injuries | Orthopaedic Procedures–veterinary | Rupture–veterinary | Rupture, Spontaneous–veterinary Classification: LCC SF991 (ebook) | LCC SF991 .A38 2018 (print) | NLM SF 991 | DDC 636.7/0897582059–dc23 LC record available at https://lccn.loc.gov/2017026733 Cover Design: Wiley Cover Images: Courtesy of Peter Muir Set in 9.5/11.5pt PalatinoStd by Aptara Inc., New Delhi, India 10 9 8 7 6 5 4 3 2 1 VetBooks.ir Dedication This book is dedicated to Susannah Sample, to my family, and to all of my colleagues who have contributed effort to advancing the understanding of canine cruciate ligament rupture, and the treatment of affected dogs. VetBooks.ir VetBooks.ir Contents About the Editor Foreword to the Second Edition Kenneth A. Johnson Foreword R. Randy Basinger, ACVS Foundation Preface Peter Muir xi xiii xvii xix Contributing Authors xxi I Structure and Function 1 Introduction Peter Muir 1 2 Biomechanics of the Cruciate Ligaments Susannah J. Sample 3 Cruciate Ligament Remodeling and Repair Connie S. Chamberlain, Erin E. Crowley, and Ray Vanderby Jr. 4 Meniscal Structure and Function Antonio Pozzi and James L. Cook 39 xv Acknowledgements Peter Muir 1 Morphology and Function of the Cruciate Ligaments Hilde de Rooster and Eithne Comerford 5 Biomechanics of the Normal and Cranial Cruciate Ligament-Deficient Stifle Antonio Pozzi and Stanley E. Kim 3 13 21 31 II Etiopathogenesis of Cruciate Ligament Rupture Introduction Peter Muir 45 45 6 Histology of Cruciate Ligament Rupture Kei Hayashi 47 7 Genetics of Cruciate Ligament Rupture Lauren A. Baker and Peter Muir 57 8 Cruciate Ligament Matrix Metabolism and Development of Laxity Eithne Comerford 9 Morphological Risk Factors for Cruciate Ligament Rupture Eithne Comerford 10 Role of Nitric Oxide Production and Matrix Protease Activity in Cruciate Ligament Degeneration David E. Spreng and Simone Forterre 11 Role of Antibodies to Collagen Type I and II Hilde de Rooster and Eithne Comerford 65 73 81 89 vii VetBooks.ir viii Contents 12 Synovitis Precedes Stifle Instability Associated with Cruciate Ligament Rupture Jason A. Bleedorn 13 Role of Synovial Immune Responses in Stifle Synovitis Peter Muir III Clinical Features Introduction Peter Muir 93 101 107 107 14 Epidemiology of Cruciate Ligament Rupture Lauren A. Baker and Peter Muir 109 15 History and Clinical Signs of Cruciate Ligament Rupture Peter Muir 115 16 Partial Rupture of the Cranial Cruciate Ligament Peter Muir 119 17 Caudal Cruciate Ligament Rupture Peter Muir 123 18 Stress Imaging of the Stifle Stanley E. Kim 127 19 Stifle Ultrasonography Cristi R. Cook 135 20 Computed Tomography (CT) of the Stifle Ingrid Gielen and Henri van Bree 141 21 Magnetic Resonance Imaging of the Stifle Peter V. Scrivani 155 22 Risk Prediction of Cruciate Ligament Rupture using Stifle Diagnostic Imaging Peter Muir IV Surgical Treatment Introduction Peter Muir 165 169 169 23 Arthroscopy and Arthrotomy of the Stifle Brian S. Beale, Donald A. Hulse, Antonio Pozzi, and Peter Muir 171 24 Joint Lavage Peter Muir 185 25 Extracapsular Stabilization Selena Tinga and Stanley E. Kim 189 26 Intra-Articular Repair for Cranial Cruciate Ligament Rupture in the Dog Jeffery J. Biskup and Michael G. Conzemius 201 27 Tibial Plateau Leveling Osteotomy Susan L. Schaefer 217 28 Tibial Tuberosity Advancement Randy J. Boudrieau 227 29 Closing Cranial Wedge Ostectomy and Triple Tibial Osteotomy Simon C. Roe 243 30 Treatment of Excessive Tibial Plateau Angle Michael P. Kowaleski 253 31 Surgical Management of Cruciate Ligament Rupture Combined with Patella Luxation Anke Langenbach and Denis J. Marcellin-Little 261 32 Biomechanics of the Cranial Cruciate Ligament-Deficient Stifle Treated by Tibial Osteotomies Antonio Pozzi, Stanley E. Kim, and Selena Tinga 271 33 Arthroscopic Follow-Up after Surgical Stabilization of the Stifle Brian S. Beale and Donald A. Hulse 34 Cranial Cruciate Ligament Debridement David E. Spreng 279 291 VetBooks.ir Contents 35 Surgical Treatment of Concurrent Meniscal Injury Samuel P. Franklin, James L. Cook, and Antonio Pozzi 36 Meniscal Release Antonio Pozzi and James L. Cook 37 Progression of Osteoarthritis after Stifle Stabilization Surgery Susannah J. Sample 38 Clinical Outcomes after Surgical Treatment of Cruciate Ligament Rupture Mary Sarah Bergh and Steven C. Budsberg 39 Success and Failure after Stifle Stabilization Surgery Michael G. Conzemius and Richard B. Evans 40 Diagnosis and Management of Orthopaedic Infection after Stifle Surgery Noël M.M. Moens V Medical Management of Cruciate Ligament Rupture Introduction Peter Muir 41 Medical Therapy for Stifle Osteoarthritis Steven C. Budsberg 295 42 Rehabilitation for Dogs with Cruciate Ligament Rupture Denis J. Marcellin-Little and Courtney J. Arnoldy ix 343 301 VI Future Directions 307 313 Introduction Peter Muir 43 Clinical Research Design and Patient-Oriented Outcomes Dorothy Cimino Brown 44 Total Knee Replacement in the Dog Matthew J. Allen, William D. Liska, and Valentina Brioschi 317 323 331 331 333 45 Regenerative Medicine and Cranial Cruciate Ligament Repair Gabriel S. Perrone, Martha M. Murray, and Patrick Vavken 353 353 355 363 371 46 Disease-Modifying Medical and Cell-Based Therapy Susannah J. Sample and Peter Muir 379 Index 385 VetBooks.ir VetBooks.ir About the Editor Peter Muir BVSc, MVetClinStud, PhD, Diplomate ACVS, ECVS. Dr Muir obtained his veterinary degree in 1985 from Bristol University in the United Kingdom. After working in private practice in the UK, he returned to Bristol and obtained a PhD in veterinary science in 1990. He then moved to The University of Sydney to undertake training in small animal surgery, obtaining a Masters degree in 1992. He completed his surgery training at the University of Wisconsin-Madison and became a Diplomate of the American College of Veterinary Surgeons in 1995. After periods on faculty at the University of California, Davis and the Royal Veterinary College, University of London, he returned to Madison as a faculty member, where he is currently the Melita Grunow Family Professor of Companion Animal Health. He has authored many peerreviewed publications on stifle osteoarthritis and cruciate ligament rupture and speaks regularly at international meetings on this work. xi VetBooks.ir VetBooks.ir Foreword to the Second Edition The popularity and success of the First Edition of this authoritative collection of work on canine cranial cruciate ligament rupture has been an impetus to launch a thoroughly revised new, Second Edition. This move is easily justifiable considering the immense clinical importance of this disease in small animal clinical practice, and also the numerous advances that have been made in knowledge about the problem in the last few years. The appeal of this book to the busy clinician is that all the latest developments are assembled under one umbrella in this volume. The editor of this volume, Dr Peter Muir, has arranged and organized the various chapters in a coherent manner that takes the reader from the basics of the disease pathophysiology, through the essence of diagnosis and treatment options, to a view of the future. As is generally the case in science, the everincreasing body of knowledge has really served to expose the apparently growing complexity of the problem of canine cruciate ligament rupture. To achieve the best possible outcome for each and every dog presented with this problem, it is no longer acceptable to have just one standard surgical treatment that we use in every case. We must be even more meticulous in objectively assessing each patient, and consider how we manage concurrent problems such as meniscal injury or patellar luxation. Also, advanced imaging is assuming an increasingly useful role in detecting variability in skeletal and articular morphology that can require modification in surgical technique. Furthermore, the development of dynamic imaging has allowed us to learn more about motion of the cruciate-deficient stifle during ambulation and full weight-bearing, before and after surgery. These are very exciting developments that we need to carefully and critically evaluate, and embrace as appropriate. Dr Muir and all the contributing authors are warmly congratulated on the production of this new edition. However, as I previously foreshadowed in my foreword to the First Edition, I do suspect that in another few years, we will again be ready for yet another new edition! Kenneth A. Johnson Sydney, Australia xiii VetBooks.ir VetBooks.ir Foreword The American College of Veterinary Surgeons Foundation is excited to present the Second Edition of Advances in the Canine Cranial Cruciate Ligament in the book series entitled Advances in Veterinary Surgery. The American College of Veterinary Surgeons (ACVS) Foundation is an independently charted philanthropic organization devoted to advancing the charitable, educational and scientific goals of the ACVS. Founded in 1965, the ACVS sets the standards for the specialty of veterinary surgery. The ACVS, which is approved by the American Veterinary Medical Association, administers the board certification process for Diplomates in veterinary surgery and advances veterinary surgery and education. One of the principle goals of the ACVS Foundation is to foster the advancement of the art and science of veterinary surgery. The Foundation achieves these goals by: supporting investigations in the diagnosis and treatment of surgical diseases; increasing educational opportunities for surgeons, surgical residents and veterinary practitioners; improving the surgical training of residents and veterinary students; and bettering animal patients’ care, treatment, and welfare. This collaboration with WileyBlackwell will benefit all who are interested in veterinary surgery by presenting the latest evidence-based information on a particular surgical topic. Advances in the Canine Cranial Cruciate Ligament is edited by Dr Peter Muir, who is well recognized as an expert in this field. He has chosen a group of strong contributing authors to detail the areas of structure and function, etiopathogenesis, clinical features, surgical and medical management, and postoperative care and rehabilitation. We are sure you will find this reference extremely valuable. The ACVS Foundation is proud to partner with Wiley-Blackwell in this important series, and is honored to present this newest book in the Advances in Veterinary Surgery series. R. Randy Basinger Chair, Board of Trustees ACVS Foundation xv VetBooks.ir VetBooks.ir Preface Although cruciate ligament rupture has been recognized clinically in dogs for more than 50 years, research into this condition has largely focused on the development of methods for surgical treatment of the unstable stifle, and not the disease mechanism. Cruciate ligament rupture is one of the most common reasons that dogs are presented to veterinarians for the treatment of lameness. It has been a long-held clinical belief that the disease mechanism for cruciate ligament rupture in dogs is similar to that for anterior cruciate ligament rupture in human beings. Over the past 10 years there has been increasing recognition that second ruptures are common in both human beings and dogs. Historically, the dog has been a common animal model for research into the surgical treatment of anterior cruciate ligament rupture. Transection of the cranial cruciate ligament in experimental dogs has also been a common ani- mal model for biomedical research studies of osteoarthritis. During the past 15 years, an increasing body of work investigating the disease mechanism for cruciate ligament rupture has been published. Cruciate ligament rupture in the dog is a complex trait, with genetic and environmental factors contributing to disease risk. This research is challenging established views about what causes cruciate ligament rupture and how affected dogs should be managed clinically. My goals for the Second Edition of this book were to produce a text that summarizes state of the art knowledge about cruciate ligament rupture in the dog, including recent advances in the past 5 years, to provide a useful reference for a broad audience, and to highlight areas for development of future work in this field. Peter Muir xvii VetBooks.ir VetBooks.ir Acknowledgements I would like to acknowledge the consistent support of Erica Judisch of Wiley Blackwell, and of Dr Mark Markel, Chair of the ACVS Foundation’s Board of Trustees for the Advances in Veterinary Surgery book series. I am extremely grateful to all of the chapter authors who have consistently been very committed to this project and have made such amazing and thoughtful contributions to this book. I am also grateful to all of the organizations that have pro- vided financial support for clinical research into canine cruciate ligament rupture. Without these gifts, my work and the work of many others that is summarized in this book would not have been possible. Lastly, I would like to thank dog owners and breeders for their interest in and enthusiasm for new knowledge regarding this important orthopaedic condition. Peter Muir xix VetBooks.ir VetBooks.ir Contributing Authors Matthew J. Allen, Vet MB, PhD, MRCVS Professor of Small Animal Surgery Director, Surgical Discovery Centre University of Cambridge Department of Veterinary Medicine Madingley Road Cambridge CB3 0ES United Kingdom e-mail: mja1000@cam.ac.uk Courtney J. Arnoldy, CCRP Physical Therapist University of Wisconsin-Madison School of Veterinary Medicine UW Veterinary Care Hospital 2015 Linden Drive Madison, Wisconsin 53706 USA e-mail: courtney.arnoldy@wisc.edu Lauren A. Baker, DVM, MS Post-doctoral Fellow Comparative Orthopaedic and Genetics Research Laboratory University of Wisconsin-Madison School of Veterinary Medicine 2015 Linden Drive Madison, Wisconsin 53706 USA e-mail: iwicki@wisc.edu Brian S. Beale, DVM, Diplomate ACVS Gulf Coast Veterinary Specialists 1111 West Loop South #160 Houston, TX 77027 USA e-mail: dogscoper@aol.com Mary Sarah Bergh, DVM, MS, Diplomate ACVS, ACVSMR Associate Professor, Orthopaedic Surgery Iowa State University College of Veterinary Medicine Department of Veterinary Clinical Sciences 1600 S. 16th Street Ames, IA 50011-1250 USA e-mail: msbergh@iastate.edu Jeffery J. Biskup, DVM, Diplomate ACVS-SA Assistant Professor University of Tennessee College of Veterinary Medicine Department of Small Animal Clinical Sciences 2407 River Drive Knoxville, TN 37996 USA e-mail: jbiskup@utk.edu Jason A. Bleedorn, DVM, MS, Dipomate ACVS Clinical Assistant Professor of Small Animal Orthopaedics University of Wisconsin-Madison School of Veterinary Medicine 2015 Linden Drive Madison, Wisconsin 53706 USA e-mail: jason.bleedorn@wisc.edu xxi VetBooks.ir xxii Contributing Authors Randy J. Boudrieau, DVM, Diplomate ACVS, ECVS Professor Tufts University Cummings School of Veterinary Medicine Department of Clinical Sciences 200 Westboro Road North Grafton, MA 01536 USA e-mail: randy.boudrieau@tufts.edu Valentina Brioschi, DVM, GPCert(SAS), MRCVS Senior Clinical Training Scholar in Small Animal Surgery University of Cambridge The Queen’s Veterinary School Hospital Madingley Road Cambridge CB3 0ES United Kingdom Dorothy Cimino Brown, MSCE, DVM, Diplomate ACVS Senior Research Advisor Translational Comparative Medical Research Elanco Animal Health 2500 Innovation Way Greenfield, IN 46140 USA e-mail: dottiedvm@gmail.com Steven C. Budsberg, DVM, MS, Diplomate ACVS Professor University of Georgia College of Veterinary Medicine Department of Small Animal Medicine & Surgery Athens, GA 30602 USA e-mail: budsberg@uga.edu Connie S. Chamberlain, PhD Assistant Scientist University of Wisconsin-Madison School of Medicine & Public Health Department of Orthopedics & Rehabilitation 1111 Highland Ave Madison, WI 53705 USA e-mail: cschamberlai@wisc.edu Eithne Comerford, BVSc, PhD, CertVR, DSAO, MRCVS Professor University of Liverpool Faculty of Veterinary Science Department of Veterinary Clinical Science Leahurst Chester High Road Neston, CH64 7TE United Kingdom e-mail: eithne.comerford@liverpool.ac.uk Michael G. Conzemius, DVM, PhD, Diplomate ACVS Endowned Professor of Surgery University of Minnesota College of Veterinary Medicine Department of Veterinary Clinical Sciences 1365 Gortner Avenue St Paul, MN 55108 USA e-mail: conze012@umn.edu Cristi R. Cook, DVM, MS, Diplomate ACVR Thompson Laboratory for Regenerative Orthopaedics Missouri Orthopaedic Institute University of Missouri-Columbia 1100 Virginia Avenue Columbia, MO 65212 USA e-mail: cookcr@missouri.edu James L. Cook, DVM, PhD, Diplomate ACVS William & Kathryn Allen Distinguished Professor in Orthopaedic Surgery Director, Comparative Orthopaedic Laboratory, Orthopaedic Research Division & Mizzou BioJoint Center Missouri Orthopaedic Institute University of Missouri 1100 Virginia Avenue Columbia, MO 65212 USA e-mail: cookjl@missouri.edu Erin E. Crowley, DVM Surgical Fellow University of Wisconsin-Madison School of Medicine & Public Health Department of Orthopedics & Rehabilitation VetBooks.ir Contributing Authors 1111 Highland Ave Madison, WI 53705 USA Hilde de Rooster, DVM, MVM, PhD, Diplomate ECVS Professor in Soft Tissue Surgery Ghent University Faculty of Veterinary Medicine Department of Small Animals Salisburylann 133 B-9820 Merelbeke Belgium e-mail: hilde.derooster@ugent.be Richard B. Evans, PhD Waukesha, WI 53189 USA e-mail: richard.bc.evans@gmail.com Simone Forterre, Dr. med. vet, PhD University of Bern Vetsuisse Faculty Bern Department of Clinical Veterinary Medicine Längassstrasse 128 CH-3012 Bern Switzerland Samuel P. Franklin, MS, DVM, PhD, Diplomate ACVS, ACVSMR Assistant Professor of Small Animal Orthopaedic Surgery University of Georgia Department of Small Animal Medicine & Surgery Veterinary Medical Center 2200 College Station Road Athens, GA 30602 USA e-mail: spfrank@uga.edu Ingrid Gielen, DVM, PhD, MSC Clinical Professor Department of Veterinary Medical Imaging & Small Animal Orthopaedics Ghent University Faculty of Veterinary Medicine Salisburylann 133 9230 Merelbeke Belgium xxiii Kei Hayashi, DVM, PhD, Diplomate ACVS Associate Professor Cornell University College of Veterinary Medicine Department of Clinical Sciences School of Veterinary Medicine Ithaca, NY 14853 USA e-mail: kh528@cornell.edu Donald A. Hulse, DVM, Diplomate ACVS Professor Texas A&M University Department of Small Animal Clinical Sciences College of Veterinary Medicine College Station, TX 77843 USA Kenneth A. Johnson, MVSc, PhD, FACVSc, Diplomate ACVS Professor The University of Sydney Faculty of Veterinary Science Sydney, NSW 2006 Australia e-mail: kennethjohnson@usyd.edu.au Stanley E. Kim, BVSc, MS, Diplomate ACVS Assistant Professor of Small Animal Surgery University of Florida College of Veterinary Medicine Department of Small Animal Clinical Sciences 2015 SW 16th Ave Gainsville, FL 32610 USA e-mail: stankim@ufl.edu Michael P. Kowaleski, DVM, Diplomate ACVS, ECVS Professor Tufts University Cummings School of Veterinary Medicine Department of Clinical Sciences 200 Westboro Road North Grafton, MA 01536 USA e-mail: mike.kowaleski@tufts.edu Anke Langenbach, Dr. med. Vet, Diplomate ACVS, ACVSMR Veterinary Surgical Centers 140 Part Street, SE VetBooks.ir xxiv Contributing Authors Vienna, VA 22180 USA USA e-mail: martha.murray@childrens.harvard.edu William D. Liska, DVM, Diplomate ACVS Global Veterinary Specialists 3130 Grants Lake Blvd Sugar Land, TX 77496 USA Gabriel S. Perrone Research Technologist Harvard University Boston Children’s Hospital Department of Orthopaedic Surgery 61 Binney Street, Enders 270.2 Boston, MA 02115 USA e-mail: gabriel.perrone@childrens.harvard.edu Denis J. Marcellin-Little, DEDV, Diplomate ACVS, ACVSMR Professor, Small Animal Orthopedic Surgery University of California, Davis School of Veterinary Medicine Department of Surgical and Radiological Sciences One Shields Avenue Davis, CA 95616 USA e-mail: djmarcel@ucdavis.edu Noël M.M. Moens, DVM, MSc, Diplomate ACVS, ECVS Associate Professor of Orthopaedic Surgery University of Guelph Ontario Veterinary College Department of Clinical Studies Guelph, ON N1G 2W1 Canada e-mail: nmoens@ovc.uoguelph.ca Peter Muir, BVSc, MVetClinStud, PhD, Diplomate ACVS, ECVS, MRCVS Melita Grunow Family Professor of Companion Animal Health University of Wisconsin-Madison School of Veterinary Medicine Department of Surgical Sciences 2015 Linden Drive Madison, Wisconsin 53706 USA e-mail: peter.muir@wisc.edu Martha M. Murray, MD Professor in Orthopedic Surgery Harvard University Boston Children’s Hospital Department of Orthopaedic Surgery Hunnewell 2 300 Longwood Avenue Boston, MA 02115 Antonio Pozzi, Prof. Dr. med. vet, Diplomate ACVS, ACVSMR University of Zurich Vetsuisse Faculty Clinic for Small Animal Surgery Winterthurerstrasse 258c 8057, Zurich Switzerland e-mail: apozzi@vetclinics.uzh.ch Simon C. Roe, BVSc, PhD, Diplomate ACVS Professor of Orthopaedic Surgery North Carolina State University College of Veterinary Medicine Department of Clinical Sciences 1052 William Moore Drive Raleigh, NC 27607 USA e-mail: simon_roe@ncsu.edu Susannah J. Sample, DVM, MS, PhD, Diplomate ACVS Assistant Scientist University of Wisconsin-Madison Comparative Orthopaedic and Genetics Research Laboratory School of Veterinary Medicine 2015 Linden Drive Madison, Wisconsin 53706 USA e-mail: susannah.sample@wisc.edu Susan L. Schaefer, DVM, MS, Diplomate ACVS Clinical Associate Professor of Small Animal Orthopaedics University of Wisconsin-Madison School of Veterinary Medicine Department of Surgical Sciences VetBooks.ir Contributing Authors 2015 Linden Drive Madison, Wisconsin 53706 USA e-mail: susan.schaefer@wisc.edu Peter V. Scrivani, DVM, Diplomate ACVR Associate Professor Cornell University College of Veterinary Medicine Department of Clinical Sciences Ithaca, NY 14853 USA e-mail: pvs2@cornell.edu David E. Spreng, Prof. Dr. Med. vet, Diplomate ECVS, ACVECC EMBA PHW University of Bern Vetsuisse Faculty Bern Department of Clinical Veterinary Medicine Längassstrasse 128 CH-3012 Bern Switzerland e-mail: david.spreng@vetsuisse.unibe.ch Selena Tinga, DVM Resident in Small Animal Surgery University of Florida College of Veterinary Medicine Department of Small Animal Clinical Sciences 2015 SW 16th Ave Gainsville, FL 32610 USA Email addresses are listed for corresponding authors for each chapter. Contact information, including email addresses, for contributors who are ACVS and ECVS Diplomates is also available from www.acvs.org and www.ecvs.org, respectively. xxv Henri Van Bree, DVM, PhD, Diplomate ECVDI, ECVS Professor Ghent University Faculty of Veterinary Medicine Department of Veterinary Medical Imaging & Small Animal Orthopaedics Salisburylann 133 B-9820 Merelbeke Belgium e-mail: henri.vanbree@ugent.be Ray Vanderby Jr., PhD Professor University of Wisconsin-Madison School of Medicine & Public Health Department of Orthopedics & Rehabilitation 1111 Highland Ave Madison, WI 53705 USA e-mail: ray.vanderby@wisc.edu Patrick Vavken, MD Lecturer in Orthopedic Surgery Harvard University Boston Children’s Hospital Department of Orthopedic Surgery Orthopedics, Enders 1016 300 Longwood Avenue Boston, MA 02115 USA e-mail: patrick.vavken@childrens.harvard.edu VetBooks.ir VetBooks.ir Section I Structure and Function Introduction The anatomy of canine stifle is complex. Our understanding of the anatomy of the cranial and caudal cruciate ligaments has gradually evolved over time, particularly with regard to the microvascular anatomy of the ligaments. Recent work suggesting the existence of a blood–cruciate ligament barrier, analogous to the blood–brain barrier, is a particularly interesting finding, which helps explain the mechanism that leads to incremental fiber rupture within the ligament matrix of both cruciate ligaments over time, and eventual rupture of the cranial cruciate ligament. In addition to their biomechanical role as joint stabilizers, the cranial and caudal cruciate ligaments likely have key functions in joint proprioception. In the future, advances in knowledge of ligament matrix homeostasis effects on cruciate ligament mechanical properties and associated joint laxity should provide insight into the ligament rupture mechanism. Variation in joint proprioception and joint laxity may ultimately explain how fiber rupture is initiated in the early phase of the disease. An important weakness with current surgical treatments for the unstable stifle is that repair of the ruptured cranial cruciate ligament is not performed. This section provides a detailed discussion of stifle anatomy, including gross and microscopic anatomy of the cruciate ligaments. Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 1 VetBooks.ir VetBooks.ir 1 Morphology and Function of the Cruciate Ligaments Hilde de Rooster and Eithne Comerford Introduction In contrast to the plethora of veterinary publications on cruciate surgery in dogs, only a few papers deal with the microanatomy and neurovascular anatomy of the canine cruciate ligaments. However, an understanding of the complex anatomy and function of these ligaments is imperative to elucidate the pathophysiology of cruciate ligament rupture, and to improve surgical intervention. Morphology Macroanatomy The cranial cruciate ligament (CrCL) attaches to the axial aspect of the lateral femoral condyle, very close to the articular margin (Figure 1.1). It extends diagonally across the joint space and attaches to the cranial intercondyloid area of the tibial plateau (Singleton 1957; Zahm 1965; Arnoczky & Marshall 1977). The proximal attachment site is bordered cranially by the cranial meniscotibial ligament of the medial meniscus and caudally by the cranial menis- cotibial ligament of the lateral meniscus (Rudy 1974; Heffron & Campbell 1978) (Figure 1.2). The CrCL is narrowest in its mid-region and fans out proximally and distally (Alm et al. 1975; Heffron & Campbell 1978). The length of the CrCL is positively correlated with body weight; taking the average length of its cranial and caudal borders, the mean length has been reported as 13.5–18.7 mm (Vasseur et al. 1985; Wingfield et al. 2000; Comerford et al. 2005). The CrCL runs cranially, medially, and distally in an outward spiral as it passes from the femur to the tibia (Zahm 1965; Haut & Little 1969). Two demonstrably separate bundles are apparent (Figure 1.1) (Arnoczky & Marshall 1977; Heffron & Campbell 1978); these components are termed craniomedial and caudolateral, based on their relative attachment sites onto the tibial plateau. The craniomedial subdivision is the most spiral and the longest, yet smaller, component, and arises more proximally from the femur and attaches more cranially on the tibial footprint area, compared with the caudolateral subdivision. The fibers of the caudolateral component arise from the most lateral and distal part of the attachment area of the lateral femoral condyle, have a straighter path, and Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 3 Structure and Function VetBooks.ir 4 2 5 6 3 4 1a 1b 7 (A) (B) Figure 1.1 Photograph (A) and line drawing (B) of a flexed right stifle joint of a dog. Cranial view after removal of the infrapatellar fat pad. In panel B: 1a, caudolateral bundle of the cranial cruciate ligament; 1b, craniomedial bundle of the cranial cruciate ligament; 2, caudal cruciate ligament; 3, medial meniscus; 4, lateral meniscus; 5, tendon of the long digital extensor; 6, medial femoral condyle; 7, tibial tuberosity. 12 11 4 10 5 1 9 3 2 6 (A) (B) 7 8 Figure 1.2 Photograph (A) and line drawing (B) of the left pelvic limb of a dog. Dorsal view on the tibial plateau after removal of the femur. In panel B: 1, cranial cruciate ligament; 2, caudal cruciate ligament; 3, medial meniscus; 4, intermeniscal ligament; 5, medial collateral ligament; 6, lateral meniscus; 7, meniscofemoral ligament; 8, popliteal tendon; 9, tendon of the long digital extensor; 10, infrapatellar fat pad; 11, patellar tendon; 12, patella. VetBooks.ir Morphology and Function of the Cruciate Ligaments attach on the most caudal region of the tibial footprint area (Arnoczky & Marshall 1977; Heffron & Campbell 1978). The caudal cruciate ligament (CaCL) is slightly longer and broader than the CrCL (Rudy 1974; Arnoczky & Marshall 1977; Harari 1993). Even its collagen fibrils are thicker compared with its cranial counterpart (Brunnberg 1989). The total mid-section diameter is smallest as it fans out from the center, making the femoral and, to a lesser extent, the tibial attachments larger (Rudy 1974). In the dog the CaCL also has two components, although they are less distinct and often inseparable (Heffron & Campbell 1978; Harari 1993). Microanatomy The cruciate ligaments are multifascicular structures, the base unit of which is collagen, that contain many wavy fascicular subunits (Figure 1.3A). Fascicles may be composed of one up to 10 subfascicles, containing bundles of collagen fibers (Heffron & Campbell 1978; Yahia & Drouin 1989). At the osseous attachment sites of the CrCL, the collagen fibers are not arranged entirely parallel to the longitudinal axis of the ligament and, especially in younger specimens, columns of 5 chondroid cells do penetrate into the ligament (Figure 1.3B) (Zahm 1965; Alm & Strömberg 1974). Where both cruciate ligaments are in contact, the collagen fibers are more densely packed and oriented tangential to the surface instead of parallel to the long axis (Vasseur et al. 1985). Fibers are formed by fibrils that are composed by organization of repeated collagen subunits (Alm & Strömberg 1974; Heffron & Campbell 1978; Vasseur et al. 1985). Their architecture is a combination of helical or planar, parallel, or twisted networks. The centrally located collagen fibrils are nearly straight, whereas those at the periphery are arranged in a helical wave pattern (Zahm 1965; Alm & Strömberg 1974; Yahia & Drouin 1989). Alongside collagen, elastin fibers and bundles of microfibrils (fibrillin 1 and 2) are abundant in cruciate ligaments, both within the collagen bundles and in the interfascicular regions (Figures 1.4AB) (Smith et al. 2011). Those fibers are predominantly orientated parallel to the collagen bundles, and this study suggested a mechanical role for their distribution during ligament deformation. As evident in other ligaments, the cruciate ligaments are characterized by relative hypocellularity. Where both cruciate ligaments are in contact, the epiligament is more cellular than anywhere else (Smith et al. 2012). In the interfascicular regions, the cells are interspersed TibialBone Cartilage B CrCL A Figure 1.3 Histologic section (H&E stain) of a normal cranial cruciate ligament (CrCL) of a 4-month-old Riezenschnauzer. (A) Along the CrCL, dense collagen is aligned parallel to the long axis of the ligament. The collagen fibers have a regular accordion-like pattern. (B) At the attachment site of the CrCL, the collagen is not arranged entirely parallel to the long axis of the ligament. Columns of chondroid cells (arrow) do penetrate into the CrCL (scale bar = 100 μm). Source: de Rooster et al. 2006. Reproduced with permission from John Wiley & Sons, Inc. (A) (B) Structure and Function VetBooks.ir 6 (A) (B) Figure 1.4 (A) Distribution of fibrillin-1 in the canine cruciate ligament complex, longitudinal section cranial cruciate ligament (CrCL), ×63 confocal laser scanning microscopy (CLSM) image, enzymatic pre-treatment. Fibrillin 1 (orange) is found pericellularly where nuclei are rounded (nuclei shown in blue). Staining of fibrillin 1 is also seen extending parallel to collagen in a fiber-like structure (arrows) from an elongated nucleus. Although some co-localization (yellow) is seen with elastin (green), elastin fibers were generally found to contain little fibrillin 1. Scale bar = 50 μm. (B) Distribution of fibrillin-2 in the canine cruciate ligament complex, longitudinal section CrCL, ×63 CLSM image from fascicular region showing fibrillin-2 (red) in long and dense fibers broadly aligned with collagen bundles, with some branching. Nuclei are stained with DAPI (blue). Scale bar = 50 μm. Source: Smith et al. 2011. Reproduced with permission from John Wiley & Sons, Inc. between bundles of collagenous fibers. Most are interconnected by cytoplasmic projections, which often branch markedly, forming a threedimensional cellular lattice around those fibers. Differences in cell morphology were also found in dog breeds with high and low risks of cruciate ligament rupture. CrCLs from lowrisk breeds have longer cytoplasmic projections, while high-risk CrCLs have rounder nuclei and shorter cytoplasmic projections. These changes may be indicative of a reduced communication between cells (Smith et al. 2012). structures (Vasseur et al. 1985). Compared with the collateral ligaments, the enveloping synovial membrane is relatively cellular (Heffron & Campbell 1978). Synovial lining does not occur on the surfaces of the cruciate ligaments that are in direct contact with each other (Vasseur et al. 1985). When examined with scanning electron microscopy, many small holes have been detected in the synovial membrane covering the cruciate ligaments, suggesting that the cruciate ligaments are also supplied with nutrients via the synovial fluid (Kobayashi et al. 2006). Synovial envelope Vascular supply Both the CrCL and the CaCL are covered by a fairly uniform fold of synovial membrane which incompletely divides the stifle joint in the sagittal plane (Arnoczky et al. 1979). These enveloping epiligamentous membranes consist mainly of dense connective tissue, small fibroblasts, and some adipocytes; an intima and a thin subintimal layer can be distinguished (Heffron & Campbell 1978). The intima is a single layer of synoviocytes, and the subintimal layer is areolar tissue containing small vascular The major vascular contribution to the center of the stifle joint occurs from branches of the middle genicular artery, which arises from the popliteal artery, penetrates the caudal joint capsule, and passes craniodistally to the fossa intercondylaris, running cranially between the cruciate ligaments (Figures 1.5 and 1.6) (Tirgari 1978). The vascular structures in the proximal part of the CrCL are more numerous and have a larger diameter compared with those on the tibial side (Zahm 1965; Alm & Strömberg 1974). VetBooks.ir Morphology and Function of the Cruciate Ligaments 7 1 4 3 3 2 5 1 2 4 Figure 1.6 Photograph of the superficial vascularization of normal cruciate ligaments after injection of latex in an ex vivo specimen of an adult dog. The infrapatellar fat pad and the synovial envelope are the most important sources of vessels. 1, cranial cruciate ligament; 2, caudal cruciate ligament; 3, lateral femoral condyle; 4, tibial plateau. Source: de Rooster et al. 2006. Reproduced with permission from John Wiley & Sons, Inc. 7 6 Figure 1.5 Line drawing of the major blood supply to the canine stifle joint. Caudal view. 1, femoral artery; 2, popliteal artery; 3, descending genicular artery; 4, proximal medial genicular artery; 5, middle genicular artery; 6, cranial tibial artery; 7, caudal tibial artery. Source: de Rooster et al. 2006. Reproduced with permission from John Wiley & Sons, Inc. The blood supply to both cruciate ligaments is predominantly of soft tissue origin; the contribution from the osseous attachments is negligible (Arnoczky et al. 1979; Kobayashi et al. 2006). The infrapatellar fat pad and the wellvascularized synovial membranes, which form an envelope around the cruciate ligaments, are the most important sources of vessels (Alm & Strömberg 1974; Tirgari 1978; Arnoczky et al. 1979, Kobayashi et al. 2006). The synovial vessels arborize into a finely meshed network of epiligamentous vessels which ensheath the cruciate ligaments throughout their entire length (Figures 1.7 and 1.8) (Arnoczky et al. 1979; 3 2 1 4 Figure 1.7 Arthroscopic view of the superficial vascularization of normal cruciate ligaments of an adult dog. The synovial vessels arborize to form a web-like network of periligamentous vessels that ensheath the cruciate ligaments. 1, cranial cruciate ligament; 2, caudal cruciate ligament; 3, lateral femoral condyle; 4, tibial plateau. Source: de Rooster et al. 2006. Reproduced with permission from John Wiley & Sons, Inc. Structure and Function VetBooks.ir 8 1 2 CrCL 3 (A) 4 CrCL SM 1 (B) Figure 1.8 Histologic section (H&E stain) of a normal cranial cruciate ligament (CrCL) of an adult dog. (A) The CrCL is ensheathed by epiligamentous vessels (scale bar = 100 μm). (B) The well-vascularized synovial membrane (SM) forms an envelope over the CrCL (scale bar = 100 μm). 1, epiligamentous vessels; 2, anastomosis between epiligamentous and endoligamentous vessels; 3, hypovascular zone; 4, synovial vessels. Source: de Rooster et al. 2006. Reproduced with permission from John Wiley & Sons, Inc. Kobayashi et al. 2006). In general, the vascular arrangement and structural characteristics of the vasculature inside the CrCL and the CaCL are similar (Alm & Strömberg 1974; Arnoczky et al. 1979; Kobayashi et al. 2006). In the inner part of the cruciate ligaments, around and along the bundles of collagen fibers, an endoligamentous vascular network courses in the supporting connective tissue (Alm & Strömberg 1974; Arnoczky et al. 1979; Hayashi et al. 2011). The larger vessels, usually one artery accompanied by two veins, mainly course in a longitudinal direction both proximally and distally and lie parallel to the collagen fascicles (Alm & Strömberg 1974). Some of them have a tortuous path in the interfascicular areolar tissue. Only small capillaries branching from the longitudinal endoligamentous vessels run in a transverse direction, encircling collagen bundles. The core of the mid-portion of the CrCL is less well vascularized compared with the remainder of the ligament (Zahm 1965; Tirgari 1978; Arnoczky et al. 1979; Vasseur et al. 1985; Hayashi et al. 2011). Anastomoses exist between extra- and intraligamentous blood networks (Alm & Strömberg 1974; Arnoczky et al. 1979; Kobayashi et al. 2006). Epiligamentous vessels penetrate transversely into the cruciate ligaments (Figure 1.8). Their branches ramify and anastomose with the endoligamentous vessels. There are numerous endosteal vessels at the ligamentous–osseous junctions; however, communications with intrinsic endoligamentous vessels are quite poor, especially at the tibial attachment where most of the endosteal vessels seem to terminate in subchondral loops instead of crossing the ligamentous–osseous junction (Alm & Strömberg 1974; Arnoczky et al. 1979; Kobayashi et al. 2006). Innervation Three major articular nerves arise from the saphenous nerve, tibial nerve, and common peroneal nerve to innervate the periarticular tissues of the canine stifle joint (Figure 1.9) (O’Connor & Woodbury 1982). The main trunk of nerve bundles is found at the femoral end of the cruciate ligaments. Other nerves may contribute afferent fibers to a variable extent to the cruciate ligaments. In dogs, the medial articular nerve, which branches from the saphenous nerve in the mid-thigh region, provides the largest contribution to stifle joint innervation (O’Connor & Woodbury 1982). Some of its branches course through the infrapatellar fat pad to terminate within the proximal or distal attachments of the cruciate ligaments or within the meniscal poles. Other branches of the medial articular nerve pass cranially through the joint capsule to VetBooks.ir Morphology and Function of the Cruciate Ligaments 9 1 1 2 2 4 5 3 3 6 Figure 1.9 Line drawing of the major nerve supply to the canine stifle joint. (A) Medial view. (B) Lateral view. 1, saphenous nerve; 2, medial articular nerve; 3, caudal articular nerve; 4, common peroneal nerve; 5, tibial nerve; 6, lateral articular nerve. Source: de Rooster et al. 2006. Reproduced with permission from John Wiley & Sons, Inc. (A) extensively innervate the femoral attachment of the CaCL. The caudal articular nerve is variably present in dogs (O’Connor & Woodbury 1982), its branches arising either directly from the tibial nerve or from a muscular branch of the tibial nerve. The caudal articular nerve runs to the caudal aspect of the joint capsule, where it may communicate with branches of the medial articular nerve. The lateral articular nerve branches from the common peroneal nerve at the level of the fibular head, deep to the biceps femoris muscle, and supplies the lateral aspect of the stifle joint (O’Connor & Woodbury 1982). Nerves of differing sizes are located in the richly vascularized synovial tissue covering the cruciate ligaments (Yahia et al. 1992). From this peripheral synovium, axons radiate towards the center of the ligaments (Yahia et al. 1992). Within the cruciate ligaments, most nerves course along the epiligamentous and endoligamentous blood vessels in the interfascicular areolar spaces. Neurohistologic studies have identified various types of sensory nerve endings (receptors and free nerve endings) in the middle of the cruciate ligaments, well beneath the synovial sheath (Yahia et al. 1992). The highest number of mechanoreceptors was found in the proximal third of the CrCL, and the lowest in the distal (B) third (Arcand et al. 2000). A high percentage of mechanoreceptors have been found in the tibia remnants of ruptured human anterior cruciate ligaments (ACLs), and it has been suggested that leaving these remnants after ACL reconstruction may be important for postoperative proprioceptive function (Sha & Zhao 2010). Functional anatomy The cruciate ligaments resist forces that would cause the tibia to translate cranially relative to the femur and, to a lesser degree, resist forces that would cause tibial rotation (Arnoczky & Marshall 1977). The two components of the CrCL are not isometric, the main difference being elongation of the craniomedial and shortening of the caudolateral component during flexion (Arnoczky & Marshall 1977; Heffron & Campbell 1978). The former is the major contributor to craniocaudal stability in stifle flexion, while the latter only contributes when the craniomedial band is damaged or severely stretched (Wingfield et al. 2000). With the stifle in extension, both components are taut, and limit cranial translation of the tibia relative to the femur (Arnoczky & Marshall 1977; Heffron & Campbell 1978). VetBooks.ir 10 Structure and Function As the stifle flexes, the cruciate ligaments are not only wrapped upon each other but also spiral on themselves (Singleton 1957; Arnoczky & Marshall 1977). The higher strain in the ligaments also limits the amount of normal internal rotation of the tibia relative to the femur (Zahm 1965; Arnoczky & Marshall 1977; Harari 1993). In extension, the medial and lateral collateral ligaments become the primary restraints of rotation, and the cruciate ligaments provide only a secondary check from the tension in both ligaments (Singleton 1957; Zahm 1965; Vasseur et al. 1985). Both cruciate ligaments together provide important secondary restraints against varus and valgus angulation. The cruciate ligaments become primary restraints if there is loss of collateral ligament support (Vasseur & Arnoczky 1981). Overextension is prevented by tension in the cruciate ligaments, where the CrCL acts as the primary restraint (Arnoczky & Marshall 1977; Heffron & Campbell 1978). The caudolateral component of the CrCL is the primary contributor to restraining hyperextension (Heffron & Campbell 1978). The slightly longer caudal component of the CaCL can only be considered a secondary restraint (Singleton 1957; Arnoczky & Marshall 1977). References Alm A, Ekström H, Strömberg B. Tensile strength of the anterior cruciate ligament in the dog. Acta Chir Scand Suppl 1975;445:15–23. Alm A, Strömberg B. Vascular anatomy of the patellar and cruciate ligaments. A microangiographic and histologic investigation in the dog. Acta Chir Scand Suppl 1974;445:25–35. Arcand MA, Rhalmi S, Rivard C-H. Quantification of mechanoreceptors in the canine anterior cruciate ligament. Int Orthop 2000;24:272–275. Arnoczky SP, Marshall JL. The cruciate ligaments of the canine stifle: an anatomical and functional analysis. Am J Vet Res 1977;38:1807–1814. Arnoczky SP, Rubin RM, Marshall JL. Microvasculature of the cruciate ligaments and its response to injury. An experimental study in dogs. J Bone Joint Surg 1979;61A:1221–1229. Brunnberg L. Klinische Untersuchungen zu Ätiologie und Pathogenese der Ruptur des Ligamentum cruciatum craniale beim Hund. 2. Mitteilung: Zur Ätiologie und Diagnose der Ruptur des Ligamentum cruciatum craniale beim Hund. Kleintierprax 1989;34:445–449. Comerford E, Tarlton J, Innes J, et al. Metabolism and composition of the canine anterior cruciate ligament relate to difference in knee joint mechanics and predisposition to ligament rupture. J Orthop Res 2005;23:61–66. de Rooster H, de Bruin T, van Bree H. Morphologic and functional features of the canine cruciate ligaments. Vet Surg 2006;35:769–780. Harari J. Caudal cruciate ligament injury. Vet Clin North Am Small Anim Pract 1993;23:821–829. Haut RC, Little RW. Rheological properties of canine anterior cruciate ligaments. J Biomech 1969;2:289– 298. Hayashi K, Bhandal J, Kim SY, et al. Immunohistochemical and histomorphometric evaluation of vascular distribution in intact canine cranial cruciate ligament. Vet Surg 2011;40:192–197. Heffron LE, Campbell JR. Morphology, histology and functional anatomy of the canine cranial cruciate ligament. Vet Rec 1978;102:280–283. Kobayashi S, Baba H, Uchida K, et al. Microvascular system of anterior cruciate ligament in dogs. J Orthop Res 2006;24:1509–1520. O’Connor BL, Woodbury P. The primary articular nerves to the dogs knee. J Anat 1982;134:563– 572. Rudy RL. Stifle joint. In: Canine Surgery, Archibald J, ed. Santa Barbara CA, American Veterinary Publications Inc. 1974, pp 1104–1115. Sha L, Zhao L. Quantitative study on mechanoreceptors in tibial remnants of ruptured anterior cruciate ligament in human knees. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2010;24:1318–1322. Singleton WB. The diagnosis and surgical treatment of some abnormal stifle conditions in the dog. Vet Rec 1957;69:1387–1394. Smith KD, Vaughan-Thomas A, Spiller DG, et al. The organisation of elastin and fibrillins 1 and 2 in the cruciate ligament complex. J Anat 2011;218:600– 607. Smith KD, Vaughan-Thomas A, Spiller DG, et al. Variations in cell morphology in the canine cruciate ligament complex. Vet J 2012;193:561–566. Tirgari M. The surgical significance of the blood supply of the canine stifle joint. J Small Anim Pract 1978;19:451–462. Vasseur PB, Arnoczky SP. Collateral ligaments of the canine stifle joint: Anatomic and functional analysis. Am J Vet Res 1981;42:1133–1137. Vasseur PB, Pool RR, Arnoczky SP, et al. Correlative biomechanical and histologic study of the cranial cruciate ligament in dogs. Am J Vet Res 1985;46:1842–1854. Wingfield C, Amis AA, Stead AC, et al. Cranial cruciate stability in the Rottweiler and racing VetBooks.ir Morphology and Function of the Cruciate Ligaments Greyhound: an in vitro study. J Small Anim Pract 2000;41:193–197. Yahia LH, Drouin G. Microscopical investigation of canine anterior cruciate ligament and patellar tendon: Collagen fascicle morphology and architecture. J Orthop Res 1989;7:243–251. 11 Yahia LH, Newman NM, St Georges M. Innervation of the canine cruciate ligaments. A neurohistological study. Anat Histol Embryol 1992;21:1–8. Zahm H. Die Ligamenta decussata in gesunden und arthrotischen Kniegelenk des Hundes. Kleintierprax 1965;10:38–47. VetBooks.ir VetBooks.ir 2 Biomechanics of the Cruciate Ligaments Susannah J. Sample Introduction Stifle joint kinematics is the result of a complex mechanical system. Stability is provided by a combination of static and dynamic structures, with the cruciate ligaments acting as main stabilizers, providing transitional and rotational constraint. The canine cranial cruciate ligament (CrCL) is the most widely studied ligament in veterinary medicine. Over the past 40 years, studies of the CrCL have been primarily focused on either surgical methods to replace its function after rupture, or advancing the understanding of histological and mechanical age-related degeneration. Unlike in humans, little is known about the specific biomechanical properties of the CrCL in dogs. More detailed biomechanical descriptions of the CrCL are needed as technologies for ligament replacement procedures in dogs evolve. Biomechanical properties refer to the relationship between the length and tension of a given biologic material. This chapter will provide a short overview of the biomechanical properties of ligaments, and summarize what is known about the biomechanics of the canine CrCL. Biologic factors and disease conditions that are known to influence the biomechanical properties of ligament will also be discussed, as will the biomechanics of graft materials that have been considered for possible cruciate repair. Ligament composition Ligaments have a hierarchical architecture (Figure 2.1) and consist of a combination of water and longitudinally running collagen fibers, which are mostly type I collagen (70–80% of tissue dry weight and >90% of collagen), with a small amount of type III collagen (3–10%). Minimal amounts of types V, X, XII and XIV collagen, elastin, and proteoglycans are also components. The hierarchical architecture of the ligament influences its mechanical properties. Ligament is made up of multiple smaller structures called fiber bundles (Figures 2.1 and 2.2). Each fiber bundle, in turn, is comprised of the basic fibers of the ligament and includes fibroblasts; fibroblasts are the primary cells that make up both ligament and tendon. Ligament fibers have a varying amount of crimp (Figure 2.2). Crimp is a sort of wave within collagen fibers (Figures 2.1 and 2.2), and is the primary driving force behind the nonlinear stress–strain relationship that exists initially when the ligament undergoes tensile loading. Crimp facilitates a progressive Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 13 VetBooks.ir 14 Structure and Function Evidence: x-ray EM x-ray EM x-ray MICROFIBRIL SUBFIBRIL x-ray EM SEM EM SEM OM SEM OM FIBRIL FIBER BUNDLES FIBER TROPOCOLLAGEN 3.5 nm staining sites 64 nm periodicity crimp structure fibroblasts fascicular (45–50 μ) membrane 1.5 nm 10–20 nm 50–500 nm 50–300 μ reticular membrane 100–500 μ 3.5 nm Size scale Figure 2.1 Diagram illustrating the hierarchical organization of ligaments and tendons. Ligament has a hierarchical structure, starting at the level of individual fibroblasts. These cells are arranged to create a series of fibril structures, which eventually results in the formation of fibers. Fiber bundles or fascicles then combine to create the ligament itself. It should be noted that tendons also possess this basic hierarchical architecture. EM, electron microscopy; SEM, scanning electron microscopy; OM, optical microscopy. Source: SEB Symposia XXXIV 1980 The mechanical properties of biological tissues. Reproduced with permission from the Society of Experimental Biology. recruitment of fibers to resist load. Crimped fibers also help to provide resistance at extremes of joint motion. The strength of ligament and tendon relates to the diameter of its composite fibrils; thicker fibrils have a greater effect on tensile strength, and are considered determinants thereof (Ottani et al. 2001). In horses, the effect of exercise on collagen fibril diameter has been of great interest, particularly with regards to superficial and deep digital flexor tendon injury. These studies have shown that exercise initially increases fibril diameter, but exerciseinduced microdamage results in a decrease in fibril diameter (Cherdchutham et al. 2001). The CrCL is unique in architecture and function. It is a continuum of fibers from a distal cranial medial orientation on the lateral femoral condyle to the cranial central interspinous area of the tibial plateau. These fibers are recruited differentially throughout stifle flexion so that fibers are often defined by functional bundles. Most commonly, two bundles are described, the cranial medial (CM) bundle and the caudal lateral (CL) bundle. In extension, both fiber bundles are tight and parallel, whereas in flexion the structure twists when the femoral attachment of the CrCL rolls back. When this occurs, the CL bundle becomes slack, while the CM bundle remains load-bearing. The reduced number of CrCL fibers which are load-bearing during flexion consequently makes them more vulnerable to overstretch damage. Biomechanical properties Because ligaments are designed to transfer load from bone to bone in a longitudinal direction, uniaxial tensile tests are used to characterize structural and material properties of ligament using force–deformation and stress–strain curves, respectively. Typically, all CrCL testing is done with the stifle extended to recruit fibers from both fiber bundles. This provides a best case scenario for strength and stiffness and comparable biomechanical properties. Stifle Biomechanics of the Cruciate Ligaments 15 VetBooks.ir during sustained loads (creep), and tensile load required to maintain a fixed position will decrease with time (relaxation). While important, these biomechanical characteristics are often considered secondary. Consequently, testing protocols ‘pre-condition’ specimens with repeated loads and testing at a constant rate of loading to minimize secondary effects, producing a standard force versus deformation curve that can be used for biomechanical comparison. Force–deformation curve (A) Structural properties are described using a force–deformation curve, which can be divided into three regions (Figure 2.3). The first is the toe region, which is nonlinear and has a low initial stiffness; in this region, due to the crimped nature of collagen fibers, small forces result in a relatively large degree of lengthening. The next region is the linear region, which displays 700 Ultimate Strength (B) Figure 2.2 Longitudinal section of intact cranial cruciate ligament (CrCL) from a 1.5-year-old female beagle viewed using bright light (A) and circularly polarized light (B). Intact CrCL from young dogs has a hierarchically organized structure. Birefringence of the extracellular matrix collagen and the crimped structure are clearly visible in polarized light as bright and dark repeating bands within ligament fibers. Crimp is a wave-like feature of ligament that exists at the level of the fiber, and is the primary reason for ligament’s nonlinear elasticity. Scale bar = 50 μm. loading in any off-axis direction and/or with some stifle flexion would result in different stiffness and strength. All ligaments are viscoelastic in their mechanical behavior. That is, their stretch will increase 500 Linear Slope 400 300 Energy-to-failure 200 100 0 5 10 Deformation (mm) Ultimate Elongation Force (N) 600 15 Figure 2.3 Typical force–deformation curve for ligament during uniaxial tensile testing. The force–deformation curve of ligament can be divided into three regions. The toe region is the initial nonlinear part of the curve, which is primarily due to the existence of crimp at the level of the fiber. In this region, small forces result in a large degree of lengthening because of the crimped nature of the collagen fibers. The second is the linear region, which occurs after crimp has been maximally stretched. The linear slope of this region is reflective of the material’s stiffness. The final region is the point at which a ligament begins to rupture; the peak of this part of the curve gives the material’s ultimate strength and ultimate elongation values. Structure and Function Stress–strain curve Stress is defined as load (MPa) divided by crosssectional area, and is calculated using known load data and a cross-sectional measurement of the ligament. Strain can be thought of as deformation, and is defined as the change in length divided by original length; during uniaxial tensile testing, strain can be directly determined. The stress–strain curve can be divided into three regions (Figure 2.4). The first is the toe region, at which point large changes in strain result in minimal stress being applied; it is in this region that the “un-crimping” of collagen fibers occurs as they are being recruited to bear load. The next is the linear region, which occurs when the ligament fibers themselves are being stretched. The slope of this linear region defines Young’s modulus (a.k.a. elastic modulus or modulus). Young’s modulus describes the properties of the composite material, including all of its solid and fluid constituents. The last region occurs when the ligament begins to rupture, when the stiffness is reduced. The point before this decrease in stiffness defines ultimate stress and ultimate strain of the tissue. When sufficient fiber damage has occurred and elongation continues, the remaining fibers rupture and the ligament breaks. The area under the curve before failure is called the strain–energy density, and reflects the energy stored in the elastic ligamentous material. 80 Yi el d Ultimate Stress 70 60 50 40 Young’s Modulus 30 Strain-energy density 20 Ultimate Strain a high degree of stiffness due to the collagen fibers being stretched. The final region is the point at which the ultimate strength has been reached, when the ligament is no longer able to sustain a given force and consequently ruptures. The structural properties of a ligament can be derived from the force–deformation curve. The linear stiffness is the slope of the linear portion of the curve; stiffness is an extensive material property, meaning that it depends both on the material being measured and its size or boundary conditions. The material’s ultimate strength and ultimate elongation are the determined at the point of rupture, and the energy to failure is the area under the curve prior to failure. Force–deformation curves can also be used to determine attachment site behavior as part of the structure. Stress (MPa) VetBooks.ir 16 10 0 10 20 30 Strain 40 50 Figure 2.4 Typical stress–strain curve for ligament during uniaxial tensile testing. A stress–strain curve is determined by calculating the amount of strain (deformation) that occurs as a result of varying levels of tensile (or compressive) loading. The slope of the linear aspect of the stress–strain curve defines Young’s modulus. A material’s yield point occurs once the material begins to plastically deform prior to rupture. The point of rupture is where the ultimate stress and ultimate strain are defined. Viscoelasticity Ligament, like all soft collagenous connective tissues, is considered a viscoelastic material, in that it exhibits both viscous and elastic properties when undergoing deformation, and, therefore, has time-dependent mechanical behavior. Two characteristic material properties that are exhibited by viscoelastic materials are creep and relaxation. Creep describes how a ligament continues to stretch under a sustained force, while relaxation describes how the tensile force required to keep a stretched ligament at a constant length diminishes over time. As a consequence of relaxation, the stiffness of a viscoelastic material depends on the rate at which load is applied. For a fast rate of loading, the viscoelastic CrCL will be stiffer than if it is stretched slowly. Another viscoelastic property is hysteresis or energy dissipation. Ligaments exhibit hysteresis during loading, which can be seen when a ligament is loaded and then unloaded, as the loading and unloading stress– strain curves do not follow the same path. This is due to a loss of energy that occurs during loading. However, during repetitive loading VetBooks.ir Biomechanics of the Cruciate Ligaments and unloading, stress–strain curves eventually synchronize, which underscores the importance for pre-conditioning before experimental ligament biomechanical testing. Biologic factors There are a number of non-disease-related factors that affect ligament biomechanical properties, including age, body weight, phenotype, whether animals are gonadectomized, and use/disuse (Laros et al. 1971; Vasseur et al. 1985; Duval et al. 1999). In dogs, the effect of age on CrCL mechanical properties has been of particular interest. Skeletal maturity has been shown to increase strength, stiffness and other mechanical properties of ligaments. In a rabbit model, stiffness and ultimate strength dramatically increase from 6 to 12 months of age, followed by insignificant changes from 1 to 4 years of age (Woo et al. 1990). However, significant weakening occurs in the CrCL with age. Decreases in modulus, ultimate stress and strain energy density have been reported, particularly in dogs weighing more than 15 kg (Vasseur et al. 1985). It is recognized that excessive body condition is a risk factor for cruciate ligament rupture (see also Chapter 14). Specific breeds of dog are also at increased risk, such as the Newfoundland, Labrador Retriever, and Rottweiler, while others, such as the Greyhound, are relatively protected from the condition (Whitehair et al. 1993; Duval et al. 1999), suggesting a genetic component to disease predisposition (Baird et al. 2014). Additionally, histologic, metabolic, anatomic and immune cell populations have also been considered possible risk factors (Wingfield et al. 2000; Comerford et al. 2005; Comerford et al. 2006; Muir et al. 2007; Ragetly et al. 2011). Neutering of either gender has been reported to increase the prevalence of CrCL rupture (Slauterbeck et al. 2004), although recent studies have reported conflicting results regarding both neuter status and gender predisposition (Adams et al. 2011; Grierson et al. 2011) (see also Chapter 14). As is seen with bone, immobilization results in significant decreases in ligament strength. A study using a 9-week rabbit stifle immobilization model showed that CrCL cross-sectional 17 area is significantly decreased and ultimate strain significantly increased with immobilization, although decreases in modulus were not significant, and no changes in ultimate stress were found (Newton et al. 1995). Pelvic limb disuse also results in impaired ligament healing; the CrCL of male rats that underwent hindlimb suspension for 3 weeks had significantly decreased ultimate strength, ultimate stress, and elastic modulus versus controls (Provenzano et al. 2003). Relatively few studies have been performed studying the biomechanical effects of remobilization on previously immobilized ligament, but over time material properties appear to be restored before structural properties (Woo et al. 1987). Sites of ligament rupture In human beings and dogs, most CrCL/anterior cruciate ligament (ACL) ruptures occur through the body of the ligament. Similar to CrCL rupture in dogs, most ACL ruptures in human beings occur via a non-contact mechanism (Cimino et al. 2010). More recent evidence has also suggested genetic predisposition for disease development (Rahim et al. 2014; StepienSlodkowska et al. 2016; Svoboda et al. 2016). It has been shown in dogs with normal stifles that tensile tests of the femur–CrCL–tibia complex result in avulsion factures of the CrCL tibial attachment site, as opposed to tears through the CrCL body (Klein et al. 1982). This suggests that the mechanism resulting in CrCL rupture in the majority of dogs is due to a pathologic process that results in the degradation of CrCL material properties. Much work has been focused on the specific histologic changes that occur in ligaments that have ruptured, such as the development of chondroid transformation of ligament fibroblasts, alterations to collagen structure, changes in collagen fiber crimp, and loss of ligament fibroblasts. However, the cause and timeline of these changes and how they relate to the progression of the cruciate ligament rupture condition and development of CrCL rupture remains unclear (Vasseur et al. 1985; Narama et al. 1996; Hayashi et al. 2003). It should be noted that avulsion fractures do occur clinically in dogs, particularly immature dogs. Such fractures are typically associated VetBooks.ir 18 Structure and Function with obvious trauma and present with an acute onset of severe lameness (Reinke 1982). Synovitis and ligament biomechanics The development of synovitis and joint degradation has been clearly associated with CrCL transection models that create joint instability (Lipowitz et al. 1985). A relationship between synovitis and joint instability in the canine cruciate rupture arthropathy has been well established over the past decade (see also Chapter 12). One of the initial studies examining the effect of synovitis on ligament biomechanics was in a rabbit model, wherein the presence of chronic synovitis significantly decreased ligament strength. Histologically, these ligaments showed a loss of normal fiber orientation, a disorganized cellular pattern, changes in the interstitial matrix, and some infiltration of inflammatory cells within the ligament body (Goldberg et al. 1982). This work has led to the hypothesis that synovitis precedes cruciate ligament rupture in affected dogs, fitting with the clinical observation that mid-body CrCL ruptures are typical. Another landmark study in this field evaluated Wistar rats that are predisposed to spontaneous synovitis. In these animals, a correlation was found between stifle synovitis and chondroid metaplasia of the cruciate ligaments; these changes were not age-related (Sasaki et al. 1998). Taken together, these data support the hypothesis that stifle synovitis is a key factor promoting joint degradation and diminished ligament strength in dogs with cruciate ligament rupture. Numerous studies undertaken over the past decade, focused on understanding the pathologic basis of canine cruciate ligament rupture, have resulted in a body of work supporting the hypothesis that osteoarthritis and progressive cruciate ligament fiber rupture is influenced by stifle synovitis (Muir et al. 2007; Erne et al. 2009; Muir et al. 2011; Chuang et al. 2014; Little et al. 2014). Further work to understand the effects of synovitis on ligament structural properties is warranted. Isometric points With finite-sized areas of CrCL attachment, it is not possible for all CrCL fibers to be isomet- ric throughout flexion, and thus the CM and CL bundles have differing biomechanical properties. Surgical protocols, however, require the most isometric points to be used for joint stabilization or ligament reconstruction. Stabilization of the cruciate-deficient canine stifle occurs primarily through either intra-articular or extracapsular techniques. Extracapsular stabilization methods are still commonly employed today. The general concept of these methods are to align a suture outside the stifle joint capsule in the direction of the previously existing CrCL. Biomechanically speaking, the placement of such a suture should not be considered so simplistically. Ideally, sutures should be placed in an isometric manner, which means that during motion the suture attachment sites should remain a constant distance apart, thus preventing laxity of the suture material and consequent cranial translation of the joint. Numerous studies have sought to identify isometric points (Guénégo et al. 2007; Roe et al. 2008; Hulse et al. 2010). It is important to note that while these techniques attempt to use isometric points, such points do not exist biomechanically in the extracapsular space of the canine stifle. Biomechanics of grafts The use of intra-articular grafts for the restoration of joint stability has been well established in human orthopaedics. However, in dogs with cruciate ligament rupture the use of grafts in CrCL-deficient stifles has fallen out of favor in the clinical setting. Various allografts, autografts, and synthetic materials have been tested in experimental animals, but none has shown to be mechanically equivalent to an intact CrCL. One challenge of using grafts to replace CrCLs in dogs is the lack of strength they display over time (Cabaud et al. 1980; Shino et al. 1984; Curtis et al. 1985; Vasseur et al. 1985; McFarland et al. 1986; van Rens et al. 1986; Yoshiya et al. 1986; Johnson et al. 1989; Thorson et al. 1989). Unlike experimental dogs used in these studies, clientowned dogs affected with cruciate ligament rupture typically exhibit moderate to severe synovitis at the time of surgical treatment. Therefore, without a disease-modifying treatment, the use of grafts in these patients would be even less likely to provide long-term stifle VetBooks.ir Biomechanics of the Cruciate Ligaments stability compared to experimental dogs, as stifle inflammation will promote graft resorption. Conclusions The biomechanical properties of the cruciate ligaments are essential for stifle joint stabilization. It is the degradation of these properties that ultimately leads to cruciate ligament rupture and loss of joint stability. Further understanding of the relationship between synovitis, ligament degradation and ligament biomechanical properties is needed, as is development of disease-modifying treatments to combat the inflammatory joint environment associated with cruciate ligament rupture in the dog. Although progress has been made, the continued lack of understanding regarding the mechanisms involved in the development of cruciate ligament rupture in affected dogs, particularly with regard to synovitis, remains a barrier to the development of better surgical treatments. References Adams P, Bolus R, Middleton S, et al. Influence of signalment on developing cranial cruciate rupture in dogs in the UK. J Small Anim Pract 2011;52:347– 352. Baird AE, Carter SD, Innes JF, et al. Genetic basis of cranial cruciate ligament rupture in dogs. Connect Tissue Res 2014;55:275–281. Cabaud EH, Feagin JA, Rodkey WG. Acute anterior cruciate ligament injury and augmented repair. Am J Sports Med 1980;8:395–401. Chuang C, Ramaker MA, Kaur S, et al. Radiographic risk factors for contralateral rupture in dogs with unilateral cranial cruciate ligament rupture. PLoS One 2014;9:e106389. Cherdchutham W, Becker CK, Spek ER, et al. Effects of exercise on the diameter of collagen fibrils in the central core and periphery of the superficial digital flexor tension in foals. Am J Vet Res 2001;62:1563– 1570. Cimino F, Volk BS, Setter D. Anterior cruciate ligament injury: diagnosis, management, and prevention. Am Fam Physician 2010;82:917–922. Comerford EJ, Tarlton JF, Innes JF, et al. Metabolism and composition of the canine anterior cruciate ligament relate to differences in knee joint mechanics and predisposition to ligament rupture. J Orthop Res 2005;23:61–66. Comerford EJ, Tarlton JF, Wales A, et al. Ultrasound differences in cranial cruciate ligaments from dogs of two breeds with a differing predisposition to 19 ligament degeneration and rupture. J Comp Path 2006;134:8–16. Curtis RJ, Delee JC, Drez DJ. Reconstruction of the anterior cruciate ligament with freeze-dried fascia lata allografts in dogs. Am J Sports Med 1985;13: 408–414. Duval JM, Budsberg SC, Flo GL, et al. Breed, sex and body weight as risk factors for rupture of the cranial cruciate ligament in young dogs. J Am Vet Med Assoc 1999;215:811–814. Erne JB, Goring RL, Kennedy FA, et al. Prevalence of lymphoplasmacytic synovitis in dogs with naturally occurring cranial cruciate ligament rupture. J Am Vet Med Assoc 2009;235:386–390. Goldberg VM, Burstein A, Dawson M. The influence of an experimental immune synovitis on the failure mode and strength of the rabbit anterior cruciate ligament. J Bone Joint Surg 1982;64A:900–906. Grierson J, Asher L, Grainger K. An investigation into risk factors for bilateral canine cruciate ligament rupture. Vet Comp Orthop Traumatol 2011;24:192– 196. Guénégo L, Zahra A, Madelénat A, et al. Cranial cruciate ligament rupture in large and giant dogs. A retrospective evaluation of a modified lateral extracapuslar stabilization. Vet Comp Orthop Traumatol 2007;20:43–50. Hayashi K, Frank JD, Dubinsky C, et al. Histologic changes in ruptured canine cranial cruciate ligament. Vet Surg 2003;32:269–277. Hulse D, Hyman W, Beale B, et al. Determination of isometric points for placement of a lateral suture in treatment of the cranial cruciate ligament deficient stifle. Vet Comp Orthop Traumatol 2010;23:163– 167. Johnson SG, Hulse DA, Hogan HA, et al. System behavior of commonly used cranial cruciate ligament reconstruction autographs. Vet Surg 1989;18: 459–465. Klein L, Player JS, Heiple KG, et al. Isotopic evidence for resorption of soft tissues and bone in immobilized dogs. J Bone Joint Surg Am 1982;64:225– 230. Laros GS, Tipton CM, Cooper RR. Influence of physical activity on the ligament insertions in the knees of dogs. J Bone Joint Surg Am 1971;53:275–285. Lipowitz AJ, Wong PL, Stevens JB. Synovial membrane changes after experimental transection of the cranial cruciate ligament in dogs. Am J Vet Res 1985;46:1166–1170. Little JP, Bleedorn JA, Sutherland BJ, et al. Arthroscopic assessment of stifle synovitis in dogs with cranial cruciate ligament rupture. PLoS One 2014;9: e97329. McFarland EG, Morrey BF, An KN, et al. The relationship of vascularity and water content to tensile strength in a patellar tendon replacement of the anterior cruciate in dogs. Am J Sports Med 1986;14: 436–448. Muir P, Schaefer SL, Manley PA, et al. Expression of immune response genes in the stifle joint of dogs VetBooks.ir 20 Structure and Function with oligoarthritis and degenerative cranial cruciate ligament rupture. Vet Immunol Immunopathol 2007;119:214–221. Muir P, Kelly JL, Marvel SJ, et al. Lymphocyte populations in joint tissues from dogs with inflammatory stifle arthritis and associated degenerative cranial cruciate ligament rupture. Vet Surg 2011;40:753– 761. Narama I, Masuoka-Nishiyama M, Matsuura T, et al. Morphogenesis of degenerative changes predisposing dogs to rupture of the cranial cruciate ligament. J Vet Med Sci 1996;58:1091–1097. Newton PO, Woo SL, MacKenna DA, et al. Immobilization of the knee joint alters the mechanical and ultrastructural properties of the rabbit anterior cruciate ligament. J Orthop Res 1995;13:191–200. Ottani V, Raspanti M, Ruggeri A. Collagen structure and functional implications. Micron 2001;32:251– 260. Provenzano PP, Martinez DA, Grindeland RE, et al. Hindlimb unloading alters ligament healing. J Appl Physiol 2003;94:314–324. Ragetly CA, Evans R, Mostafa AA, et al. Multivariate analysis of morphometric characteristics to evaluate risk factors for cranial cruciate ligament deficiency in Labrador retrievers. Vet Surg 2011;40:327– 333. Rahim M, Gibbon A, Hobbs H, et al. The association of genes involved in the angiogenesis-associated signaling pathway with risk of anterior cruciate ligament rupture. J Orthop Res 2014;32:1612–1618. Reinke JD. Cruciate ligament avulsion injury in the dog. J Am Hosp Assoc 1982;18:257–264. Roe SC, Kue J, Gemma J. Isometry of potential suture attachment sites for the cranial cruciate ligament deficient canine stifle. Vet Comp Orthop Traumatol 2008;21:215–220. Sasaki S, Nagai H, Mori I, et al. Spontaneous synovitis in Wistar Rats. Toxicol Pathol 1998;26:687–690. Shino K, Kawasaki T, Hirose H, et al. Replacement of the anterior cruciate ligament by an allogeneic tendon graft. J Bone Joint Surg Br 1984;66:672–681. Slauterbeck JR, Pankratz K, Xu KT, et al. Canine ovariohysterectomy and orchiectomy increases the prevalence of ACL injury. Clin Orthop Relat Res 2004;429:301–305. Stepien-Slodkowska M, Ficek K, Zeitek P, et al. Whether the combination of COL1A1 gene polymorphisms may be a marker of the risk of injury? J Sport Rehabil 2016; [Epub ahead of print]. Svodoba SJ, Owens BD, Harvey TM, et al. The association between serum anterior biomarkers of collagen turnover and subsequent cruciate ligament rupture. Am J Sports Med 2016;44:1687– 1693. Thorson E, Rodrigo JJ, Vasseur P, et al. Replacement of the anterior cruciate ligament. A comparison of autografts and allografts in dogs. Acta Orthop Scand 1989;60:555–560. van Rens TJ, van den Berg AF, Huiskes R, et al. Substitution of the anterior cruciate ligament: A long-term histologic and biomechanical study with autogenous pedicled grafts of the iliotibial band in dogs. Arthroscopy 1986;2:139–154. Vasseur PB, Pool RR, Arnoczky SP, et al. Correlative biomechanical and histologic study of the cranial cruciate ligament in dogs. Am J Vet Res 1985;46: 1842–1854. Whitehair JG, Vasseur PB, Willits NH. Epidemiology of cranial cruciate ligament rupture in dogs. J Am Vet Med Assoc 1993;203:1016–1019. Wingfield C, Amis AA, Stead AC, et al. Comparison of the biomechanical properties of Rottweiler and racing greyhound cranial cruciate ligaments. J Small Anim Pract 2000;41:303–307. Woo SL, Ohland KJ, Weiss JA. Aging and sex-related changes in the biomechanical properties of the rabbit medial collateral ligament. Mech Ageing Dev 1990;56:129–142. Woo SL, Gomez MA, Sites TJ, et al. The biomechanical and morphological changes in the medial collateral ligament of the rabbit after immobilization and remobilization. J Bone Joint Surg Am 1987;69:1200– 1211. Yoshiya S, Andrish JT, Manley MT, et al. Augmentation of anterior cruciate ligament reconstruction in dogs with prostheses of different stiffnesses. J Orthop Res 1986;4:475–485. VetBooks.ir 3 Cruciate Ligament Remodeling and Repair Connie S. Chamberlain, Erin E. Crowley, and Ray Vanderby Jr. Introduction Multiple factors adversely affect the healing capacity of the cranial cruciate ligament (CrCL), including complex ligament anatomy, biomechanical forces, nutritional delivery, as well as the biologic milieu. These factors prevent a ruptured CrCL from regenerating its native tissue or recapitulating mechanical function. With little intrinsic healing potential, ruptures of the CrCL are often reconstructed. The repair process may extend from months to years and the injured ligament or replacement graft never fully recovers the original mechanical properties (Levenson et al. 1965; Lin et al. 2004). CrCL grafts usually lengthen, and their initial tissue strength can drop by approximately 50% after remodeling (Feagin & Curl 1976; Sherman & Bonamo 1988; Kaplan et al. 1990). Reconstructed stifles are often less stable and fail to restore normal joint kinematics. These deficiencies contribute to premature joint degeneration, osteoarthritis, and compromised function. This chapter will briefly discuss the biologic processes for natural CrCL healing, as well as the biological steps occurring during the healing of a reconstructed CrCL graft. Healing potential of the extracapsular ligament For comparison, consider healing of an extracapsular ligament (e.g., a medial collateral ligament, MCL; Figure 3.1). A robust healing cascade occurs consisting of hemostasis and inflammation, proliferation, and remodeling (Frank et al. 1983; Clark 1985; Clark 1993; Chamberlain et al. 2009). Hemostasis and inflammation immediately follow injury, and are characterized by the formation of a hematoma organized into a fibrinogen mesh and the accumulation of neutrophils, monocytes/ macrophages, and T-lymphocytes (Chamberlain et al. 2009). These inflammatory cells rid injured tissue of debris, and secrete cytokines and growth factors that modulate inflammation, attract fibroblasts to the injury, and stimulate subsequent activities in the healing cascade. The proliferative phase follows the inflammatory stage, and consists of increased fibroblasts, myofibroblasts, additional macrophages, and endothelial cells (Chamberlain et al. 2009). These cells and their products form granulation tissue within the injured region. Remodeling is the final phase Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 21 Structure and Function VetBooks.ir 22 Remodeling Proliferation Decorin (↓↓) Hemostasis Inflammation Type I Collagen (↓↓) Type I Collagen (↓↓) Type III Collagen Relative Level Fibromodulin Total Cells VEGF Neutrophils Apoptosis Apoptosis Hematopoietic Cells Myofibroblasts Mitotic Cells Macrophages Largest Wound Region Angiogenesis T-Lymphocytes MCL Edema Injury 1 3 5 7 9 11 14 21 28 Days Post-Injury Figure 3.1 Process of normal, extracapsular healing by the rat medial collateral ligament. Healing involves three complex and overlapping processes, including hemostasis and inflammation, proliferation, and remodeling. Hemostasis and inflammation involves clot formation and the infiltration of inflammatory cells, such as neutrophils, macrophages and T lymphocytes, immediately after injury. Proliferation is characterized by the formation of granulation tissue, including fibroblast proliferation and angiogenesis. Remodeling is the final phase and involves cell number reduction and scar formation. Source: Chamberlain et al. 2009. Reproduced with permission from John Wiley & Sons, Inc. of healing and follows proliferation. The earlier infiltration of fibroblasts, inflammatory cells, and endothelial cells diminish to basal levels during this stage (Chamberlain et al. 2009). This phase of healing lasts many months in ligaments and results in scar-like neo-ligamentous tissue that can still be found two years post injury (Frank et al. 1983). The cellular profile of the remodeling ligament is somewhat similar to uninjured tissue compared to the previous inflammatory or proliferative phases, but complete functional recovery may never occur. With or without surgical intervention, the injured MCL will heal, but it results in tissue that is more scar-like than the native tissue and is mechanically inferior. Healing potential of the completely ruptured CrCL Unlike the extracapsular MCL, the intracapsular CrCL does not heal without early surgical intervention. A native CrCL is a highly organized, dense connective tissue composed of dense parallel collagen bundles, exhibiting birefringence and crimping under polarized light (Hayashi et al. 2003a). Small blood vessels and fusiform- and ovoid-shaped fibroblasts surround the collagen bundles. A synovial membrane surrounds the CrCL and consists of dense connective tissue, small fibroblasts, and some adipocytes (Heffron & Campbell 1978; Hayashi et al. 2003a). Healing phases are summarized VetBooks.ir Cruciate Ligament Remodeling and Repair 23 Table 3.1 Healing response over the course of 10 weeks by the CrCL after complete or partial rupture, or surgical repair. Time post injury Complete rupture Partial rupture Immediately No hematoma Possible hematoma 1 week Necrosis Inflammation Necrosis Inflammation Provisional matrix Fibroblast proliferation throughout Inflammation Provisional matrix 2 weeks Edema Ligament retraction Fibroblast proliferation of ends Necrosis No granulation tissue formation Fibroblast proliferation throughout ligament Proliferation Granulation tissue 4 weeks Collagen formation Ligament resorption No granulation tissue formation Fibroblast proliferation throughout ligament Collagen formation Fibroblast proliferation Collagen formation 6 weeks Collagen formation Ligament resorption Fibroblast proliferation Collagen formation 8 weeks Collagen formation Ligament resorption Fibroblast proliferation Collagen formation 10 weeks Collagen formation Ligament resorption in Table 3.1. Immediately after complete CrCL rupture the synovial joint fluid bathes the ligament, and prevents clot formation and union of the ligament ends (O’Donoghue et al. 1966). The lack of hematoma precludes the formation of a provisional matrix and granulation tissue to start the healing process. One week after rupture, the CrCL undergoes necrosis and inflammatory cell infiltration; B and T lymphocytes, macrophages, dendritic cells, and IgG, IgM, and IgA plasma cells infiltrate the inflamed synovium (O’Donoghue et al. 1966; Lemburg et al. 2004). The extracellular matrix (ECM) collagenous structure is partially lost or disorganized, lacks birefringence, and exhibits little or no crimp (Hayashi et al. 2003b). At 2 weeks the CrCL becomes edematous, the injured ends retract, and fibroblasts proliferate and accumulate near the ruptured ends and decrease within the inner ligament (O’Donoghue et al. 1966; Hayashi et al. 2003b). Atypical spheroid-shaped fibroblasts appear with the typical fusiformand ovoid-shaped fibroblasts (Hayashi et al. 2003b). Surviving centralized spheroid fibroblasts undergo chondroid transformation and become devitalized as a result of inadequate blood flow, tissue hypoxia, and oxidative Surgical repair Collagen formation stress (Hayashi et al. 2003a,b). A diminished blood supply to the ruptured ligament also results in resorption of the ligament (O’Donoghue et al. 1966). Occasionally, the ruptured CrCL will fuse to the caudal cruciate ligament and maintain vascularity. Similar to a partial CrCL rupture, contact to a blood supply limits necrosis. By 8 weeks, the remaining CrCL segment shortens, precluding the possibility of suturing the ends together (O’Donoghue et al. 1966). Similar to the rabbit, after 3–12 months very few remnants of ligament exist and stifles show signs of osteoarthritis, with cartilaginous damage localizing primarily at the femoral condyle (Hefti et al. 1991). Healing potential of the partially ruptured CrCL The partially torn CrCL initially exhibits a weak healing response (Table 3.1). Partial CrCL ruptures form a hematoma and produce an organized fibrin meshwork to promote an early inflammatory response (Hefti et al. 1991). At 1 week post injury the ligaments remain intact, and a gelatinous provisional matrix fills the VetBooks.ir 24 Structure and Function gap (O’Donoghue et al. 1966). Between 2 and 4 weeks, proliferating fibroblasts infiltrate the entire ligament, but the formation of granulation tissue is delayed (O’Donoghue et al. 1966). Fibroblast proliferation continues throughout the ligament, and the partially torn CrCL develops longitudinally oriented collagen fibers in the defect by 10 weeks (O’Donoghue et al. 1966). Although partial ruptures form a hematoma and provisional matrix (unlike complete ruptures), the partial defect remains incompletely filled and therefore functionally deficient. Healing potential of the surgically repaired CrCL Surgical repair of the CrCL via suturing the ligament ends together immediately after injury can provide some degree of healing (Table 3.1). Similar to the extracapsular MCL, the sutured CrCL undergoes inflammation, proliferation and remodeling, albeit a slower process. Granulation tissue forms in the sutured region, the inflammatory response progressively subsides, and the region of scar formation stabilizes. At 1 and 2 weeks post surgery the ligament forms a provisional matrix consisting of inflammatory cells (O’Donoghue et al. 1966). By week 4, fibroblast proliferation and collagen formation increases within the defect (O’Donoghue et al. 1966). Between 6–10 weeks, the newly formed collagen within the defect blends with the intact portion of the CrCL. However, the tensile strength of the ligament remains substantially weaker than that of the uninjured CrCL (O’Donoghue et al. 1966). This promising healing outcome is found when the surgically repaired ligament was initially transected. A typical injury results in frayed ends, which complicates successful closure of the ligament ends. Additionally, if the repair is not completed immediately after rupture the ligament ends undergo necrosis and resorption, thereby inhibiting successful surgical intervention. Healing potential of the reconstructed CrCL graft Rupture of the CrCL often involves reconstruction with an autograft or allograft due to the poor functional outcomes with non-operative treatment. In a process that is slower and less efficient than MCL healing, a CrCL graft undergoes a complex healing process which includes synovialization, avascular necrosis, revascularization, cellular proliferation, and remodeling. At the time of transplantation, the central core of the graft is avascular. After transplantation, a synovial layer forms around the graft, providing a blood supply to the transplanted tissue. The inner core remains avascular and acellular for up to 3 months post surgery, but the peripheral graft repopulates with fibroblasts. The lack of vascularity and cellularity within the ligament core results in central graft necrosis, leading to collagen destruction. Eventually, vascular buds originating from the infrapatellar fat pad and synovial tissue form within the graft. The vessels progress from the epiligament to the central portion of the graft, and by 4–6 months the specimens typically revascularize. Vascularization helps to transport inflammatory cells and supply nutrients to the healing tissue; infiltrating vessels also contribute to cellular repopulation of the graft. Avascular necrosis may be limited or prevented if using vascularized autografts or grafts with preserved peritendinous connective tissue (Lambert 1983; van Rens et al. 1986; Butler 1989; Butler et al. 1989; Sckell et al. 1999). Cell proliferation follows revascularization of the ligament graft. A limited proliferation of intrinsic graft tendon cells occurs, even without a peritendinous connective tissue or vascularized graft. However, allografts need further processing (e.g., deep freezing, etc.) to eradicate the intrinsic cells. Fresh allografts cause a severe inflammatory reaction and rejection response, implying some degree of intrinsic cellular influence after grafting. Proliferating cells, including fibroblasts, neutrophils, circulating M1 and resident M2 macrophages, initially appear within the bone–tendon interface (Kawamura et al. 2005). Circulating M1 macrophages remain in the bloodstream until the initiation of an immune response. After injury, cells travel to the compromised site and promote inflammation, resulting in phagocytosis and tissue destruction. In contrast, the resident M2 macrophages are intrinsic cells that reduce inflammation and stimulate healing. With time, cell proliferation progresses from the interface to the outer and inner tendon VetBooks.ir Cruciate Ligament Remodeling and Repair (A) Week 1 (B) Week 7 Figure 3.2 Macrophage localization within the reconstructed cranial cruciate ligament (CrCL). Immunohistochemistry of the circulating M1 macrophages within a reconstructed rat CrCL at 1 week (A) and 7 weeks (B) after transplantation. Similar to the canine reconstructed CrCL, few macrophages localize to the graft at week 1 after injury. As time progresses, more cells infiltrate the ligament. Original magnification, ×600. (Figure 3.2). Neutrophils and macrophages, derived from the bone marrow or synovial membrane, accumulate within the outer graft by day 4 (Kawamura et al. 2005). Proliferating cells and M1 and M2 macrophages continue to progress into the inner tendon and are evident by 14 days post-transplantation (Kawamura et al. 2005). Few to no neutrophils or T lymphocytes localize to the inner graft (Kawamura et al. 2005). Evidence suggests that the macrophages differentiate into a fibroblast phenotype to synthesize collagen (Vaage & Lindblad 1990). During remodeling, the graft undergoes ligamentization, with characteristic restructuring of the graft towards the properties of the intact CrCL (Amiel et al. 1984; Amiel et al. 1986; 25 Murray et al. 2000; Marumo et al. 2005). Collagen fibers regain organization, which resembles the appearance of the intact CrCL. However, the initial loss of collagen crimp, size of collagen fibrils, and parallel alignment is only partially restored (Liu et al. 1995; Scheffler et al. 2008). Additionally, the graft remains mechanically inferior when compared to the uninjured tissue. Grafts initially pull from the osseous tunnel. A study in sheep showed that load to failure of the reconstructed graft averaged 5% of the normal ligament at 3 weeks (graft 37.8 ± 17.8 N versus intact 759.2 ± 114.1 N), and typically fails in the intra-articular portion (Meller et al. 2008). Graft load to failure improved to 15% of the normal ligament by 6 weeks, and exhibited a decline in grip-to-grip elongation (Meller et al. 2008). By 12 and 24 weeks, the strength of the graft had improved to 41% and 69% of the normal ligament, respectively, but the graft strength remained far less than the normal CrCL at even 52 weeks after transplantation (Meller et al. 2008). Healing potential of the reconstructed graft interface tissue CrCL reconstruction requires healing of the tendon graft and bone tunnels in the femur and tibia. Repair of the CrCL proceeds via the formation of a fibrovascular interface tissue (Figure 3.3) between the graft and bone, bone in-growth into the graft–bone interface, and the progression of collagen fiber continuity between tendon and bone to result in a reestablished tendo-osseous junction (Rodeo et al. 1993; Rodeo et al. 1999). After CrCL reconstruction, the graft and original cancellous bone fills with fibroblast-deposited fibrovascular interface tissue (Figure 3.4). Inflammatory cells and type III collagen initially accumulate in the interface granulation tissue. A few neutrophils and T lymphocytes are found within the granulation tissue the first week after surgery (Kawamura et al. 2005). After the neutrophil numbers have decreased, M1 macrophages, followed by M2 macrophages, appear. While the inflammatory cells infiltrate the granulation tissue, new bone also permeates the interface. Chondroid cells then appear from the side of the bone tunnel and degrade the granulation tissue and 2.0 2.5 3.0 5 3 Weeks Post-Repair Inflammation 7 0 0.5 Figure 3.3 H&E staining of the rat reconstructed cranial cruciate ligament graft at 1 week and 7 weeks after surgery. Similar to the dog at 1 week (A) and 2 weeks (B) after repair, the graft exhibits little cellularity, whereas the interface is cellularly active and inflamed. The graft displays more disorganization and cellularity by 3 weeks, whereas the interface becomes less inflamed (C). By 5 weeks, the graft organization is improving while the cell infiltration remains similar to that after 3 weeks (D). The 7-week reconstructed CrCL shows reduced cell numbers, more organization, and smaller interface as the tendon remodels (E). (F) Graph summarizing graft tissue organization and inflammation post reconstruction. B, bone; IF, interface; G, graft. (F) 0 0.5 1.0 2 2.0 2.5 3.0 1.0 Organization 0 - None 1 - Mild 2 - Moderate Inflammation 3 - Marked 1.5 1 Graft Organization 3 - Markedly Disorganized 2 - Moderately Disorganized 1 - Mildly Disorganized 0 - Organized VetBooks.ir Rank 1.5 Rank 26 Structure and Function Figure 3.4 H&E and respective multiphoton microscopy images of the reconstructed CrCL graft. H&E (upper row) and multiphoton images (lower row) demonstrate an inflamed and cellular interface tissue at weeks 1, 2, and 3 after repair. By weeks 5 and 7, the interface is less inflamed and less cellular. Yellow lines indicate the interface area. VetBooks.ir Cruciate Ligament Remodeling and Repair 27 VetBooks.ir 28 Structure and Function deposit type II collagen. The granulation tissue is progressively replaced with maturing lamellar bone. As healing progresses, numerous cells consisting of osteoblasts and osteoclasts scatter throughout the tunnel. Graft incorporation initiates at the fixation sites and progresses towards the articular tunnel entrance, where graft motion may impair early graft incorporation. At approximately 3–4 weeks after surgery, an indirect graft insertion forms perpendicular collagen fibers resembling Sharpey’s fibers (Gulotta & Rodeo 2007). The type III collagenpositive fibers are present 1 year after surgery, and the number and size are associated with the pull-out strength of the graft (Gulotta & Rodeo 2007). Summary Without surgical repair, the ruptured CrCL cannot form a hematoma or subsequent granulation tissue, and the ligament eventually degenerates. Healing of repaired tissue in a synovial environment is incomplete and functionally undesirable. Surgical reconstruction of the CrCL can improve outcome, but launches a healing and remodeling cascade that is slow and not functionally regenerative. Many factors modulate the ineffective healing response between tendon and bone, including the presence of inflammatory cells in the graft, limited bone ingrowth into the tendon graft, graft-tunnel motion, the paucity of undifferentiated progenitor cells, and lack of a coordinated signaling cascade towards regenerative healing (Gulotta & Rodeo 2007). Reconstruction of a CrCL using graft tissue improves healing, but does not regenerate native ligament tissue. The reconstructed CrCL undergoes synovialization, avascular necrosis, vascularization, cellular proliferation and remodeling, but this still results in a mechanically compromised tissue. The interface between graft and bone likewise undergoes a repair process involving development of a fibrovascular interface, bone in-growth, and collagen fiber continuity. Studies have quantified deficiencies in the healing and remodeling processes in repaired or reconstructed CrCLs. Recent advances to modulate the CrCL healing or graft-healing processes documented above (advances such as tissue engineering, targeted delivery of bioactive molecules, platelet-rich plasma, or healing augmented with mesenchymal stromal cells) provide optimism for improved and accelerated mechanisms to repair or reconstruct the ruptured CrCL (Linon et al. 2014; Proffen et al. 2015; LaPrade et al. 2016). References Amiel D, Frank C, Harwood F, et al. Tendons and ligaments: a morphological and biochemical comparison. J Orthop Res 1984;1:257–265. Amiel D, Kleiner JB, Roux RD, et al. The phenomenon of ‘ligamentization’: anterior cruciate ligament reconstruction with autogenous patellar tendon. J Orthop Res 1986;4:162–172. Butler DL. Kappa Delta Award paper. Anterior cruciate ligament: its normal response and replacement. J Orthop Res 1989;7:910–921. Butler DL, Grood ES, Noyes FR, et al. Mechanical properties of primate vascularized vs. nonvascularized patellar tendon grafts; changes over time. J Orthop Res 1989;7:68–79. Chamberlain CS, Crowley E, Vanderby R. The spatiotemporal dynamics of ligament healing. Wound Repair Regen 2009;17:206–215. Clark RA. Cutaneous tissue repair: basic biologic considerations. I. J Am Acad Dermatol 1985;13:701– 725. Clark RA. Biology of dermal wound repair. Dermatol Clin 1993;11:647–666. Feagin JA, Jr, Curl WW. Isolated tear of the anterior cruciate ligament: 5-year follow-up study. Am J Sports Med 1976;4:95–100. Frank C, Schachar N, Dittrich D. Natural history of healing in the repaired medial collateral ligament. J Orthop Res 1983;1:179–188. Gulotta LV, Rodeo SA. Biology of autograft and allograft healing in anterior cruciate ligament reconstruction. Clin Sports Med 2007;26:509–524. Hayashi K, Frank JD, Dubinsky C, et al. Histologic changes in ruptured canine cranial cruciate ligament. Vet Surg 2003a;32:269–277. Hayashi K, Frank JD, Hao Z, et al. Evaluation of ligament fibroblast viability in ruptured cranial cruciate ligament of dogs. Am J Vet Res 2003b;64:1010– 1016. Heffron LE, Campbell JR. Morphology, histology and functional anatomy of the canine cranial cruciate ligament. Vet Rec 1978;102:280–283. Hefti FL, Kress A, Fasel J, et al. Healing of the transected anterior cruciate ligament in the rabbit. J Bone Joint Surg 1991;73A:373–383. Kaplan N, Wickiewicz TL, Warren RF. Primary surgical treatment of anterior cruciate ligament ruptures: a long-term follow-up study. Am J Sports Med 1990;18:354–358. VetBooks.ir Cruciate Ligament Remodeling and Repair Kawamura S, Ying L, Kim HJ, et al. Macrophages accumulate in the early phase of tendon-bone healing. J Orthop Res 2005;23:1425–1432. Lambert KL. Vascularized patellar tendon graft with rigid internal fixation for anterior cruciate ligament insufficiency. Clin Orthop Relat Res 1983;172:85–89. LaPrade RF, Dragoo JL, Koh JL, et al. AAOS Research Symposium Updates and Consensus: Biologic Treatment of Orthopaedic Injuries. J Am Acad Orthop Surg 2016;24:e62–e78. Lemburg AK, Meyer-Lindenberg A, HewickerTrautwein M. Immunohistochemical characterization of inflammatory cell populations and adhesion molecule expression in synovial membranes from dogs with spontaneous cranial cruciate ligament rupture. Vet Immunol Immunopathol 2004;97:231– 240. Levenson SM, Geever EF, Crowley LV, et al. The Healing of Rat Skin Wounds. Ann Surg 1965;161: 293– 308. Lin TW, Cardenas L, Soslowsky LJ. Biomechanics of tendon injury and repair. J Biomech 2004;37:865– 877. Linon E, Spreng D, Rytz U, et al. Engraftment of autologous bone marrow cells into the injured cranial cruciate ligament in dogs. Vet J 2014;202:448–454. Liu SH, Yang RS, al-Shaikh R, et al. Collagen in tendon, ligament, and bone healing. A current review. Clin Orthop Rel Res 1995;318:265–278. Marumo K, Saito M, Yamagishi T, et al. The ‘ligamentization’ process in human anterior cruciate ligament reconstruction with autogenous patellar and hamstring tendons: a biochemical study. Am J Sports Med 2005;33:1166–1173. Meller R, Willbold E, Hesse E, et al. Histologic and biomechanical analysis of anterior cruciate ligament graft to bone healing in skeletally immature sheep. Arthroscopy 2008;24:1221–1231. 29 Murray MM, Martin SD, Martin TL, et al. Histological changes in the human anterior cruciate ligament after rupture. J Bone Joint Surg 2000;82A:1387– 1397. O’Donoghue DH, Rockwood CA, Jr, Frank GR, et al. Repair of the anterior cruciate ligament in dogs. J Bone Joint Surg Am 1966;48:503–519. Proffen BL, Perrone GS, Roberts G, et al. Bridgeenhanced ACL repair: A review of the science and the pathway through FDA investigational device approval. Ann Biomed Eng 2015;43:805–818. Rodeo SA, Arnoczky SP, Torzilli PA, et al. Tendonhealing in a bone tunnel. A biomechanical and histological study in the dog. J Bone Joint Surg Am 1993;75:1795–1803. Rodeo SA, Suzuki K, Deng XH, et al. Use of recombinant human bone morphogenetic protein-2 to enhance tendon healing in a bone tunnel. Am J Sports Med 1999;27:476–488. Scheffler SU, Unterhauser FN, Weiler A. Graft remodeling and ligamentization after cruciate ligament reconstruction. Knee Surg Sports Traumatol Arthrosc 2008;16:834–842. Sckell A, Leunig M, Fraitzl CR, et al. The connectivetissue envelope in revascularisation of patellar tendon grafts. J Bone Joint Surg 1999;81B:915– 920. Sherman MF, Bonamo JR. Primary repair of the anterior cruciate ligament. Clin Sports Med 1988;7:739– 750. Vaage J, Lindblad WJ. Production of collagen type I by mouse peritoneal macrophages. J Leukoc Biol 1990;48:274–280. van Rens TJ, van den Berg AF, Huiskes R, et al. Substitution of the anterior cruciate ligament: a long-term histologic and biomechanical study with autogenous pedicled grafts of the iliotibial band in dogs. Arthroscopy 1986;2:139–154. VetBooks.ir VetBooks.ir 4 Meniscal Structure and Function Antonio Pozzi and James L. Cook Surgical anatomy The menisci are crescent-shaped wedges of fibrocartilage that rest on the peripheral aspects of the articular surfaces of the proximal tibia. They function to effectively deepen the medial and lateral tibial fossae for articulation with the condyles of the femur (Figure 4.1). They are thickest abaxially and taper to thin, unattached edges axially. The superior femoral surfaces are slightly concave to accommodate the femoral condyles, thus providing greater articular contact area and improved stifle joint congruity. In dogs, the medial meniscus is larger than the lateral and more ovoid in shape. The lateral meniscus is smaller and more circular (Hulse & Shires 1983; Arnoczky 1993; Evans 1993; Carpenter & Cooper 2000). Both medial and lateral menisci have attachments that influence their mobility and function (Figure 4.2). The medial meniscus is firmly attached to the tibia through cranial and caudal menisco-tibial ligaments. Strong attachments are also present between the abaxial aspect of the medial meniscus and the medial collateral ligament. The abaxial periphery of the medial meniscus is also attached to the joint capsule via short ligaments that blend with the joint capsule (sometimes referred to as the coronal ligaments). A cranial menisco-tibial ligament anchors the lateral meniscus to the tibial plateau caudo-lateral to the cranial cruciate ligament (CrCL). Small caudal menisco-tibial ligament(s) may or may not be present in dogs, and can be attached cranial or caudal to the caudal cruciate ligament (CaCL) attachment when present. The lateral meniscus differs from the medial meniscus, however, in that the caudal pole of the lateral meniscus is attached firmly to the femur through the menisco-femoral ligament, which attaches onto the caudo-medial aspect of the intercondylar notch, caudal to the CaCL. In addition, the abaxial border of the lateral meniscus lacks a firm attachment to the lateral collateral ligament or joint capsule, and instead forms a groove where the popliteal tendon slides between the meniscus and joint capsule during stifle motion. The resultant mobility of the lateral meniscus helps to explain the decreased incidence of severe lateral meniscal tears concurrent to CrCL insufficiency when compared to the medial meniscus in dogs (Ralphs & Whitney 2002). The intermeniscal or transverse ligament connects the cranial poles of the lateral and medial menisci, and blends with fibers from the cranial menisco-tibial ligaments. The intermeniscal ligament lies just cranial to the tibial attachment of the CrCL and is covered Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 31 Structure and Function VetBooks.ir 32 Figure 4.1 Frontal plane image of an ex vivo specimen showing the congruity provided by the menisci to the femoral and tibial articulation. The wedge-shaped menisci fill the space between the femoral and the tibial condyles. by the infrapatellar fat pad. A comprehensive understanding of meniscal anatomy is integral to understanding disease mechanisms, and for avoiding iatrogenic damage to these important structures during surgical treatment of stifle disorders. Structure and composition The menisci consist of highly differentiated cells of various phenotypes within an intricately arranged extracellular matrix (ECM). Meniscal cells vary from fusiform, fibroblastic to rounded, chondrocytic phenotypes, depending on location. The morphological similarities of these meniscal cells to those of other musculoskeletal tissues suggest specific functions in connective tissue synthesis and maintenance for each phenotype. For example, cells in the periphery of menisci are similar to those in ligament and tendon, while cells in the central region are similar to hyaline cartilage (Helio Le Graverand et al. 2001). The ECM associated with the cells in these different regions also mimics the composition and function of the respective tissues. The ECM of menisci is composed primarily of water, collagens, and proteoglycan aggregates (Adams & Ho 1987; Stephan et al. 1998; Cook et al. 1999; Noone et al. 2002). Although meniscal tissue contains several different molecular types of collagen, type I collagen accounts for about 90% of the total collagen present (Eyre & Wu 1983). Other types of collagen are also present and demonstrate regional differences. For example, type I collagen is more abundant in the periphery, while type II is predominant in the axial third of the meniscus (Cheung 1987). This arrangement is most likely related to the specific biomechanical functions of each region (Bullough et al. 1970). On the meniscal surfaces, the collagen fibrils are randomly oriented and form a mesh. Just beneath this layer the collagen bundles show a more irregular orientation. Deep to these layers in the peripheral meniscus, the collagen fibers are organized in large bundles, which are circumferentially arranged from cranial to caudal attachments sites. Small radial fibers, also called ‘tie fibers,’ are arranged across the circumferential fibers and connect the abaxial region to the axial regions, where collagen II fibers and proteoglycan predominate. The tie fibers provide structural rigidity by resisting the splitting force that arises from compressive loading to the axial region and helping to transfer it to a radial load, which the circumferential fibers can resist. Several types of proteoglycan exist in the meniscus. In the adult dog a relatively constant distribution of 60% chondroitin-6-sulfate, 25% chondroitin-4-sulfate, 10% chondroitin, and 5% dermatan sulfate is found (Adams & Muir 1981). The distribution of the proteoglycan depends on the region of the meniscus, the inner third being approximately 8% proteoglycan and the outer third only 2% proteoglycan. Neurovascular anatomy The menisci are relatively avascular. Both menisci demonstrate a common pattern and distribution of blood vessels that arise from the medial and lateral genicular arteries (Arnoczky & Warren 1983). Within the synovial and capsular tissue of the stifle, an extensive perimeniscal capillary plexus supplies the peripheral border of the meniscus throughout VetBooks.ir Meniscal Structure and Function (A) 33 Meniscal ligaments Cranial and caudal cruciate ligaments Medial collateral ligament Coronal ligament (C) Patellar tendon Cranial cruciate ligament Transverse ligament Cranial menisco-tibial ligament Cranial menisco-tibial ligament Medial collateral ligament Lateral collateral ligament Medial meniscus Caudal menisco-tibial ligament (B) Lateral meniscus Caudal menisco-tibial ligament Caudal cruciate ligament Menisco-femoral ligament Figure 4.2 (A) Photograph of right tibial plateau illustrating the meniscal attachments and their relationship to the other intra-articular structures. (B) Line drawing of the tibial plateau, showing the meniscal ligaments. (C) Line drawing of the tibial plateau after removal of the menisci and the other structures, showing the footprints of the meniscal ligaments and cruciate ligaments. Copyright © Samantha J. Elmhurst at www.livingart.org.uk. its attachment to the joint capsule. These vessels are limited to the peripheral 10% to 25% of the meniscus. Synovial vessels are also found in regions where there is no direct contact between meniscus and cartilage (Arnoczky & Warren 1983). Although the peripheral portion of the menisci is vascularized, most of the meniscus is avascular and must rely to a large degree on synovial sources of nutrition. Alternative mechanisms for nutrition are diffusion or mechanical pumping of synovial fluid from compression of the tissue during stifle motion (Arnoczky et al. 1980). These regional differences have profound implications for meniscal pathology and treatment considerations (Figure 4.3). The innervation of the meniscus is not as well delineated as its blood supply. Nerve fibers originating from the perimeniscal tissue radiate into the peripheral third of the meniscus, and are most dense in the cranial and caudal poles. Structure and Function VetBooks.ir 34 F M PCP T (A) (B) Figure 4.3 (A) Frontal plane section of the medial compartment of a dog’s stifle prepared with the Spalteholz technique, showing the perimeniscal capillary plexus forming the red-red zone of the meniscus. Note that the red-red or vascular zone is only about 25% of the radial width, which corresponds to about 2 mm-wide peripheral tissue. PCP, perimeniscal capillary plexus; F, femur; M, avascular zone of the meniscus; T, tibia. (B) View of the entire medial meniscus. The avascular axial margin of the medial meniscus is indicated (arrows). Sources: (A) Arnoczky & Warren 1983. Reproduced with permission from SAGE Publications. (B) Courtesy of Dr Steven Arnoczky. Nerve fibers in the menisci appear to predominately serve propioceptive and mechanoreceptive roles, with little if any nociceptive function recognized. Meniscal-derived sensory signals during loading may contribute to protective neuromuscular reflex control of joint motion. Biomechanical and material properties The meniscus demonstrates a complex set of material properties that vary nonlinearly with location (inhomogeneous) and direction (anisotropic). These properties are important for the biomechanical functions of the meniscus, such as load transmission at the tibiofemoral articulation, shock absorption, and stability. These functions are important for normal homeostasis of the cartilage and the function of the stifle. The tensile properties of meniscal tissue are closely related to the collagen fiber architecture. Variations in tensile stiffness and strength of meniscal tissue correspond to local differences in collagen ultrastructure and fiber bundle orientation. In compression, the meniscal tissue should be considered as a biphasic composite material because of its composition of 75% water and 25% collagen and proteoglycan. During loading, most of the water is forced to flow through the matrix to redistribute within the tissue or to exude from the tissue. The high frictional drag forces associated with water flow through the porous-permeable solid matrix give rise to timedependent viscoelastic behaviors such as creep and stress relaxation. The significance of the viscoelastic behavior of the meniscus is that when the joint is loaded for long periods the contact area increases, thereby reducing the stress per unit area of the tissue. The concentration of VetBooks.ir Meniscal Structure and Function proteoglycans influences the viscoelastic behavior of the meniscus because their negative charges counteract fluid flow. The material properties of the meniscus are also very important for its behavior in tension. Variations in tensile stiffness and strength are found in different regions, and relate to local differences in collagen fiber ultrastructure and fiber bundle orientation. Intact tie fibers are also very important as they restrain motion between circumferential fibers and improve the stiffness characteristics of meniscus (Bullough et al. 1970). The importance of the integrity of the collagen network cannot be overemphasized, because disruption of this precise collagen ultrastructure results directly in alterations in tissue biomechanics, predisposing to tearing and a clinically significant loss of meniscal function (Thieman et al. 2009). Meniscal function The material properties of the meniscus are closely related to its function. The combination of low compressive stiffness and low permeability suggests that the menisci are highly efficient shock absorbers in the stifle. This is crucial for the activities of dogs. When the menisci are subjected to loading during weightbearing activities, they act as ‘firm pillows’ between the femoral and tibial condyles. Based on their viscoelastic properties the wedgeshaped menisci also adapt to the incongruent articular surfaces until fluid flow ceases as equilibrium is reached. Repeated compressive loading and unloading of menisci create a circulation pathway that is important for tissue nutrition and joint lubrication (Arnoczky et al. 1980). Another important concept for understanding the role of the meniscus as a shock absorber is the hoop tension theory. Shrive et al. (1978) proposed that the meniscus is able to absorb high loads across the joint by converting the compressive forces into radially directed forces. This theory has been confirmed in dogs by direct measurements of hoop strain and contact pressures of the medial meniscus (Pozzi et al. 2010a). As the meniscus is loaded, the cranial and caudal attachments of the meniscus are tensioned, along with the circumferential fibers, to prevent the meniscus from extruding 35 (Figure 4.4). The tension developed in the circumferential fibers from the cranial to the caudal attachments is called ‘hoop tension.’ The integrity of both collagen network and meniscal attachments is critical for the hoop tension to develop. A transection of the meniscus or its attachments disrupts completely the primary functions of the meniscus because it eliminates the hoop tension (Pozzi et al. 2008; Pozzi et al. 2010b). The meniscus contributes to stifle stability and joint kinematics by enhancing congruity between the convex tibial plateau and the round femoral condyle. The effect of the meniscus on joint congruity is evident when assessing meniscal motion during flexion–extension. Both menisci translate more than 13 mm caudally on average as the stifle goes from extension to flexion. Meniscal displacement maintains congruity during the pronounced roll-back of the femoral condyle (Park et al. 2016). This increased congruity is important for joint stability. In the normal stifle, the CrCL is considered a primary restraint, while the menisci act as secondary stabilizers. However, in the CrCL-deficient stifle the menisci become primary stabilizers of the uncontrolled translation and rotation of the joint. The caudal pole of the medial meniscus is particularly important in providing this stability, and as such is at highest risk of injury if excessive femoro-tibial motion is present, such as in the CrCL-deficient stifle (Pozzi et al. 2006). The contributions of the menisci to joint congruity and stability in both intact and CrCLdeficient stifles suggest that a functionally intact meniscus should be preserved whenever possible. This approach may be especially important in the CrCL-deficient stifle, which may benefit significantly from the stabilizing effects of the meniscus for improving already disrupted joint kinematics. In a weight-bearing radiographic study evaluating joint stability after tibial plateau leveling osteotomy (TPLO), dogs with an intact meniscus had a normal femorotibial alignment while dogs that underwent meniscectomy had a small degree of tibial subluxation (Kim et al. 2012). For meniscal preservation it becomes crucial to protect the menisci by stabilizing the joint with a technique that most optimally reestablishes normal kinematics, neutralizing both cranio-caudal and rotational instability. On the other hand, it could be Structure and Function VetBooks.ir 36 (A) (B) (C) Figure 4.4 Schematic depiction of the hoop tension theory. (A,B) The intact meniscus acts as a hammock hanging under tension between the palms. The hammock holds a person only if it is firmly secured to the palms. Similarly, the meniscus acts as a load-bearing structure only if its ligaments are firmly anchored to the tibia. (C) If the anchorage of the hammock is cut, the person falls to the ground. The failure of the hammock is caused by its inability to develop the tension between the two palms. Similarly, a transected meniscus (meniscal release) cannot develop the hoop tension (tension between the palms) to function as a load-bearing structure. Copyright © Samantha J. Elmhurst at www.livingart.org.uk. argued that leaving intact menisci in a CrCLdeficient stifle places them at unacceptable risk for subsequent damage, driving the need for additional surgery. This latter argument has been used as the rationale for meniscal release or meniscectomy in TPLO-, tibial tuberosity advancement (TTA)-, and extracapsular-treated CrCL-deficient stifles for the past 15 years (see Chapters 25, 27, and 28). Meniscal release eliminates important functions in the stifle joint, but may decrease the risk of subsequent meniscal tear. As such, the surgeon needs to make treatment decisions regarding the menisci carefully and with informed client consent (see Chapters 35 and 36). References Adams ME, Muir H. The glycosaminoglycans of canine menisci. Biochem J 1981;197:385–389. Adams ME, Ho YA. Localization of glycosaminoglycans in human and canine menisci and their attachments. Connect Tissue Res. 1987;16:269– 279. Arnoczky SP. Pathomechanics of cruciate ligaments and meniscal injuries. In: Disease Mechanisms in Small Animal Surgery, Bojrab MJ, ed, second edition. Philadelphia PA, Lea & Febiger. 1993, pp. 764– 776. Arnoczky SP, Warren RF. The microvasculature of the meniscus and its response to injury: an experimental study in the dog. Am J Sports Med 1983;11:131– 141. Arnoczky SP, Marshall JL, Joseph A, et al. Meniscal diffusion: an experimental study in the dog. Trans Orthop Res Soc 1980;5:42. Bullough PG, Munuera L, Murphy J, et al. The strength of the menisci of the knee as it relates to their fine structure. J Bone Joint Surg 1970;52B:564– 567. Carpenter DH, Cooper RC. Mini review of canine stifle joint anatomy. Anat Histol Embryol 2000;29:321–329. VetBooks.ir Meniscal Structure and Function Cheung HS. Distribution of type I, II, III, V in the pepsin solubilized collagen in bovine menisci. Connect Tissue Res 1987;16:343–356. Cook JL, Tomlinson JL, Kreeger JM, et al. Induction of meniscal regeneration in dogs using a novel biomaterial. Am J Sports Med 1999;27:658–665. Evans HE. The skeleton, arthrology, the muscular system. In: Miller’s Anatomy of the Dog, third edition. Philadelphia PA, WB Saunders. 1993, pp. 122–384. Eyre DR, Wu JJ. Collagen of fibrocartilage: a distinctive molecular phenotype in bovine meniscus. FEBS Lett 1983;158:265–270. Helio Le Graverand MP, Ou Y, Schield-Yee T, et al. The cells of the rabbit meniscus: their arrangement, interrelationship, morphological variations and cytoarchitecture. J Anat 2001;198:525–535. Hulse DA, Shires PK. The meniscus: anatomy, function and treatment. Comp Cont Ed Pract Vet 1983;5:765–774. Kim SE, Lewis DD, Pozzi A. Effect of tibial plateau leveling osteotomy on femorotibial subluxation: in vivo analysis during standing. Vet Surg 2012;41:465–470. Noone TJ, Millis DL, Korvick DL, et al. Influence of canine recombinant somatotropin hormone on biomechanical and biochemical properties of the medial meniscus in stifles with altered stability. Am J Vet Res 2002;63:419–426. Park B, Banks S, Pozzi A. Meniscal kinematics through automatic 3D meniscus model extraction from MR images: validation and application in 37 canine stifles. Annual Veterinary Orthopedic Society Meeting, Snowbird, Utah, March 12–18, 2016. Pozzi A, Tonks CA, Ling H. Femorotibial contact mechanics and meniscal strain after serial meniscectomy. Vet Surg 2010a;39:482–488. Pozzi A, Kowaleski MP, Apelt D, et al. Effect of medial meniscal release on tibial translation following tibial plateau leveling osteotomy. Vet Surg 2006;35:486–494. Pozzi A, Kim SE, Lewis DD. Effect of transection of the caudal menisco-tibial ligament on medial femorotibial contact mechanics. Vet Surg 2010b;39:489–495. Pozzi A, Litsky AS, Field J, et al. Effect of medial meniscal release on load transmission following tibial plateau leveling osteotomy. Vet Comp Orthop Traumatol 2008;17:198–203. Ralphs SC, Whitney WO. Arthroscopic evaluation of menisci in dogs with cranial cruciate ligament injuries: 100 cases (1999–2000). J Am Vet Med Assoc. 2002;221:1601–1604. Stephan JS, McLaughlin RM, Griffith G. Water content and glycosaminoglycan disaccharide concentration of the canine meniscus. Am J Vet Res 1998;59:213–216. Shrive NG, O’Connor JJ, Goodfellow JW, et al. Loadbearing in the knee joint. Clin Orthop 1978;131:279– 287. Thieman KM, Pozzi A, Ling HY, et al. Contact mechanics of simulated meniscal tears in cadaveric canine stifles. Vet Surg 2009;38:803–810. VetBooks.ir VetBooks.ir 5 Biomechanics of the Normal and Cranial Cruciate Ligament-Deficient Stifle Antonio Pozzi and Stanley E. Kim Normal stifle The stifle is a complex, diarthrodial, synovial joint that allows motion in three planes (Figure 5.1). The round femoral condyles articulate with the flat tibial condyles with a range of motion about the medial-lateral axis of approximately 120◦ . Normal stifle angles range from 160◦ in full extension, to 40◦ in full flexion (Jaegger et al. 2002; Allen et al. 2009). Based on fluoroscopic kinematics during trot, walk, stair ascent and sit, the stifle flexes to 35◦ and extends to 145◦ during these activities (Kim et al. 2015). The flexion–extension motion occurs through a combination of rolling and gliding of the femur on the tibia. With rolling alone, the femoral condyle would roll off the tibial plateau before maximum flexion was achieved, whereas with gliding alone the femoral shaft would impinge on the tibia. Rollback is asymmetric: femorotibial contact translates more caudally on the lateral than on the medial plateau, resulting in internal tibial rotation during stifle flexion with a range of motion that can vary from 6◦ to 15◦ during sitting and trot (Vasseur & Arnoczky 1981). This change in rotational constraint over a range of motion, which also occurs in the human knee, has been termed the ‘screw-home’ mechanism. Due to the slight tibial translation in the sagittal plane that is coupled with flexion and extension, it is clear that the stifle does not function as a pure hinge joint. Medial-lateral and proximaldistal translation is tightly constrained by the collateral ligaments, but still allows for rotation about the medial-lateral and longitudinal axes. Although the rotational motion about the medial-lateral axis far exceeds the motion about the other two axes, approximately 20◦ of varus–valgus and internal–external rotation occurs over an entire walking–gait cycle in normal dogs (Korvick et al. 1994). Understanding stifle kinematics in three dimensions rather than simply attempting to address cranio-caudal stability is important for the treatment of cranial cruciate ligament (CrCL) deficiency. Both a lack of neutralization (e.g., tibial osteotomies) or absolute constraint (e.g., extracapsular stabilization) of internal–external rotation may lead to abnormal mechanical stresses on the articular surfaces and progression of osteoarthritis (Chailleux et al. 2007; Kim et al. 2008). The patellofemoral joint is an important contributor to complex stifle biomechanics (Moore et al. 2016). Patellofemoral kinematics is closely coupled with femorotibial kinematics, as patellar flexion angle increases and the patella translates distally as the femorotibial Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 39 VetBooks.ir 40 Structure and Function TRANSLATIONS Proximo-Distal ROTATIONS Internal–External Medio-Lateral Flexion–Extension Cranio-Caudal Adduction–Abduction Figure 5.1 Line drawing illustrating the six degrees-of-freedom of the femoro-tibial articulation. The femur and the tibia rotate and translate about the three axes shown in the drawing. Copyright © Samantha J. Elmhurst at www.livingart.org.uk. joint flexes (Moore et al. 2016). The patella acts as a pulley mechanism to improve the efficiency of stifle extension, as it increases the lever arm of the quadriceps mechanism by lengthening the distance between the quadriceps muscle force and the center of flexion–extension rotation of the stifle. In doing so, a significant force compressing the patella against the femoral condyle is generated as the muscle contracts. This retropatellar force is an important contributor to the stability of the patello-femoral joint, and results in a force acting on the distal femur in the cranial–caudal direction. The balance of extensor and flexor moment acting at the stifle joint contributes to dynamic stability (Tepic et al. 2002). Unlike most other diarthrodial joints in the dog, the bony congruency between the femoral condyle and the tibial plateau adds little to the stability of the stifle. Rather, primary and secondary soft-tissue stabilizers provide stability to the stifle. The CrCL acts as primary stabilizer for both cranial–caudal translation and internal–external rotation. The caudal cruciate ligament (CaCL) has a primary role in limiting caudal tibial translation, and also helps to limit excessive internal–external rotation (Arnockzky & Marshall 1977). The menisci act as secondary stabilizers. The degree to which they contribute to joint stability is dependent on the condition of the primary stabilizers, in particular the CrCL. In a CrCL-deficient stifle the medial meniscus plays a role in primary stabilization, acting as a wedge opposing femoral condyle translation and rotation (Pozzi et al. 2006). The increased mobility of the lateral meniscus does not allow it to act as a wedge between the femur and the tibia, and may protect it from impingement and tearing. Other passive stabilizers include the collateral ligaments and the joint capsule. The dynamic stability of the stifle in the various daily activities is provided by a delicate interplay between passive stabilizers and active musculature. The stifle is controlled mostly by two-joint muscles that cross either the hip and the stifle, or the stifle and the hock. Contraction of one of these muscles alone produces movement of all the joints that the muscle crosses. To isolate movement at a single joint, twojoint muscles contract with other muscles, frequently with a one-joint synergist. The quadriceps and the hamstrings act as synergists in the stifle and simultaneously contract during activity (co-contraction). Co-contraction is considered an important mechanism in functional adaptation in human patients with anterior cruciate ligament rupture, but further research is needed to understand its role in dogs. The clinician needs to understand all the motions in the stifle joint that are normally limited by the ligaments to perform and interpret manual stress tests and correctly determine the abnormality. The term instability has been used to describe an abnormal motion that exists in the joint due to a ligament injury. The term laxity simply indicates increases in motion or looseness, without providing any direct indication of whether abnormal motion occurs in vivo. The goal of a comprehensive stifle examination is to detect an increase in the amount of motion (translation or rotation) or an abnormal position (subluxation) to determine the specific anatomic defect that is present. The manual stress examinations are designed to test only one or two motions at a time, and therefore the diagnosis cannot be based solely on the abnormal motion detected with a single manual stress. The diagnosis requires knowledge of stifle biomechanics, and which ligaments limit each of the possible motions in the stifle. Ultimately, the clinical examination must be interpreted considering the stifle in a six-degrees of freedom system, recognizing that six possible motions may occur in three dimensions. 30 25 The CrCL contributes to passive restraint of the stifle by limiting cranial translation of the tibia relative to the femur, excessive internal rotation of the tibia, and hyperextension of the stifle (Arnoczky & Marshall 1977). In vivo kinematic studies have demonstrated that most changes after CrCL transection are noted in the stance phase of the gait (Korvick et al. 1994; Tashman et al. 2004). Approximately 10 mm of cranial tibial translation is consistently observed and sustained throughout stance. Femorotibial alignment is restored during the swing phase, and is, therefore, largely unaffected by CrCL deficiency at a walk. The initial pattern of cranial translation progressively changes over time. Tashman et al. (2004) demonstrated that by two years after CrCL transection, the position of the tibia at the terminal swing is shifted cranially by approximately 5 mm (Figure 5.2). Thus, the decrease in dynamic instability was considered to be an indication of more persistent tibial subluxation throughout the gait cycle, rather than a return towards normal stifle kinematics (Tashman et al. 2004). The in vivo investigations by Tashman et al. and Korvick et al. were performed in normal dogs with acute, experimental CrCL transection. It is likely that stifles affected by naturally occurring CrCL rupture in clinical dogs 30 Pre-Treatment 2 Months 24 Months 20 15 (A) Pre-Treatment 2 Months 24 Months 25 20 15 10 10 -0.05 41 Cranial cruciate ligament-deficient stifle Cranial Translation (mm) Cranial Translation (mm) VetBooks.ir Biomechanics of the Normal and Cranial Cruciate Ligament-Deficient Stifle 0 0.05 0.1 Time (s) 0.15 0.2 -0.05 (B) 0 0.05 0.1 Time (s) 0.15 0.2 Figure 5.2 Craniocaudal translation of the canine stifle during the stance phase of gait in cranial cruciate ligament (CrCL) intact (A) and CrCL-deficient (B) dogs. Data represent baseline before CrCL transection or sham CrCL-transection, 2 months after surgery, and 24 months after surgery. Note that there are obvious changes in tibial translation after CrCL transection, whereas there is relatively little laxity in the intact CrCL during locomotion. Over time, cranial translation of the tibia becomes incrementally worse, suggesting that periarticular fibrosis does not provide much dynamic stability to the CrCL-deficient stifle. Source: Tashman et al. 2004. Reproduced with permission from John Wiley & Sons, Inc. VetBooks.ir 42 Structure and Function may not exhibit the same magnitude of subluxation, as periarticular fibrosis often exists at the time of complete CrCL rupture (Hayashi et al. 2004). The cranial tibial subluxation occurring during the stance phase of gait may be driven by the quadriceps contraction, among other factors (Korvick et al. 1994; Tashman et al. 2004). In the dog, the moment across the joint is flexor from ground contact until mid-stance, and then extensor until the end of the stance phase (Colborne et al. 2005). Quadriceps contraction at extended joint angles produces CrCL strain, but in the CrCL-deficient stifle in flexion, quadriceps contraction cannot load the CrCL or cause tibial subluxation. Thus, during the swing phase quadriceps activation on a flexed stifle does not cause subluxation, suggesting that the swing phase is CrCL-independent in the dog (Korvick et al. 1994; Tashman et al. 2004). The CrCL is a passive restraint to excessive internal tibial rotation, and ex vivo studies simulating weight-bearing demonstrated 14◦ of internal tibial rotation after CrCL transection (Warzee et al. 2001; Kim et al. 2009). Articular surface geometry and lower tension in the lateral collateral ligament with the stifle in extension were thought to have induced this axial rotational malalignment (Warzee et al., 2001, Kim et al. 2009). Excessive peak internal rotation in CrCL-deficient stifles, however, has not been observed in vivo (Tashman et al. 2004). This suggests that the muscular forces about the stifle, which have not been reproduced in bench-top studies, are the primary stabilizers against abnormal axial rotation, and the CrCL is a secondary rotational stabilizer at a walk or trot. High-demand activities, however, may generate higher axial torques that overcome muscular compensation, and elicit abnormal rotational stability in CrCL-deficient stifles. Such investigations have yet to be performed in the dog. Joints and joint structures are complex systems whose components are interdependent on one another and are constantly altering their cellular and molecular mechanisms to maintain and restore tissue homeostasis. In the stifle, CrCL function is fundamentally important in maintaining tissue homeostasis of other structures such as the meniscus and cartilage. In an attempt to maintain stifle function and tissue homeostasis, these abnormal stresses on compensating joint structures can then result in their adaptation or their failure. This concept has led to the idea that there is an envelope of function or a range of loading that is compatible with overall homeostasis. Loads above or below this ‘zone of homeostasis’ may lead to pathologic changes. In vivo three-dimensional kinematic studies have shown that the dog has little capability for eliminating cranio-caudal instability via neuromuscular compensation to stay in the ‘zone of homeostasis’ (Korvick et al. 1994; Tashman et al. 2004; Anderst & Tashman 2009). In addition, both ex vivo and in vivo studies have reported abnormal contact mechanics and increased tangential shear loading caused by femoro-tibial subluxation (Pozzi et al. 2006; Anderst & Tashman 2009). These alterations in stifle biomechanics are likely an important factor in osteoarthritis progression in the CrCLdeficient stifle. Cranial tibial subluxation results in a spatial shift of loading patterns to where articular cartilage is unable to accommodate these loads, inducing osteoarthritis (Andriacchi et al. 2004) (Figure 5.3). Cartilage metabolism is dependent on maintenance of the mechanical stimuli that chondrocytes are adapted for (Carter et al. 2004). Therefore, reduced or increased loading of specific regions of the articular cartilage may trigger cartilage breakdown. To prevent osteoarthritis, surgical treatment of the CrCL-deficient stifle should aim at restoring normal joint function. For an optimal outcome, not only should cranio-caudal instability be restored but normal three-dimensional kinematics and contact mechanics should be obtained after surgical stabilization of the joint. While aiming for normal joint biomechanics is crucial when selecting surgical techniques for stifle stabilization or CrCL repair, joint adaptation should be taken in account when selecting the treatment for the CrCL-deficient stifle. For example, a dog with a chronic CrCL-deficient stifle may be at a too-advanced adaptation stage to allow significant improvement of its joint biomechanics. In this case, arthroscopy or arthrotomy and meniscal treatment, followed by rehabilitation, may be selected over a stabilization technique (Tivers et al. 2009). Further work needs to be done to understand how differences in stage of CrCL rupture may play a role in treatment selection. VetBooks.ir Biomechanics of the Normal and Cranial Cruciate Ligament-Deficient Stifle 43 HEALTHY CARTILAGE TOLERATES HIGH TO LOW PHYSIOLOGIC LOAD BIOLOGIC TRIGGER Metabolic or enzymatic en matic changes MECHANICAL TRIGGER Loading g shifts or increases FAILURE OF ADAPTATION OF THE CARTILAGE Chondrocyte death Collagen breakage / fibrillation Loss of macromolecules INITIATION OF OA HIGH LOAD DEGENERATIVE CARTILAGE Unable to tolerate physiologic loads RAPID PROGRESSION LOW LOAD SLOW PROGRESSION Figure 5.3 Diagram illustrating the pathomechanics theory of osteoarthritis (OA) proposed by Andriacchi. This theory suggests that the mechanical environment of the stifle influences the initiation and progression of stifle osteoarthritis. A healthy stifle can tolerate increased loads on cartilage without developing osteoarthritis. In contrast, a joint with abnormal kinematics and contact pressure (i.e. shift of contact areas) responds to high loads with progression of osteoarthritis. Therefore, decreasing load on degenerated cartilage may decrease progression of osteoarthritis. Notice that biological as well as mechanical factors can act as the trigger for osteoarthritis. References Allen MJ, Leone KA, Lamonte K, et al. Cemented total knee replacement in 24 dogs. Vet Surg 2009;38:555– 567. Anderst WJ, Tashman. The association between velocity of the center of closest proximity on subchondral bones and osteoarthritis progression. J Orthop Res 2009;27:71–77. Andriacchi TP, Mündermann A, Smith RL, et al. A framework for the in vivo pathomechanics of osteoarthritis at the knee. Ann Biomed Eng 2004;32:447–457. Arnoczky SP, Marshall JL. The cruciate ligaments of the canine stifle: an anatomical and functional analysis. Am J Vet Res 1977;38:1807–1814. Carter DR, Beaupre GS, Wong M, et al. The mechanobiology of articular cartilage development and degeneration. Clin Orthop Relat Res 2004;427:S69–S77. Chailleux N, Lussier B, De Guise J, et al. In vitro 3dimensional kinematic evaluation of 2 corrective operations for cranial cruciate ligament-deficient stifle. Can J Vet Res 2007;71:175–180. Colborne GR, Innes JF, Comerford EJ, et al. Distribution of power across the hind limb joints in Labrador Retrievers and Greyhounds. Am J Vet Res 2005;66:1563–1571. Hayashi K, Manley PA, Muir P. Cranial cruciate ligament physiology in dogs with cruciate disease: a review. J Am Anim Hosp 2004;40:385– 390. VetBooks.ir 44 Structure and Function Jaegger G, Marcellin-Little DJ, Levine D. Reliability of goniometry in Labrador Retrievers. Am J Vet Res 2002;63:979–986. Kim SE, Pozzi A, Banks SA, et al. Effect of tibial plateau leveling osteotomy on femorotibial contact mechanics and stifle kinematics. Vet Surg 2009;38:33–39. Kim SE, Pozzi A, Kowaleski MP, et al. Tibial osteotomies for cranial cruciate ligament insufficiency in dogs. Vet Surg 2008;37:111–125. Kim SE, Jones SC, Lewis DD, et al. In vivo three dimensional knee kinematics during daily activities in dogs. J Orthop Res 2015;33:1603– 1610. Korvick DL, Pijanowski GJ, Schaeffer DJ. Threedimensional kinematics of the intact and cranial cruciate ligament-deficient stifle of dogs. J Biomech 1994;27:77–87. Moore EJ, Kim SE, Banks SA, et al. Normal patellofemoral kinematic patterns during daily activities in dogs. BMC Vet Res. 2016;12:262. Pozzi A, Kowaleski MP, Apelt D, et al. Effect of medial meniscal release on tibial translation after tibial plateau leveling osteotomy. Vet Surg 2006;35:486– 494. Tashman S, Anderst W, Kolowich P, et al. Kinematics of the ACL deficient canine knee during gait: serial changes over two years. J Orthop Res 2004;22:931– 941. Tivers MS, Commerford EJ, Owen MR. Does a fabellatibial suture alter the outcome for dogs with cranial cruciate ligament insufficiency undergoing arthrotomy and caudal pole medial meniscectomy? Vet Comp Orthop Traumatol 2009;22:283–288. Tepic S, Damur DM, Montavon PM. Biomechanics of the stifle joint. Proceedings, 1st World Orthopaedic Veterinary Congress. Munich, Germany. 2002, pp. 189–190. Vasseur PB, Arnoczky SP. Collateral ligaments of the canine stifle joint: anatomic and functional analysis. Am J Vet Res 1981;42:1133–1137. Warzee CC, Dejardin LM, Arnoczky SP, et al. Effect of tibial plateau leveling on cranial and caudal tibial thrusts in canine cranial cruciate-deficient stifles: an in vitro experimental study. Vet Surg 2001;30:278–286. VetBooks.ir Section II Etiopathogenesis of Cruciate Ligament Rupture Introduction Historically, cruciate ligament rupture (CR) in the dog has been considered a consequence of accidental injury, with subsequent development of stifle arthritis. However, particularly since the late 1980s, this paradigm has been challenged. Second cruciate ruptures were found to be common in affected dogs, with many dogs initially presenting with bilateral CR. More recent work has shown that stifle arthritis is present during the early phase of the disease as cruciate ligament fiber rupture develops in the stable stifle. Disease progres- sion then leads to the development of complete CR and associated stifle instability in most affected dogs. Recent publications have shown that stifle synovitis is a significant factor in progression of the disease over time. Although, a substantial genetic contribution to risk of CR exists, the specific events that initiate the disease remain poorly understood. Recent genetic research has highlighted the polygenic nature of the trait and confirmed moderate heritability. Future research should be focused on advancing understanding of the factors that lead to disease initiation, particularly causal genetic variants. Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 45 VetBooks.ir VetBooks.ir 6 Histology of Cruciate Ligament Rupture Kei Hayashi Pathology of cranial cruciate ligament rupture The exact etiopathogenesis of canine cruciate ligament rupture (CR) is not defined. Although acute cranial cruciate ligament injury does occur with trauma, a number of previous studies have suggested that the majority of CR cases are the result of chronic degenerative changes within the ligament (Vasseur et al. 1985; Hayashi et al. 2003a). The development of progressive CR appears to involve a gradual degeneration of both cruciate ligaments, inflammatory disease in the stifle joint, partial CR, and eventually complete rupture. After rupture, secondary changes such as progressive arthritis and meniscal injury often develop. Initially, slight weakening or stretching of the cranial cruciate ligament (CrCL) may not cause lameness, but can produce mild instability within the joint, and therefore initiate arthritic joint degeneration. However, it is unclear whether this represents the initial phase of the condition, or whether the development of stifle synovitis is an initial event. Dogs with incipient or partial CR have a stable joint, but are presented with lameness, effusion of the stifle joint, and synovitis. Complete CR produces obvious instability of the stifle joint, resulting in more severe joint pain, lameness, and progressive degenerative changes within the joint. Clinical observations have demonstrated that these changes consist of periarticular osteophyte formation, capsular thickening, and meniscal damage. As these changes progress, the joints may become more stable, although a recent experimental study suggested that periarticular fibrosis does little to improve dynamic instability during locomotion (Tashman et al. 2004). Dogs with advanced or end-stage pathologic changes within the stifle may have little palpable passive instability because of extensive periarticular fibrosis. After a partial or complete CR, some degree of tissue repair response arises in the epiligamentous region of the CrCL (Hayashi et al. 2003a). In the human anterior cruciate ligament (ACL), distinct histologic phases of tissue repair, including an inflammatory phase, a epiligamentous repair phase, a proliferative phase and a remodeling phase, develop after rupture (Murray et al. 2000). Whether similar phases exist in dogs is not known. Expansion of the volume of the epiligamentous tissue does occur in the dog during a repair phase that lasts many weeks. However, a bridging scar does not form in the rupture site. Eventually, synovial tissue covers the ruptured ends of the CrCL. Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 47 VetBooks.ir 48 Etiopathogenesis of Cruciate Ligament Rupture Histologic features of cruciate ligament The CrCL is a complex structure consisting of an extracellular matrix (ECM) and a diverse population of cells. It has distinctive histologic features typical of dense collagenous connective tissues (ligaments and tendons). The ECM proteins in CrCL are primarily composed of type I collagen. Bundles of collagen fibers are longitudinally oriented, mostly running parallel to one another. Normal CrCL collagen fibers have a recurrent undulating wave or crimped structure (Figure 6.1) (Hayashi et al. 2003a). The human ACL has been shown to also contain collagen types III, IV, V and VI and other ECM components, including glycosaminogly- cans, fibronectin, laminin, entactin, tenascin, and undulin (Neurath & Stofft 1992). The matrix of the CrCL represents a complicated regulatory network of proteins, glycoproteins, viscoelastic fibers and glycosaminoglycans with multiple functional interactions. The predominant cell type in the CrCL is the fibroblast. Ligament fibroblasts are arranged in long parallel rows between collagen fiber bundles. In the human ACL, three different phenotypes of fibroblasts have been described: fusiform or spindle-shaped, ovoid, and spheroid (Murray & Spector 1999). The cytoplasm of fusiform fibroblasts is intimately attached to the extracellular collagen and follows the crimped waveform of the fibers. Ovoid and spheroid fibroblasts are situated in Figure 6.1 Longitudinal sections of intact (A,B) and ruptured CrCL (C,D) from a 2-year-old ovariohysterectomized Beagle and a 7-year-old castrated male Golden Retriever, respectively, viewed using bright-light (A,C) and circularly polarized light (B,D) microscopy. (A,B) Intact CrCL from young dogs has a hierarchically organized structure. Birefringence of the extracellular matrix (ECM) collagen and the crimped structure of collagen fiber bundles are clearly visible in polarized light. (C,D) The disorganized regions of the ECM in ruptured CrCL exhibit a loss of birefringence and crimp, as well as a loss of ligament fibroblasts. Scale bars = 100 μm. Source: Hayashi et al. 2003a. Reproduced with permission from John Wiley & Sons, Inc. VetBooks.ir Histology of Cruciate Ligament Rupture the loose connective tissue between collagen fibers. It is presently unclear whether these cells represent differing metabolic states of the same cells or whether they are distinctly different fibroblasts. A histologic study of the human ACL identified three histologically different zones along the anteromedial bundle as it coursed from the femoral to the tibial attachment (Murray & Spector 1999). Two of the zones, the fusiform and ovoid, were located in the proximal onequarter of the bundle, while the third spheroid zone occupied the distal three-quarters of the fiber bundles. The fusiform cell zone was characterized by a high number density of longitudinally oriented cells with a fusiform-shaped nucleus, longitudinal blood vessels, and high crimp length. The cytoplasm of the cells in this zone appeared to be intimately attached to the extracellular collagen and followed the crimp waveform of the fibers. The ovoid cell zone was characterized by a high number density of cells with an ovoid-shaped nucleus, longitudinal vessels, and a high crimp length. Also in this zone, the cytoplasm of the cells appeared to follow the waveform of the adjacent collagen. The spheroid cell zone was characterized by a low density of spheroid cells, few blood vessels, and a short crimp length. Cells were noted within and among fascicles, as well as within lacunae. The role of the various fibroblast phenotypes in the maintenance of the human ACL is not known. The histologic structure of the cruciate ligament is not homogeneous. In ACL, it has been reported that there is a zone where the tissue resembles fibrocartilage (Petersen & Tillmann 1999). The fibrocartilaginous zone is located 5–10 mm proximal to the tibial attachment in the anterior portion of the ligament. Within this zone, the cells are arranged in columns and the cell shape is round to ovoid. Transmission electron microscopy reveals typical features of chondrocytes. These chondrocyte-like cells are surrounded by a felt-like pericellular matrix, a high content of cellular organelles, and short processes on the cell surface. The pericellular collagen is positive for type II collagen. An avascular zone is located within the fibrocartilage of the anterior part where the ligament faces the anterior rim of the intercondylar fossa. It has been proposed that the stimulus 49 for the development of fibrocartilage within dense connective tissue is shearing and compressive stress (Milz et al. 2005). In the ACL, this biomechanical situation may occur when the ligament impinges on the anterior rim of the intercondylar fossa when the knee is fully extended (Quasnichka et al. 2005). Histologic features of both the ligament cells and the ECM appear to change with aging (Hasegawa et al. 2013). In a study characterizing age-related changes in ACL from 80 subjects (age 23–94 years), the total cell number in normal ACL decreased with aging but increased in degenerated ACL with the formation of perivascular cell aggregates and islands of chondrocyte-like cells. Based on immunohistochemical staining, collagen I was expressed throughout normal and degenerated ACL. Collagen II and X were detected only in the areas with chondroid metaplasia. This study suggested that the chondrocyte-like phenotype produces an abnormal ECM and may predispose ACL to mechanical failure. Similar agerelated changes are reported in canine CrCL, as described later in this chapter. Histopathology of the canine cranial cruciate ligament Cell morphology was studied in normal cruciate ligaments from disease-free stifle joints from dogs with a high (Labrador Retriever) and low (Greyhound) risk of CR (Smith et al. 2012). Both CrCL and caudal cruciate ligament (CdCL) contained cells of heterogeneous morphologies, where cells were arranged between collagen bundles and frequently had cytoplasmic processes. Some of these processes were long (type A cells), others were shorter, thicker and more branched (type B cells), and some had no processes (type C cells). Processes were frequently shown to contact other cells, extending longitudinally and transversely through the cruciate ligaments. Cells with longer processes had fusiform nuclei, and those with no processes had rounded nuclei and were more frequent in the mid-substance of both the CrCL and the CdCL. Cells with long processes were more commonly noted in the cruciate ligaments of the Greyhound. As contact between cells may VetBooks.ir 50 Etiopathogenesis of Cruciate Ligament Rupture facilitate direct communication, variation in cell morphology between breeds with a different risk of CrCL rupture may reflect differences in cruciate ligament physiology. The canine CrCL undergoes a partial fibrocartilagenous transformation as described in human ACL, which may represent chronic and irreversible degeneration. This idiopathic degeneration is a common histologic finding of intact CrCL, despite its grossly normal appearance. A histologic study reported that the CrCL of dogs weighing greater than 15 kg consistently had microscopic evidence of degenerative changes by 5 years of age (Vasseur et al. 1985). These changes are characterized by a loss of ligament fibroblasts, metaplasia of surviving fibroblasts to chondrocytes, and failure to maintain collagen fiber bundles, which progressed in severity with age. The CrCL in dogs weighing less than 15 kg generally had less severe alterations than those in heavier dogs, and the onset of the degenerative process was delayed by several years. The deep core region of the CrCL deteriorates earlier than the superficial epiligamentous region, and the mid-portion of the CrCL deteriorates earlier than regions close to bony attachments. In ruptured CrCL, more severe changes such as hyalinization, mineralization, and cloning of chondrocyte-like cells can also occur. However, inflammatory or reparative responses are rarely observed (Hayashi et al. 2003a). Significant loss of fibroblasts from the core region of ruptured CrCL occurs. In contrast, cell number densities are similar in ruptured and intact CrCL in the epiligamentous region (Hayashi et al. 2003a,b). In ruptured CrCL, the numbers of typical ligament fibroblasts (fusiform and ovoid cells) are decreased, while numbers of cells exhibiting chondroid transformation (spheroid cells) are increased in the core region (Figures 6.1–6.3). The structure of the ECM collagen in the core region is extensively disrupted in ruptured CrCL. Rupture of the CrCL is also associated with disruption of the hierarchical architecture of ECM collagen, with a loss of the normal crimp and loss of birefringence (Figures 6.1, 6.2, and 6.4). A histological study reported that crimp was no longer detectable in many ligament specimens from dogs with CrCL rupture (Figures 6.1, 6.4, and 6.5) (Hayashi et al. 2003a). Interestingly, in the 50 μm 50 μm (A) (B) Figure 6.2 Photomicrographs of longitudinal frozen sections of intact cranial cruciate ligament (CrCL) from a 2-year-old ovariohysterectomized Beagle (A) and an 8-year-old ovariohysterectomized Labrador Retriever (B) obtained via bright-light microscopy. Specimens were stained histochemically for lactate dehydrogenase (LDH), a marker of cell viability. (A) Central part of the core region of the intact CrCL from a young dog. Notice parallel rows of fusiform and ovoid LDH-stained ligament fibroblasts, with an organized extracellular matrix (ECM) containing crimped collagen fibers. (B) Central part of the core region of the intact CCL from an old dog. Note the decreased number of ligament fibroblasts; many cells are devitalized (low LDH) with an ovoid phenotype. Collagen fibers within the ECM have also been disrupted. ruptured CrCL specimens in which crimp was still detectable, crimp length was significantly increased, and the crimp angle tended to be lower compared with intact CrCL from young dogs (Figure 6.5) (Hayashi et al. 2003a). These data suggest that the remaining organized collagen experiences mechanical overload that elongates the crimp within the collagen fibers, as progressive CrCL rupture develops over time, Fusiform Phenotype Ovoid Phenotype Spheroid Phenotype 600 500 400 300 * 200 * * 100 0 (A) 5000 4000 Intact Ruptured CrCL Status Fusiform Phenotype Ovoid Phenotype Spheroid Phenotype Epiligamentous Region 3000 2000 1000 * 0 (B) Intact Ruptured CrCL Status Figure 6.3 Relationship of cell number densities to cranial cruciate ligament (CrCL) rupture status in the core (A) and epiligamentous (B) regions-of-interest. ∗ Columns are significantly different from intact CrCL (P < 0.05). Source: Hayashi et al. 2003a. Reproduced with permission from John Wiley & Sons, Inc. thereby causing the collagen to have a longer crimp length and a smaller crimp angle. These findings also support the general hypothesis that microinjury to the ligament from mechanical overload may form an important part of the mechanically induced signaling events that orchestrate CrCL remodeling, and may be a key factor in the mechanism that leads to gradual CR over time. Fibroblast viability and metabolism are different in young intact, aged intact, and ruptured CrCL (Hayashi et al. 2003b). Metabolically active viable fibroblasts detected by a metabolic marker, lactate dehydrogenase (LDH), were seen in all intact and ruptured CrCLs. However, the number of nonviable cells in the core region of ruptured CrCLs was greater than that in intact CrCLs of young and aged dogs (Figures 6.6 and 6.7). Extracellular Matrix Grade 3.0 Core Region 51 * 2.5 2.0 1.5 1.0 0.5 0.0 (A) Percentage Birefringent Collagen Cell Number Density (#/mm2) 700 Cell Number Density (#/mm2) VetBooks.ir Histology of Cruciate Ligament Rupture Intact Ruptured CrCL Status 100 (B) 80 60 40 * 20 0 Intact Ruptured CrCL Status Figure 6.4 Relationship of extracellular matrix (ECM) organization (A) and collagen birefringence (B) to cranial cruciate ligament (CrCL) rupture status in the core region-of-interest. CrCL were graded using a numerical rating scale (1, highly organized fibrous tissue structure with parallel alignment and dense packing of collagen fibers; 2, partially disrupted organized fibrous structure of collagen fibers; 3, total loss of organized fibrous structure of collagen with homogenous appearance of the ECM). Values represent the mean of five fields-of-view. ∗ Columns are significantly different from intact CrCL (P < 0.05). Source: Hayashi et al. 2003a. Reproduced with permission from John Wiley & Sons, Inc. Cruciate ligament adaptation and repair The CrCL is a hypovascular tissue and its vascular distribution is not homogeneous (Hayashi et al. 2011a). In a study describing vascular distribution in grossly intact canine CrCL using immunohistochemical staining for two components of blood vessels (factor VIII for endothelial cells, and laminin for basement membrane), vascular staining was sparsely identified Etiopathogenesis of Cruciate Ligament Rupture Crimp Angle (degree) 60 50 # 40 30 20 10 0 Intact Ruptured CrCL Status (A) 60 Crimp Length (μm) VetBooks.ir 52 * 40 20 0 (B) (A) Intact Ruptured CrCL Status Figure 6.5 Relationship of crimp angle (A) and crimp length (B) to cranial cruciate ligament (CrCL) rupture. ∗ Significantly different from intact CrCL (P < 0.05). # Lower crimp angle compared with intact CrCL (P < 0.15). Source: Hayashi et al. 2003a. Reproduced with permission from John Wiley & Sons, Inc. throughout the entire CrCL. However, the proximal portion of the CrCL appears to have a greater number of vessels than the middle or distal portions of the ligament. In a study determining the microanatomic vascular distribution in ruptured canine CrCL using specific vascular immunohistochemical staining, the ruptured CrCL was more vascular than intact CrCL. However, there was no difference in vascular density between the torn end and the remaining core area of the ruptured CrCL (Hayashi et al. 2011b) (Figure 6.8). It remains to be determined whether this finding is associated with the cause of CrCL rupture, or is a result of CrCL rupture. Ruptured CrCLs have significantly higher amounts of immature collagen crosslinks, total and sulfated glycosaminoglycans and water (B) Figure 6.6 Photomicrographs of longitudinal frozen sections of ruptured cranial cruciate ligament (CrCL) from a 6-year-old ovariohysterectomized Labrador Retriever obtained via bright-light microscopy. Specimens were stained histochemically for lactate dehydrogenase (LDH), a marker of cell viability. (A) Periphery of the main axial tissue component (core) region of the ruptured CrCL. Note the parallel rows of fusiform and ovoid LDH-positive ligament fibroblasts, with an organized extracellular matrix (ECM) containing crimped collagen fibers. (B) Central part of the core region of the ruptured CrCL. Note the low number of ligament fibroblasts; many cells are devitalized (no LDH staining) with a spheroid phenotype (arrows). Most of the collagen fibrils within the ECM have been disrupted. Scale bar = 50 μm. Source: Hayashi et al. 2003b. Reproduced with permission from the American Veterinary Medical Association. content (cartilage-like material), and concentration of pro-matrix metalloproteinase 2 (gelatinase), compared to those of the intact ligament (Comerford et al. 2004). These findings suggest that the ECM of ruptured CrCL has an increased matrix turnover. Cartilage-like tissue is more vulnerable to disruption under normal tensile loading, and therefore CrCL degeneration with 3500 Total cell density (#/mm2) 3000 Epiligamentous region Core region A,I 53 A,I A,I 2500 2000 1500 1000 a,ll a,b,ll b,ll 500 0 (A) Young - Intact Aged - Intact dogs dogs Group Ruptured (A) 140 Non viable LDH– cell density (#/mm2) VetBooks.ir Histology of Cruciate Ligament Rupture b,ll Epiligamentous region 120 Core region 100 (B) 80 60 40 20 0 A,I a,ll Young - Intact dogs a,l A,I Aged - Intact dogs Group A,I Ruptured (B) Figure 6.7 Relationship of total cell number densities to CrCL disease status in the epiligamentous and core regions of the CrCL (A), and relationship of non-viable LDH– cell densities to CrCL disease status in the epiligamentous and core regions of the CrCL (B). Columns within a region with differing upper- or lower-case letters are significantly different (P < 0.05). Columns within a CrCL status group with differing Roman numerals are significantly different. Source: Hayashi et al. 2003b. Reproduced with permission from the American Veterinary Medical Association. fibrocartilaginous transformation may predispose CrCL to pathological rupture. Areas of fibrocartilage are also observed, however, in grossly normal CrCL in lowrisk breeds (Greyhounds), when intrinsic ECM changes in the CrCLs of Labrador Retriever (high-risk breed) are compared with those in Greyhounds (Comerford et al. 2006). Transmission electron microscopy revealed that the collagen fibril diameters of Greyhound CrCL were larger than those of Labrador Retrievers, which may relate to tissue maturity and the tissue’s mechanical properties. Histology revealed the (C) Figure 6.8 Immunohistochemical staining for factor VIII in the core region of intact (A) and ruptured (B) canine cranial cruciate ligaments, and the torn end of ruptured canine cruciate ligament (C). Scale bars = 50 μm. Positive red staining can be identified in the lumen of vascular structures. Source: Hayashi et al. 2011b. Reproduced with permission from John Wiley & Sons, Inc. VetBooks.ir 54 Etiopathogenesis of Cruciate Ligament Rupture presence of fibrocartilagenous areas in both breeds. Elastin fibers, composed of an elastin core and fibrillin containing microfibrils, are traditionally considered minor components of the ligament ECM. The elastin content is high in Greyhound CrCL, and is associated with histological signs of degeneration (Smith et al. 2014). The appearance of oxytalan fibers (bundles of microfibrils) in degenerative CrCL ECM may reflect an adaptive or reparative response to normal or increased loads (Smith et al. 2014). These observations suggest that the formation of fibrocartilage is clearly not a disadvantage to healthy racing Greyhounds, and cannot be regarded as pathological degeneration in this breed. Fibrocartilage would appear to protect CrCLs in Greyhounds, but in high-risk breeds it may be indicative of a mild degenerative change that is a risk factor for ligament rupture. It is currently unclear whether CrCL degeneration and transformation into fibrocartilage is a key pathologic change that is an important risk factor for eventual CrCL rupture in certain breeds of dog. Elastin fibers may have an adaptive or reparative role secondary to normal or increased loads. Conclusions Taken together, the current literature suggests that progressive CrCL fiber tearing during the development of stifle instability is associated with histologic changes to the matrix that include a loss of ligament fibroblasts and chondroid transformation of surviving cells. The disruption of matrix collagen includes a loss of crimp. Two central hypotheses have been proposed regarding the initial mechanism that leads to cruciate ligament degeneration and then rupture: (1) A primary defect in the ligament tissue itself or in the metabolism of the cruciate ligaments that leads to fiber rupture and eventual partial rupture, particularly of the CrCL, with development of microinstability of the stifle; and (2) a dysregulation of synovial immune responses and the development of a chronic synovitis that promotes cruciate ligament degeneration, as ligament nutrition and metabolism are related to synovial fluid phys- iology. These hypotheses are discussed further in other chapters in this section. Confirmation that one or both of these hypotheses is correct should be a focus of future work studying the CR mechanism in the dog. References Comerford EJ, Innes JF, Tarlton JF, et al. Investigation of the composition, turnover, and thermal properties of rupture cranial cruciate ligaments of dogs. Am J Vet Res 2004;65:1136–1141. Comerford EJ, Tarlton JF, Wales A, et al. Ultrastructural differences in cranial cruciate ligaments from dogs of two breeds with a differing predisposition to ligament degeneration and rupture. J Comp Pathol 2006;134:8–16. Hayashi K, Frank JD, Dubinsky C, et al. Histologic changes in ruptured canine cranial cruciate ligament. Vet Surg 2003a; 32:269–277. Hayashi K, Frank JD, Hao Z, et al. Evaluation of ligament fibroblast viability in ruptured cranial cruciate ligament of dogs. Am J Vet Res 2003b;64:1010– 1016. Hayashi K, Bhandal J, Kim SY, et al. Immunohistochemical and histomorphometric evaluation of vascular distribution in intact canine cranial cruciate ligament. Vet Surg 2011a;40:192–197. Hayashi K, Bhandal J, Rodriguez CO, Jr, et al. Vascular distribution in ruptured canine cranial cruciate ligament. Vet Surg 2011b; 40:198–203. Hasegawa A, Nakahara H, Kinoshita M, et al. Cellular and extracellular matrix changes in anterior cruciate ligaments during human knee aging and osteoarthritis. Arthritis Res Ther 2013;15:R29. Milz S, Benjamin M, Putz R. Molecular parameters indicating adaptation to mechanical stress in fibrous connective tissue. Adv Anat Embryol Cell Biol 2005;178:1–71. Murray MM, Spector M. Fibroblast distribution in the anteromedial bundle of the human anterior cruciate ligament: the presence of alpha-smooth muscle actin-positive cells. J Orthop Res 1999;17:18–27. Murray MM, Martin SD, Martin TL, et al. Histological changes in the human anterior cruciate ligament after rupture. J Bone Joint Surg Am 2000;82A:1387– 1397. Neurath MF, Stofft E. Structure and function of matrix components in the cruciate ligaments. An immunohistochemical, electron-microscopic, and immunoelectron-microscopic study. Acta Anat 1992;145:387–394. Petersen W, Tillmann B. Structure and vascularization of the cruciate ligaments of the human knee joint. Anat Embryol 1999;200:325–334. Quasnichka HL, Anderson-MacKenzie JM, Tarlton JF, et al. Cruciate ligament laxity and femoral VetBooks.ir Histology of Cruciate Ligament Rupture intercondylar notch narrowing in early-stage knee osteoarthritis. Arthritis Rheum 2005;52:3100–3109. Smith KD, Vaughan-Thomas A, Spiller DG, et al. Variations in cell morphology in the canine cruciate ligament complex. Vet J. 2012;193:561–566. Smith KD, Clegg PD, Innes JF, et al. Elastin content is high in the canine cruciate ligament and is associated with degeneration. Vet J. 2014;199:169–74. 55 Tashman S, Anderst W, Kolowich P, et al. Kinematics of the ACL-deficient canine knee during gait: serial changes over two years. J Orthop Res 2004;22:931– 941. Vasseur PB, Pool RR, Arnoczky SP, et al. Correlative biomechanical and histologic study of the cranial cruciate ligament in dogs. Am J Vet Res 1985;46: 1842–1854. VetBooks.ir VetBooks.ir 7 Genetics of Cruciate Ligament Rupture Lauren A. Baker and Peter Muir Introduction Multiple epidemiologic factors have been identified that may influence the risk of cruciate ligament rupture (CR) (for a full discussion, see Chapter 14). Of these, the most important risk factor for disease initiation is breed. Dogs of high-risk breeds tend to present with CR at an earlier age, and are more likely to present with bilateral rupture (Harasen 2008; Guthrie et al. 2012). The effect of breed on CR presentation suggests that genetic factors play a role in CR pathogenesis. It is likely that genetic risk factors combine with environmental modifiers such as body condition score or neuter status to affect expression of the CR trait. Identification of valid genetic risk factors influencing CR may lead to the discovery of targets for medical intervention and aid in the development of a predictive genetic test for the condition. A predictive test of CR risk may be used to screen young dogs for predisposition to the disease. This information can then be used to develop selective breeding strategies or to counsel clients on environmental modifications to minimize the impact of the clinical course of the disease. In order to meet these goals, several recent investigations have been conducted to discover the genetic basis of CR. Heritability Statistically, heritability is defined as the proportion of phenotypic variance that may be explained by genetic variance. It may be loosely defined as the extent to which individual genetic differences contribute to changes in observable phenotype. Heritability is expressed as a number between 0.0 and 1.0. For example, a heritability of 0.5 says that approximately 50% of a disease risk is genetic, and the other 50% must come from environmental influences. A disease that is 100% genetic would have a heritability of 1. The heritability of CR has been assessed in three high-risk breeds: the Boxer, the Newfoundland, and the Labrador Retriever (Nielen et al. 2001; Wilke et al. 2006; Baker et al. 2017). Newfoundlands have the highest prevalence of CR compared to any other breed. A study of 411 Newfoundlands (92 cases, 319 controls) estimated narrow-sense heritability derived from an 11-generation pedigree at 0.27 (Wilke et al. 2006). Nielen et al. (2001) reported heritability of Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 57 VetBooks.ir 58 Etiopathogenesis of Cruciate Ligament Rupture CR at 0.28 in a prospective study of 414 Boxer litters. Both of these studies used restricted maximum likelihood (REML) analysis for calculating heritability estimates. In a study of 237 Labrador Retrievers, the present authors’ group employed a Bayesian method (Pérez & de los Campos 2014) to estimate narrow-sense heritability from single nucleotide polymorphism (SNP) markers, as well as from pedigrees. Both methods gave similar results, with a heritability of CR in Labrador Retrievers estimated at 0.49 and 0.48, respectively (Baker et al. 2017). It is unclear whether the higher heritability indicates that CR is truly more heritable in the Labrador Retriever, or if it is a reflection of the Bayesian method used. Taken together, these results suggest that canine CR is moderately heritable within the range of 0.3–0.5. Heritability estimates of this level indicate that a reasonable reduction can be expected in overall prevalence of the condition through genetic screening applied to a selective breeding program (Nielen et al. 2001). While it has previously been suggested that CR has an autosomal recessive mode of inheritance (Wilke et al. 2006), recent research suggests that CR is a complex polygenic trait (Baird et al. 2014a,b; Baker et al. 2017). Complex trait genetics Complex traits or diseases are simply defined as phenotypic traits that are determined by both genetic and non-genetic (environmental) factors. The genetic factors that influence complex traits are typically composed of many small-effect mutations and fewer large-effect mutations that contribute predominantly additively to phenotypic variation (Robinson et al. 2014). These mutations are expected to be large in number, and so their contribution to variance on a population level is quite small (Robinson et al. 2014). The relatively small contribution of individual mutations makes all but the largest effect mutations difficult to detect without very large sample sizes. Complete discovery of genetic variants contributing to CR (and other complex traits) will likely require a combination of complementary analyses including candidate gene analyses, large-scale genome-wide association studies (GWAS), and next-generation sequencing. Candidate gene analyses For many, the candidate gene approach represents the first logical step for genetic association testing. Prior knowledge of gene function is used to choose candidate genes to test for association, based on their potential role in disease etiology. Candidate gene studies have been successful in identifying large-effect mutations, and mutations associated with Mendelian (monogenic) traits. However, this approach has faced criticism as current knowledge of gene functions is limited, and thus disease associations may be missed when they are not within ‘obvious’ genes (Tabor et al. 2002; Baird et al. 2014a). Additionally, the genetic contribution to complex traits, such as CR, likely includes many small-effect variants. Therefore, it is doubtful that associations identified in a candidate gene study would explain a large proportion of the genetic variance for the trait. With that being said, associations identified in these studies are still valuable as part of genetic discovery, and should be considered complementary to genome-wide approaches. In a study of a population of Newfoundland dogs, several genes were selected for analysis based on their known association with joint hypermobility in cattle or development of primary arthritis in humans. These included Cartilage Oligomeric Matrix Protein (COMP), Matrilin-3 (MATN), Collagen Type 9 alpha 1, 2, and 3 (COL9A1, COL9A2, COL9A3), Fibrillin-1 (FBN1), and Interleukin Receptor 4 (IL4R). Single nucleotide polymorphisms (SNPs) were identified in COMP, COL9A1, COL9A2, and FBN1. Based on chi-square analyses, there was no significant association between the SNPs and CR status (affected and unaffected), although some suggestion of an association was found between COL9A1 (located on CFA 12) and CR affected status (P = 0.10) (Wilke et al. 2005). Another study evaluated microsatellite markers closely located to the genes Collagen Type 9 alpha 1, 2, and 3 (COL9A1, COL9A2, and COL9A3) in a population of Boxers with a high incidence of CR (Temwichitr et al. 2007). Data arising from this study suggested that the VetBooks.ir Genetics of Cruciate Ligament Rupture candidate genes were not related to CR in the population studied. However, the microsatellites they identified could be possible candidates for other collagenopathies. More recently, a candidate gene SNP genotyping approach was used to evaluate several potential CR genes in high-risk breeds including the Newfoundland, Labrador Retriever, Rottweiler, and Staffordshire Bull Terrier (Baird et al. 2014a). Genes tested for association included collagen genes: COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, COL5A3, COL6A1, COL6A3, COL11A1, COL11A2, COL14A1, and COL24A1; fibril/elastic fiber formation genes: FMOD (fibromodulin), DCN (decorin), ELN (elastin), OPTC (opticin), LTBP2 (latent transforming growth factor beta binding protein 2), and BGN (biglycan); extracellular matrix genes: FBN1 (fibrillin 1), COMP (cartilage oligomeric matrix protein), and ACAN (aggrecan); collagen-formation genes: SERPINH1 (serpin pertidase inhibitor clade H (heat shock protein 47) member 1 (collagen binding protein 1), PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dehydrogenase), and LOX (lysyl oxidase); collagen cleavage genes: MMP1 (matrix metallopeptidase 1) and CTSK (cathepsin K); and ligament/tendon/limb development gene SIX1 (SIX homeobox 1). When breeds were analyzed separately, two significant SNPs were identified: one in the Labrador Retriever (corrected P < 0.001) and one in the Rottweiler (corrected P = 0.02). The SNP identified in Labrador Retrievers was located within COL24A1. The SNP identified in Rottweilers was initially considered to be located within the elastin gene, but was remapped to an intergenic region when the data were updated to the newest build of the canine genome. When all breeds were considered together, three significant SNPs were identified: two were located in COL5A1 and the third was located within COL1A1. These results suggest that collagen genes, particularly COL24A1, COL5A1, and COL1A1, play some role in CR pathogenesis. It is also important to note that the associations on COL5A1 and COL1A1 were shared across all four breeds. This provides evidence that these mutations occurred in the canine genome before breed formation (Karlsson et al. 2008). The discovery of genetic mutations that are shared across 59 multiple breeds has the most potential for clinical impact. Genome-wide association Genome-wide association studies (GWAS) use genetic markers across the entire set of DNA for an individual (genome) to first identify a chromosomal region that is associated with a disorder, and then identify all genes located in that region. The genes are then organized by function and selected for further investigation according to possible involvement in the development of the disease or trait being investigated. Before the advent of commercial SNP arrays, GWAS could be performed using microsatellites (MSATs). A microsatellite is a variable repeating segment of DNA, usually found in a non-coding segment. Microsatellites can be highly polymorphic and very informative. However, recent advances in DNA sequencing technology, computational hardware and bioinformatics have made SNP arrays the tool of choice for GWAS. Using microsatellites, a GWAS for CR was performed using 90 Newfoundlands that were selected for the GWAS based on their degree of inter-relatedness and the statistical likelihood that they segregated into homozygous unaffected and homozygous affected animals (Macrossan et al. 2005). Age and other potential contributors to the cause of CR were not considered in this analysis. A total of 495 MSATs was used to compare genotypes and allele frequencies between CR-affected and unaffected dogs. Four markers (located on four chromosomes) were significant after the false discovery rate was controlled at the 0.05 level using the Storey and Tibshirani method (Storey & Tibshirani 2003; Wilke et al. 2009; Wilke 2010). The MSATs were CPH19 located on chromosome 3, FH3702 on chromosome 5, REN147D07 located on chromosome 13, and FH3750 located on chromosome 24. Initial validation of the four markers confirmed significance of three; canine chromosomes 3, 5, and 13. Positional candidate genes located on chromosome 3 were sequenced for mutation identification; Versican core protein precursor (VCAN) and aggrecan core protein precursor (cartilage-specific protein core protein; CSPCP). Proteoglycans are major components VetBooks.ir 60 Etiopathogenesis of Cruciate Ligament Rupture of the extracellular matrix (ECM) of cartilage (Schwartz & Domowicz 2002). A significant association was identified with a SNP found in CSPCP, but not VCAN, and the trait, suggesting a role for aggrecan in CR pathogenesis. More recently, an updated GWAS of CR was performed in a population of Newfoundlands using SNP genotyping (Baird et al. 2014b). Initially, 96 dogs (48 cases, 48 controls) were genotyped using a SNP array with >170,000 SNP markers evenly spaced across the canine genome. Clinical diagnoses were confirmed by a veterinary surgeon. Control dogs were defined as dogs over the age of 5 years with no history of stifle injury, stifle instability, or pelvic limb lameness. After quality control, the samples were analyzed using the Cochran–Mantel– Haenszel (CMH) test as well as Efficient MixedModel Association Expedited (EMMAX) analysis. Both the CMH test and EMMAX are used to correct for relatedness that may exist in the population, an important step for canine GWAS studies. The 65 most significant SNPs from this analysis were re-genotyped in a larger group of 271 Newfoundlands (96 from the preliminary GWAS and 175 new) using Sequenom genotyping, and case-control association was re-analyzed. Three main associations were identified on chromosomes 1, 3, and 33. The association on chromosome 1 included SNPs within the RNF152 gene, the association on chromosome 3 included SNPs within the SORCS2 gene, and the association on chromosome 33 included SNPs within SEMA5B, DIRC2, and ZDHHC23. SEMA5B, SORCS2, and ZDHHC23 all have various roles in the nervous system. Other nervous system genes were also identified in regions that did not maintain statistical significance after correction for multiple testing. This provides evidence for the potential role of neurological pathways in CR disease risk. The authors cited the importance of mechanoreceptors for appropriate proprioception, as reduced proprioception may prevent appropriate response to mechanical loading, placing the CrCL at increased risk of matrix damage and fiber rupture (Baird et al. 2014b). These regions did not overlap with the regions identified in the earlier Newfoundland CR GWAS (Wilke et al. 2009). Most recently, a GWAS of CR was performed in another high-risk breed, the Labrador Retriever (Baker et al. 2017). Purebred Labrador Retrievers (237 dogs consisting of 98 cases, 139 controls) were genotyped using an array with >170,000 SNPs evenly spaced across the canine genome. Clinical diagnosis of CR was confirmed by a veterinary surgeon. Controls were over the age of 8 years (Reif & Probst 2003) with a normal orthopaedic examination. Additionally, lateral standing stifle radiographs were taken of all control dogs to confirm that there were no signs of stifle pathology before enrollment (Chuang et al. 2014). This level of phenotyping is more stringent than in previous studies (Wilke et al. 2009; Baird et al. 2014b). After quality control, ∼119,000 SNPs remained for linear mixed model association using two algorithms, GEMMA (Zhou & Stephens 2012) and GCTA (Yang et al. 2011), as well as Penalized Unified Multiple-locus Association using PUMA (Hoffman et al. 2013). Genome-wide significance was defined separately for each algorithm using a permutation procedure (Baker et al. 2017). To facilitate pathway analysis, an additional set of candidate loci was identified with a cutoff of P < 5E-04 (Karlsson et al. 2013), and results from all three algorithms were combined. This approach identified 129 SNPs associated with CR. These SNPs were grouped into 99 regions based on linkage disequilibrium (r2 > 0.8). One region containing two SNPs on chromosome 24 met genome-wide significance. Nine genes were identified in this region with diverse physiological effects on cellular and tissue homeostasis. These included bactericidal/permeability-increased protein (BPI), lipopolysaccharide-binding protein (LBP), Ral GTPase activation protein beta subunit (RALGAPB), adipogenin (ADIG), solute carrier family 32, member 1 (SLC32A1), ARP5 actin-related protein 5 (ACTR5), protein phosphatase 1, regulatory subunit 16B (PPP1R16B), family with sequence similarity 83, member D (FAM83D), and DEAH (Asp-Glu-Ala-His) box polypeptide 35 (DHX35). An additional 98 regions were identified at the candidate level. All regions were combined for pathway analysis using DAVID (Huang et al. 2009). Pathway analysis revealed an association with a cluster of 11 genes encoding proteins with antimicrobial activity (corrected P = 0.02) and a cluster of 24 genes encoding carbohydrate-binding proteins (corrected P = 1.21E-04). Notably, the cluster of antimicrobial genes included LBP and BPI, which were also present in the genome-wide VetBooks.ir Genetics of Cruciate Ligament Rupture significant locus on chromosome 24. The majority of the carbohydrate-binding genes also had a role in immune function as pattern-recognition receptors. Of note, this cluster also included aggrecan (ACAN), hyaluronan and proteoglycan link protein 3 (HAPLN3), also known as cartilage link protein. Aggrecan and link protein are important for maintaining hydration in collagenous tissues. Tissue hydration is important for the efficient distribution of mechanical load and cellular repair. A link between aggrecan and canine CR is also supported by earlier work (Wilke et al. 2009; Wilke 2010), which identified an association with a microsatellite within aggrecan core protein precursor. The upregulation of aggrecan has also been associated with human ACL rupture (Mannion et al. 2014; Johnson et al. 2015), as well as equine degenerative suspensory ligament desmitis (DSLD), a debilitating disorder of horses that leads to collagen disruption and eventual rupture of the suspensory ligament (Plaas et al. 2011). While GWAS has most often been used for the identification of candidate genes and biological pathways that may be contributing to disease pathogenesis, this approach may also be used to develop genomic prediction algorithms for genetic screening. Here, research is less concerned with the biological effect of a mutation tagged by a SNP, but instead focuses on the statistical effect of a particular genotype and its ability to predict a disease outcome, often in combination with other SNP genotypes. In a recent study, GWA was performed separately in a population of 46 Newfoundlands (22 cases and 24 controls) and 333 Labrador Retrievers (190 cases and 143 controls) using a mixed linear model approach. Associated SNPs from GWAS were used to develop a classification tree, which is a statistical method that evaluates each SNP for its classifying ability and selects the best SNPs to create a classification model. In Newfoundlands, 19 SNPs were used for diagnostic model assessment. The model selected three SNPs for best classification. Cross-validation of the model yielded an area under the receiver operator characteristic (ROC) curve of 95.5%, indicating that the model had a good ability to classify cases and controls in the sample population. In Labrador Retrievers, 13 SNPs were used in the same procedure. The diagnostic model selected all 13 SNPs for best classification, with an area under the ROC 61 curve of 88.4%, indicating that the model was also able to classify cases and controls in the sample population, but slightly reduced compared to Newfoundland dogs (Wilke et al. 2015). The SNPs identified in this GWAS did not overlap with regions identified in other Newfoundland or Labrador GWAS (Wilke et al. 2009; Baird et al. 2014b; Baker et al. 2017). While the results of these studies are promising, they should not be over-interpreted as the population used for GWAS was also used for diagnostic model development and testing. A truly predictive model must be tested in new populations that were not used to train the model. Nevertheless, these results speak to the concept that development of a genetic test for CR is an achievable research goal, as accurate stratification of cases and controls can be achieved (Wilke et al. 2015; Baker et al. 2017). Canine and human cruciate ligament rupture The young (human) female athlete is another cohort that shares characteristics of the CR phenotype found in dogs. This cohort experiences anterior cruciate ligament (ACL) injuries two to eight fold more frequently than their counterpart young athletic males (Arendt & Dick 1995; Gwinn et al. 2000; Lohmander et al. 2004). ACL tears in people often involve contact trauma; however, in this select population ACL rupture usually occurs via a non-contact mechanism (Arendt & Dick 1995). Several studies have evaluated the potential genetic contribution to ACL injuries in humans. The first was a case-control study that found those with an ACL injury to be twice as likely to have had a family member with an ACL injury as those study participants that did not have an ACL injury (Flynn et al. 2005). Additionally, a more recent study noted that individuals with a first-degree relative with an ACL injury were at 2.2 times greater risk of both graft rupture and contralateral injury (Webster et al. 2014). These findings support a familial predisposition to ACL rupture. Further research has targeted mutations in collagen genes as risk factors for ACL injuries. Two separate studies have evaluated a mutation (G1023T; rs1800012) in intron 1 of Collagen Type 1 alpha 1 (COL1A1), the binding site VetBooks.ir 62 Etiopathogenesis of Cruciate Ligament Rupture for the transcription factor Sp1, in relation to ACL injury (Khoschnau et al. 2008; Posthumus et al. 2009). Although the TT genotype was rare, both studies concluded that the homozygous TT genotype seemed to have a protective effect on the development of ACL rupture. It is proposed that the increased binding of the Sp1 transcription factor increases the expression of the alpha 1 chain, but it is unknown how this protects against ACL injury. In another study, female participants with an ACL injury were 2.4-fold more likely to have the AA homozygous genotype for the SNP (rs970547, S3058G) in exon 65 of Collagen Type 12 alpha 1 (COL12A1) (Posthumus et al. 2010). This finding was confirmed in a separate cohort (O’Connell et al. 2015). This study also reported an interaction between the COL5A1 rs12722 and COL12A1 rs970547, such that individuals with the T+A– pseudo-haplotype were at greater risk of experiencing ACL rupture (O’Connell et al. 2015). Another candidate gene study identified an association between matrix metalloproteinase genes and ACL rupture, particularly MMP12 rs2276109, where the AA genotype is significantly more prevalent among individuals with confirmed non-contact cruciate rupture (Posthumus et al. 2012). Angiogenesis signaling may also play a role in ACL rupture risk, as the VEGFA rs699947 CC genotype is also significantly over-represented among individuals with non-contact ACL rupture (Rahim et al. 2014). Proteoglycans have also been identified as a potential factor influencing the risk of ACL rupture in human beings. Proteoglycans play important roles in fibrillogenesis and ECM collagen. A candidate gene study identified loci in ACAN (aggrecan) and DCN (decorin) that were associated with ACL injury susceptibility (Mannion et al. 2014). A separate study evaluated gene expression in biopsies taken from ruptured ACL ligament, and noted that the expression of ACAN was significantly upregulated in female compared to male patients. This suggests that aggrecan may be playing a role in the observed sex-related differences regarding susceptibility to ACL rupture (Johnson et al. 2015). Summary and future recommendations The combined results of these studies suggest that canine CR is a moderately heritable (Nielen et al. 2001; Wilke et al. 2006; Baker et al. 2017), highly polygenic complex trait disease. Biological networks that control collagen genes (Wilke et al. 2005; Baird et al. 2014b), neurologic pathways (Baird et al. 2014a), innate immune mechanisms (Baker et al. 2017), and aggrecan signaling (Wilke et al. 2009; Wilke 2010; Baker et al. 2017) may all play a role in CR pathogenesis and warrant further investigation. The overlap between the results of canine, equine, and human discovery research implicating aggrecan in susceptibility to ACL rupture makes ACAN a particularly interesting target for further genetic investigation. Given the complex nature of this condition, further investigation of mutations with larger effects will likely require a combination of high-powered GWAS with large sample sizes and next-generation sequencing. A genetic test for CR is possible and should remain a goal of current research efforts. Genotyping dogs at individual loci is not likely to be predictive, as individual genetic mutations most likely contribute small amounts to phenotypic variance. A predictive test for CR is more likely to resemble genomic prediction methods commonly employed in animal and dairy science (Vazquez et al. 2012). These approaches consider the additive effect of all non-null-effect SNPs, which may be used to develop a genetic risk assessment tool. The comparative value of the canine model for complex trait disease has received much attention during recent years (Karlsson & Lindblad-Toh 2008; Shearin & Ostrander 2010; Hayward et al. 2016; van Steenbeek et al. 2016). There are many similarities between canine CR and human ACL rupture. It is very likely that advances made in understanding how genetic variants may affect biological pathways that influence disease risk in the dog will lead to similar advancements in the understanding and treatment of ACL rupture in human beings. References Arendt E, Dick R. Knee injury patterns among men and women in collegiate basketball and soccer. NCAA data and review of literature. Am J Sports Med 1995;23:694–701. Baird AEG, Carter SD, Innes JF, et al. Genetic basis of cranial cruciate ligament rupture (CCLR) in dogs. Connect Tissue Res, 2014a;55;275–281. VetBooks.ir Genetics of Cruciate Ligament Rupture Baird AEG, Carter SD, Innes JF, et al. Genome-wide association study identifies genomic regions of association for cruciate ligament rupture in Newfoundland dogs. Anim Genet 2014b;45:542–549. Baker LA, Kirkpatrick B, Rosa GJM, et al. Genomewide association analysis in dogs implicates 99 loci as risk variants for anterior cruciate ligament rupture. PLoS One 2017;12;e0173810. Chuang C, Ramaker MA, Kaur S, et al. Radiographic risk factors for contralateral rupture in dogs with unilateral cranial cruciate ligament rupture. PLoS One 2014;9:e106389. Flynn RK, Pedersen CL, Birmingham TB, et al. The familial predisposition toward tearing the anterior cruciate ligament. Am J Sports Med 2005;33:23–28. Guthrie JW, Keeley BJ, Maddock E, et al. Effect of signalment on the presentation of canine patients suffering from cranial cruciate ligament disease. J Small Anim Pract 2012;53:273–277. Gwinn DE, Wilckens JH, McDevitt ER, et al. The relative incidence of anterior cruciate ligament injury in men and women at the United States Naval Academy. Am J Sp Med 2000;28:98–102. Harasen G. Canine cranial cruciate ligament rupture in profile: 2002–2007. Canadian Vet J 2008;49:193– 194. Hayward JJ, Castelhano MG, Oliveira KC, et al. Complex disease and phenotype mapping in the domestic dog. Nat Commun 2016;7:10460. Hoffman, GE, Logsdon BA, Mezey JG. PUMA: A unified framework for penalized multiple regression analysis of GWAS data. PLoS Comput Biol 2013;9:p.e1003101. Huang DW, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009;37:1–13. Johnson JS, Morscher MA, Jones KC, et al. Gene expression differences between ruptured anterior cruciate ligaments in young male and female subjects. J Bone Joint Surg 2015;97:71–79. Karlsson EK, Lindblad-Toh K. Leader of the pack: gene mapping in dogs and other model organisms. Nat Rev Genet 2008;9:713–725. Karlsson EK, Sigurdsson S, Ivansson E, et al. Genomewide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B. Genome Biol 2013;14:R132. Khoschnau S, Melhus H, Jacobson A, et al. Type 1 collagen α1 Sp1 polymorphism and the risk of cruciate ligaments ruptures or shoulder dislocations. Am J Sports Med 2008;36:2432–2436. Lohmander LS, Ostenberg A, Englund M, et al. High prevalence of knee osteoarthritis, pain, and functional limitations in female soccer players twelve years after anterior cruciate ligament injury. Arthritis Rheum 2004;50:3145–3152. Macrossan PE, Kinghorn BP, Wilke VL, et al. Selective genotyping for determination of a major gene associated with cranial cruciate ligament disease in 63 the Newfoundland dog. Proc Assoc Adv Animal Breeding Genet 2005;16:346–349. Mannion S, Mtintsilana A, Posthumus M, et al. Genes encoding proteoglycans are associated with the risk of anterior cruciate ligament ruptures. Br J Sports Med 2014;48:1640–1646. Nielen AL, Janss LLG, Knol BW. Heritability estimations for diseases, coat color, body weight, and height in a birth cohort of Boxers. Am J Vet Res 2001;62:1198–1206. O’Connell K, Knight H, Ficek K, et al. Interactions between collagen gene variants and risk of anterior cruciate ligament rupture. Eur J Sport Sci 2015;15:341–350. Pérez P, de los Campos G. Genome-wide regression and prediction with the BGLR statistical package. Genetics 2014;198:483–495. Plaas A, Sandy J, Liu H, et al. Biochemical identification and immunolocalizaton of aggrecan, ADAMTS5 and inter-alpha-trypsin-inhibitor in equine degenerative suspensory ligament desmitis. J Orthop Res 2011;29:900–906. Posthumus M, September AV, Keegan M, et al. Genetic risk factors for anterior cruciate ligament ruptures: COL1A1 gene variant. Br J Sports Med 2009:43:352–356. Posthumus M, September AV, O’Cuinneagain D, et al. The association between the COL12a1 gene and anterior cruciate ligament ruptures. Br J Sports Med 2010;44:1160–1165. Posthumus M, Collins M, van der Merwe L, et al. Matrix metalloproteinase genes on chromosome 11q22 and the risk of anterior cruciate ligament (ACL) rupture. Scand J Med Sci Sports 2012;22:523– 533. Rahim M, Gibbon A, Hobbs H, et al. The association of genes involved in the angiogenesis-associated signaling pathway with risk of anterior cruciate ligament rupture. J Orthop Res 2014;32:1612– 1618. Reif U, Probst CW. Comparison of tibial plateau angles in normal and cranial cruciate deficient stifles of Labrador Retrievers. Vet Surg 2003;32:385– 389. Robinson MR, Wray NR, Visscher PM. Explaining additional genetic variation in complex traits. Trends Genet 2014;30:124–132. Schwartz NB, Domowicz M. Chondrodysplasias due to proteoglycan defects. Glycobiology 2002;12:57– 68. Shearin AL, Ostrander EA. Leading the way: canine models of genomics and disease. Dis Model Mech 2010;3:27–34. Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003;100:9440–9445. Tabor HK, Risch NJ, Myers RM. Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet 2002;3: 391–397. VetBooks.ir 64 Etiopathogenesis of Cruciate Ligament Rupture Temwichitr J, Hazewinkel AW, van Hagen MA, et al. Polymorphic microsatellite markers for genetic analysis of collagen genes in suspected collagenopathies in dogs. J Vet Med A 2007;54:522– 526. van Steenbeek FG, Hytonen MK, Leegwater PAJ, et al. The canine era: the rise of a biomedical model. Anim Genet 2016;47:519–527. Vazquez AI, de los Campos G, Klimentidis YC, et al. A comprehensive genetic approach for improving prediction of skin cancer risk in humans. Genetics 2012;192:1493–1502. Webster KE, Feller JA, Leigh WB, et al. Younger patients are at increased risk for graft rupture and contralateral injury following anterior cruciate ligament reconstruction surgery. Am J Sports Med 2014;42;641–647. Wilke VL, Conzemius MG, Kinghorn BP, et al. Inheritance of rupture of the cranial cruciate ligament in Newfoundlands. J Am Vet Med A 2006;228: 61–64. Wilke VL, Conzemius MC, Rothschild MF. SNP detection and association analyses of candidate genes for rupture of the cranial cruciate ligament in the dog. Anim Genet 2005;36:519–521. Wilke VL, Zhang S, Evans RB, et al. Identification of chromosomal regions associated with cranial cruciate ligament rupture in a population of Newfoundlands. Am J Vet Res 2009;70:1013–1017. Wilke VL. Genetics of cruciate ligament rupture. Advances in The Canine Cranial Cruciate Ligament. P Muir, editor. Wiley Blackwell. 2010, pp. 53–58. Wilke VL, Zaldivar-Lopez S, Ekenstedt K, et al. Genotype influences risk of cranial cruciate ligament disease in the Newfoundland and Labrador retriever breeds. J Vet Med Res 2015;2:1028. Yang J, Lee H, Goddard ME, Visscher PM. GCTA: A tool for genome-wide complex trait analysis. Am J Hum Genet 2011;88:76–82. Zhou X, Stephens M. Genome-wide efficient mixedmodel analysis for association studies. Nat Genet 2012;44:821–824. VetBooks.ir 8 Cruciate Ligament Matrix Metabolism and Development of Laxity Eithne Comerford Introduction Cruciate ligaments are comprised of cells and extracellular matrix (ECM). Most skeletal ligaments contain approximately 60–80% water, while nearly 70–80% of the dry weight of ligament is collagen (Frank et al. 1985). Up to 90% of the ligamentous collagens is type I collagen, the principle tensile-resistant fiber, but smaller quantities of types III, V, and VI are also present (Waggett et al. 1996). Smaller proportions of matrix are composed of elastin, proteoglycans and other biochemical substances such as DNA from cells, enzymes, glycoproteins, lipoproteins and integrins (Frank et al. 1985; Amiel et al. 1995; Smith et al. 2014; Kharaz et al. 2016; Ruschke et al. 2016). The majority of cells in ligaments are fibroblasts (sometimes referred to as ligamentocytes) (Vasseur et al. 1985), although fibrocartilage cells are present at attachment sites. The fibroblasts have multiple small cellular processes or microvilli which may alter in cruciate ligaments from dog breeds with differing risk of cruciate ligament rupture (CR) (Smith et al. 2012) (Figure 8.1). The cells are linked both within the same row and in adjacent rows by connexins, allowing a three-dimensional communicating network that extends throughout the ligament (Benjamin & Ralphs 1998). The mechanical properties of cruciate ligaments are dependent on the composition and structure of the ECM, in particular collagen. Collagen turnover is a balance between its synthesis and degradation (Cawston 1998). To date, most interest in cruciate ligament ECM metabolism has centered on degradation (Comerford et al. 2005; Hasegawa et al. 2013; Nakahara et al. 2013). However, some research has been conducted into the synthesis of ECM components (e.g., collagen) in ligament, by measuring terminal propeptide levels (Sluss et al. 2001; Quasnichka et al. 2005), but this has yet to be evaluated in the canine cranial cruciate ligament (CrCL). The synthesis of ECM components after mechanical load has been evaluated in canine CrCL cells (Breshears et al. 2010a). Proteases, such as the cathepsins (Muir et al. 2002; Barrett et al. 2005; Muir et al. 2005a,b) and matrix metalloproteinases (MMPs; collagenases, stromelysins, and gelatinases) (Muir et al. 2005a,b; Comerford et al. 2006; Breshears et al. 2010b) have been mainly implicated in ECM degradation. Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 65 Etiopathogenesis of Cruciate Ligament Rupture VetBooks.ir 66 Figure 8.1 Confocal microscopy images of canine cranial cruciate ligament (CrCL) cellular matrix. Greyhound CrCL longitudinal sections. Vimentin and α-tubulin immunohistochemistry (green) with DAPI for nuclear staining (blue). Scale bars = 50 μm. (A) Interfascicular region showing dense cellularity with multiple branching processes. (B) Type A cells with thin longitudinal processes of moderate length and minimal branching. (C) Type B cells showing shorter thicker processes with branching. (D) Type C cell morphology showing rounded nuclei and an absence of processes. Source: Smith et al. 2012. Reproduced with permission from Elsevier. VetBooks.ir Cruciate Ligament Matrix Metabolism and Development of Laxity Cruciate ligament metabolism and laxity in human beings and other species Ligament metabolism may affect ligament strength, and it has been suggested that upregulated anterior cruciate ligament (ACL) remodeling may predispose women to ACL injury (Foos et al. 2001). Hormonal factors have been shown to play an important role in ligament metabolism and increased anterior knee laxity (Park et al. 2009). In a systematic review (Hewett et al. 2007), it was demonstrated that women were at risk for ACL injuries in the first half or pre-ovulatory phase of their menstrual cycle, with one recent study advising that female athletes should not exercise aggressively during this part of their cycle (Stijak et al. 2015). Estrogen and progesterone appear to influence collagen metabolism in both animal models and human beings. Estrogen (i.e., estradiol) has been shown to decrease fibroblast proliferation and type I pro-collagen, whereas progesterone counterbalances the inhibitory effect of estrogen on female ACLs (Yu et al. 1999). Estrogen-primed ACL cells are also very responsive to relaxin, decreasing collagen type I and III gene expression as well increasing the expression of degradative enzymes such as MMP-1 and 3 (Konopka et al. 2016). Most studies concerning knee laxity have been conducted on the ACL, and most have involved ex vivo cadaveric testing. Ex vivo, varus–valgus laxity and angulation is increased greatly by sectioning the collateral ligaments (Markolf et al. 1976). Anterior–posterior stability is affected by the transection of most ligaments, with ACL sectioning showing the greatest increase at full joint extension (Markolf et al. 1976). Varus–valgus and anteroposterior laxity is thought to be an important contributor in the pathogenesis of human knee arthritis (Sharma et al. 1999). Increased laxity may contribute to abnormal knee biomechanics and abnormally distributed joint loads that likely lead to or accelerate arthritis. Increased knee laxity was demonstrated in the ovulatory or post-ovulatory phases of the female menstrual cycle (Zazulak et al. 2006; Park et al. 2009; Lee et al. 2013). A significantly higher anterior–posterior joint laxity and hyperextension has been identified in non-contact ACL 67 injury in females compared to males (Uhorchak et al. 2003). Although studies have examined the effects of sex hormones on ACL metabolism, there are few reports of normal ACL ECM remodeling/degradation and its relationship to joint laxity. It has been suggested that increased collagen remodeling of the normal guinea pig ACL by gelatinases (MMP-2 and MMP-9) may contribute to ligament and, therefore, knee joint laxity (Quasnichka et al. 2005). Increased remodeling was demonstrated in CrCLs from a strain of guinea pigs predisposed to the development of spontaneous arthritis (i.e., Dunkin Hartley) at 12 weeks compared to a control strain (i.e., Bristol Strain-2). All of the biochemical and mechanical changes in the predisposed CrCLs occurred before subchondral bone and cartilage changes at 24 weeks (Anderson-MacKenzie et al. 2005). These studies suggest that increased remodeling of the CrCL may contribute to ligament and, therefore, knee joint laxity. Canine cruciate ligament metabolism and laxity Introduction Most interest in ECM degradation of canine articular tissue has centered on the MMPs (collagenases, stromelysins and gelatinases), cathepsins (serine, cysteine and aspartic proteases), and the ADAMTs family of enzymes. The MMPs are regulated by several natural inhibitors, such as the tissue inhibitors of metalloproteinases (TIMPs) and α2 -macroglobulin, in order to prevent excessive activity and resulting matrix degradation. The collagenases (MMP-1, -8, and -13) (which cleave the fibrillar collagens at a specific site within their helical domain, generating 3/4 and 1/4 fragments) have been demonstrated in normal and in experimental arthritic canine cartilage (Fernandes et al. 1998). The stromelysins (MMP-3 and -10) and gelatinases (MMP-2 and -9) have been identified in canine synovial fluid associated with experimentally induced and rheumatoid arthritis, respectively (Coughlan et al. 1998; Panula et al. 1998). Increased concentrations of the N-terminal (393) Alanine-Arginine-Glycine-Serine (ARGS) neoepitope (or ARGS-aggrecan), a breakdown product of cartilage, have been found to be elevated in human synovial fluid after acute ACL injury. An increase in TIMP-3 at six months after the injury was reported, suggesting an inhibitory effect on further cartilage degradation (Tourville et al. 2015). However, little attention has been centered on the presence and expression of these proteases in the normal canine CrCL. The role that the CrCL plays in the mechanical integrity of the canine stifle joint has been well described (Stouffer et al. 1983; Vasseur 1993; Wingfield et al. 2000). Excessive motion of the canine stifle joint is prevented by ligamentous constraints (the CrCL primarily resisting cranial tibial displacement) and a complex system of reflex arcs from surrounding muscle groups (Vasseur & Arnoczky 1981; Vasseur 1993). Although the joint capsule has also been shown to contribute significantly to craniocaudal stability in the canine stifle, the role of the CrCL surpasses this contribution (Lopez et al. 2003). Metabolism in ruptured canine cruciate ligaments ECM metabolism in ruptured canine CrCLs has been investigated (Muir et al. 2002; Comerford et al. 2004). In one study (Comerford et al. 2004), CrCLs from normal Labrador Retrievers, a breed at high-risk of CR, and from Labrador Retrievers with CR were examined. Ruptured CrCLs had significantly higher amounts of immature crosslinks, total and sulfated glycosoaminoglycans (GAGs), and water content, compared with that of the intact ligaments. Compared with intact CrCLs, the concentration of pro-MMP-2 (inactive MMP-2) was significantly higher, and the maximum temperature of collagen denaturation was significantly lower in the ruptured CrCLs (Figures 8.2 and 8.3) (Comerford et al. 2004). These studies suggested that the ECM of ruptured CrCLs had an increased matrix turnover, as indicated by a higher collagen and GAG synthesis, compared with that of intact CrCLs. It is likely that the ECM changes may have occurred before ligament rupture. However, it is possible that these observed changes may form part of a reparative Percentage of MMP-2 standard Etiopathogenesis of Cruciate Ligament Rupture 300 p = 0.02 200 100 0 Ruptured CrCLs Intact CrCLs Figure 8.2 Dot diagram of the pro-form of matrix metalloproteinase 2 (pro-MMP-2) as a percentage of the MMP-2 standard indicative of collagen remodeling in seven ruptured and 11 intact cranial cruciate ligaments (CrCLs) from 18 dogs. Horizontal lines represent the mean values of each data set. Source: Comerford et al. 2004. Reproduced with permission from the American Veterinary Medical Association. process after rupture. Interestingly, the opposite was found recently in ruptured human ACLs, compared to non-ruptured ACLs, with a reduction in collagen and proteoglycans content noted. The authors suggested that these changes occurred before or very soon after rupture. However, the non-ruptured ligaments were collected from aged donors during total knee replacement, and may not indicate normal ECM levels (Young et al. 2011). Ruptured CrCLs also contain greater numbers of cells with the proteinases TRAP and 75.0 Temperature (°C) VetBooks.ir 68 p = 0.004 72.5 70.0 67.5 65.0 Ruptured CrCLs Intact CrCLs Figure 8.3 Dot diagram of the maximum temperature of denaturation determined via differential scanning calorimetry in eight ruptured and 11 intact cranial cruciate ligaments (CrCLs) from 19 dogs. Horizontal lines represent the mean values of each data set. Source: Comerford et al. 2004. Reproduced with permission from the American Veterinary Medical Association. VetBooks.ir Cruciate Ligament Matrix Metabolism and Development of Laxity 69 cathepsin K, when compared with CrCLs from healthy, young, or aged dogs (Muir et al. 2002). Therefore, cell-signaling pathways that regulate expression of these proteinases may form part of the mechanism that leads to upregulation of collagen remodeling within the CrCL (Muir et al. 2002). Levels of cathepsin K and tartrate-resistant protein (TRAP) expression in the canine synovium and CrCL were also found to be significantly correlated in dogs with CR (Muir et al. 2005a). The relationship of cruciate ligament metabolism and stifle laxity Detailed comparisons of joint laxity and other mechanical parameters in stifle joints with normal CrCLs with other ligament parameters (e.g., collagen and ECM biochemistry) have been reported infrequently (Vasseur et al. 1985). The latter authors compared the biomechanical and histological properties in dogs, and found a positive relationship with age, increasing weight, and degenerative changes in the canine CrCL (Vasseur et al. 1985). However, only a mixed population of dogs of different breeds, ages, gender, and weight was examined in this study. The present authors’ group hypothesized that increased cranio-caudal stifle joint laxity would be present in normal stifle joints from a breed at high risk of developing CR (Labrador Retriever), compared to a low-risk breed (Greyhound). It was also hypothesized that the stifle joints with increased cranio-caudal laxity (highrisk breeds) would demonstrate increased ECM metabolism of their CrCLs. This increased ECM metabolism could result in reduced ligament strength and increased joint laxity contributing to eventual ligament rupture. Mechanical, biochemical and thermal analyses were used to test the above hypothesis (Comerford 2002; Comerford et al. 2005). Mechanical analyses involved the measurement of cranio-caudal laxity and tensile testing of the CrCL. Ex vivo mechanical testing of the stifles from both high- and low-risk breeds was performed as previously described (Amis & Dawkins 1991). The stifle joints were mounted in two different test positions (30◦ and 90◦ of flexion) (Figure 8.4), after which the Figure 8.4 Photograph of a canine stifle joint positioned in a materials testing machine (Instron 1122, Instron Ltd, High Wycombe, UK) for cranio-caudal mechanical testing. The tibia is positioned in the uppermost stainless steel pot and the load cell is positioned to the top of the picture. CrCL dimensions were measured and the ligaments tested to failure (Woo et al. 1991). Biochemical and thermal analyses to assess ECM metabolism, such as collagen crosslink analysis, gelatin and reverse gelatin zymography (to measure MMPs and TIMPs, respectively), total and sulfated GAGs, and differential scanning calorimetry, were performed on the CrCLs from the stifles which had undergone mechanical testing. Cranio-caudal laxity measurements showed the mean tibial displacements of the Labrador Retriever stifle joints to be significantly greater than those of the Greyhound stifle joints at 30◦ and 90◦ of flexion, indicating increased laxity within the high-risk stifle joints (Figure 8.5) (Comerford et al. 2005). There was a significantly higher expression of pro-MMP-2 in the high-risk CrCLs (Labrador Retrievers) compared to the low-risk (Greyhound) CrCLs (Figure 8.6). Higher pro-MMP-2 levels can be associated with increased collagen turnover, though this was not confirmed by changes in immature collagen crosslinks in this study. The concentrations of pro-MMP-2 had a positive correlation (r = 0.5, P = 0.02) with cranio-caudal laxity at 90◦ , once both dog groups were combined. The enthalpy of collagen denaturation (indicating the amount of heat required to denature the collagen triple helices) was significantly lower in the Labrador CrCLs, compared to that of Etiopathogenesis of Cruciate Ligament Rupture p = 0.04 p = 0.04 100 CC Laxity (mm) (Mean+/– SEM) ** 5.0 * * ** 2.5 0.0 30 30 90 Knee joint flexion (°) Greyhound Labrador Retriever 75 p = 0.02 50 25 Greyhound Labrador Retriever Figure 8.6 Levels of pro-MMP-2 (% inactive zymogen) in Labrador Retriever and Greyhound cranial cruciate ligaments. Source: Comerford et al. 2005. Reproduced with permission from John Wiley & Sons, Inc. Greyhounds (Figure 8.7). This implies the presence of partially degraded collagen triple helices in Labrador CrCLs. Increased collagen degradation, as indicated by the high levels of MMP-2, is consistent with the thermal properties of the collagenous matrix of the Labrador CrCL, as well as the increased stifle joint laxity within this breed. Interestingly, gender or bodyweight did not correlate significantly with any of the mechanical, biochemical, or thermal analyses in this study. Conclusions Differences in cruciate ligament metabolism (ACL and CrCL) indicated by greater MMP-2 expression and collagen denaturation are p = 0.05 75 50 25 0 90 Figure 8.5 Cranio-caudal (CC) laxity testing in Greyhounds (n = 11) and Labrador Retrievers (n = 11) at 100 N with the joint in 30◦ and 90◦ of flexion. Source: Comerford et al. 2005. Reproduced with permission from John Wiley & Sons, Inc. 0 Enthalpy (J/g collagen) (Mean+/– SEM) 7.5 Expression of pro-MMP–2 (% std) (Mean+/– SEM) VetBooks.ir 70 Greyhounds Labrador Retrievers Figure 8.7 The enthalpy of denaturation (J/g collagen) of the differential scanning calorimetry thermograms from Labrador Retriever and Greyhound cranial cruciate ligaments. Source: Comerford et al. 2005. Reproduced with permission from John Wiley & Sons, Inc. consistent with identified mechanical properties in guinea pigs and dogs. The ligaments examined in these studies had no apparent pathology and, therefore, the changes identified may be intrinsic to ligament metabolism. This may be related to genetics (influencing factors such as stifle joint morphology), and may account for the differing breed predisposition to CR within these two species. Therefore, subtle changes in cruciate ligament metabolism and its influence on joint mechanics may play a role in canine CrCL, and possibly human, ACL rupture. References Amiel D, Chu CR, Lee J. Effect of loading on metabolism and repair of tendons and ligaments. Repetitive motion disorders of the upper extremity. S Gordon, Blair, SJ, Fine, LJ, eds. Rosemount, IL, American Academy of Orthopaedic Surgeons, 1995. pp. 217–230. Amis AA, Dawkins GP. Functional anatomy of the anterior cruciate ligament. Fibre bundle actions related to ligament replacements and injuries. J Bone Joint Surg Br 1991;73:260–267. Anderson-MacKenzie JM, Quasnichka HL, Starr RL, et al. Fundamental subchondral bone changes in spontaneous knee osteoarthritis. Int J Biochem Cell Biol 2005;37:224–236. Barrett JG, Hao Z, Graf BK, et al. Inflammatory changes in ruptured canine cranial and human anterior cruciate ligaments. Am J Vet Res 2005;66:2073–2080. Benjamin M, Ralphs JR. Fibrocartilage in tendons and ligaments – an adaptation to compressive load. J Anat 1998;193:481–494. VetBooks.ir Cruciate Ligament Matrix Metabolism and Development of Laxity Breshears LA, Cook JL, Stoker AM, et al. The effect of uniaxial cyclic tensile load on gene expression in canine cranial cruciate ligamentocytes. Vet Surg 2010a;39:433–443. Breshears LA, Cook JL, Stoker AM, et al. Detection and evaluation of matrix metalloproteinases involved in cruciate ligament disease in dogs using multiplex bead technology. Vet Surg 2010b;39:306– 314. Cawston T. Matrix metalloproteinases and TIMPs: properties and implications for the rheumatic diseases. Mol Med Today 1998;4:130–137. Comerford E. Evaluation of extracellular matrix composition, metabolism, joint mechanics and joint conformation as potential predisposing factors of cranial cruciate ligament rupture in three dog breeds. Thesis, Doctor of Philosophy, University of Bristol, 2002. Comerford EJ, Innes JF, Tarlton JF, et al. Investigation of the composition, turnover, and thermal properties of ruptured cranial cruciate ligaments of dogs. Am J Vet Res 2004;65:1136–1141. Comerford EJ, Tarlton JF, Avery NC, et al. Distal femoral intercondylar notch dimensions and their relationship to composition and metabolism of the canine anterior cruciate ligament. Osteoarthritis Cartilage 2006;14:273–278. Comerford EJ, Tarlton JF, Innes JF, et al. Metabolism and composition of the canine anterior cruciate ligament relate to differences in knee joint mechanics and predisposition to ligament rupture. J Orthop Res 2005;23:61–66. Coughlan AR, Robertson DH, Bennett D, et al. Matrix metalloproteinases 2 and 9 in canine rheumatoid arthritis. Vet Rec 1998;143:219–223. Fernandes JC, Martel-Pelletier J, Lascau-Coman V, et al. Collagenase-1 and collagenase-3 synthesis in normal and early experimental osteoarthritic canine cartilage: an immunohistochemical study. J Rheumatol 1998;25:1585–1594. Foos MJ, Hickox JR, Mansour PG, et al. Expression of matrix metalloprotease and tissue inhibitor of metalloprotease genes in human anterior cruciate ligament. J Orthop Res 2001;19:642–649. Frank C, Amiel D, Woo SL, et al. Normal ligament properties and ligament healing. Clin Orthop Relat Res 1985:15–25. Hasegawa A, Nakahara H, Kinoshita M, et al. Cellular and extracellular matrix changes in anterior cruciate ligaments during human knee aging and osteoarthritis. Arthritis Res Ther 2013;15:R29. Hewett TE, Zazulak BT, Myer GD. Effects of the menstrual cycle on anterior cruciate ligament injury risk: a systematic review. Am J Sports Med 2007;35:659–668. Kharaz YA, Tew SR, Peffers M, et al. Proteomic differences between native and tissue-engineered tendon and ligament. Proteomics 2016;16:1547–1556. Konopka JA, DeBaun MR, Chang W, et al. The intracellular effect of relaxin on female anterior cruciate 71 ligament cells. Am J Sports Med 2016;44: 2384–2392. Lee H, Petrofsky JS, Daher N, et al. Anterior cruciate ligament elasticity and force for flexion during the menstrual cycle. Med Sci Monit 2013;19:1080– 1088. Lopez MJ, Kunz D, Vanderby R, Jr, et al. A comparison of joint stability between anterior cruciate intact and deficient knees: a new canine model of anterior cruciate ligament disruption. J Orthop Res 2003;21:224–230. Markolf KL, Mensch JS, Amstutz HC. Stiffness and laxity of the knee – the contributions of the supporting structures. A quantitative in vitro study. J Bone Joint Surg Am 1976;58:583–594. Muir P, Hayashi K, Manley PA, et al. Evaluation of tartrate-resistant acid phosphatase and cathepsin K in ruptured cranial cruciate ligaments in dogs. Am J Vet Res 2002;63:1279–1284. Muir P, Danova NA, Argyle DJ, et al. Collagenolytic protease expression in cranial cruciate ligament and stifle synovial fluid in dogs with cranial cruciate ligament rupture. Vet Surg 2005a;34:482–490. Muir P, Schamberger GM, Manley PA, et al. Localization of cathepsin K and tartrate-resistant acid phosphatase in synovium and cranial cruciate ligament in dogs with cruciate disease. Vet Surg 2005b;34:239–246. Nakahara H, Hasegawa A, Otabe K, et al. Transcription factor Mohawk and the pathogenesis of human anterior cruciate ligament degradation. Arthritis Rheum 2013;65:2081–2089. Panula HE, Lohmander LS, Ronkko S, et al. Elevated levels of synovial fluid PLA2, stromelysin (MMP3) and TIMP in early osteoarthrosis after tibial valgus osteotomy in young beagle dogs. Acta Orthop Scand 1998;69:152–158. Park SK, Stefanyshyn DJ, Loitz-Ramage B, et al. Changing hormone levels during the menstrual cycle affect knee laxity and stiffness in healthy female subjects. Am J Sports Med 2009;37:588–598. Quasnichka HL, Anderson-MacKenzie JM, Tarlton JF, et al. Cruciate ligament laxity and femoral intercondylar notch narrowing in early-stage knee osteoarthritis. Arthritis Rheum 2005;52:3100–3109. Ruschke K, Meier C, Ullah M, et al. Bone morphogenetic protein 2/SMAD signalling in human ligamentocytes of degenerated and aged anterior cruciate ligaments. Osteoarthritis Cartilage 2016;24:1816–1825. Sharma L, Lou C, Felson DT, et al. Laxity in healthy and osteoarthritic knees. Arthritis Rheum 1999;42:861–870. Sluss JR, Liberti JP, Jiranek WA, et al. pN collagen type III within tendon grafts used for anterior cruciate ligament reconstruction. J Orthop Res 2001;19:852– 857. Smith KD, Clegg PD, Innes JF, et al. Elastin content is high in the canine cruciate ligament and is associated with degeneration. Vet J 2014;199:169–174. VetBooks.ir 72 Etiopathogenesis of Cruciate Ligament Rupture Smith KD, Vaughan-Thomas A, Spiller DG, et al. Variations in cell morphology in the canine cruciate ligament complex. Vet J 2012;193:561–566. Stijak L, Kadija M, Djulejic V, et al. The influence of sex hormones on anterior cruciate ligament rupture: female study. Knee Surg Sports Traumatol Arthrosc 2015;23:2742–2749. Stouffer DC, Butler DL, Kim H. Tension–torsion characteristics of the canine anterior cruciate ligament – Part I: Theoretical framework. J Biomech Eng 1983;105:154–159. Tourville TW, Poynter ME, DeSarno MJ, et al. Relationship between synovial fluid ARGS-aggrecan fragments, cytokines, MMPs, and TIMPs following acute ACL injury: A cross-sectional study. J Orthop Res 2015;33:1796–1803. Uhorchak JM, Scoville CR, Williams GN, et al. Risk factors associated with noncontact injury of the anterior cruciate ligament: a prospective four-year evaluation of 859 West Point cadets. Am J Sports Med 2003;31:831–842. Vasseur P. Stifle joint. In: Textbook of Small Animal Surgery. Slatter D, ed. New York, WB Saunders, 1993. pp. 1817–1867. Vasseur PB, Arnoczky SP. Collateral ligaments of the canine stifle joint: anatomic and functional analysis. Am J Vet Res 1981;42:1133–1137. Vasseur PB, Pool RR, Arnoczky SP, et al. Correlative biomechanical and histologic study of the cranial cruciate ligament in dogs. Am J Vet Res 1985;46:1842–1854. Waggett A, Kwan A, Woodnutt D. Collagens in fibrocartilages at the Achilles tendon insertion – a biochemical, molecular biological and immunohistochemical study. Trans Orthop Res Soc 1996: 25. Wingfield C, Amis AA, Stead AC, et al. Comparison of the biomechanical properties of Rottweiler and racing greyhound cranial cruciate ligaments. J Small Anim Pract 2000;41:303–307. Woo SL, Hollis JM, Adams DJ, et al. Tensile properties of the human femur–anterior cruciate ligament– tibia complex. The effects of specimen age and orientation. Am J Sports Med 1991;19:217–225. Young K, Samiric T, Feller J, et al. Extracellular matrix content of ruptured anterior cruciate ligament tissue. Knee 2011;18:242–246. Yu WD, Liu SH, Hatch JD, et al. Effect of estrogen on cellular metabolism of the human anterior cruciate ligament. Clin Orthop Relat Res 1999:229– 238. Zazulak BT, Paterno M, Myer GD, et al. The effects of the menstrual cycle on anterior knee laxity: a systematic review. Sports Med 2006;36:847–862. VetBooks.ir 9 Morphological Risk Factors for Cruciate Ligament Rupture Eithne Comerford Introduction Biologists use the term ‘morphology’ to describe the size, shape, and structure of an organism or one of its parts. The morphology and function of the cruciate ligaments has been discussed in Chapter 1. This chapter will describe the morphology of the bones involved in stifle joint articulation in dogs, and highlight comparative aspects of knee joint morphology in non-contact anterior cruciate ligament (ACL) injury in human beings. Stifle joint morphology may play a causative role in canine cruciate ligament degeneration and rupture (CR). Conformational variation of canine pelvic limbs such as a straight stifle joint, narrow intercondylar notch, steep tibial plateau slope and increased distal femoral torsion, may contribute to cruciate ligament microinjury, which in turn has been hypothesized to cause progressive ligament rupture and arthritis (Aiken et al. 1995; Comerford et al. 2006; Duerr et al. 2007; Mostafa et al. 2014). Distal femur The distal femoral intercondylar notch (ICN) contains both the cranial cruciate ligament (CrCL) and the caudal cruciate ligament, as they twist around each other from their femoral attachment to their tibial attachment sites. The distal femoral ICN is narrowed in dogs and human beings with CR/ACL rupture and arthritis because of increased osteophyte formation (Aiken et al. 1995; Wada et al. 1996; Lewis et al. 2008; Chen et al. 2016). Stenotic or narrowed ICNs have been implicated as a risk factor in a recent meta-analysis of human ACL injuries (Zeng et al. 2013). A stenotic ICN causes impingement by the medial aspect of the lateral femoral condyle or the intercondylar roof on the CrCL/ACL (Aiken et al. 1995). If a normal-sized ACL passes through a narrowed ICN, the reduced space could impede the normal function of the ACL, causing impingement and therefore damage to the ACL (Muneta et al. 1997). One study suggested that ACL impingement may occur at the anterior and posterior roof of the notch during tibia external rotation and abduction, resulting in ligament microinjury (Dienst et al. 2007). This study also found a significant correlation between ACL cross-sectional area to notch surface area, with a smaller notch being associated with a smaller mid-substance crosssectional area of the ACL. Some patients with Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 73 VetBooks.ir 74 Etiopathogenesis of Cruciate Ligament Rupture congenital stenosis who sustained an ACL tear by non-contact means were found to be young, with small ICN width index measurements (Souryal et al. 1988). It is also thought that knee laxity may contribute to ICN narrowing and then result in further ACL impingement and damage (Wada et al. 1996). To date, notch width (NW) or notch width index (NWI) have been the parameters used to determine the width of the human and canine ICN. The shape of the notch is also thought to be a critical factor in the role of the ICN in ACL injury. ICN shapes have been described as bell- or inverted U-shaped, A-shaped, or Wshaped (wave/crest-shaped) (Anderson et al. 2001; Chen et al. 2016). In dogs, the ICN is bell-shaped (Fitch et al. 1995). Normal ICNs tend to be inverted U-shaped, whereas narrower notches tend to more A- or W-shaped (Anderson et al. 2001). The notch shape may also change during life (Hirtler et al. 2016). Recent studies have suggested that A-shaped notches can predispose to ACL injury (Al-Saeed et al. 2013). It has also been suggested that determination of the notch shape index (NSI) (Tillman et al. 2002; Geng et al. 2016) may be a more useful measurement, as it is a relative measure of the notch width in a medial/lateral direction to the notch height in the anterior/posterior direction. A low NSI will cause the ACL to be pushed into a smaller anterior outlet of the ICN, with the joint in extension (Figure 9.1) (Tillman et al. 2002). In a multivariate model of knee joint geometry, gender-related differences were found with regard to intercondylar notch size and shape, with women having a narrower notch and men having a smaller ACL volume being predisposed to ACL injury (Sturnick et al. 2015). Differences in the ICN and its width have been investigated in normal and CrCL-deficient stifle joints, as well as ‘at-risk’ stifle joints from dog breeds with differing predispositions to CR (Comerford et al. 2006; Lewis et al. 2008; Mostafa et al. 2009; Ragetly et al. 2011). An ex vivo study found that dogs at high-risk for CR (Labrador and Golden Retrievers) had smaller ICNs than dogs at a low-risk (Greyhounds) (Comerford et al. 2006). This study hypothesized that smaller ICNs may cause ligament impingement with associated cartilaginous changes within the extracellular matrix F A B E C D Figure 9.1 Measurements of the canine intercondylar notch (ICN) (adapted from Fitch et al. 1995). A, cranial notch width; B, central notch width; C, caudal notch width; D, condylar notch width; E, ICN height; F, femoral condyle height. The cranial notch width index (NWI) is A/D, the central NWI is B/D, and the caudal NWI is C/D, the notch shape index (NSI) is B/E and ICN height index is E/F). Source: Comerford et al. 2006. Reproduced with permission from Elsevier. (ECM), leading to CrCL inflammation and degeneration. Cranial NWIs were significantly greater in the low-risk breeds (e.g., Greyhounds), compared to high-risk breeds (Retrievers) (Comerford et al. 2006). However, there was no significant difference in the NSI between highand low-risk dog breeds (Figure 9.2). As part of this study, the stifle joints of the three dog breeds were placed in full extension and the areas of the CrCLs impinged by the ICN were marked and removed. Analyses of biochemical parameters such as collagen content and crosslinks, matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and sulfated and total glycosaminosglycans (GAGs) were then performed as previously described (Comerford et al. 2004). The expression of pro and active MMP2 was significantly increased in CrCLs of the high-risk breeds, compared to the low-risk breed, suggesting increased collagen remodeling (Figure 9.3). There were significantly more sulfated GAGs in the impinged areas of the high-risk CrCLs, compared to those of the low-risk breeds p < 0.001 0.05 (A) 0.2 Greyhound G. Retriever Labrador Central ** p < 0.02 50 ** 25 0 (A) 0.0 (B) 0.3 Greyhound G. Retriever Caudal Labrador p < 0.05 ActiveMMP-2 20 0.0 Greyhound G. Retriever Labrador Figure 9.2 Intercondylar notch (ICN) width indices (ICN width indices (cranial (A), central (B) and caudal (C) in Greyhound (n = 60), Golden Retriever (n = 23), and Labrador Retriever (n = 26) femurs). ∗∗ Denotes stated statistical significance to the other two groups. Source: Comerford et al. 2006. Reproduced with permission from Elsevier. (Figure 9.4). Interestingly, the bodyweight of the Labrador Retrievers was correlated with a decrease in the central NWI (P = 0.004, r = 0.50), whilst age did not correlate with any of the ICN parameters. It is possible that an increased load on the Labrador Retriever stifle joints alters the joint mechanics, and that this may contribute to ICN remodeling and narrowing. NSI was not a factor in the predisposed dogs. Taken together, these data suggest that impingement by the ICN on the CrCLs of the high-risk breeds may result in reduced structural integrity of the ligament, predisposing the ligament to ** 10 0 Greyhound G. Retriever L. Retriever Figure 9.3 The levels of proMMP-2 (A) and active MMP-2 (B) (% of standard) in the impinged parts of Greyhound (n = 10), Golden Retriever (n = 8), and Labrador Retriever (n = 10) cranial cruciate ligaments. ∗∗ Denotes stated statistical significance to the other two groups. SEM, standard error of the mean. Source: Comerford et al. 2006. Reproduced with permission from Elsevier. p < 0.001 1.5 % Sulphated GAG of total wet weight (mg) +/– SEM 0.1 p < 0.001 30 (B) 0.2 G. Retriever L. Retriever 40 ** (C) Greyhound 50 0.1 75 p < 0.003 ProMMP-2 75 % MMP-2 std + SEM 0.10 0.00 ICN width index (mm/mm) Cranial ** % MMP2 std + SEM ICN width index (mm/mm) 0.15 ICN width index (mm/mm) VetBooks.ir Morphological Risk Factors for Cruciate Ligament Rupture 1.0 ** 0.5 0.0 Greyhound G. Retriever L. Retriever Figure 9.4 Levels of sulfated GAG (% total weight) in the impinged parts of Greyhound (n = 10), Golden Retriever (n = 8) and Labrador Retriever (n = 10) cranial cruciate ligaments. ∗∗ Denotes stated statistical significance to the other two groups. Source: Comerford et al. 2006. Reproduced with permission from Elsevier. VetBooks.ir 76 Etiopathogenesis of Cruciate Ligament Rupture increased laxity and eventual joint degeneration. However, a recent study which examined the morphometric characteristics of the pelvic limbs of Labrador Retrievers with and without CR (Mostafa et al. 2009) found ICN stenosis not to contribute to the risk of CR, though ligament changes were not examined in this study. The contribution of other aspects of femoral conformation such as femoral varus and anteversion angles have been described (Ragetly et al. 2011). The latter authors found that an increased femoral anteversion angle (FAA) (Figure 9.5) and body fat composition was greater in predisposed pelvic limbs from Labrador Retrievers. In a recent study the measurement of FAA, using Figure 9.5 The femoral anteversion angle (FAA) equals the value of the tangent of ‘a’ divided by ‘b’. The long axis of the femoral shaft is drawn on the lateral (A) and craniocaudal (B) femoral views between two points centered in the proximal femoral shaft. These two points were identified by bisecting the two femoral cortices, respectively, at one-fourth (25% line) and one-half (50% line) of the total femoral length. (A) The distance ‘a’ from the center of the femoral head to the extended axis of the femoral shaft was measured on the lateral view of the femur. (B) The distance ‘b’ from the center of the femoral head to the extended axis of the femoral shaft was measured on the craniocaudal view of the femur. Source: Ragetly et al. 2011. Reproduced with permission from John Wiley & Sons, Inc. computed tomography (CT), has been found to be more accurate than using a single lateral radiograph (Mostafa et al. 2014). Tibia The stifle joint is subjected to external ground reaction forces at weight-bearing and internal forces generated by muscular contraction. These forces not only compress the femoral and tibial articular surfaces, but also generate a cranially directed shear force in the tibia known as cranial tibial thrust (CTT). CTT is present in the stifle as the tibial plateau is not perpendicular to a line drawn between the center of motion of the stifle and hock joints, but is directed caudodistally (Slocum & Devine 1983). Numerous studies have been conducted to evaluate the association of the tibial plateau angle (TPA) and CR (Read & Robins 1982; Macias et al. 2002; Duerr et al. 2007). Although anatomic differences in the shape of the proximal tibia have been documented in dogs with CR, its role in the rupture mechanism is unclear (Wilke et al. 2002; Guastella et al. 2008). The mean TPA in dogs varies between 23◦ and 25◦ , while a wide range of TPA has been reported (13–34◦ ) in normal dogs and can vary according to breed (Aertsens et al. 2015). A study conducted by Wilke and others revealed that the functional TPA is approximately parallel to the ground in most dogs (Wilke et al. 2002). Although pathological increases in TPA (>55◦ ) have been correlated with CR (Read & Robins 1982; Macias et al. 2002), whether a general association between TPA and CR exists in dogs remains controversial. A recent study found that an excessive TPA may contribute to CR, as demonstrated in experimental Beagles where TPAs >40◦ resulted in chondroid changes in the ligament ECM which could lead eventually to non-contact ligament degeneration (Ichinohe et al. 2015). Studies have shown that the TPAs are not significantly different in Labrador Retrievers with and without CR, and also in a comparison between Greyhounds and Labrador Retrievers (Wilke et al. 2002; Reif & Probst 2003). Interestingly, German Shepherd dogs have an increased TPA when compared to dogs of high-risk breeds such as the Rottweiler (Guastella et al. 2008), but have a low risk of CR. The true effect VetBooks.ir Morphological Risk Factors for Cruciate Ligament Rupture of TPA on CrCL stresses in vivo is currently unknown, as muscular force, body size, obesity, rapid weight gain, relative inactivity, and exercise can all modify the amount of stress sustained by the CrCL, in addition to the TPA (Colborne et al. 2005). The TPA was more likely to be predictive of CR in predisposed pelvic limbs, in combination with morphometric characteristics such as the FAA (as described above) and body fat composition (Ragetly et al. 2011). Muscular imbalance may also be a risk factor in the development of CR in at-risk breeds, where atrophy of the quadriceps muscle may lead to an overdominance of the gastrocnemius increasing cranial tibial thrust in predisposed pelvic limbs (Mostafa et al. 2010). Development of the tibial tuberosity and the shape (convexity) of tibial condyles may also be relevant in the pathogenesis of CR (Guerrero et al. 2007). Smaller tibial tuberosity widths are thought to increase CTT and promote CrCL degeneration, thus leading to rupture in a younger population of dogs (Inauen et al. 2009). In a multivariate analysis performed by Mostafa and others in Labrador Retrievers, cranial angulation of the proximal portion of the tibia, excessive steepness of the tibial plateau, and distal femoral torsion appeared more likely to be associated with CR than femoral angulation, tibial torsion, intercondylar notch stenosis and increased inclination of the patellar tendon (Mostafa et al. 2009). In human beings, controversy also exists over whether posterior tibial slope is an anatomic risk factor for ACL injuries. Meister and others failed to demonstrate any relationship between non-contact ACL injuries and the posterior tibia slope (Meister et al. 1998). However, in more recent studies, tibial slope has been found to be a risk factor for ACL rupture (Sonnery-Cottet et al. 2011; Sturnick et al. 2015). Patella/quadriceps mechanism and Q-angle Conformational abnormalities of the distal femur, such as genu varum and malalignment of the quadriceps mechanism associated with medial patellar luxation (MPL), can cause increased internal stress on the CrCL (Duval et al. 1999). In human beings, the quadriceps 77 (Q-angle) may contribute to an increased risk of ACL injury (Shambaugh et al. 1991), although its role in non-contact ACL injuries is unclear. The Q-angle is the angle formed by a line directed from the insertion of the m. rectus femoris on the ilium to the middle to the trochlear groove and a second line from the tibial tuberosity to the trochlear groove mirroring the course of the patella tendon. In normal dogs, the Q-angle is reported to be 10.5◦ medially and can increase with different grades of MPL (Mortari et al. 2009), increasing up to 36.6◦ for a grade III MPL. The average Q-angle in dogs with isolated CR was reported to be 19.3◦ in this study, because of loss of CrCL restraint on internal rotation of the tibia (Kaiser et al. 2001). Ragetly and others did not find any effect of Q-angle in their multivariate approach to predict CR risk in predisposed Labrador Retriever pelvic limbs (Ragetly et al. 2011). The angles between the patellar tendon and the tibial plateau have also been measured in humans (Nisell 1985) and in healthy dogs (Dennler et al. 2006) as a function of stifle joint flexion. Dogs with partially torn CrCLs, anatomically, have marginally larger angles between the patellar tendon and tibial plateau compared with joints with intact CrCLs (Schwandt et al. 2006). Fabella A recent study found that 70% of West Highland White Terriers had a mediodistal position of their medial fabella, compared to other small- and large-breed dogs. This finding was not associated with MPL or CR, and is considered to be a normal anatomic finding for this breed (Stork et al. 2009). Conclusion Stifle joint morphology, in particular the distal femoral ICN, femoral anteversion, the TPA and muscular imbalance, may play a contributing role in CrCL degeneration and CR in the dog. The ICN has been shown to be smaller in dog breeds with an increased predisposition to CR, resulting in an altered ECM turnover. Morphometric characteristics of the anatomy of the stifle VetBooks.ir 78 Etiopathogenesis of Cruciate Ligament Rupture joint associated with increased risk of CR have recently been well described in the Labrador Retriever. However, the role of these factors in vivo, along with neuromuscular forces, has yet to be elucidated. References Aertsens A, Rincon Alvarez J, Poncet CM, et al. Comparison of the tibia plateau angle between small and large dogs with cranial cruciate ligament disease. Vet Comp Orthop Traumatol 2015;28:385–390. Aiken S, Kass PH, Toombs JP. Intercondylar notch width in dogs with and without cranial cruciate ligament injuries. Vet Comp Orthop Traumatol 1995; 8:128–132. Al-Saeed O, Brown M, Athyal R, et al. Association of femoral intercondylar notch morphology, width index and the risk of anterior cruciate ligament injury. Knee Surg Sports Traumatol Arthrosc 2013;21:678–682. Anderson AF, Dome DC, Gautam S, et al. Correlation of anthropometric measurements, strength, anterior cruciate ligament size, and intercondylar notch characteristics to sex differences in anterior cruciate ligament tear rates. Am J Sports Med 2001;29:58–66. Chen C, Ma Y, Geng B, et al. Intercondylar notch stenosis of knee osteoarthritis and relationship between stenosis and osteoarthritis complicated with anterior cruciate ligament injury: A study in MRI. Medicine (Baltimore) 2016;95:e3439. Colborne GR, Innes JF, Comerford EJ, et al. Distribution of power across the hind limb joints in Labrador Retrievers and Greyhounds. Am J Vet Res 2005;66:1563–1571. Comerford EJ, Innes JF, Tarlton JF, et al. Investigation of the composition, turnover, and thermal properties of ruptured cranial cruciate ligaments of dogs. Am J Vet Res 2004;65:1136–1141. Comerford EJ, Tarlton JF, Avery NC, et al. Distal femoral intercondylar notch dimensions and their relationship to composition and metabolism of the canine anterior cruciate ligament. Osteoarthritis Cartilage 2006;14:273–278. Dennler R, Kipfer NM, Tepic S, et al. Inclination of the patellar ligament in relation to flexion angle in stifle joints of dogs without degenerative joint disease. Am J Vet Res 2006;67:1849–1854. Dienst M, Schneider G, Altmeyer K, et al. Correlation of intercondylar notch cross sections to the ACL size: a high resolution MR tomographic in vivo analysis. Arch Orthop Trauma Surg 2007;127:253– 260. Duerr FM, Duncan CG, Savicky RS, et al. Risk factors for excessive tibial plateau angle in large-breed dogs with cranial cruciate ligament disease. J Am Vet Med Assoc 2007;231:1688–1691. Duval JM, Budsberg SC, Flo GL, et al. Breed, sex, and body weight as risk factors for rupture of the cranial cruciate ligament in young dogs. J Am Vet Med Assoc 1999;215:811–814. Fitch RB, Montgomery RD, Milton JL, et al. The intercondylar fossa of the normal canine stifle an anatomic and radiographic study. Vet Surg 1995; 24:148–155. Geng B, Wang J, Ma JL, et al. Narrow intercondylar notch and anterior cruciate ligament injury in female nonathletes with knee osteoarthritis aged 41–65 years in plateau region. Chin Med J (Engl) 2016;129:2540–2545. Guastella DB, Fox DB, Cook JL. Tibial plateau angle in four common canine breeds with cranial cruciate ligament rupture, and its relationship to meniscal tears. Vet Comp Orthop Traumatol 2008;21:125– 128. Guerrero TG, Geyer H, Hassig M, et al. Effect of conformation of the distal portion of the femur and proximal portion of the tibia on the pathogenesis of cranial cruciate ligament disease in dogs. Am J Vet Res 2007;68:1332–1337. Hirtler L, Rohrich S, Kainberger F. The femoral intercondylar notch during life: An anatomic redefinition with patterns predisposing to cruciate ligament impingement. Am J Roentgenol 2016: 1–10. Ichinohe T, Kanno N, Harada Y, et al. Histological and immunohistological analysis of degenerative changes in the cranial cruciate ligament in a canine model of excessive tibial plateau angle. Vet Comp Orthop Traumatol 2015;28:240–249. Inauen R, Koch D, Bass M, et al. Tibial tuberosity conformation as a risk factor for cranial cruciate ligament rupture in the dog. Vet Comp Orthop Traumatol 2009;22:16–20. Kaiser S, Cornely D, Golder W, et al. The correlation of canine patellar luxation and the anteversion angle as measured using magnetic resonance images. Vet Radiol Ultrasound 2001;42:113–118. Lewis BA, Allen DA, Henrikson TD, et al. Computed tomographic evaluation of the canine intercondylar notch in normal and cruciate deficient stifles. Vet Comp Orthop Traumatol 2008;21:119–124. Macias C, McKee WM, May C. Caudal proximal tibial deformity and cranial cruciate ligament rupture in small-breed dogs. J Small Anim Pract 2002;43:433– 438. Meister K, Talley MC, Horodyski MB, et al. Caudal slope of the tibia and its relationship to noncontact injuries to the ACL. Am J Knee Surg 1998;11:217– 219. Mortari AC, Rahal SC, Vulcano LC, et al. Use of radiographic measurements in the evaluation of dogs with medial patellar luxation. Can Vet J 2009; 50:1064–1068. Mostafa AA, Griffon DJ, Thomas MW, et al. Morphometric characteristics of the pelvic limbs of VetBooks.ir Morphological Risk Factors for Cruciate Ligament Rupture Labrador Retrievers with and without cranial cruciate ligament deficiency. Am J Vet Res 2009;70: 498–507. Mostafa AA, Griffon DJ, Thomas MW, et al. Morphometric characteristics of the pelvic limb musculature of Labrador Retrievers with and without cranial cruciate ligament deficiency. Vet Surg 2010;39:380–389. Mostafa AA, Griffon DJ, Thomas MW, et al. Radiographic evaluation of femoral torsion and correlation with computed tomographic techniques in Labrador Retrievers with and without cranial cruciate ligament disease. Vet Surg 2014;43:534– 541. Muneta T, Takakuda K, Yamamoto H. Intercondylar notch width and its relation to the configuration and cross-sectional area of the anterior cruciate ligament. A cadaveric knee study. Am J Sports Med 1997;25:69–72. Nisell R. Mechanics of the knee. A study of joint and muscle load with clinical applications. Acta Orthop Scand Suppl 1985;216:1–42. Ragetly CA, Evans R, Mostafa AA, et al. Multivariate analysis of morphometric characteristics to evaluate risk factors for cranial cruciate ligament deficiency in Labrador Retrievers. Vet Surg 2011;40:327–333. Read RA, Robins GM. Deformity of the proximal tibia in dogs. Vet Rec 1982;111:295–298. Reif U, Probst CW. Comparison of tibial plateau angles in normal and cranial cruciate deficient stifles of Labrador Retrievers. Vet Surg 2003;32:385– 389. Schwandt CS, Bohorquez-Vanelli A, Tepic S, et al. Angle between the patellar ligament and tibial plateau in dogs with partial rupture of the cranial cruciate ligament. Am J Vet Res 2006;67:1855– 1860. 79 Shambaugh JP, Klein A, Herbert JH. Structural measures as predictors of injury basketball players. Med Sci Sports Exerc 1991;23:522–527. Slocum B, Devine T. Cranial tibial thrust: a primary force in the canine stifle. J Am Vet Med Assoc 1983;183:456–459. Sonnery-Cottet B, Archbold P, Cucurulo T, et al. The influence of the tibial slope and the size of the intercondylar notch on rupture of the anterior cruciate ligament. J Bone Joint Surg Br 2011;93:1475–1478. Souryal TO, Moore HA, Evans JP. Bilaterality in anterior cruciate ligament injuries: associated intercondylar notch stenosis. Am J Sports Med 1988;16:449–454. Stork CK, Petite AF, Norrie RA, et al. Variation in position of the medial fabella in West Highland white terriers and other dogs. J Small Anim Pract 2009;50:236–240. Sturnick DR, Vacek PM, DeSarno MJ, et al. Combined anatomic factors predicting risk of anterior cruciate ligament injury for males and females. Am J Sports Med 2015;43:839–847. Tillman MD, Smith KR, Bauer JA, et al. Differences in three intercondylar notch geometry indices between males and females: a cadaver study. Knee 2002;9:41–46. Wada M, Imura S, Baba H, et al. Knee laxity in patients with osteoarthritis and rheumatoid arthritis. Br J Rheumatol 1996;35:560–563. Wilke VL, Conzemius MG, Besancon MF, et al. Comparison of tibial plateau angle between clinically normal Greyhounds and Labrador Retrievers with and without rupture of the cranial cruciate ligament. J Am Vet Med Assoc 2002;221:1426–1429. Zeng C, Gao SG, Wei J, et al. The influence of the intercondylar notch dimensions on injury of the anterior cruciate ligament: a meta-analysis. Knee Surg Sports Traumatol Arthrosc 2013;21:804–815. VetBooks.ir VetBooks.ir 10 Role of Nitric Oxide Production and Matrix Protease Activity in Cruciate Ligament Degeneration David E. Spreng and Simone Forterre Nitric oxide: An overview Nitric oxide (NO) is an important mediator in physiologic and pathophysiologic pathways in the body. As a nonpolar, highly reactive gas, NO diffuses freely through cell membranes and reacts with transition metals, binds to reactive cysteine thiol, or forms reactive oxygen molecules. Initially, it has been identified as the small-molecular-weight mediator released from endothelial cells that promotes the relaxation of adjacent vascular smooth muscle. This explains its earlier acronym ‘endotheliumderived relaxing factor.’ The generation of NO occurs when nitric oxide synthase (NOS) catalyzes the conversion of L-arginine to NO and L-citrulline in a two-step process (Figure 10.1; Marletta 1993). Under aerobic conditions, NO is not stable and is promptly oxidized to higher nitrogen oxides called reactive nitrogen or nitrogen oxide intermediates such as peroxynitrite (ONOO– ). Three isoforms of NOS with characteristic tissue distribution have been described: the constitutive endothelial (eNOS) and neuronal (nNOS) isoforms, and the inducible isoform (iNOS). The activities of isoforms differ in that the constitutive isoforms are Ca2+ -dependent and produce relatively low levels of NO. Physiological low amounts of NO released by eNOS in vascular endothelial cells regulate blood vessel tone, platelet aggregation, or cell diapedesis. In the neuronal system, NO derived from nNOS has been identified as a neurotransmitter of certain non-adrenergic, non-cholinergic nerve fibers in various organs such as cerebral arteries, myocardium, and pancreas in the dog. In contrast, the iNOS forms a tight complex with calmodulin independent from intracellular calcium levels, and once activated produces large amounts of NO over extended periods of time (Weinberg et al. 2007). Pro-inflammatory cytokines known to induce iNOS include interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ), whereas transforming growth factor beta (TGFβ), IL-4, IL-10 or even glucocorticoids can inhibit the expression of iNOS (Kroncke et al. 1995). iNOS is expressed in nearly all eukaryotic cells, including monocytes/macrophages, hepatocytes, synovial cells, and chondrocytes (Kroncke et al. 1995). Depending on the amount of NO released and the NOS involved, effects of NO vary at sites of inflammation. NO in higher concentrations regulates the T-cell balance by Th1 downregulation and Th2 upregulation, inhibits viral replication in macrophages, Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 81 VetBooks.ir 82 Etiopathogenesis of Cruciate Ligament Rupture L-arginine O2, NADPH iNOS, cNOS H2O, NADP+ N-hydroxy-L-arginine O2, 1/2 equiv NADPH iNOS, cNOS H2O, 1/2 equiv NADP+ L-citrulline + NO Figure 10.1 Production of nitric oxide via the oxidation of L-arginine by a family of nitric oxide synthase (NOS) enzymes. suppresses different cellular protein synthesis in various cell types, and produces marked cytotoxicity by inhibiting mitochondrial respiration or inducing DNA alterations. Reaction of NO with the superoxide anion (O2 .– ), another product of activated macrophages, may yield peroxynitrite (ONOO– ) which mediates oxidative DNA damage and subsequently programmed cell death described for several cell types, including chondrocytes (Del Carlo & Loeser 2002). The list of diseases where iNOS is currently thought to be involved is large and rapidly increasing. In multiple organ failure following septic shock, type I diabetes or ulcerative colitis, massive NO formation due to iNOS activation was characterized. Another chronic local inflammatory process with iNOS participation occurs in the arthritic joint (Del Carlo & Loeser 2008). Nitric oxide activity in articular tissues Apart from iNOS, the isoforms cNOS and nNOS which produce lower amounts of NO, have also been detected in different healthy and osteoarthritic joint tissues (Amin et al. 1995; Pelletier et al. 2000; Di Mauro et al. 2006). However, nNOS was more frequently expressed in normal than in osteoarthritis (OA) chondrocytes (Rosa et al. 2008). Within joints, NO is mainly produced by superficial cartilage chondrocytes and by synoviocytes or macrophages in the inflamed synovial membrane; all cells in which iNOS expression is upregulated during OA (Amin et al. 1995; Häuselmann et al. 1998). The importance of iNOS expression and the subsequent increase of NO in the pathogenesis of OA is endorsed by experiments in vivo demonstrating that specific inhibition of iNOS results in decreased production of cytokines, matrix metalloproteinases (MMPs) and peroxynitrite (Pelletier et al. 1999). Furthermore, ex vivo studies demonstrated that the canine cranial cruciate ligament (CrCL) actively produces NO mainly derived from the inducible NOS pathway (Spreng et al. 2000), suggesting that ligament fibroblasts are actively involved in extracellular matrix (ECM) homeostasis. Additionally, the activation of CrCL with a proinflammatory mixture of lipopolysaccharide (LPS)/IL-1/TNF leads to increased NO production and iNOS activity, indicating that ligament fibroblasts indeed produce substantial amounts of NO under a specific stimulus (Louis et al. 2006). Upon exposure to pro-inflammatory cytokines, including IL-1β, IL-17, TNFα, IFNγ, and LPS, as well as to shear stress, iNOS expression is upregulated, resulting in an increased NO production that perpetuates the release of inflammatory cytokines and other catabolic processes. As assessment of the unstable NO is extremely difficult, NO production must be calculated by measuring its stable end products nitrite or nitrate. In ligament tissue, especially in partially or totally ruptured CrCL, the assessment of NO production is difficult. Specimens of naturally diseased CrCL are usually retrieved from canine patients during surgical repair, leading to the problem that highly traumatized tissue is examined without knowing if a measured production of NO and NO metabolites is triggered by the original CrCL pathology, or is only a consequence of the mechanical trauma of ligament disruption. Interestingly, normal CrCL produces more NO compared to torn CrCL, normal cartilage or normal medial collateral ligaments of the stifle in dogs (Spreng et al. 2000) 83 VetBooks.ir Role of Nitric Oxide Production and Matrix Protease Activity in Cruciate Ligament Degeneration Figure 10.2 The catabolic actions of NO and matrix metalloproteinases (MMPs) on CrCL matrix homeostasis. Role of NO and reactive oxygen species in the joint NO is believed to be mainly a catabolic player in joint physiology (see Figure 10.2). NO is a predominant mediator in the progression of OA by inhibiting proteoglycan and collagen synthesis, and promoting activation of metalloproteinases or chondrocyte apoptosis which could further contribute to ECM reduction in OA (Taskiran et al. 1994; Goggs et al. 2003; Nakagawa et al. 2010). In pathological situations such as OA, additional reactive molecules, so-called reactive oxygen species (ROS), are abnormally produced and contribute directly or indirectly to cartilage degradation, MMP activation and cell death induction (Lepetsos & Papavassiliou 2016). ROS are free radicals containing oxygen molecules including hydroxyl radical, hydrogen peroxide, superoxide anion and nitric oxide, and are generated mainly by the mitochondria. Peroxynitrite, a redox derivative of NO, has been implicated in pro-inflammatory and proapoptotic effects by triggering the oxidative damage of cellular proteins, oxidizing lipids, and DNA in human articular cartilage (Pacher et al. 2007). Chondrocyte death is regarded as a major factor in OA pathogenesis. NO has been reported to be the primary inducer of chondrocyte apoptosis mediated by a caspase- and mitochondria-dependent pathway (Maneiro et al. 2005), while other studies have shown that endogenous NO alone does not induce cell death; rather, the generation of additional ROS is also required (Del Carlo & Loeser 2002; Liang et al. 2014). Studies of human chondrocytes showed that peroxynitrite induced apoptosis via a caspase-independent pathway (Whiteman et al. 2004). NO-induced apoptosis of chondrocytes depends on crosstalk between the iNOS and cyclooxygenase 2 (COX-2) systems, which is linked to the activation of mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/2) and p38 mitogen-activated protein kinase pathways. Apoptosis has also been detected in healthy and ruptured canine CrCLs, with a moderate but significant correlation to NO (Gyger et al. 2007). Analyzing the VetBooks.ir 84 Etiopathogenesis of Cruciate Ligament Rupture distribution of apoptotic cells in different segments of partially torn CrCLs suggests that apoptosis in ligament fibroblasts is present before mechanical disruption of the ligament (Krayer et al. 2008). Recent evidence has shown that ROS may have an opposing activity in cytokinestimulated chondrocytes, suggesting that the role of NO in OA may be more complex than originally believed. Chondrocytes respond to NO or ROS differently depending on the intensity, duration of the signaling, and the cellular redox status. For example, in a zymosaninduced arthritis model, NO and peroxynitrite induced inflammation and proteoglycan loss. While the addition of a selective iNOS inhibitor ameliorated only synovial inflammation, uric acid (a peroxynitrite scavenger) was able to decrease inflammation and proteoglycan loss, suggesting that targeting peroxynitrite might be more effective for protection against OA (Bezerra et al. 2004). It has also been shown that NO mediates the expression of pro-inflammatory cytokines such as IL-18 and IL-1 converting enzyme (Boileau et al. 2002). Pro-inflammatory mediators such as NO, IL-1, TNF, and prostaglandins are all overproduced in chondrocytes from patients with OA (Weinberg et al. 2007). MMP: An overview The matrix metalloproteinases (MMPs) are a group of structurally and functionally related enzymes responsible for the proteolytic degradation of ECM and basal membrane components. Broad functions in defense, injury, inflammation and normal tissue remodeling have been attributed to MMPs (Manicone & McGuire 2008). The role of MMPs in matrix degradation and remodeling is considered to be most important in the context of cruciate ligament rupture (CR) and stifle arthritis. Due to their potential detrimental effects, MMPs are highly regulated at different levels. At the level of transcription, MMP expression is controlled by multiple cytokines and growth factors. Moreover, MMPs are secreted as inactive proMMPs (also called latent MMP or zymogen), which then require activation that is initiated by plasmin or membrane-type MMP. A third level of regulation includes the local production of specific tissue inhibitors of metalloproteinases (TIMPs) (Ries & Petrides 1995; Nagase et al. 2006). TIMP concentrations generally far exceed the concentrations of MMPs in tissue, thereby limiting their proteolytic activity in the pericellular environment. MMPs in the articular environment are produced by synovial cells, osteoblasts, chondrocytes and ligament fibroblasts, as well as by monocyte/macrophages or neutrophils. MMPs capable of degrading the macromolecules of the ECM comprise three subclasses with respect to their substrate specificity: collagenases, gelatinases, and stromelysins. The collagenases (MMP-1, -8, and 13) are responsible for the first degradation step of collagen by cleaving the interstitial collagens I, II, and III. Collagen II is the main collagen type of hyaline cartilage, while collagen I forms the principal tensileresistant fiber of ligaments. The denatured collagen, or gelatin, is further degraded by the gelatinases (MMP-2, and -9). Among these, MMP-13 has been frequently reported to be the most important player in OA cartilage due to its ability to degrade collagens more effectively (Murphy & Nagase 2008). Stromelysins (MMP-3, -10, and 11) have a broader specificity, including collagen type III, IV, V, VII, IX, XI, as well as proteoglycans, gelatin, laminin and fibronectin, and can also activate other MMPs. MMP-2 and MMP-9 also cleave gelatin, fibronectin and elastin beside collagen type IV and V (Manicone & McGuire 2008). Although details in signaling and control mechanisms involved in MMP regulation remain to be elucidated, recent findings have been useful in developing an understanding of the complex regulation of MMP synthesis and activity. The role of MMPs in the stifle joint MMPs play a key role in the progression of various joint diseases and influence joint inflammation and matrix degradation. Most actions of MMPs in joints are catabolic in nature (Figure 10.2). They are associated with increased ECM degeneration of cartilage or ligaments, and serve as significant cofactors in inflammatory reactions (Foos et al. 2001; Muir et al. VetBooks.ir Role of Nitric Oxide Production and Matrix Protease Activity in Cruciate Ligament Degeneration 2005; Doom et al. 2008). However, some MMPs have opposite roles in the development of specific diseases. For example, MMP-2 and MMP9 (Gelatinase A and B) have very similar substrate specificities for matrix proteins, but have opposite non-matrix-related actions: MMP-2 is important for the degradation of inflammatory factors, whereas MMP-9 is an important product of macrophages and neutrophils. Experimentally, MMP-2 deficiency leads to exacerbated arthritis, whereas a deficiency of MMP-9 reduces arthritis (Itoh et al. 2002). Various studies have detected MMPs in CrCL tissue during aging, degeneration, or in torn CrCLs. Results of a study on cellular and ECM changes in the human anterior cruciate ligament (ACL) showed that constitutive MMP expression (MMP-1, -3, and -13) declines with aging, while a marked upregulation occurs in degenerated ACL, mainly in chondrocyte-like cells but not in fibroblast-like cells (Hasegawa et al. 2013). It was suggested that decreased MMP expression with aging may reflect a reduced capacity to remodel and maintain the tissue, whereas an increase in ACLs from OA knees may be caused by phenotypic changes and contribute to degeneration. These findings are supported by examination of MMP gene expression in ruptured and intact CrCLs from dogs separated into different age groups. MMP-13 and both gelatinases were significantly increased in ruptured CrCLs only, whereas the collagen I degrading enzymes MMP-1 and MMP-3 were present in torn and in intact aged CrCLs (Muir et al. 2005). The similar pattern of metalloprotease expression in torn and aging human and canine cruciate ligaments suggests that changes in collagenolytic enzymes influence the development of subtle joint laxity over time, and subsequently induces the progression of CR (Foos et al. 2001; Muir et al. 2005). Degradative enzymes have the potential to diffuse from the ligament into the synovial fluid, particularly if there are defects in the synovial lining and exposure of ligament to the joint environment. Thus, many studies have evaluated MMP activity in synovial fluid of dogs with CR. In the synovial fluid of dogs with acute CR, MMP-2 and MMP-9 activities are significantly elevated compared to synovial fluid of unaffected or contralateral joints (Rabillard et al. 2012; Boland et al. 2014; Murakami et al. 85 2016). The activity of MMP-13, however, was similar and MMP-3 was not detected in synovial fluid in either healthy or affected joints. Moreover, activity levels were not influenced by surgical stabilization and postoperative doxycycline treatment (Rabillard et al. 2012). MMP measurement in synovial fluid is only of limited value in understanding pathophysiologic pathways because it is not possible to differentiate the origin of the MMP production when measured in synovial fluid (Fujita et al. 2006; Salinardi et al. 2006). Beside CrCL tissue, elevated MMPs originate from other joint tissues, particularly inflamed synovium or cartilage. Influence of NO and MMPs on CrCL structure The pathogenesis of canine CR involves the complex processes that change a normal, healthy ligament into an altered, nonfunctional, and potentially torn ligament. Alterations have been evaluated in both the ligament fibroblasts and the ECM, and characterized from the molecular to the macroscopic level, yet the exact role still remains to be verified. One of the main reasons for this is the difficulty in studying the early phase of the disease process that leads to CR. There is good evidence that NO and MMPs modulate the consequences of CR, for example OA (Abramson 2008). On the other hand, almost all scientific information on NO and MMP involvement in the early and subclinical stages of the CR condition is only descriptive and fragmented, and does not allow any definite conclusions to be made on the exact pathway that leads to CrCL fiber rupture. Some of these data concerning direct actions of NO and MMP on the ligament are described below. External stimuli induce NO and MMP in ligaments Recent findings of a study using a novel canine model revealed that synovial debridement of the CrCL has detrimental effects on clinical signs such as pain, and also on effusion, function, and histology (Bozynski et al. 2015). VetBooks.ir 86 Etiopathogenesis of Cruciate Ligament Rupture Synoviectomy of the rabbit CrCL induces a significant increase in collagenase activity within the ligament, indicating that the synovial sheath is a critically important structure for joint health (Amiel et al. 1990). The released collagenase after synoviectomy may reflect the reaction of the CrCL to synovial fluid mediators released from inflamed synovium. Canine CrCL explant cultures, as well as ligament fibroblast monolayer cultures activated with an inflammatory stimulus, produce significantly more NO and MMP compared to non-stimulated cultures over a period of 48 hours (Riitano et al. 2002). The same stimulus induces a significantly higher iNOS expression in CrCL compared to medial collateral ligaments and femoral head ligaments (Louis et al. 2006). Different patterns of NO activity may reflect the different underlying abilities to react, and the different susceptibilities to pathological processes, between the ligaments. High NO levels inhibit collagen synthesis in ligament fibroblasts CrCL has been shown to produce more NO compared to other ligaments (Cao et al. 2000; Spreng et al. 2000). Experiments performed by Cao and colleagues showed that NO production was increased due to iNOS induction, particularly in CrCL cells, and inhibited normal collagen synthesis. High NO concentrations could, therefore, be a reason for the insufficient healing capacities of ruptured CrCL in humans and in dogs. Moreover, high NO concentrations in canine CrCL may contribute to matrix homeostasis disturbance, leading to an intrinsic weakness of the ligament. NO combined with peroxynitrite induces apoptosis in the ligament In vitro experiments have demonstrated that different NO donors induce apoptosis in CrCL cells (Murakami et al. 2005; Forterre et al. 2011). In addition, fibroblasts from the CrCL were more susceptible to NO-induced apoptosis than cells from the caudal cruciate ligament or from the medial collateral ligament. CrCL apoptosis is influenced by inhibition of caspase3 (Murakami et al. 2005), and is attenuated by treatment with ROS scavengers or a tyrosine kinase inhibitor (Forterre et al. 2012). On the other hand, oral treatment with L-NIL, a specific iNOS inhibitor, did not have a direct influence on the amount of apoptotic ligament fibroblasts in dogs with CR (Hofer et al. 2009). Consequently, NO alone is not responsible for increased levels of apoptosis in the CrCL. This corresponds to other reports on chondrocytes indicating that only the combination of NO and ROS induces apoptosis (Del Carlo & Loeser 2002). Increased NO production could be an early step in development of CR, and may contribute to the induction of cell death followed by catabolic derangement of the homeostasis of the ligament. Conclusions All of the above described observations correspond with the theory that an initial event leads to inflammation of the cruciate ligament complex (Hayashi et al. 2004). Ligament fibroblasts develop a dysregulation of matrix homeostasis as a reaction to the inflammatory stimulus, including an upregulation of matrix-degrading enzymes, a downregulation of matrix production, and peroxynitrite-induced premature ligament fibroblast death (see Figure 10.2). The role of NO, however, is less simple. By extrapolating data from in vitro cartilage experiments it seems that inhibition of NOS generation is able to decrease inflammation, but alone has little effect on protecting the joint from cartilage loss. On the other hand, peroxynitrite inhibition reduces intra-articular inflammation and loss of articular cartilage (Bezerra et al. 2004). Other studies, however, have shown the opposite: OA dogs treated with a specific iNOS inhibitor showed a reduction in osteophyte formation, a decrease in the severity of histological cartilage lesions, and a reduced levels of apoptosis in cartilage compared to untreated dogs (Pelletier et al. 2000). Adding to the complexity of the known catabolic effects of NO, the latter has also been shown to promote cartilage deposition, thereby highlighting a protective role of NO in tenocytes and human chronic OA (Xia et al. 2006; Hancock & Riegger-Krugh 2008). These conflicting results suggest that the role of NO in OA needs to be further elucidated. VetBooks.ir Role of Nitric Oxide Production and Matrix Protease Activity in Cruciate Ligament Degeneration References Abramson SB. Nitric oxide in inflammation and pain associated with osteoarthritis. Arthritis Res Ther 2008;10:S2. Amiel D, Billings E, Jr, Harwood FL. Collagenase activity in anterior cruciate ligament: protective role of the synovial sheath. J Appl Physiol 1990;69:902–906. Amin AR, Di Cesare PE, Vyas P, et al. The expression and regulation of nitric oxide synthase in human osteoarthritis-affected chondrocytes: evidence for up-regulated neuronal nitric oxide synthase. J Exp Med 1995;182:2097–2102. Bezerra MM, Brain SD, Greenacre S, et al. Reactive nitrogen species scavenging, rather than nitric oxide inhibition, protects from articular cartilage damage in rat zymosan-induced arthritis. Br J Pharmacol 2004;141:172–182. Boileau C, Martel-Pelletier J, Moldovan F, et al. The in situ up-regulation of chondrocyte interleukin1-converting enzyme and interleukin-18 levels in experimental osteoarthritis is mediated by nitric oxide. Arthritis Rheum 2002;46:2637– 2647. Boland L, Danger R, Cabon Q, et al. MMP-2 as an early synovial biomarker for cranial cruciate ligament disease in dogs. Vet Comp Orthop Traumatol 2014;27:210–215. Bozynski CC, Kuroki K, Stannard JP, et al. Evaluation of partial transection versus synovial debridement of the ACL as novel canine models for management of ACL injuries. J Knee Surg 2015;28:404– 410. Cao M, Stefanovic-Racic M, Georgescu HI, et al. Does nitric oxide help explain the differential healing capacity of the anterior cruciate, posterior cruciate, and medial collateral ligaments? Am J Sports Med 2000;28:176–182. Del Carlo M, Jr, Loeser RF. Nitric oxide-mediated chondrocyte cell death requires the generation of additional reactive oxygen species. Arthritis Rheum 2002;46:394–403. Del Carlo M, Jr, Loeser RF. Cell death in osteoarthritis. Curr Rheumatol Rep 2008;10:37–42. Di Mauro D, Bitto L, D’Andrea L, et al. Behaviour of nitric oxide synthase isoforms in inflammatory human joint diseases: an immunohistochemical study. Ital J Anat Embryol. 2006;111:111–123. Doom M, de Bruin T, de Rooster H, et al. Immunopathological mechanisms in dogs with rupture of the cranial cruciate ligament. Vet Immunol Immunopathol 2008;125:143–161. Foos MJ, Hickox JR, Mansour PG, et al. Expression of matrix metalloprotease and tissue inhibitor of metalloprotease genes in human anterior cruciate ligament. J Orthop Res 2001;19:642–649. Forterre S, Zurbriggen A, Spreng D. In vitro effect of different mediators of apoptosis on canine cranial and caudal cruciate ligament fibroblasts and 87 its reversibility by pancaspase inhibitor zVAD.fmk. Vet Immunol Immunopathol 2011;139:264–270. Forterre S, Zurbriggen A, Spreng D. Nitric oxide induces cell death in canine cruciate ligament cells by activation of tyrosine kinase and reactive oxygen species. BMC Vet Res 2012;8:40. Fujita Y, Hara Y, Nezu Y, et al. Proinflammatory cytokine activities, matrix metalloproteinase3 activity, and sulfated glycosaminoglycan content in synovial fluid of dogs with naturally acquired cranial cruciate ligament rupture. Vet Surg 2006;35:369–376. Goggs R, Carter SD, Schulze-Tanzil G, et al. Apoptosis and the loss of chondrocyte survival signals contribute to articular cartilage degradation in osteoarthritis. Vet J 2003;166:140–158. Gyger O, Botteron C, Doherr M, et al. Detection and distribution of apoptotic cell death in normal and diseased canine cranial cruciate ligaments. Vet J 2007;174:371–377. Hancock CM, Riegger-Krugh C. Modulation of pain in osteoarthritis: the role of nitric oxide. Clin J Pain 2008;24:353–365. Hayashi K, Manley PA, Muir P. Cranial cruciate ligament pathophysiology in dogs with cruciate disease: a review. J Am Anim Hosp Assoc 2004;40:385– 390. Hasegawa A, Nakahara H, Kinoshita M, et al. Cellular and extracellular matrix changes in anterior cruciate ligaments during human knee aging and osteoarthritis. Arthritis Res Ther 2013;15:R29. Häuselmann HJ, Stefanovic-Racic M, Michel BA, et al. Differences in nitric oxide production by superficial and deep human articular chondrocytes: implications for proteoglycan turnover in inflammatory joint diseases. J Immunol 1998;160:1444–1448. Hofer D, Forterre S, Schweighauser A, et al. Selective iNOS-inhibition does not influence apoptosis in ruptured canine cranial cruciate ligaments. Vet Comp Orthop Traumatol 2009;22:198–203. Itoh T, Matsuda H, Tanioka M, et al. The role of matrix metalloproteinase-2 and matrix metalloproteinase9 in antibody-induced arthritis. J Immunol 2002;169:2643–2647. Krayer M, Rytz U, Oevermann A, et al. Apoptosis of ligamentous cells of the cranial cruciate ligament from stable stifle joints of dogs with partial cranial cruciate ligament rupture. Am J Vet Res 2008;69:625–630. Kroncke KD, Fehsel K, Kolb-Bachofen V. Inducible nitric oxide synthase and its product nitric oxide, a small molecule with complex biological activities. Biol Chem Hoppe Seyler 1995;376:327–343. Lepetsos P, Papavassiliou AG. ROS/oxidative stress signaling in osteoarthritis. Biochim Biophys Acta 2016;1862:576–591. Liang Q, Wang XP, Chen TS. Resveratrol protects rabbit articular chondrocyte against sodium nitroprusside-induced apoptosis via scavenging ROS. Apoptosis 2014;19:1354–1363. VetBooks.ir 88 Etiopathogenesis of Cruciate Ligament Rupture Louis E, Remer KA, Doherr MG, et al. Nitric oxide and metalloproteinases in canine articular ligaments: a comparison between the cranial cruciate, the medial genual collateral and the femoral head ligament. Vet J 2006;172:466–472. Maneiro E, Lopez-Armada MJ, de Andres MC, et al. Effect of nitric oxide on mitochondrial respiratory activity of human articular chondrocytes. Ann Rheum Dis 2005;64:388–395. Manicone AM, McGuire JK. Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol 2008;19:34–41. Marletta MA. Nitric oxide synthase structure and mechanism. J Biol Chem 1993;268:12231–12234. Muir P, Danova NA, Argyle DJ, et al. Collagenolytic protease expression in cranial cruciate ligament and stifle synovial fluid in dogs with cranial cruciate ligament rupture. Vet Surg 2005;34:482– 490. Murakami H, Shinomiya N, Kikuchi T, et al. Differential sensitivity to NO-induced apoptosis between anterior cruciate and medial collateral ligament cells. J Orthop Sci 2005;10:84–90. Murakami K, Maeda S, Yonezawa T, et al. Synovial fluid matrix metalloproteinase-2 and -9 activities in dogs suffering from joint disorders. J Vet Med Sci 2016;78:1051–1054. Murphy G, Nagase H. Reappraising metalloproteinases in rheumatoid arthritis and osteoarthritis: destruction or repair? Nat Clin Pract Rheumatol 2008;4:128–135. Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006;69:562–573. Nakagawa S, Arai Y, Mazda O, et al. N-acetylcysteine prevents nitric oxide-induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis. J Orthop Res 2010;28:156– 163. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007;87:315–424. Pelletier J, Jovanovic D, Fernandes JC, et al. Reduction in the structural changes of experimental osteoarthritis by a nitric oxide inhibitor. Osteoarthritis Cartilage 1999;7:416–418. Pelletier JP, Jovanovic DV, Lascau-Coman V, et al. Selective inhibition of inducible nitric oxide synthase reduces progression of experimental osteoarthritis in vivo: possible link with the reduction in chondrocyte apoptosis and caspase 3 level. Arthritis Rheum 2000;43:1290–1299. Rabillard M, Danger R, Doran IP, et al. Matrix metalloproteinase activity in stifle synovial fluid of cranial cruciate ligament deficient dogs and effect of postoperative doxycycline treatment. Vet J 2012;193:271–273. Ries C, Petrides PE. Cytokine regulation of matrix metalloproteinase activity and its regulatory dysfunction in disease. Biol Chem Hoppe Seyler 1995;376:345–355. Riitano MC, Pfister H, Engelhardt P, et al. Effects of stimulus with proinflammatory mediators on nitric oxide production and matrix metalloproteinase activity in explants of cranial cruciate ligaments obtained from dogs. Am J Vet Res 2002;63:1423– 1428. Rosa SC, Judas F, Lopes MC, et al. Nitric oxide synthase isoforms and NF-kappaB activity in normal and osteoarthritic human chondrocytes: regulation by inducible nitric oxide. Nitric Oxide 2008;19:276– 283. Salinardi BJ, Roush JK, Schermerhorn T, et al. Matrix metalloproteinase and tissue inhibitor of metalloproteinase in serum and synovial fluid of osteoarthritic dogs. Vet Comp Orthop Traumatol 2006;19:49–55. Spreng D, Sigrist N, Jungi T, et al. Nitric oxide metabolite production in the cranial cruciate ligament, synovial membrane, and articular cartilage of dogs with cranial cruciate ligament rupture. Am J Vet Res 2000;61:530–536. Taskiran D, Stefanovic-Racic M, Georgescu H, et al. Nitric oxide mediates suppression of cartilage proteoglycan synthesis by interleukin-1. Biochem Biophys Res Commun 1994;200:142–148. Weinberg JB, Fermor B, Guilak F. Nitric oxide synthase and cyclooxygenase interactions in cartilage and meniscus: relationships to joint physiology, arthritis, and tissue repair. Subcell Biochem 2007;42:31–62. Whiteman M, Armstrong JS, Cheung NS, et al. Peroxynitrite mediates calcium-dependent mitochondrial dysfunction and cell death via activation of calpains. FASEB J 2004;18:1395–1397. Xia W, Szomor Z, Wang Y, et al. Nitric oxide enhances collagen synthesis in cultured human tendon cells. J Orthop Res 2006;24:159–172. VetBooks.ir 11 Role of Antibodies to Collagen Type I and II Hilde de Rooster and Eithne Comerford Introduction One of the major limitations in many investigations on the etiopathogenesis of cruciate rupture (CR) in dogs is that most studies have focused on the affected stifle joint after rupture; the end-stage of the condition. Only a few studies have been carried out on humoral and cellular immunopathological mechanisms in predisposed dogs before clinical rupture of the contralateral cranial cruciate ligament (CrCL) (de Bruin et al. 2007a,b). Antigenicity of collagen The CrCL has a microstructure of collagen bundles of multiple types, but mostly type I. The menisci are also mainly composed of collagen type I, whereas the articular cartilage is mainly composed of collagen type II (van Sickle et al. 1993). The cruciate ligaments are covered by a fold of synovial membrane and, although they have an intra-articular position, they are extrasynovial (Alm & Strömberg 1974; Arnoczky et al. 1979). Scanning electron microscopy studies ascertained the presence of many small holes in the enveloping membrane, allowing infiltration of the cruciate ligaments by synovial fluid (Kobayashi et al. 2006). Local inflammatory processes and/or trauma may result in the exposure of macromolecules, such as collagen, that trigger immune-mediated inflammatory responses (Figure 11.1). Once autoantibodies have been produced, newly released collagen type I can enhance joint inflammation by forming immune complexes with these antibodies resulting in activation of complement and phagocytes (Bari et al. 1989; Carter et al. 1999). Prevalence of antibodies to collagen types I and II Anti-collagen type I and II antibodies have been detected in dogs affected with CR (Niebauer & Menzel 1982; Niebauer et al. 1987; Bari et al. 1989; de Rooster et al. 2000). Antibodies are present in both sera and synovial fluid aspirated from the affected stifle joint, with a higher incidence in the synovial fluid (Niebauer & Menzel 1982; Niebauer et al. 1987; Bari et al. 1989), thus indicating local antibody production. This finding is supported by histological studies on synovial tissue from stifle joints of dogs with CR (Tirgari 1977; Galloway & Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 89 VetBooks.ir 90 Etiopathogenesis of Cruciate Ligament Rupture Femur Synovial tissue NT CaCL CAg CrCL 1 Mq 3 4 B 1 Joint space 1 2 5 6 Ab Immune complex Tibia Lester 1995; Lawrence et al. 1998; Hewicker et al. 1999). The main cell types detected in the synovial tissue are macrophages, T lymphocytes, B lymphocytes and plasma cells belonging predominantly to the IgG isotype (Tirgari 1977; Galloway & Lester 1995; Lawrence et al. 1998; Hewicker et al. 1999; Lemburg et al. 2004). Furthermore, a significantly higher amount of IgG and IgM has been detected in the synovial tissue of stifle joints of dogs with CR compared to normal stifle joints (Lawrence et al. 1998). In addition, lymphoplasmacytic synovitis seems common in dogs with CR, with up to 67% of patients having distinct lymphoplasmacytic nodules within the synovial tissue (Galloway & Lester 1995; Erne et al. 2009). Studies on cellular immune mechanisms suggest that there is an inflammatory process in the contralateral joints of predisposed dogs preceding detectable joint instability (de Bruin et al. 2007a). Anti-collagen type I antibodies have been measured sequentially in the synovial fluid aspirated from multiple joints. In predisposed dogs, higher anti-collagen type I titers were found in the stifle joints that eventually sustained CR, compared to the titers in a remote joint (de Bruin et al. 2007a). Relevance of antibodies to collagen types I and II It remains uncertain whether antibodies play an active role in the initiation of CR. Prospective studies on dogs which initially presented with unilateral CR did not provide evidence for this, Figure 11.1 Schematic representation of immune-mediated inflammatory responses in dogs with cranial cruciate ligament (CrCL) rupture. Step 1, impaired CrCL with release of collagen type I (CAg); Step 2, collagen uptake by macrophage (Mq); Step 3, antigen presentation to naive T cell (NT); Step 4, B cell (B) activation/differentiation with antibody production (Ab); Step 5, release of antibodies in synovial tissue; Step 6, release of antibodies in the synovial fluid and formation of immune complexes with collagen type I. CaCL, caudal cruciate ligament. as not all dogs with high antibodies developed contralateral CR (de Bruin et al. 2007a). Nevertheless, it is possible that anti-collagen antibodies perpetuate chronic joint inflammation in some dogs with cruciate degeneration or fiber rupture, even if collagen is not the primary arthritogenic agent. The finding of higher anti-collagen type I titers in the stifle joints that did not yet have a clinically detectable CR at the time of measurement, compared to the titers in a remote joint, suggests that there was an inflammatory process with production of collagen-specific antibodies in these contralateral stifle joints (de Bruin et al. 2007a). Histologic studies on synovial tissue from stifle joints of dogs with CR detected plasma cells belonging predominantly to the IgG isotype (Tirgari 1977; Galloway & Lester 1995; Lawrence et al. 1998; Hewicker et al. 1999; Lemburg et al. 2004) and lymphoplasmacytic nodules (Galloway & Lester 1995; Erne et al. 2009). However, to date no synovial tissue cells from dogs with CR have been cultured to discover if they effectively produce antibodies and, if so, against which antigens. Anti-collagen type I and II antibodies have also been detected in the synovial fluid of stifle joints with arthritis secondary to arthropathies other than CR (Niebauer et al. 1987; Bari et al. 1989), which suggests that these antibodies are not specific for the type of joint disorder (de Rooster et al. 2000). However, in dogs with complete CR, unexpectedly low or undetectable anticollagen type I antibodies titers were found in the synovial fluid of the affected stifle (de Bruin et al. 2007a). This either suggests that the VetBooks.ir Role of Antibodies to Collagen Type I and II autoimmune response stops after the rupture, or that antibodies cannot be detected since they are all present in immune complexes of these antibodies and collagen. The latter situation seems most likely. There is recent in vitro documentation supporting the idea that CrCL remnants exposed to the intrasynovial environment have the potential to trigger further degradation (Breshears et al. 2010). References Alm A, Strömberg B. Vascular anatomy of the patellar and cruciate ligaments. A microangiographic and histologic investigation in the dog. Acta Chir Scand Suppl 1974;445:25–35. Arnoczky SP, Rubin RM, Marshall JL. Microvasculature of the cruciate ligaments and its response to injury. An experimental study in dogs. J Bone Joint Surg 1979;61A:1221–1229. Bari AS, Carter SD, Bell SC, et al. Anti-type II collagen antibody in naturally occurring canine joint diseases. Br J Rheumatol 1989;28:480–486. Breshears LA, Cook JL, Stoker AM, et al. Detection and evaluation of matrix metalloproteinases involved in cruciate ligament disease in dogs using multiplex bead technology. Vet Surg 2010;39:306– 314. Carter SD, Barnes A, Gilmore WH. Canine rheumatoid arthritis and inflammatory cytokines. Vet Immunol Immunopathol 1999;69:201–214. de Bruin T, de Rooster H, van Bree H, et al. Evaluation of anticollagen type I antibody titers in synovial fluid of both stifle joints and the left shoulder joint of dogs with unilateral cranial cruciate disease. Am J Vet Res 2007a;68:283–289. de Bruin T, de Rooster H, van Bree H, et al. Lymphocyte proliferation to collagen type I in dogs. J Vet Med A Physiol Pathol Clin Med 2007b;54:292– 296. de Rooster H, Cox E, van Bree H. Prevalence and relevance of antibodies to type-I and -II collagen in 91 synovial fluid of dogs with cranial cruciate ligament damage. Am J Vet Res 2000;61:1456–1461. Erne JB, Goring RL, Kennedy FA, et al. Prevalence of lymphoplasmacytic synovitis in dogs with naturally occurring cranial cruciate ligament rupture. J Am Vet Med Assoc 2009;235:386–390. Galloway RH, Lester SJ. Histopathological evaluation of canine stifle joint synovial membrane collected at the time of repair of cranial cruciate ligament rupture. J Am Anim Hosp Assoc 1995;31:289–294. Hewicker TM, Carter SD, Bennett D. Immunocytochemical demonstration of lymphocyte subsets and MHC class II antigen expression in synovial membranes from dogs with rheumatoid arthritis and degenerative joint disease. Vet Immunol Immunopathol 1999;67:341–357. Kobayashi S, Baba H, Uchida K, et al. Microvascular system of anterior cruciate ligament in dogs. J Orthop Res 2006;24:1509–1520. Lawrence D, Bao S, Canfield PJ, et al. Elevation of immunoglobulin deposition in the synovial membrane of dogs with cranial cruciate ligament rupture. Vet Immunol Immunopathol 1998;65:89–96. Lemburg AK, Meyer-Lindenberg A, HewickerTrautwein M. Immunohistochemical characterization of inflammatory cell populations and adhesion molecule expression in synovial membranes from dogs with spontaneous cranial cruciate ligament rupture. Vet Immunol Immunopathol 2004;97:231– 240. Niebauer GW, Menzel EJ. Immunological changes in canine cruciate ligament rupture. Res Vet Sci 1982;32:235–241. Niebauer GW, Wolf B, Bashey RI, et al. Antibodies to canine collagen types I and II in dogs with spontaneous cruciate ligament rupture and osteoarthritis. Arthritis Rheum 1987;30:319–327. Tirgari M. Changes in the canine stifle joint following rupture of the anterior cruciate ligament. J Small Anim Pract 1977;19:17–26. van Sickle DC, Delleman DH, Brown EM. Connective and supportive tissues. In: Textbook of Veterinary Histology, Dellmann H, van Sickle DC, Brown EM, eds. Philadelphia PA, Lea & Febiger. 1993, pp. 29– 53. VetBooks.ir VetBooks.ir 12 Synovitis Precedes Stifle Instability Associated with Cruciate Ligament Rupture Jason A. Bleedorn Introduction Joint inflammation is an expected and central feature of cruciate ligament rupture (CR) in dogs. Inflammation involves all joint tissues and, in particular, the synovium. Synovitis leads to joint pain and promotes joint degradation. However, the underlying trigger for the development of synovitis, and its contribution to disease progression, remain unclear. This chapter will describe the characteristics of synovial inflammation in dogs with CR and its impact on cruciate ligament and joint degeneration. Knowledge of joint inflammation in dogs with CR has grown substantially during the past decade. CR represents the end-stage of a complex disease condition and, in some cases, a long course of disease. Many of the investigations in the field have focused on the end-stage of the disease, representing complete mechanical or organ failure. However, clinical, radiographic and arthroscopic evidence of stifle synovitis and arthritis can be found early in the course of the disease (Bleedorn et al. 2011). Recent studies have used the contralateral stifle joint as a model for studying incipient CR. The use of arthroscopy in dogs has also increased awareness of profound changes in the synovial membrane and allows for objective assess- ment. These are important steps for advancing the understanding of early changes in the joint before the development of stifle instability associated with complete CR. Normal synovium The synovial membrane is a specialized collagenous tissue lining the interior and all structures within a synovial joint, except articular cartilage. It can be identified macroscopically as a thin (0.5–5 mm thickness), translucent, connective tissue layer with numerous villous projections (Figure 12.1) (Iwanaga et al. 2000). It is similar to vascular or peritoneal endothelium, but lacks a continuous basement membrane (Iwanaga et al. 2000). The synovium has two distinct layers: an inner synovial intima containing a rich vascular, nervous, and lymphatic network, and an outer, supportive layer that is continuous with the fibrous joint capsule (Sutton et al. 2009). Sensory nerve endings are abundant and located within or adjacent to the fibrous capsular layer (Schenk et al. 1996). Synoviocytes are loosely arranged within the membrane and have an integral function in maintaining joint health (Iwanaga et al. 2000). Two main morphologic and functional types exist: (i) Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 93 Etiopathogenesis of Cruciate Ligament Rupture VetBooks.ir 94 CdCL SM LFC CrCL Figure 12.1 Arthroscopy image from a normal stifle joint of a young female hound. In this lateral compartment view, a white synovial lining lacking vascular ingrowth or proliferation is evident. SM, synovial membrane; LFC, lateral femoral condyle. macrophages (type A) that are immunoreactive and mainly phagocytic; and (ii) fibroblast-like (type B) cells that produce collagens, fibronectin and hyaluronan (Iwanaga et al. 2000). Collectively, the synovial membrane provides many key functions, including the secretion of synovial fluid to lubricate and nourish joint tissues, the clearance of intra-articular debris, and the regulation of immunological events. In the normal joint, cruciate ligaments are covered by a synovial reflection, so although being intra-articular they are extrasynovial (Figure 12.2) (Arnoczky & Marshall 1977). The surrounding membrane contains many small fenestrations that allow exchange of synovial fluid and provide nutrients to the ligaments (Kobayashi et al. 2006). Abundant vessels from the synovium and fat pad penetrate the ligament as the predominant blood supply (Arnoczky and Marshall 1977; Kobayashi et al. 2006). Compounds injected into the joint space rapidly pass through the synovial membrane and enter the capillary lumen of the cruciate ligaments. However, intravenous injections do not reach the ligament perivascular space (Kobayashi et al. 2006). The existence of a blood–cruciate barrier function has been Figure 12.2 Arthroscopic image of the intercondylar notch from a normal stifle joint of a young female hound. Both cruciate ligaments are visible with a thin overlying synovial reflection. Several filamentous synovial projections are present with the adjacent infrapatellar fat pad. CrCL, cranial cruciate ligament; CdCL, caudal cruciate ligament. postulated to be analogous to the blood– brain barrier (Kobayashi et al. 2006), and may be important in the pathophysiology of CR. Although debated, it is likely that joint inflammation has an adverse effect on synovial barrier function and metabolism of the cruciate ligaments. Synovitis Synovitis is characterized by infiltration of the synovial membrane with inflammatory cells, resulting in vascularization and hyperplasia of the synovium (Sutton et al. 2009). In dogs with CR and osteoarthritis (OA), the cellular distribution is typically a mononuclear infiltrate of B and T lymphocytes, macrophages, and plasma cells (Figure 12.3) (Sutton et al. 2009). Synovial fluid contains byproducts of this inflammatory response. Although total nucleated cell counts are often normal or mildly increased (<5000 cells μl–1 ), this does not accurately reflect the true magnitude of joint inflammation. Many studies have demonstrated evidence of immune dysregulation in the synovial VetBooks.ir Synovitis Precedes Stifle Instability Associated with Cruciate Ligament Rupture (A) 95 (B) 300μm 100μm Figure 12.3 Biopsy specimens from dog with complete cranial cruciate ligament rupture. (A) There is marked cellular infiltration and lymphoid nodule formation resulting in expansion of the synovial intimal margin. (B) Higher magnification of the area designated by the box in panel (A) demonstrates a focal region of predominantly mononuclear cell infiltration. Frozen section with hematoxylin and eosin stain. Low magnification, scale bar = 300 μm; high magnification, scale bar = 100 μm. Source: Bleedorn et al. 2011. Reproduced with permission from John Wiley & Sons, Inc. tissues of dogs with CR. The synovial fluid contains immune complexes and antibodies to collagen types I and II (Neibauer & Menzel 1982; de Rooster et al. 2000; de Bruin et al. 2007). The inflamed synovial membrane contains mononuclear infiltrate and, at times, nodular lymphoplasmacytic aggregates (Galloway & Lester 1995). Activated B and T lymphocytes and major histocompatibility complex class II antigen-positive cells with a dendritic morphology are also typically found. These cell populations are similar to those found in erosive immune-mediated polyarthritis, albeit at lower levels (Lemburg et al. 2004; Muir et al. 2005; Muir et al. 2011). Collectively, these changes reflect the substantial inflammatory changes that develop in stifle synovial tissues of dogs with CR. Synovitis is believed to contribute to the development of pain, joint inflammation and the progression of OA (Sutton et al. 2009). Pro-inflammatory cytokines synthesized in the synovium potentiate the cascade of biologically active substances that contribute to degradation of the joint (Doom et al. 2008). Synovial macrophages, the main promoters of disease activity in human rheumatoid arthritis, may have a similar role in OA (Bondeson et al. 2006). Synovial macrophage numbers are increased in the joint capsule of dogs with CR, and are associated with the severity of OA (Klocke et al. 2005). Furthermore, macrophage-like cells in the synovium produce matrix-degradative enzymes (Muir et al. 2005). It is likely this hostile environment results in the progression of OA and may have deleterious effects on cranial cruciate ligament (CrCL) homeostasis. Use of the canine stifle as a translational model for OA research provides useful information regarding the pathogenesis of CR. Experimental CrCL transection leads to joint instability, synovitis, and osteophyte formation (Gardner et al. 1984; Lipowitz et al. 1985; Myers et al. 1990). Similarly, the induction of an immune synovitis results in a significant reduction in CrCL strength and leads to structural failure and mid-substance rupture (Goldberg et al. 1982). Decades ago, Arnoczky and others eloquently showed that the synovium provides a vigorous and extensive vascular response to iatrogenic cruciate injury, which is decreased with synovial resection (Arnoczky et al. 1979). Recent evidence in a canine model demonstrated that synovial debridement alone leads to joint effusion, pain, lameness, and compromised clinical function, comparable to partial cruciate resection (Bozynski et al. 2015). Stifle radiographic arthritis and cruciate VetBooks.ir 96 Etiopathogenesis of Cruciate Ligament Rupture histologic scores were also higher with synovial debridement than in sham controls, but less severe than in dogs with a partial cruciate transection (Bozynski et al. 2015). Although these models may not accurately represent the clinical scenario of degenerative non-contact CR, they reinforce the intimate association between synovitis and CrCL health. Synovial assessment Objective evaluation of the synovial membrane is not routine in clinical veterinary practice or research, despite the increased use of arthroscopy and the importance of synovitis in joint disease. The value of synovial tissue assessment has been documented in humans with OA, rheumatoid arthritis, and other joint conditions (Guermazi et al. 2011; Hayashi et al. 2011). Ultrasound and contrast-enhanced magnetic resonance imaging (MRI) have been used extensively to evaluate synovial membrane pathology and joint effusion severity in the human knee, but lack clinical validation in dogs (Tarhan & Unlu 2003; Guermazi et al. 2011). These non-invasive modalities correlate well with arthroscopic and histologic grading (Karim et al. 2004; de Lange-Brokaar et al. 2014). However, direct macroscopic evaluation of the synovial membrane using arthroscopy remains the ‘gold standard’ for the assessment of articular cartilage and synovium in human joints (Ayral 1996; Ayral et al. 1996). Arthroscopy also allows for the collection of synovial tissue for microscopic assessment and, importantly, correlates well with histologic characteristics of disease severity (Lindblad & Hedfors 1985). Arthroscopic features of synovitis are well described in the human knee and defined by three baseline parameters: intensity, extent, and location (Ayral 1996; Ayral et al. 1996). Af Klint developed an arthroscopic scoring system that includes the assessment of synovial hypertrophy, vascularity, and global synovitis (af Klint et al. 2009). This method is simple, efficient, and reliable across different joint diseases in the clinical setting. The terms early, late, active, or chronic synovitis are often used to further characterize joint assessment in people in an attempt to understand mechanisms of initiation of synovitis. Early comparative advances have been made to provide objective measures of synovial inflammation in dogs. Arthroscopic features of synovitis in dogs were identified (Bleedorn et al. 2011) and later refined (Little et al. 2014), using the aforementioned arthroscopic scoring system from human knee synovitis (af Klint et al. 2009). Identical features can be scored with high intra- and inter-observer reliability in the canine stifle joint (Figure 12.4) (Little et al. 2014). Although some regional variation within the joint exists, it is unclear if this relates to local areas of cartilage damage as in human OA (Lindblad & Hedfors 1985). The arthroscopic features identified correlate well with histologic assessment in dogs (Bleedorn et al. 2011; Little et al. 2014). The need for a standardized system for joint evaluation was a key objective of the Osteoarthritis Research Society International (OARSI) histopathology initiative in canine research studies (Cook et al. 2010). Key questions arise with the establishment of criteria for synovial grading. First, what are the initial, dominant characteristics of CR? Second, how do synovial thickening or vascular patterns relate to disease mechanisms? Finally, can these criteria be used to classify populations by severity or time course? Synovitis in early cruciate rupture The synovium in stable stifle joints with early clinical or radiographic evidence of arthritis is inflamed (Bleedorn et al. 2011; Little et al. 2014). Radiographic arthritis correlates with arthroscopic observations of synovitis but generally underestimates the severity (Bleedorn et al. 2011). In a recent case series, synovitis was present without arthroscopically apparent fraying of the CrCL in dogs with lameness and stifle arthritis. Superficial fraying of the CrCL and, occasionally, the caudal cruciate ligament, was seen together with synovitis in the remaining dogs (Bleedorn et al. 2011; Little et al. 2014). The synovial reflection surrounding the cruciate ligaments in dogs is no longer intact in early CR, particularly once fiber bundle damage has occurred. Interestingly, dogs with more severe synovitis in the unstable stifle had more severe changes in the stable contralateral joint, suggesting that disease in joint pairs is related, 1 1 1 2 2 2 3 3 3 4 4 4 Figure 12.4 Arthroscopic appearance of stifle synovium in dogs with cruciate ligament rupture. Examples of the spectrum of arthroscopic hypertrophy (upper row), vascularity (middle row), and synovitis (lower row) scoring in various regions of the canine stifle joint. Arthroscopic scoring ranged from 1–4. Source: Little et al. 2014; http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097329. Used under CC BY 4.0, https://creativecommons.org/licenses/by/4.0/. S y n o v i t i s V a s c u l a r i t y H y p e r t r o p h y VetBooks.ir Synovitis Precedes Stifle Instability Associated with Cruciate Ligament Rupture 97 VetBooks.ir 98 Etiopathogenesis of Cruciate Ligament Rupture whereby the stable stifles represent an earlier phase of the disease process (Bleedorn et al. 2011). Further studies are required to understand the specific features that are present early in the disease process and what mechanisms are responsible for this change. A substantial proportion of affected dogs have partial CR with a stable stifle joint. Surgical treatment for dogs with CR has historically focused on the elimination of joint instability, rather than the mitigation of joint inflammation. For example, Hulse and others observed the preservation of intact CrCL fibers during second-look arthroscopy in 17 dogs with stable partial tears treated by tibial plateau leveling osteotomy (TPLO), which implied some protective effect of TPLO in these cases (Hulse et al. 2010). Cartilage damage was less severe with an intact, functional CrCL (Hulse et al. 2010). It would have been interesting to compare serial synovitis scores to identify a potential relationship with treatment outcomes in this study. Ultimately, arthritis progression is expected with varying degrees of associated lameness despite stifle stabilization in dogs with CR (Girling et al. 2006; Au et al. 2010). Whether this represents the effects of chronic persistent synovitis or some subtle mechanical cause is unknown. Although mechanical instability exists in CR stifles, a thorough understanding of the associated joint pathology is important when considering treatment options for individual patients. Conclusions Stifle synovitis is an established feature of CR in dogs. Synovitis occurs early during the course of the disease, is profound, and plays a role in the progression of joint disease and eventual CrCL and caudal cruciate ligament fiber rupture. Many similarities exist between CR, OA, and immune-mediated or rheumatoid arthritis that help to inform an understanding of the CR disease mechanism. Synovial membrane evaluation may facilitate identification of early features associated with CR, assessment of disease severity, and allow for outcome assessment following disease-modifying treatment. The underlying trigger for the development of synovitis and its mechanistic contribution to disease progression should be a focus of future work. References af Klint E, Catrina A, Matt P, et al. Evaluation of arthroscopy and macroscopic scoring. Arthritis Res Ther 2009;11:1–13. Arnoczky SP, Marshall JL. The cruciate ligaments of the canine stifle: An anatomical and functional analysis. Am J Vet Res 1977;38:1807–1814. Arnoczky SP, Rubin RM, Marshall JL. Microvasculature of the cruciate ligaments and its response to injury. J Bone Joint Surg Am 1979;61:1221– 1229. Au KK, Gordon-Evans WJ, Dunning D, et al. Comparison of short- and long-term function and radiographic osteoarthrosis in dogs after postoperative physical rehabilitation and tibial plateau leveling osteotomy or lateral fabellar suture stabilization. Vet Surg 2010;39:173–180. Ayral X. Diagnostic and quantitative arthroscopy: quantitative arthroscopy. Baillières Clin Rheumatol 1996;10:477–494. Ayral X, Mayoux-Benhamou A, Dougados M. Proposed scoring system for assessing synovial membrane abnormalities at arthroscopy in knee osteoarthritis. Br J Rheumatol 1996;35:14–17. Bleedorn JA, Greuel EN, Manley PA, et al. Synovitis in dogs with stable stifle joints and incipient cranial cruciate ligament rupture: A cross-sectional study. Vet Surg 2011;40:531–543. Bondeson J, Wainwright SD, Lauder S, et al. The role of synovial macrophages and macrophageproduced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis. Arthritis Res Ther 2006;8:R187. Bozynski C, Kuroki K, Stannard J, et al. Evaluation of partial transection versus synovial debridement of the ACL as novel canine models for management of ACL injuries. J Knee Surg 2015;28:404–410. Cook JL, Kuroki K, Visco D, et al. The OARSI histopathology initiative. Osteoarthritis Cartilage 2010;18:S66–S79. de Bruin T, van Bree H, Cox E. Evaluation of anticollagen type I antibody titers in synovial fluid of both stifle joints and the left shoulder joint of dogs with unilateral cranial cruciate disease. Am J Vet Res 2007;68:283–389. de Lange-Brokaar BJE, Ioan-Facsinay A, Yusuf E, et al. Degree of synovitis on MRI by comprehensive whole knee semi-quantitative scoring method correlates with histologic and macroscopic features of synovial tissue in knee osteoarthritis. Osteoarthritis Cartilage 2014;22:1606–1613. de Rooster H, Cox E, van Bree H. Prevalence and relevance of antibodies to type-I and -II collagen in VetBooks.ir Synovitis Precedes Stifle Instability Associated with Cruciate Ligament Rupture synovial fluid of dogs with cranial cruciate ligament damage. Am J Vet Res 2000;61:1456–1461. Doom M, de Bruin T, de Rooster H, et al. Immunopathological mechanisms in dogs with rupture of the cranial cruciate ligament. Vet Immunol Immunopathol 2008;125:143–161. Galloway RH, Lester SJ. Histopathological evaluation of canine stifle joint synovial membrane collected at the time of repair of cranial cruciate ligament rupture. J Am Anim Hosp Assoc 1995;31:289– 294. Gardner DL, Bradley WA, O’Conner P, et al. Synovitis after surgical division of the anterior cruciate ligament of the dog. Clin Exp Rheumatol 1984;2: 11–15. Girling SL, Bell SC, Whitelock RG, et al. Use of biochemical markers of osteoarthritis to investigate the potential disease-modifying effect of tibial plateau levelling osteotomy. J Small Anim Pract 2006;47:708–714. Goldberg VM, Burstein A, Dawson M. The influence of an experimental immune synovitis on the failure mode and strength of the rabbit anterior cruciate ligament. J Bone Joint Surg Br 1982;64:900– 906. Guermazi A, Roemer FW, Hayashi D, et al. Assessment of synovitis with contrast-enhanced MRI using a whole-joint semiquantitative scoring system in people with, or at high risk of, knee osteoarthritis: the MOST study. Ann Rheum Dis 2011;70:805–811. Hayashi D, Roemer FW, Katur A, et al. Imaging of synovitis in osteoarthritis: Current status and outlook. Semin Arthritis Rheum 2011;41:116–130. Hulse D, Beale BS, Kerwin S. Second-look arthroscopic findings after tibial plateau leveling osteotomy. Vet Surg 2010;39:350–354. Iwanaga T, Shikichi M, Katamura H, et al. Morphology and functional roles of synoviocytes in the joint. Arch Histol Cytol 2000;63:17–31. Karim Z, Wakefield RJ, Quinn M, et al. Validation and reproducibility of ultrasonography in the detection of synovitis in the knee: A comparison with arthroscopy and clinical examination. Arthritis Rheum 2004;50:387–394. Klocke NW, Snyder PW, Widmer WR, et al. Detection of synovial macrophages in the joint capsule of dogs with naturally occurring rupture of the cranial cruciate ligament. Am J Vet Res 2005;66:493– 499. 99 Kobayashi S, Baba H, Uchida K, et al. Microvascular system of anterior cruciate ligament in dogs. J Orthop Res 2006;24:1509–1520. Lemburg AK, Meyer-Lindenberg A, HewickerTrautwein M. Immunohistochemical characterization of inflammatory cell populations and adhesion molecule expression in synovial membranes from dogs with spontaneous cranial cruciate ligament rupture. Vet Immunol Immunopathol 2004;97:231– 240. Lindblad S, Hedfors E. Intraarticular variation in synovitis: Local macroscopic and microscopic signs of inflammatory activity are significantly correlated. Arthritis Rheum 1985;28:977–86. Lipowitz AJ, Wong PL, Stevens JB. Synovial membrane changes after experimental transection of the cranial cruciate ligament in dogs. Am J Vet Res 1985;46:1166–1170. Little JP, Bleedorn JA, Sutherland BJ, et al. Arthroscopic assessment of stifle synovitis in dogs with cranial cruciate ligament rupture. PLoS One 2014; 9:e97329. Muir P, Kelly JL, Marvel SJ, et al. Lymphocyte populations in joint tissues from dogs with inflammatory stifle arthritis and associated degenerative cranial cruciate ligament rupture. Vet Surg 2011;40:753– 761. Muir P, Schamberger GM, Manley PA, et al. Localization of cathepsin K and tartrate-resistant acid phosphatase in synovium and cranial cruciate ligament in dogs with cruciate disease. Vet Surg 2005;34:239– 246. Myers SL, Brandt KD, O’Connor BL, et al. Synovitis and osteoarthritic changes in canine articular cartilage after anterior cruciate ligament transection. Arthritis Rheum 1990;33:1406–1415. Neibauer GW, Menzel EJ. Immunological changes in canine cruciate ligament rupture. Res Vet Sci 1982;32:235–241. Schenk I, Spaethe A, Halata Z. The structure of sensory nerve endings in the knee joint capsule of the dog. Ann Anat 1996;178:515–521. Sutton S, Clutterbuck A, Harris P, et al. The contribution of the synovium, synovial derived inflammatory cytokines and neuropeptides to the pathogenesis of osteoarthritis. Vet J 2009;179:10–24. Tarhan S, Unlu Z. Magnetic resonance imaging and ultrasonographic evaluation of the patients with knee osteoarthritis: a comparative study. Clin Rheumatol 2003; 22:181–188. VetBooks.ir VetBooks.ir 13 Role of Synovial Immune Responses in Stifle Synovitis Peter Muir Introduction The historical paradigm for the cruciate ligament rupture (CR) mechanism has been that ligament rupture is largely a consequence of trauma, with arthritis developing secondary to joint instability. However, a growing body of evidence suggests that this relationship is incorrect, and that in dogs with naturally occurring CR, synovitis and arthritis typically precede the development of complete ligament rupture and associated stifle instability. In dogs with CR, epidemiological studies suggest that if subtle radiographic change is present in the contralateral stifle, the risk of contralateral rupture at 16 months is as high as 65% (Doverspike et al. 1993; Chuang et al. 2014). Whilst it is clear that cranial cruciate ligament (CrCL) transection and associated stifle instability contributes to the development of synovitis (Lipowitz et al. 1985), the growing use of arthroscopy for stifle evaluation in the dog, and the use of tibial plateau leveling osteotomy surgery to treat dogs with partial CR and a stable stifle, has led to a greater appreciation that synovitis is present in stable stifles of affected dogs (Bleedorn et al. 2011). The cruciate ligaments are intra-articular, but extrasynovial, and are covered in synovium. Experimentally, persistent synovitis induces a substantial degradation of CrCL tensile strength (Goldberg et al. 1982). The deleterious effects of chronic joint inflammation on the tissue matrix of the cruciate ligaments is likely due to disruption of the blood–cruciate barrier in the ligament microvasculature, such that cruciate ligament metabolism is closely related to changes in synovial fluid (Kobayashi et al. 2006). A logical extension of this shift in thinking is to focus on understanding the disease mechanism that leads to the development of stifle synovitis in dogs. Current evidence suggests that synovial immune responses promote progressive degradation of intra-articular structures over time, including the cruciate ligaments (Doom et al. 2008). Inflammatory cell populations within the stifle joint Synovitis involves the intima of the CrCL epiligament. The inflammatory cell population is typically a mixed mononuclear one, and includes activated tartrate-resistant acid phosphatase-positive (TRAP) macrophages (Figure 13.1), T and B lymphocytes (Figure 13.2), plasma cells, and major histocompatibility complex (MHC) class II-positive Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 101 (B) VetBooks.ir (A) Figure 13.1 Photomicrographs of frozen sections of (A) synovium and (B) ruptured cranial cruciate ligament (CrCL) from a 5-year-old dog with cruciate ligament rupture. (A) In this specimen, aggregates of mononuclear cells are present in the synovial intima (white arrows), including activated macrophages stained red for tartrate-resistant acid phosphatase (TRAP) (black arrows). (B) In ruptured CrCL from the same dog, aggregates of TRAP+ activated macrophages can also be seen infiltrating the CrCL. TRAP histochemical stain, with Mayer’s hematoxylin counterstain; scale bar = 100 μm. Panel (A) source: Muir et al. 2005. Reproduced with permission from John Wiley & Sons, Inc. Synovial tissue Femur Stimulation Inhibition AMq TGF-β NT MO IFN-γ Ag presentation CaCl CD4+T IL-10 PDGF bFGF TGF-β IL-4 DC IFN-γ CAg IFN-γ IL-1Ra, sIL-1R, sTNF-αR IGFs B IL-8 F Proteinase inhibitors IL-1,TNF-α PC IL-10 IL-8 Matrix synthesis Ab IL-1Ra, sIL-1R, sTNF-αR Proteinase Cartilage degradation IL-6 C Tibia Joint space S Proliferation and formation of joint fibrosis Figure 13.2 Schematic representation of the possible cytokine cascade in dogs with cruciate ligament rupture (begin at antigen presentation in the synovial tissue; red lines: stimulation; black lines: inhibition; red boxes: pro-inflammatory; yellow boxes: anti-inflammatory). Antigen-stimulated dendritic cells present antigens to naive T lymphocytes. Activated CD4+ T lymphocytes can then stimulate different cells (macrophages, monocytes, B lymphocytes, fibroblasts and synoviocytes) by cytokine release to produce antibodies, osteophytes, ligament degeneration and synovial tissue proliferation (red lines). Next to the pro-inflammatory reactions, anti-inflammatory responses are seen (black lines). Ab, antibodies; Ag, antigen; AMq, activated macrophage; B, B lymphocyte; bFGF, basic fibroblast growth factor; C, chondrocyte; CaCL, caudal cruciate ligament; CAg, collagen antigen; CD4+ T, CD4+ T lymphocyte; DC, dendritic cell; IFN-γ, interferon gamma; IGFs, insulin-like growth factors; IL, interleukin; IL-1Ra, interleukin 1 receptor antagonist; F, fibroblast; Mo, monocyte; NT, naı̈ve T lymphocyte; PC, plasma cell; PDGF, platelet-derived growth factor; S, synoviocyte; sIL-1R, soluble IL-1 receptor; sTNF-αR, soluble TNF-α receptor; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha. Source: Doom et al. 2008. Reproduced with permission from Elsevier. VetBooks.ir Role of Synovial Immune Responses in Stifle Synovitis 103 dendritic cells (Faldyna et al. 2004; Lemburg et al. 2004; Klocke et al. 2005; Muir et al. 2005; Muir et al. 2007a; Muir et al. 2009; Muir et al. 2011). The proportion of T lymphocytes within synovial tissues is increased in dogs with CR compared with samples from healthy dogs (Faldyna et al. 2004). Expression of the T-cell antigen receptor complex is also increased in synovium and synovial fluid in affected dogs (Muir et al. 2009). While lymphocytes play a key role in antigen-specific immunity, activated macrophages and their inflammatory products play a key role in innate immunity and the pathogenesis of tissue inflammation. et al. 2007b). A polymicrobial population of bacteria, many of which that are not recognized joint pathogens, is typically present, particularly Gram-negative organisms (Muir et al. 2010). Similar microbial populations are found in human arthritic joints (Kempsell et al. 2000). It seems most likely that the translocation of small amounts of bacterial material to the stifle synovium from the circulation may act to maintain synovial inflammation, but not necessarily initiate disease (Bhandal et al. 2013). Antigen-specific immune responses within joint tissues Although antigen-specific immune responses within the stifle have a role in the development of synovial inflammation in dogs with CR, innate immune responses within the stifle synovium are also likely important. Patternrecognition receptors (PRR) are expressed by leukocytes and epithelial cells, and are used by the innate immune system to detect the presence of infection (Akira et al. 2006). The activation of PRR contributes to disease pathology in inflammatory and autoimmune conditions (e.g., Bryant & Fitzgerald 2009). The activation of PRR, such as toll-like receptor (TLR) and nucleotide-binding oligomerization domain (NOD) -containing proteins leads to the activation of nuclear factor kappa B (NFκβ) and upregulation of immune response genes and pro-inflammatory cytokines. Innate immune responses to PRR also regulate subsequent adaptive immune responses via dendritic cell signaling (Iwasaki & Medzhitov 2015). Defective PRR function has been implicated in various chronic inflammatory conditions, such as Crohn’s disease in human beings and perianal fistulae in dogs (House et al. 2008). Analysis of synovial fluid cells from dogs with CR suggests that expression of TRAP is increased relative to that in healthy dogs and dogs with osteoarthritis (Figure 13.3A) (Muir et al. 2007a). Higher expression of TLR-2 in arthritic joints was also been found (Figure 13.3B) (Muir et al. 2007a). Increased expression of complement component 3, CXCL8, which is primarily expressed by macrophages, and intercellular cell adhesion molecule-1 (ICAM-1), is also found in the synovium of dogs with CR (El-Hadi et al. 2012; The upregulation of T lymphocytes within joints is a key pro-inflammatory feature of arthritis, and also occurs in joint diseases that have traditionally been considered to be associated with minimal inflammation (Sakkas & Platsoukas 2007). The identification of large populations of lymphocytes within synovial tissues of dogs with CR suggests that the disturbance of antigen-specific immune responses is an important component of the disease mechanism. A MHC class II genetic risk has been identified in many immune-mediated joint diseases in human beings. Although immunogenetic risk for inflammatory arthritis exists in dogs (Ollier et al. 2001), MHC class II immunogenetic risk with canine CR was not confirmed in a recent study (Clements et al. 2011). However, MHC class I immunogenetic association has not been investigated in dogs with CR to date. At the present time, the explanatory mechanism for chronic stifle synovitis in dogs with CR remains a critical but unanswered question. Several studies have explored the hypothesis that neo-epitopes of type I and type II collagen may be important in this regard (Niebauer et al. 1987; de Bruin et al. 2007a,b) (see Chapter 11). Collectively, these studies have not confirmed that neo-epitopes of collagen are the primary immunological trigger in dogs with CR, and further investigations are needed. The translocation of bacterial material into the stifle joint is a common event in dogs (Muir Innate immune responses within joint tissues Etiopathogenesis of Cruciate Ligament Rupture (A) TRAP Expression (18S rRNA normalized) (A) p < 0.05 1000 p < 0.005 5 μm 100 10 1 0.1 0.01 (B) 300 Relative TLR-2 Expression (18S rRNA normalized) VetBooks.ir 104 250 #Stifle oligoarthritis Healthy (n = 27) (n = 8) Other arthritis (n = 9) (B) 500 nm 200 150 p = 0.08 100 50 0 #Stifle oligoarthritis Healthy (n = 21) (n = 9) Other arthritis (n = 9) Figure 13.3 (A) Relative expression of tartrate-resistant acid phosphatase (TRAP), and (B) toll-like receptor 2 (TLR-2) in synovial fluid cells collected from dogs with stifle (oligo) arthritis and cruciate ligament rupture, healthy dogs, and dogs with other forms of arthritis characterized by cartilage loss (osteoarthritis). Gene expression was normalized to peripheral blood mononuclear cells (PBMC) as an internal control using the −ΔΔCt method. 18S rRNA was used as the house-keeping gene. # indicates a significant difference from internal PBMC controls (P < 0.05). Boxes represent median and the 25th and 75th percentiles. Whiskers represent 10th and 90th percentiles. Outliers are also plotted. Significant differences between groups are as indicated. Source: Muir et al. 2007a. Reproduced with permission from Elsevier. Figure 13.4 Sub-rupture loading of tendon and ligament collagen creates strain-induced discrete plasticity damage with kinked collagen fibrils (Veres et al. 2013). In an in vitro study, macrophage-like U937 cells found on collagen fibrils with strain-induced discrete plasticity were morphologically distinct from those found on undamaged fibrils. The cells showed a greater uniformity, being mostly of the ruffled type (∗ in panel A). Rather than maintaining a rounded shape, as on the undamaged fibrils, many of the ruffled cells had acquired a dome-shape, increasing their contact area with the damaged fibrils (arrows in panel A). (B) Magnified view of the boxed location in panel (A) showing structure of the discrete plasticity fibril array that formed the substrate for these cells. Source: Veres et al. 2015. Reproduced with permission from John Wiley & Sons, Inc. Garner et al. 2013). Collectively, these observations suggest that macrophage activation and neutrophil trafficking are important factors in the development of chronic stifle synovitis in dogs with CR. Collagen in ruptured CrCL tissue appears damaged, with loss of crimp in collagen fibers (Hayashi et al. 2003). Interestingly, recent research has shown that repeated subrupture overload of ligament/tendon induces nanoscale discrete plasticity damage to collagen fibrils (Veres et al. 2013). U937 macrophage-like cells recognize collagen fibrils with straininduced plasticity damage, bind to damaged areas for collagen degradation, alter their functional morphology (Figure 13.4), and secrete matrix, which is hypothesized to be fibronectin in vitro (Veres et al. 2015). Further studies are needed to understand how macrophages and fibroblasts interact with mechanically damaged collagen when ligament homeostasis is disturbed in dogs with CR. VetBooks.ir Role of Synovial Immune Responses in Stifle Synovitis In conclusion, both antigen-specific and innate immune responses within the stifle synovium overlying the cruciate ligament complex appear important to the development of synovitis and joint degeneration over time. In this regard, the overlying synovium has an important barrier function (Bozynski et al. 2015) that is poorly understood. A functional connection between ligament loading and disturbances to ligament homeostasis, that includes the development of inflammation in the synovium overlying the cruciate ligaments, may occur through macrophages, since macrophages respond to specific motifs in mechanically damaged collagen. T lymphocytes and macrophages likely represent important therapeutic targets in dogs with CR. If disturbances to ligament homeostasis, matrix remodeling and the development of synovitis can be successfully managed with medical therapy, then such a treatment may block the development of CR and associated joint instability in affected dogs. References Akira S, Uematus S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124:783– 801. Bhandal J, Hayashi K, Kim S-Y, et al. Detection of bacterial DNA by PCR in dogs with stifle pathology. Vet Surg 2013;42:814–818. Bleedorn JA, Greuel EN, Manley PA, et al. Synovitis in dogs with stable stifle joints and incipient cranial cruciate ligament rupture: A cross-sectional study. Vet Surg 2011;40,531–543. Boyzynski CC, Kuroki K, Stannard JP, et al. Evaluation of partial transection versus synovial debridement of the ACL as novel canine models for management of ACL injuries. J Knee Surg 2015;28:404– 410. de Bruin T, de Rooster H, van Bree H, et al. Evaluation of anticollagen type I antibody titers in synovial fluid of both stifles and the left shoulder of dogs with unilateral cranial cruciate disease. Am J Vet Res 2007a;68:283–289. de Bruin T, de Rooster H, van Bree H, et al. Lymphocyte proliferation to collagen type I in dogs. J Vet Med A 2007b;54:292–296. Bryant C, Fitzgerald KA. Molecular mechanisms involved in inflammasome activation. Trends Cell Biol 2009;19:455–464. Chuang C, Ramaker MA, Kaur S, et al. Radiographic risk factors for contralateral rupture in dogs with unilateral cranial cruciate ligament rupture. PLoS One 2014;9: e106389. 105 Clements DN, Kennedy LJ, Short AD, et al. Risk of canine cruciate ligament rupture is not associated with the major histocompatibility complex. Vet Comp Orthop Traumatol 2011;24:262–265. Doom M, de Bruin T, de Rooster H, et al. Immunopathological mechanisms in dogs with rupture of the cranial cruciate ligament. Vet Immunol Immunopathol 2008;125:143–161. Doverspike M, Vasseur PB, Walls CM. Contralateral cranial cruciate ligament rupture: Incidence in 114 dogs. J Am Anim Hosp Assoc 1993;29:167– 170. El-Hadi M, Charavaryamath C, Aebischer A, et al. Expression of interleukin 8 and intercellular cell adhesion molecule-1 in the synovial membrane and cranial cruciate ligament of dogs after rupture of the ligament. Can J Vet Res 2012;76:8–15. Faldyna M, Zatloukal J, Leva L, et al. Lymphocyte subsets in stifle joint synovial fluid of dogs with spontaneous rupture of the cranial cruciate ligament. Acta Vet Brno 2004;73:79–84. Garner BC, Kuroki K, Stoker AM, et al. Expression of proteins in serum, synovial fluid, synovial membrane, and articular cartilage samples obtained from dogs with stifle joint osteoarthritis secondary to cranial cruciate ligament disease and dogs without stifle arthritis. Am J Vet Res 2013;74:386– 394. Goldberg VM, Burstein A, Dawson M. The influence of an experimental immune synovitis on the failure mode and strength of the rabbit anterior cruciate ligament. J Bone Joint Surg 1982;64A:900–906. Hayashi K, Frank JD, Dubinsky C, et al. Histologic changes in ruptured canine cranial cruciate ligament. Vet Surg 2003;32:269–277. House AK, Gregory SP, Catchpole B. Patternrecognition receptor mRNA expression and function in canine monocyte/macrophages and relevance to canine anal furunculosis. Vet Immunol Immunopathol 2008;124:230–240. Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol 2015;16:343–353. Kempsell KE, Cox CJ, Hurle M, et al. Reverse transcriptase-PCR analysis of bacterial rRNA for detection and characterization of bacterial species in arthritis synovial tissue. Infect Immun 2000;68:6012–6026. Klocke NW, Snyder PW, Widmer WR, et al. Detection of synovial macrophages in the joint capsule of dogs with naturally occurring rupture of the cranial cruciate ligament. Am J Vet Res 2005;66:493–499. Kobayashi S, Baba H, Uchida K, K, et al. Microvascular system of the anterior cruciate ligament in dogs. J. Orthop Res 2006;24:1509–1520. Lemburg AK, Meyer-Linenberg A, HewickerTrautwein M. Immunohistochemical characterization of inflammatory cell populations and adhesion molecule expression in synovial membranes from dogs with spontaneous cranial cruciate ligament VetBooks.ir 106 Etiopathogenesis of Cruciate Ligament Rupture rupture. Vet Immunol Immunopathol 2004;97:231– 240. Lipowitz AJ, Wong PL, Stevens JB. Synovial membrane changes after experimental transection of the cranial cruciate ligament in dogs. Am J Vet Res 1985;46:1166–1170. Muir P, Schamberger GM, Manley PA, et al. Localization of cathepsin K and tartrate-resistant acid phosphatase in synovium and cranial cruciate ligament in dogs with cruciate disease. Vet Surg 2005;34:239– 246. Muir P, Kelly JL, Marvel SJ, et al. Lymphocyte populations in joint tissues from dogs with inflammatory stifle arthritis and associated degenerative cranial cruciate ligament rupture. Vet Surg 2011;40,753– 761. Muir P, Schaefer SL, Manley PA, et al. Expression of immune response genes in the stifle joint of dogs with oligoarthritis and degenerative cranial cruciate ligament rupture. Vet Immunol Immunopathol 2007a;119:214–221. Muir P, Oldenhoff WE, Hudson AP, et al. Detection of DNA from a range of bacterial species in the knee joints of dogs with inflammatory knee arthritis and associated degenerative anterior cruciate ligament rupture. Microb Pathog 2007b;42:47–55. Muir P, Schaefer SL, Manley PA, et al. T Lymphocyte antigen receptor expression in dogs with inflammatory stifle arthritis and degenerative cranial cruciate ligament rupture. Vet Surg 2009;38: E40. Muir P, Rox R, Wu Q, et al. Seasonal variation in detection of bacterial DNA in the stifle joints of dogs with inflammatory arthritis and degenerative cranial cruciate ligament rupture. Vet Microbiol 2010;141:127–133. Niebauer GW, Wolf B, Bashey RI, et al. Antibodies to canine collagen types I and II in dogs with spontaneous cruciate ligament rupture and osteoarthritis. Arthritis Rheum 1987;30:319–327. Ollier WER, Kennedy LJ, Thomson W, et al. Dog MHC alleles containing the human RA shared epitope confer susceptibility to canine rheumatoid arthritis. Immunogenetics 2001;53:669–673. Sakkas LI, Platsoucas CD. The role of T cells in the pathogenesis of osteoarthritis. Arthritis Rheum 2007;56:409–424. Veres SP, Harrison JM, Lee JM. Repeated subrupture overload causes progression of nanoscaled discrete plasticity damage in tendon collagen fibrils. J Orthop Res 2013;31:731–737. Veres SP, Brennan-Pierce EP, Lee JM. Macrophagelike U937 cells recognize collagen fibrials with strain-induced discrete plasticity damage. J Biomed Mater Res A 2015;103:397–408. VetBooks.ir Section III Clinical Features Introduction Over the past 25 years, veterinarians have become increasingly aware that it is difficult to relate the typical clinical features of cruciate ligament rupture (CR) in dogs with the concept that stifle osteoarthritis (OA) is simply a consequence of ligament rupture and stifle instability. Moderate to severe OA is often found at initial presentation in dogs with CR. Advances in diagnostic imaging, including the development of methods for stress radiography of the stifle, have helped to more thoroughly determine the extent of cranial cruciate ligament fiber rupture during patient evaluation. It is important to relate any knowledge of ligament biomechanics to assessment of the cruciate ligaments clinically in dogs with stifle OA. By definition, unstable joints have experienced complete ligament rupture. Since publication of the First Edition of this book, several studies have shown that radiographic changes in partial CR stifles are quite predictive of risk for complete CR. Collectively, these studies have also defined a clinical model for the evaluation of disease-modifying therapy for the early phase of the disease. Recent research findings have shed new light on which components of stifle pathology in affected dogs contribute to joint pain and lameness. This section provides a detailed discussion of the clinical features of CR. Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 107 VetBooks.ir VetBooks.ir 14 Epidemiology of Cruciate Ligament Rupture Lauren A. Baker and Peter Muir Introduction Cruciate ligament rupture (CR) is one of the most common causes of pelvic limb lameness in dogs (Witsberger et al. 2008). The condition is a chronic, progressive disease that results in eventual rupture of the cranial cruciate ligament (CrCL) (Bleedorn et al. 2011; Comerford et al. 2011; Muir et al. 2011). A great deal of time and effort has been spent characterizing the epidemiological aspects of canine CR. Through these investigations, it has been determined that CR is a complex disease process with multiple contributing genetic and environmental risk factors. Furthermore, it is clear that there is no single combination of risk factors that will invariably lead to CrCL degeneration and eventual ligament rupture. Every dog should be considered an individual with a certain amount of inborn genetic risk on which environmental variables act to influence development of the disease. The following paragraphs include a summary of investigations of risk factors known to contribute to CR. A thorough understanding of these risk factors can aid in the identification of dogs with increased sus- ceptibility to the condition, and thereby guide patient management. Age As CR is a chronic degenerative process, it follows that it is a condition of primarily middleaged dogs (Whitehair et al. 1993; Reif & Probst 2003; Witsberger et al. 2008). A study examining medical records data of over one million dogs reported that dogs aged 1–4 years were significantly less likely than dogs in other age groups to experience CR (Witsberger et al. 2008). While the peak age of onset for CR has been reported at 7–10 years (Whitehair et al. 1993), a more recent study of 166 Labrador Retrievers reported a peak age of onset of approximately 4 years. Notably, only 6% of these dogs had an age of onset over 8 years, and there were no dogs over 10 years of age. This suggests that older dogs are also at a decreased risk for CR (Reif & Probst 2003). Notably, there is an interaction with age and other risk factors. For example, large-breed dogs tend to present at younger ages than small breeds (Duval et al. 1999). Dogs Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 109 VetBooks.ir 110 Clinical Features that experience bilateral CrCL rupture tend to be younger than dogs with unilateral ruptures (Cabrera et al. 2008; Grierson et al. 2011). Gender It is unclear whether gender differences have an effect on the incidence of CR. Multiple studies have reported an increased prevalence of CR in spayed females compared to other gender groups (Whitehair et al. 1993; Lampman et al. 2003; Powers et al. 2005; Adams et al. 2011), while others have reported no significant differences (Witsberger et al. 2008) or an increased risk in males (Grierson et al. 2011). The majority of study results agree that neutered dogs of either gender are at increased odds of developing CR compared to intact dogs (Whitehair et al. 1993; Duval et al. 1999; Lampman et al. 2003; Slauterbeck et al. 2004; Duerr et al. 2007; Witsberger et al. 2008; de la Riva et al. 2013). A recent study of 360 Golden Retrievers (de la Riva et al. 2013) reported that early neutering (<1 year) significantly increased the likelihood of CR. In fact, there was no occurrence of CR in studied dogs that were intact (n = 122). Occurrence in early neutered males and females was reported at 5.1% and 7.7%, respectively. The effect of early neutering persisted after adjusting for differences in body condition score (de la Riva et al. 2013). This is an important observation, as weight gain is often cited as an explanation for the increased incidence of orthopaedic disease among neutered dogs (Whitehair et al. 1993; Duval et al. 1999; Buote et al. 2009). If not through weight gain, how does early neutering affect the CrCL? It has been suggested that an absence of gonadal hormones leads to atypical growth plate closure and thus altered conformation (de la Riva et al. 2013). Indeed, early neutering has been reported to be a significant risk factor for the development of excessive tibial plateau angles in large-breed dogs (Duerr et al. 2007). Additionally, an absence of gonadal hormones may affect the size, shape, or material properties of the CrCL itself (Slauterbeck et al. 2004). A study investigating the effect of gonadectomy on CrCL collagen homeostasis in rabbits found that collagen concentrations were lower and fiber diameters greater in the absence of gonadal hormones, which may predispose them to rupture (Light et al. 2012). Research confirming a direct role for gonadal hormones on the canine CrCL matrix architecture is not currently available. Obesity An association between higher body weight and increased risk of CR has been reported (Whitehair et al. 1993; Duval et al. 1999). While this is an important finding, evaluating weight alone does not distinguish between large-size dogs and dogs that are truly overweight. Other work has attempted to evaluate body condition more objectively. A study of 755 dogs reported that those with overweight or obese body condition scores were twice as likely to be diagnosed with CR compared to dogs of normal weight (Lampman et al. 2003). A similar study evaluated body weight as a percentage of recommended breed weight and found that dogs in the obese category were nearly fourfold more likely to sustain a CR compared to dogs of normal weight (Adams et al. 2011). Mechanical, as well as metabolic, factors explain the increased risk associated with obesity. From a mechanical standpoint, obese animals experience increased loading in their limbs, which in turn may overstress the CrCL and predispose it to rupture (Whitehair et al. 1993; Adams et al. 2011). Additionally, there has been interest in the endocrine function of adipose tissue and its role in CR pathophysiology. Pro-inflammatory adipokines released by adipose tissue may contribute to the degenerative process underlying CR (Pallu et al. 2010; Adams et al. 2011; Comerford et al. 2011; Koskinen et al. 2011). Conformation The anatomy of the stifle joint has been evaluated extensively for risk factors that may be associated with the development of CR. Anatomic features investigated include intercondylar notch dimensions (Comerford et al. 2006; Lewis et al. 2008), overall limb alignment (Dismukes et al. 2008; Mostafa et al. 2009), and proximal tibial conformation (Selmi & Padilha Filho 2001; Macias et al. 2002; Reif & Probst 2003; Dennler et al. 2006; Osmond et al. 2006; VetBooks.ir Epidemiology of Cruciate Ligament Rupture 111 Table 14.1 Potential risk factors for cruciate ligament rupture in dogs based on current evidence. Category Potential risk factors Age 4–8 years Reproductive status Neutered (before 1 year may increase further) Breed Newfoundland Rottweiler Labrador Retriever Bulldog Boxer Chow Chow American Staffordshire Terrier Weight >22 kg Body condition Overweight or obese Intended function Unknown Stifle anatomy Narrow intercondylar notch Excessive tibial plateau angle (degree varies among reports, >28◦ , >32◦ , >35◦ ) Relatively small proximal tibial craniocaudal width Cranial angulation of the proximal tibia Distal femoral torsion Schwandt et al. 2006; Guerrero et al. 2007; Cabrera et al. 2008; Inauen et al. 2009; Ragetly et al. 2011; Fuller et al. 2014b; Haynes et al. 2015). Anatomic factors that are associated with a predisposition to CR include a narrow intercondylar notch, excessive or pathologic (i.e., outside the 95% confidence intervals for the population) tibial plateau angle, a relatively small proximal tibial width, cranial angulation of the proximal tibia, and distal femoral torsion (Table 14.1). While a great number of studies have focused on the effects of tibial plateau angle and patellar tendon angle, no study has definitively shown either of these as significant risk factors for CR in dogs. Theories and ex vivo research have suggested that increased CrCL strain and an increased shear component of total joint force when each of these angles is considered high based on reference ranges in dogs (Warzee et al. 2001; Reif & Probst 2003; Kowaleski et al. 2005; Shahar & Milgram 2006; Apelt et al. 2007; Duerr et al. 2007; Kim et al. 2008; Kipfer et al. 2008; Haynes et al. 2015). One study reported that a multiple logistic regression model using the combination of tibial plateau angle and femoral anteversion angle was able to discriminate between case and control limbs with an area under the ROC curve of 96% (Ragetly et al. 2011). This suggested that a multivariate approach may provide further insight into the effect of tibial morphology as a risk factor. Other studies have reported no significant effect of proximal tibial morphology on the risk of CrCL rupture (Wilke et al. 2002; Reif & Probst 2003; Guastella et al. 2008; Fuller et al. 2014a). The wide spectrum of results supporting or negating the effect of conformational variables on the risk of CR provides further support for the overall complexity of the condition. While bony conformation may contribute to CR in some way, there remains no definitive evidence that it is a primary causal factor. Bilateral CrCL rupture Perhaps one of the greatest risk factors for developing a CR is having already been diagnosed with the condition. The incidence of bilateral ruptures diagnosed on initial clinical presentation is in the range of 11% to 17% (de Bruin et al. 2007; Cabrera et al. 2008; Buote et al. 2009). The incidence of contralateral rupture after initial diagnosis is between 22% and 54% (de Bruin et al. 2007; Cabrera et al. 2008; Buote et al. 2009; Grierson et al. 2011; Fuller VetBooks.ir 112 Clinical Features et al. 2014b). Dogs diagnosed with unilateral CR often have signs of moderate to severe osteoarthritis (OA) in the stable contralateral stifle (de Bruin et al. 2007; Grierson et al. 2011; Muir et al. 2011; Fuller et al. 2014a; Chuang et al. 2014). The median time to contralateral CR has been reported in the range of 405 to 1688 days (Grierson et al. 2011; Muir et al. 2011; Fuller et al. 2014a). Stifle synovitis is likely an early event that contributes to the progression of CR (Erne et al. 2009; Bleedorn et al. 2011; Muir et al. 2011; Little et al. 2014). The radiographic assessment of OA present in stable stifle joints is correlated with arthroscopic assessment of synovitis (Bleedorn et al. 2011). Therefore, dogs at greater risk for bilateral rupture can be identified through radiographic assessment. The presence of radiographic synovial effusion and osteophytosis in the stable contralateral stifle at the time of diagnosis is a significant risk factor for the development of contralateral CR (Chuang et al. 2014; Fuller et al. 2014a), with more severe radiographic change associated with decreased time to contralateral rupture (Chuang et al. 2014). These results support the practice of obtaining bilateral stifle radiographs when evaluating a dog for unilateral CR. The evaluation of both joints for OA is valuable for patient management, as well as client education, and represents the ‘gold standard’ of care in small animal practice. Genetics The aforementioned risk factors primarily affect CR disease progression. The only risk factor that seems to affect the initiation of CR is genetic effects from breed. It has long been recognized that certain breeds (e.g., Newfoundlands, Rottweilers, and Labrador Retrievers) are predisposed to CR while others, such as the Greyhound, are almost never diagnosed with the condition (Whitehair et al. 1993; Witsberger et al. 2008). Many recent studies have been performed to characterize the genetic basis of CR (Wilke et al. 2009; Baird et al. 2014; Baker et al. 2017). The heritability of CR is moderate, with estimates calculated for the Boxer, Newfoundland, and Labrador Retriever ranging from 0.26 to 0.48 (Nielen et al. 2003; Wilke et al. 2006; Baker et al. 2017). Genome-wide association studies have been carried out in the Newfoundland and the Labrador Retriever (Baird et al. 2014; Baker et al. 2017), the results of which suggest that canine CR is a highly polygenic complex trait. Genetic risk is variable for each individual, and this risk sets the stage for environmental influence, the progression of disease, and eventual rupture. A full discussion on the genetics of CR is presented in Chapter 7. References Adams P, Bolus R, Middleton S, et al. Influence of signalment on developing cranial cruciate rupture in dogs in the UK. J Small Anim Pract 2011;52:347– 352. Apelt D, Kowaleski MP, Boudrieau RJ. Effect of tibial tuberosity advancement on cranial tibial subluxation in canine cranial cruciate-deficient stifle joints: an in vitro experimental study. Vet Surg 2007;36:170–177. Baird AEG, Carter SD, Innes JF, et al. Genome-wide association study identifies genomic regions of association for cruciate ligament rupture in Newfoundland dogs. Anim Genet 2014;45:542–549. Baker LA, Kirkpatrick B, Rosa GJM, et al. Genomewide association analysis in dogs implicates 99 loci as risk variants for Anterior Cruciate Ligament Rupture. PLoS One 2017;12:e0173810. Bleedorn JA, Greuel EN, Manley PA, et al. Synovitis in dogs with stable stifle joints and incipient cranial cruciate ligament rupture: a cross-sectional study. Vet Surg 2011;40:531–543. Buote N, Fusco J, Radasch R. Age, tibial plateau angle, sex, and weight as risk factors for contralateral rupture of the cranial cruciate ligament in Labradors. Vet Surg 2009;38:481–489. Cabrera SY, Owen TJ, Mueller, MG. Comparison of tibial plateau angles in dogs with unilateral versus bilateral cranial cruciate ligament rupture: 150 cases (2000–2006). J Am Vet Med Assoc 2008;232:889–892. Chuang C, Ramaker MA, Kaur S, et al. Radiographic risk factors for contralateral rupture in dogs with unilateral cranial cruciate ligament rupture. PLoS One 2014:9:e106389. Comerford EJ, Tarlton JF, Avery NC, et al. Distal femoral intercondylar notch dimensions and their relationship to composition and metabolism of the canine anterior cruciate ligament. Osteoarthritis Cartilage 2006;14:273–278. Comerford EJ, Smith K, Hayashi K. Update on the aetiopathogenesis of canine cranial cruciate ligament disease. Vet Comp Orthop Traumatol 2011;24:91–98. de Bruin T, de Rooster H, van Bree H, et al. Radiographic assessment of the progression of VetBooks.ir Epidemiology of Cruciate Ligament Rupture osteoarthrosis in the contralateral stifle joint of dogs with a ruptured cranial cruciate ligament. Vet Rec 2007;161:745–750. de la Riva GT, Hart BL, Farver TB, et al. Neutering dogs: effects on joint disorders and cancers in Golden Retrievers. PLoS One 2013;8:e55937. Dennler R, Kipfer NM, Tepic S, et al. Inclination of the patellar ligament in relation to flexion angle in stifle joints of dogs without degenerative joint disease. Am J Vet Res 2006;67:1849–1854. Dismukes DI, Fox DB, Tomlinson JL, et al. Determination of pelvic limb alignment in the large-breed dog: a cadaveric radiographic study in the frontal plane. Vet Surg 2008;37:674–682. Duerr FM, Duncan CG, Savicky RS, et al. Risk factors for excessive tibial plateau angle in large-breed dogs with cranial cruciate ligament disease. J Am Vet Med Assoc 2007;231:1688–1691. Duval JM, Budsberg SC, Flo GL, et al. Breed, sex, and body weight as risk factors for rupture of the cranial cruciate ligament in young dogs. J Am Vet Med Assoc 1999;215:811–814. Erne JB, Goring RL, Kennedy FA, et al. Prevalence of lymphoplasmacytic synovitis in dogs with naturally occurring cranial cruciate ligament rupture. J Am Vet Med Assoc 2009;235:386–390. Fuller MC, Hayashi K, Bruecker KA, et al. Evaluation of the radiographic infrapatellar fat pad sign of the contralateral stifle joint as a risk factor for subsequent contralateral cranial cruciate ligament rupture in dogs with unilateral rupture: 96 cases (2006– 2007). J Am Vet Med Assoc 2014a;244;328–338. Fuller MC, Kapatkin AS, Bruecker KA, et al. Comparison of the tibial mechanical joint orientation angles in dogs with cranial cruciate ligament rupture. Can Vet J 2014b;55:757–764. Grierson J, Asher L, Grainger K. An investigation into risk factors for bilateral canine cruciate ligament rupture. Vet Comp Orthop Traumatol 2011;24:192– 196. Guastella DB, Fox DB, Cook JL. Tibial plateau angle in four common canine breeds with cranial cruciate ligament rupture, and its relationship to meniscal tears. Vet Comp Orthop Traumatol 2008;21:125– 128. Guerrero TG, Geyer H, Hässig M, et al. Effect of conformation of the distal portion of the femur and proximal portion of the tibia on the pathogenesis of cranial cruciate ligament disease in dogs. Am J Vet Res 2007;68:1332–1337. Haynes KH, Biskup J, Freeman A, et al. Effect of tibial plateau angle on cranial cruciate ligament strain: an ex vivo study in the dog. Vet Surg 2015;44:46–49. Inauen R, Koch D, Bass M, et al. Tibial tuberosity conformation as a risk factor for cranial cruciate ligament rupture in the dog. Vet Comp Orthop Traumatol 2009;22:16–20. Kim SE, Pozzi A, Kowaleski MP, et al. Tibial osteotomies for cranial cruciate ligament insufficiency in dogs. Vet Surg 2008;37:111–125. 113 Kipfer NM, Tepic S, Damur DM, et al. Effect of tibial tuberosity advancement on femorotibial shear in cranial cruciate-deficient stifles. An in vitro study. Vet Comp Orthop Traumatol 2008;21:385–290. Koskinen A, Juslin S, Nieminen R, et al. Adiponectin associates with markers of cartilage degradation in osteoarthritis and induces production of proinflammatory and catabolic factors through mitogenactivated protein kinase pathways. Arthritis Res Ther 2011;13:R184. Kowaleski MP, Apelt D, Mattoon JS, et al. The effect of tibial plateau leveling osteotomy position on cranial tibial subluxation: an in vitro study. Vet Surg 2005;34:332–336. Lampman TJ, Lund EM, Lipowitz AJ. Cranial cruciate disease: current status of diagnosis, surgery, and risk for disease. Vet Comp Orthop Traumatol 2003;16:122–126. Lewis BA, Allen DA, Henrikson TD, et al. Computed tomographic evaluation of the canine intercondylar notch in normal and cruciate deficient stifles. Vet Comp Orthop Traumatol 2008;21:119–124. Light VA, Montgomery RD, Akingbemi BT. Sex hormone regulation of collagen concentrations in cranial cruciate ligaments of sexually immature male rabbits. Am J Vet Res 2012;73:1186–1193. Little JP, Bleedorn JA, Sutherland BJ, et al. Arthroscopic assessment of stifle synovitis in dogs with cranial cruciate ligament rupture. PLoS One 2014;9:e97329. Macias C, McKee WM, May C. Caudal proximal tibial deformity and cranial cruciate ligament rupture in small-breed dogs. J Small Anim Pract 2002;43:433– 438. Mostafa AA, Griffon DJ, Thomas MW, et al. Morphometric characteristics of the pelvic limbs of Labrador Retrievers with and without cranial cruciate ligament rupture. Am J Vet Res 2009;70:498– 507. Muir P, Schwartz Z, Malek S, et al. Contralateral cruciate survival in dogs with unilateral noncontact cranial cruciate ligament rupture. PLoS One 2011;6:e25331. Nielen AL, Knol BW, van Hagen MA et al. Genetic and epidemiological investigation of a birth cohort of boxers. Tijdschr Diergeneeskd 2003:128;586–590. Osmond CS, Marcellin-Little DJ, Harrysson OL, et al. Morphometric assessment of the proximal portion of the tibia in dogs with and without cranial cruciate ligament rupture. Vet Radiol Ultrasound 2006;47:136–141. Pallu S, Francin PJ, Guillaume C, et al. Obesity affects the chondrocyte responsiveness to leptin in patients with osteoarthritis. Arthritis Res Ther 2010;12:R112. Powers MY, Martinez SA, Lincoln JD, et al. Prevalence of cranial cruciate ligament rupture in a population of dogs with lameness previously attributed to hip dysplasia: 369 cases (1994–2003). J Am Vet Med Assoc 2005;227:1109–1111. VetBooks.ir 114 Clinical Features Ragetly CA, Evans R, Mostafa AA, et al. Multivariate analysis of morphometric characteristics to evaluate risk factors for cranial cruciate ligament deficiency in Labrador Retrievers. Vet Surg 2011;40:327–333. Reif U, Probst CW. Comparison of tibial plateau angles in normal and cranial cruciate deficient stifles of Labrador Retrievers. Vet Surg 2003;32:385– 389. Schwandt CS, Bohorquez-Vanelli A, Tepic S, et al. Angle between the patellar ligament and tibial plateau in dogs with partial rupture of the cranial cruciate ligament. Am J Vet Res 2006;67:1855– 1860. Selmi AL, Padilha Filho JG. Rupture of the cranial cruciate ligament associated with deformity of the proximal tibia in five dogs. J Small Anim Pract 2001;42:390–393. Shahar R, Milgram J. Biomechanics of tibial plateau leveling of the canine cruciate-deficient stifle joint: a theoretical model. Vet Surg 2006;35:144– 149. Slauterbeck JR, Pankratz K, Xu KT, et al. Canine ovariohysterectomy and orchiectomy increases the prevalence of ACL injury. Clin Orthop Relat Res 2004;429:301–305. Warzee CC, Dejardin LM, Arnoczky SP, et al. Effect of tibial plateau leveling on cranial and caudal tibial thrusts in canine cranial cruciate-deficient stifles: an in vitro experimental study. Vet Surg 2001;30:278–286. Whitehair JG, Vasseur PB, Willits NH. Epidemiology of cranial cruciate ligament rupture in dogs. J Am Vet Med Assoc 1993;203:1016–1019. Wilke VL, Conzemius MG, Besancon MF, et al. Comparison of tibial plateau angle between clinically normal Greyhounds and Labrador Retrievers with and without rupture of the cranial cruciate ligament. J Am Vet Med Assoc 2002;221:1426– 1429. Wilke VL, Conzemius MG, Kinghorn BP, et al. Inheritance of rupture of the cranial cruciate ligament in Newfoundlands. J Am Vet Med Assoc 2006;228:61– 64. Wilke VL, Zhang S, Evans RB, et al. Identification of chromosomal regions associated with cranial cruciate ligament rupture in a population of Newfoundlands. Am J Vet Res 2009;70:1013–1017. Witsberger TH, Villamil JA, Schultz LG, et al. Prevalence of and risk factors for hip dysplasia and cranial cruciate ligament deficiency in dogs. J Am Vet Med Assoc 2008;232:1818–1824. VetBooks.ir 15 History and Clinical Signs of Cruciate Ligament Rupture Peter Muir Introduction Cruciate ligament rupture (CR) has been recognized since the early part of the twentieth century. Although this condition was initially considered a traumatic injury, during the past 25 years it has become widely accepted that it is a complex trait disease with both genetic and environmental contributions to the risk of disease, with development of stifle instability because of progressive fiber tearing in the cruciate ligament complex (Bennett et al. 1988). It is important to exclude CR before making recommendations about the management of hip dysplasia in dogs because of the high prevalence of CR and associated stifle arthritis in dogs with pelvic limb lameness and hip dysplasia (Powers et al. 2005). History Although owners will often provide a history suggestive of trauma, careful analysis typically reveals that the onset of lameness was either insidious, or that lameness was observed to develop by the owner after an incident of minor trauma associated with normal daily activity. In a proportion of patients, owners will provide a clear history of major trauma, such as injury in a motor vehicle accident, suggesting that a traumatic rupture of the cranial cruciate ligament (CrCL) has occurred. This is rare, and further investigation of such patients will often reveal an avulsion fracture of a cruciate ligament attachment site. Epidemiologically, this proportion is not clearly documented, although in medium- to large-breed dogs this incidence appears less than 1% of patients; a very large majority of dogs do not have a history of trauma or contact injury. Currently, CR is considered a progressive, acquired, degenerative condition. Lameness in affected dogs is usually weightbearing and is typically worse after exercise. The duration of lameness described by owners is highly variable. Occasionally, owners may report an audible ‘clicking’ during walking. It is also common for dogs to be presented for treatment because of subtle pelvic lameness, which is usually continuously present and fairly unresponsive to medical therapy with nonsteroidal anti-inflammatory drugs. Observant owners may notice that bilateral lameness is present, with the dog exhibiting a stiff pelvic limb gait with weight-shifting to the thoracic limbs. Lameness may also appear to shift from one pelvic limb to the ipsilateral limb in patients with bilateral CR. Such patients typically have Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 115 VetBooks.ir 116 Clinical Features stifle arthritis, but a stable stifle with a partial CR on further investigation. Clinical signs On physical examination, affected dogs usually exhibit unilateral or bilateral weight-bearing pelvic limb lameness. If the lameness is bilateral, dogs will often lean forward and alter their stance to unload the pelvic limbs (Figure 15.1). Occasionally, a non weight-bearing lameness may be evident. In dogs with unilateral lameness, external rotation of the affected limb may be evident when walking. Similarly, during sitting, affected dogs will often position the affected limb so that limb is externally rotated and stifle flexion is reduced, compared with a normal symmetric sitting posture. This is sometimes referred to as the ‘sit test’. In this posture, the calcaneus is not directly underneath the tuber ischii, because the stifle is not fully flexed. On general examination, atrophy of pelvic limb musculature in the affected limb(s) is usually evident. Occasionally, an audible clicking may be heard during walking or during stifle manipulation, and is usually indicative of meniscal damage, most commonly a bucket-handle tear. Careful physical examination is important as neurological disease may initially be suspected in dogs that have difficulty rising from a sitting to a standing position because of bilateral CR. During examination of the stifle, effusion is typically found, with the lateral and medial margins of the patella tendon feeling indistinct on palpation. Subtle effusion can be hard to Figure 15.1 Photograph of a female Rottweiler with bilateral pelvic limb lameness and bilateral cruciate ligament rupture. Notice that she is leaning forward to unload the pelvic limbs. detect on physical examination, but is an important clinical sign. Stifle radiography is a more sensitive diagnostic test for stifle effusion than physical examination. As CR is so prevalent, if there is any uncertainty about this aspect of stifle examination, bilateral orthogonal stifle radiographs should be made in dogs with pelvic limb lameness and examined for effusion and arthritic degeneration. Radiographs also underestimate pathological change, so an obvious stifle synovitis may be present, with only subtle radiographic change. Even very mild stifle synovial effusion should be considered an important sign of partial CR (Chuang et al. 2014) (see also Chapter 16). Palpation of the medial side of the stifle will often reveal a firm thickening, indicative of periarticular fibrosis (Figure 15.2) or ‘medial buttress.’ This pathological change is almost always indicative of CR. Crepitation and resentment to range of motion manipulation may be found on flexion and extension of the stifle. CR may also lead to excessive internal rotation of the tibia relative to the femur, which may be apparent on physical examination. In dogs with partial CR and a stable stifle, internal rotation of the tibia relative to the femur or stifle hyperextension will usually elicit resentment as load is applied to the CrCL with these joint manipulations (see also Chapter 16). Medial and lateral stress to the stifle should also be applied during physical examination to assess the stability of the collateral ligaments Figure 15.2 Photograph of the medial aspect of the right stifle. Prominent periarticular fibrosis of the stifle is evident. It is important to check for firm swelling of the medial aspect of the stifle or ‘medial buttress.’ This sign is typical of chronic cruciate ligament rupture. 117 VetBooks.ir History and Clinical Signs of Cruciate Ligament Rupture Figure 15.3 Photograph of the left pelvic limb of a Siberian Husky. When checking for cranial drawer motion in the stifle, it is important to place the fingertips on the tibial crest, the fibular head, the patella, and the lateral fabella to avoid interpreting compression of soft tissue or internal rotation as cranial drawer motion. of the stifle, as collateral ligament rupture combined with cruciate ligament rupture can be a consequence of traumatic injury to the stifle. Cranial-caudal instability between the tibia and femur may be identified by use of the cranial drawer test or the cranial tibial thrust test (Figures 15.3 and 15.4, respectively) (Henderson & Milton 1978; Muir 1997). During application of these tests to the stifle, it is important to place the examining fingers directly on the bony prominences of the stifle, to avoid interpreting movement of the skin and overlying soft tissues as translation of the tibia relative to the femur. It is often helpful to repeat these tests after sedation or general anesthesia of the patient to ensure that subtle instability has not been missed on physical examination. This is particularly important in dogs with chronic stifle arthritis. Here, periarticular fibrosis may reduce, but not eliminate, cranial translation of the tibia relative to the femur. It is also important in nervous dogs with tense muscles, where stifle instability may be less apparent. The cranial drawer and cranial tibial thrust tests are best performed with the dog in lateral recumbency and the stifle in partial flexion at a Figure 15.4 Photograph of the left pelvic limb of a Siberian Husky. With the stifle extended, an index finger is placed on the tibial crest to determine whether cranial displacement of the tibia occurs when the hock is flexed. If cranial translation of the tibia relative to the femur is identified, this is a positive cranial tibial thrust test and is indicative of cranial cruciate ligament rupture. normal standing angle. Testing should be performed in both flexion and extension, although instability at any stifle flexion angle likely reflects complete CR (Heffron & Campbell 1978). Detection of stifle instability and cranial translation of the tibia relative to the femur is indicative of complete biomechanical disruption of the CrCL. In young puppies, a small degree of cranial translation of the tibia relative to the femur of a few millimeters is normal and is indicative of mild laxity in the ligament. Here, the small amount of tibio-femoral translation during the cranial drawer maneuver will come to an abrupt stop. In contrast, in dogs with partial CR (Grade II sprain), the small degree of tibio-femoral translation will end in a soft or spongy stop (see also Chapter 16). During physical examination, the stifle should also be palpated carefully for caudal drawer motion. Here, the cranial drawer test will elicit an abrupt stop with minimal VetBooks.ir 118 Clinical Features translation, whereas caudal drawer motion will be elicited. Isolated rupture of the caudal cruciate ligament (CaCL) is rare. A small proportion of dogs affected with the CR condition and diagnosed with CrCL rupture will also have CaCL rupture. In CR dogs with rupture of both cruciate ligaments, it can be particularly difficult to recognize that both cruciate ligaments are ruptured during physical examination of the stifle (Might et al. 2013). Conclusions Detection of cranial drawer and cranial tibial thrust on physical examination remains a key part of patient investigation in dogs with CR. However, the detection of stifle instability can often be difficult to distinguish from mild laxity, which might be normal in puppies, or a soft stop to the cranial drawer test (Grade II sprain). The cranial drawer test alone or in combination with the cranial tibial thrust test poorly differentiates cranial and caudal cruciate rupture in model studies (Might et al. 2013). Therefore, clinical findings from these tests should be interpreted with caution and the diagnosis of CR should also consider other physical examination findings and observations from other diagnostic testing, particularly orthogonal stifle radiographs. These limitations will likely change in the future as knowledge of stifle kinematics improves, as discussed elsewhere in the book. Development of better teaching models for veterinary students may also enhance clinical diagnosis of CR over time (Troy & Berg 2015). In future investigations, development of a stifle arthrometer that objectively measures subtle translation of the tibia relative to the femur may aid early identification of dogs with partial CR. References Bennett D, Tennant B, Lewis DG, et al. A reappraisal of anterior cruciate ligament disease in the dog. J Small Anim Pract 1988;29:275–297. Chuang C, Ramaker MA, Kaur S, et al. Radiographic risk factors for contralateral rupture in dogs with unilateral cranial cruciate ligament rupture. PLoS One 2014;9:e106389. Heffron LE, Campbell JR. Morphology, histology, and functional anatomy of the canine cranial cruciate ligament. Vet Rec 1978;102:280–283. Henderson RA, Milton JL. The tibial compression mechanism: A diagnostic aid in stifle injuries. J Am Anim Hosp Assoc 1978;14:474–479. Might KR, Bachelez A, Martinez SA, et al. Evaluation of the drawer test and the tibial compression test for differentiating between cranial and caudal stifle subluxation associated with cruciate ligament instability. Vet Surg 2013;42:392–397. Muir P. Physical examination of lame dogs. Compend Cont Ed Pract Vet 1997;19:1149–1161. Powers MY, Martinez SA, Lincoln JD, et al. Prevalence of cranial cruciate ligament rupture in a population of dogs with lameness previously attributed to hip dysplasia: 369 cases (1994–2003). J Am Vet Med Assoc 2005;227:1109–1111. Troy JR, Bergh MS. Development and efficacy of a canine pelvic limb model used to teach the cranial drawer and tibial compression tests in the stifle joint. J Vet Med Educ 2015;42:127–132. VetBooks.ir 16 Partial Rupture of the Cranial Cruciate Ligament Peter Muir Introduction Ligament sprains are classified as Grade I through III, depending on the severity of the matrix damage. Ligament sprains are defined biomechanically. Grade I sprains do not affect joint instability and are associated with subfailure damage to the ligament tissue (Provenzano et al. 2002). Grade II sprains are associated with moderate fiber damage and a stretch to the point of detectable instability. Grade III sprains are associated with severe disruption of ligament fibers and obvious joint laxity (Provenzano et al. 2002). Consequently, dogs with a stable stifle have partial cruciate ligament rupture (CR) and dogs with an unstable stifle have complete CR. Historically, CR has been classified as partial or complete, based on an anatomic definition in some reports. In human beings, the assessment and grading of partial anterior cruciate ligament injuries is controversial, as these lesions may involve a variable amount of the cross-section of the ligament during arthroscopic evaluation (Hong et al. 2003). Partial cranial cruciate ligament rupture In the dog, the cranial cruciate ligament (CrCL) has cranio-medial and caudo-lateral components containing bundles of longitudinally orientated collagen fibers (Heffron & Campbell 1978). The cranio-medial component is taut in both flexion and extension, whereas the caudo-lateral component is only taut in extension (Arnoczky & Marshall 1977). Biomechanically, ex vivo sectioning of either the cranio-medial component or the caudo-lateral component of the CrCL induces the development of mild joint instability in partial flexion, with ≤3 mm of cranial drawer motion that is little influenced by stifle flexion angle (Heffron & Campbell 1978). This small amount of cranial drawer motion would be difficult to detect on physical examination (Table 16.1) (Heffron & Campbell 1978). Collectively, these observations suggest that clinicians can infer that the majority of the CrCL has been disrupted biomechanically when cranial drawer instability is detected by physical examination (Heffron & Campbell 1978). In the human patient, joint translation can also be measured using an arthrometer (Bach et al. 1990). In dogs, the development of weight-bearing standing radiography (Kim et al. 2011) or recumbent stress radiography (Bleedorn et al. 2011) have helped quantify cranial tibial subluxation in affected dogs. Future development of an arthrometer for the dog stifle that can Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 119 VetBooks.ir 120 Clinical Features Table 16.1 Results of partial and total sectioning of the canine cranial cruciate ligament (CrCL). Degree of stifle flexion from maximal extension Cranio-medial component cut (n = 5) 0◦ 20◦ 40◦ 60◦ 1.5 (0,2) 2 (2,3) 1 (1,2.5) 1 (0,1) Caudo-lateral component cut (n = 5) 0 (0,1.5) 1 (1,1) 0.5 (0,1) 0 (0,0) Whole CrCL cut (n = 10) 7.7 ± 3.4 13.0 ± 1.4 10.4 ± 2.0 7.6 ± 1.6 Note: Results represent cranial translation of the tibia relative to the femur in millimeters. For the whole CrCL cut, data represent mean ± standard deviation. For the other two experiments, data represent median (range). Source: Heffron & Campbell 1978. Reproduced with permission from the British Veterinary Association. objectively measure cranial tibial translation may further aid in the early diagnosis of canine partial CR. Clinically, diagnosis of partial rupture of the CrCL (Grade I sprain) should be limited to dogs that are determined to have a stable stifle with no cranial drawer or cranial tibial thrust. The detection of cranial drawer motion in only partial flexion is not a reliable indicator of disruption to only the cranio-medial component of the CrCL (Scavelli et al. 1990). During cranial drawer testing of the stifle, a soft stop to the test can be detected with minimal to no cranial translation of the tibia. This clinical finding reflects more severe matrix damage to the CrCL (Grade II sprain). Although it has been previously questioned whether a lack of cranial drawer motion during the physical examination of dogs with partial CrCL rupture (A) (B) may be a consequence of periarticular fibrosis (Scavelli et al. 1990), some degree of clinical instability is typically found in dogs with chronic CR (Tashman et al. 2004). Radiographically, stifle synovial effusion and osteophyte formation are important signs that support the diagnosis of partial CR. Even subtle radiographic change should be considered clinically important (Chuang et al. 2014). CrCL fiber damage can be inferred from degenerative changes radiographically (Sample et al. 2017). The increasing use of arthroscopy to examine the stifle joint of dogs with mild arthritis and a clinically stable stifle suggests that superficial fraying of the CrCL and the caudal cruciate ligament (see also Chapter 17), superficial and deep splits in the ligament tissue, and fiber rupture are typically seen in the early phase of the condition (Figure 16.1) (Bleedorn et al. 2011). (C) Figure 16.1 Arthroscopic images of the intercondylar notch region of the distal femur of three dogs with partial cranial cruciate ligament (CrCL) rupture. No cranial drawer or cranial tibial thrust was evident on physical examination. All of the dogs had complete contralateral cruciate ligament rupture and an unstable stifle. Disruption of fibers or fiber bundles is evident in the CrCL (arrows) (A,B). Splits in the fiber bundles often become more evident when examined with an arthroscopic probe (C). Inflammation of adjacent synovium is typically evident (A). Ruptured fiber bundles often have a pale yellow appearance (B). Thickening of the ends of torn fibers suggests a healing response that is not successful at repair and remodeling of fiber bundles (∗ ). In this regard, the surrounding synovial fluid is known to promote fibrinolysis of any provisional scaffold for repair of fiber damage. Right stifle (A,B), left stifle (C). CaCL, caudal cruciate ligament. VetBooks.ir Partial Rupture of the Cranial Cruciate Ligament Conclusions In conclusion, if stifle joint instability is detected clinically, this is indicative of substantial disruption to the CrCL biomechanically, and complete CR. In this type of patient, the remaining ligament tissue, if present, is typically stretched out and slack. The remaining CrCL fibers often have an abnormal arthroscopic appearance, have a yellow coloration, and are inflamed. The diagnosis of partial CR should be limited to stifles that are stable. In the future, careful evaluation of clinical outcomes after the treatment of dogs with partial CR using surgical stabilization, particularly tibial plateau leveling osteotomy, is needed, as there is some evidence that this approach may protect the CrCL from progressive fiber tearing (Hulse et al. 2010; Barger et al. 2016). Further studies are also needed to develop disease-modifying therapies aimed at blocking progressive deterioration in the biomechanical properties of the CrCL and eventual complete CR. References Arnoczky SP, Marshall JL. The cruciate ligaments of the canine stifle: An anatomical and functional analysis. Am J Vet Res 1977;38:1807–1814. Bach BR, Warren RF, Flynn WM, et al. Arthrometric evaluation of knees that have a torn anterior cruciate ligament. J Bone Joint Surg 1990;72A:1299–1306. Barger B, Piazza A, Muir P. Treatment of stable partial cruciate rupture (Grade I sprain) in five dogs with 121 tibial plateau levelling osteotomy. Vet Rec Case Rep 2016;4:e000315. Bleedorn JA, Greuel E, Manley PA, et al. Synovitis in dogs with stable stifle joints and incipient cranial cruciate ligament rupture: A cross-sectional study. Vet Surg 2011;40:531–543. Chuang C, Ramaker MA, Kaur S, et al. Radiographic risk factors for contralateral rupture in dogs with unilateral cranial cruciate ligament rupture. PLoS One 2014;9:e106389. Heffron LE, Campbell JR. Morphology, histology, and functional anatomy of the canine cranial cruciate ligament. Vet Rec 1978;102:280–283. Hong SH, Choi J-Y, Lee GK, et al. Grading of anterior cruciate ligament injury. J Comput Assist Tomogr 2003;27:814–819. Hulse D, Beale B, Kerwin S. Second look arthroscopic findings after tibial plateau leveling osteotomy. Vet Surg 2010;39:350–354. Kim SE, Lewis DD, Pozzi A, et al. Radiographic quantitative assessment of cranial tibial subluxation before and after tibial plateau leveling osteotomy in dogs. Am J Vet Res 2011;72:420–416. Provenzano PP, Heisey D, Hayashi K, et al. Subfailure damage in ligament: a structural and cellular evaluation. J Appl Physiol 2002;92:362–371. Sample SJ, Racette MA, Hans EC, et al. Radiographic and magnetic resonance imaging predicts severity of cruciate ligament fiber damage and synovitis in dogs with cranial cruciate ligament rupture. PLoS One 2017;12:e0178086. Scavelli TD, Schrader SC, Matthiesen DR, Skorup DE. Partial rupture of the cranial cruciate ligament in the stifle in dogs (1982–1988). J Am Vet Med Assoc 1990;196:1135–1138. Tashman S, Anderst W, Kolowich P, et al. Kinematics of the ACL-deficient canine knee during gait: serial changes over two years. J Orthop Res 2004;22:931– 941. VetBooks.ir VetBooks.ir 17 Caudal Cruciate Ligament Rupture Peter Muir Introduction Rupture of the caudal cruciate ligament (CaCL) is less common than rupture of the cranial cruciate ligament (CrCL). Isolated disruption of the CaCL is found in less than 2% of stifle surgery patients (Harari 1993). Experimentally, transection of the CaCL does not cause an obvious lameness, and only leads to mild internal rotation of the tibia relative to the femur (Harari et al. 1987). Although caudal drawer motion was detectable during a six-month study period, minimal degeneration of the articular cartilage with very little osteophyte formation was found experimentally (Pournas et al. 1983; Harari et al. 1987). Meniscal damage was not found after experimental transection of the CaCL (Pournas et al. 1983; Harari et al. 1987). Therefore, whether naturally occurring isolated disruption of the CaCL causes lameness clinically in the dog is unclear. Rupture of the CaCL often involves avulsion fracture of an attachment site. Affected dogs are usually immature or adolescent patients with history of trauma and often additional injuries (Johnson & Olmstead 1987). Complete rupture of the CaCL is also seen in dogs with stifle luxation, in combination with rupture of the CrCL and the medial collateral ligament, secondary to stifle trauma (Hulse & Shires 1986; Aron 1988). Mild damage to the CaCL is underappreciated clinically (Sumner et al. 2010). Superficial fraying, splits in the ligament matrix and fiber rupture of the CaCL are often found in dogs with degenerative cruciate ligament rupture (CR) in both partial and complete CR cases. Some degree of damage to both cruciate ligaments is often found in dogs with a stable stifle during arthroscopic examination of the stifle (Figures 17.1 and 17.2). Clinical presentation Mid-substance tears Dogs with isolated mid-substance tears usually have a history and clinical signs that are similar to dogs affected with the typical CR condition. A history of trauma may be described by the owner in some patients. Although stifle instability is often appreciated on physical examination, caudal drawer motion is difficult to recognize specifically (Might et al. 2013), and may be misinterpreted as cranial drawer motion. Consequently, it is easy to fail to diagnose CaCL rupture clinically during patient examination. Radiographic signs are also similar to dogs Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 123 Clinical Features VetBooks.ir 124 MC most likely to be made during arthroscopy or arthrotomy of the stifle (Johnson & Olmstead 1987). In dogs with CaCL rupture, ligament degeneration and inflammation, and rupture of CrCL fibers is typically present in many affected dogs. These dogs are essentially affected with CR (Sumner et al. 2010). Menisci are typically intact in dogs with isolated CaCL rupture (Johnson & Olmstead 1987). Avulsion fracture Figure 17.1 Arthroscopic image of the intercondylar notch region of the distal femur of the right stifle of a 7-year-old neutered female mix-breed dog with a stable stifle and very mild stifle arthritis radiographically. Mild disruption of some of the fibers of the caudal cruciate ligament is evident, particularly adjacent to the femoral attachment site (arrows). MC, medial condyle. with CR. Caudal displacement of the tibia relative to the femur may be evident on a lateral radiograph of the stifle (Soderstrom et al. 1998). Unless magnetic resonance imaging (MRI) of the stifle is performed, a specific diagnosis is MC Dogs with an avulsion fracture of the proximal or distal attachment site of the CaCL are usually young patients presented with a clear history of trauma and a persistent lameness (Reinke 1982). Stifle swelling and instability is often detected on physical examination. Avulsion fracture fragments are usually evident radiographically, with careful examination of high-quality radiographs. However, if an avulsion fracture fragment is identified radiographically, it may be difficult to determine which cruciate ligament it is associated with. Multiple ligamentous injuries to the stifle In dogs with severe stifle trauma and disruption to multiple stifle ligaments, the CaCL is ruptured in more than 80% of patients (Aron 1988). The presence of CaCL rupture is often masked by stifle instability because of disruption to other supporting structures, such as the CrCL and the medial collateral ligament (Hulse & Shires 1986; Aron 1988). Treatment Figure 17.2 Photograph of the intercondylar notch region of the distal femur of the right stifle of a 1-year-old neutered male Labrador with an unstable stifle, moderate arthritis, and rupture of the cranial cruciate ligament. Complete disruption of the cranial cruciate ligament (arrowheads), together with partial rupture of the caudal cruciate ligament, with disruption of ligament fascicles was found at surgery (arrow). MC, medial condyle. In dogs with isolated CaCL rupture the need for surgical treatment is unclear, particularly as experimental transection of the CaCL does not lead to lameness. Although various extracapsular and intra-articular stabilization methods have been proposed, objective long-term evaluation of these procedures is lacking (Harari 1993). If tibial plateau leveling osteotomy (TPLO) surgery is planned as a treatment for CR, it is particularly important to determine whether caudal drawer motion may be present before surgery, and whether substantial CaCL VetBooks.ir Caudal Cruciate Ligament Rupture damage or rupture is present during surgery, as this is a contraindication for the TPLO procedure. TPLO increases CaCL loading, and the joint-stabilizing effect of TPLO depends on a biomechanically intact CaCL being present (Warzee et al. 2001; Zachos et al. 2002). In dogs with avulsion fractures, if the fracture fragment is sufficiently large, fracture repair with a lag screw is recommended (Reinke 1982; Harari 1993). In patients where the fracture fragment is small, debridement of the fragment is indicated. Again, the need for a stifle stabilization procedure in these patients is unclear (Harari 1993). In dogs with multiple ligamentous injury, surgical treatment for CrCL rupture, medial collateral ligament rupture, and menisci injury should be a priority. Menisci and their supporting structures should be preserved where possible. Collateral ligament rupture should be repaired with sutures if possible. A number of procedures are available for stifle stabilization to protect reconstructed ligaments, including extracapsular stabilization and the use of a transarticular external skeletal fixator. Conclusions In conclusion, in dogs affected with CR, fiber damage in both the CrCL and the CaCL is often found during arthroscopy or arthrotomy (Sumner et al. 2010). Fraying of the CaCL is underappreciated unless a probe is used specifically to examine the ligament during surgery. Occasionally, substantial damage to the CaCL will be identified in dogs diagnosed with CR. This is important, as substantial disruption of the CaCL is a contraindication for TPLO. 125 References Aron DN. Traumatic dislocation of the stifle joint: Treatment of 12 dogs and one cat. J Am Anim Hosp 1988;24:333–340. Harari J, Johnson AL, Stein LE, et al. Evaluation of experimental transection and partial excision of the caudal cruciate ligament in dogs. Vet Surg 1987;16:151–154. Harari J. Caudal cruciate ligament injury. Vet Clin North Am Small Anim Pract 1993;23:821–829. Hulse DA, Shires P. Multiple ligament injury of the stifle joint in the dog. J Am Anim Hosp Assoc 1986;22:105–110. Johnson AL, Olmstead ML. Caudal cruciate ligament rupture. A retrospective analysis of 14 dogs. Vet Surg 1987;16:202–206. Might KR, Bachelez A, Martinez SA, et al. Evaluation of the drawer test and the tibial compression test for differentiating cranial and caudal stifle subluxation associated with cruciate ligament instability. Vet Surg 2013;42:392–397. Pournas J, Symeonides PP, Karkavelas G. The significance of the posterior cruciate ligament in the stability of the knee. An experimental study in dogs. J Bone Joint Surg 1983;65B:204–209. Reinke JD. Cruciate ligament avulsion injury in the dog. J Am Anim Hosp Assoc 1982;18:257–264. Soderstrom MJ, Rochat MC, Drost WT. Radiographic diagnosis: avulasion fracture of the caudal cruciate ligament. Vet Radiol Ultrasound 1998;39:536– 538. Sumner JP, Markel MD, Muir P. Caudal cruciate ligament damage in dogs with cranial cruciate ligament rupture. Vet Surg 2010;39:936–941. Warzee CC, Dejardin LM, Arnoczly SP, et al. Effect of tibial plateau leveling on cranial and caudal tibial thrusts in canine cranial cruciate deficient stifles. Vet Surg 2001;30:278–286. Zachos TA, Arnoczky SP, Lavagnino M, et al. The effect of cranial cruciate ligament insufficiency on caudal cruciate ligament morphology: An experimental study in dogs. Vet Surg 2002;31:596– 603. VetBooks.ir VetBooks.ir 18 Stress Imaging of the Stifle Stanley E. Kim Introduction Plain radiography is an excellent diagnostic tool for evaluating stifles for cruciate ligament rupture (CR) (Carobbi & Ness 2009). Stress imaging for dogs with CR is not commonly performed, as the most clinically significant information is typically found when high-quality plain radiographs are evaluated, together with accurate clinical findings such as signalment, history, and orthopaedic examination. However, stress imaging of the cranial cruciate ligament (CrCL)deficient stifle still does carry some value in both clinical and research settings. The detection of excessive cranial tibial translation is pathognomonic for CrCL insufficiency. Instability is classically assessed by examination using two physical tests: the cranial drawer test (Muir 1997); and the tibial compression test (Henderson & Milton 1978). Unfortunately, it can be difficult to elicit a positive result with either of these tests in dogs with CR, as laxity may be overcome by factors such as poor execution of the maneuver by the operator, high muscle tone, and periarticular fibrosis in the dog (Flo & DeYoung 1978). In some dogs with partial CR, no palpable laxity is present because the vast majority of the CrCL remains intact. Thus, a non-operative diagnosis of CR often relies on other examination findings such as periarticular thickening, stifle effusion, and pain. The simple combination of palpating the stifle for the presence of effusion and detecting stifle effusion on radiographs was shown to be a highly accurate method for diagnosing CR. Nevertheless, stress radiography has been advocated to improve diagnostic accuracy by quantifying cranial tibial translation radiographically. This can be achieved by acquiring radiographs while performing a modified tibial compression test (de Rooster et al. 1998; de Rooster & van Bree 1999a–c). Laxity may also be detected on radiography by using specially designed devices that attempt to force the stifle into drawer (Lopez et al. 2004). Standing radiography may be considered as another ‘stressradiographic’ technique, where the intrinsic forces that are present during standing promote cranial tibial translation in CrCL-deficient stifles (Kim et al. 2011). Finally, stress magnetic resonance imaging (MRI) of the stifle has been described for the purposes of evaluating meniscal integrity in CR stifles. This chapter will outline each of these stress imaging techniques and discuss their potential clinical and research utility. It should be noted that coronal instability (i.e., assessment of varus/valgus laxity), which typically occurs Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 127 VetBooks.ir 128 Clinical Features with collateral ligament rupture, is not covered in this chapter. Stress radiography for assessing collateral ligament integrity may be indicated in some cases of CR, where severe trauma results in multi-ligament injury; a thorough discussion of these injuries is beyond the scope of this text. * Measuring subluxation For all of the described stress-imaging techniques, the detection of subluxation is made possible by assessing the cranial-caudal alignment of the tibia relative to the femur on lateral views of the stifle after applying a cranial tibial translational load. When palpable instability caused by CR is present, altered femorotibial alignment is usually obvious upon subjective comparisons between stressed and non-stressed images (Figure 18.1). In one of the original descriptions for stress radiography, the stress test was considered positive when a vertical line running tangential to the femoral condyles fell behind the caudal aspect of the tibial plateau (de Rooster et al. 1998). Other subjective findings considered to be indicative of subluxation included cranial displacement of the intercondylar eminence relative to the lateral femoral condyle (Figure 18.1), and caudal displacement of the popliteal sesamoid relative to the tibial plateau. Because the accuracy of subjective assessments is likely dependent on the expertise of the observer, numerous methods for the objective quantification of cranial tibial subluxation have been described. For most methods, the distance between a specified femoral landmark and tibial landmark along a defined axis of translation is calculated (de Rooster et al. 1998; Plesman et al. 2012). In the first description by de Rooster and van Bree, cranial-caudal laxity was best assessed by using the tibial plateau as the axis of translation, and the caudal margins of the femoral and tibial condyles. The distance from the caudal margin of the tibial condyles to a line passing tangential to the femoral condyles and perpendicular to the tibial plateau is measured on stressed and nonstressed radiographs, where the difference in the distance defines the amount of laxity. Laxity indices can also be made where the values are normalized to a particular femoral dimension. (A) * (B) Figure 18.1 Neutral (A) and compressed (B) lateral projection radiographs of a stifle with cruciate ligament rupture. Note the change in position of a vertical line (red dotted line) tangential to the caudal femoral condyles, relative to the caudal margin of the tibial plateau. The direction of change in position is also represented by the black arrows. Note also the distal position of the popliteal sesamoid (white arrow). Note the position of the intercondylar eminence (∗ ), which is adjacent to the cranial aspect of the femoral condyles on the compressed view. In a recent ex vivo study defining landmarks for measuring cranial tibial subluxation, the tibial intercondylar eminence and the caudal margin of the femoral intercondylar notch had the best repeatability (Plesman et al. 2012). Any of the described measurements are affected by radiographic positioning, where even minor obliquity of the projection will significantly alter the calculated alignment. Thus, it is imperative that perfect lateral projections of both the femur and tibia are obtained, regardless of the method used to calculate subluxation. This can be challenging for inexperienced operators in some cases for several reasons, VetBooks.ir Stress Imaging of the Stifle including the presence of moderate rotational stifle laxity and limb deformity. Furthermore, these measurements are sensitive to changes in stifle flexion angle because the femur ‘rolls’ caudally on the tibial plateau as the stifle flexes. Flexion angle must, therefore, be kept consistent between stressed and non-stressed views. Most techniques advocate using a flexion angle of 90◦ . In functional in vivo studies where subjects are imaged during activities (e.g., standing), it may not be possible to keep the flexion angle consistent between stressed and non-stressed views. This renders the techniques for quantifying subluxation described above inaccurate. An alternate method for quantifying alignment is available when flexion angle cannot be controlled, which involves simply measuring the direct distance between the proximal and distal attachment sites of the CrCL (Figure 18.2); increases in this distance under stress views are interpreted as being indicative of cranial tibial subluxation. The measurement is also unaffected by any change in tibial geometry due to tibial plateau leveling osteotomy. However, there is still a susceptibility to error associated with oblique projections. When stressed views are compared to non-stressed views, it is important to assess whether there is already cranial tibial subluxation present on the non-stressed image. As the detection of subluxation is pathognomonic for CR, performing an additional stress view is probably unnecessary. Furthermore, the magnitude of calculated subluxation will be lower if the difference in alignment between the two views is quantified, and it may thus be possible to get a false-negative result. One potentially helpful method of more objectively assessing for subluxation if cranial tibial subluxation is suspected in the non-stressed stifle is to compare femorotibial alignment to the contralateral stifle, provided that the contralateral stifle is normal. Tibial compression radiography With tibial compression radiography, the stressed views are obtained while performing the tibial compression test. With the dog in lateral recumbency, a standard lateral 129 Figure 18.2 Lateral projection radiograph showing the method by which the proximal and distal attachment sites of cranial cruciate ligament were defined. The proximal attachment was defined as the point on the cranioproximal margin of the femoral condyles immediately caudal to the roof of the intercondylar notch, and the distal attachment site was defined as the point at the cranial margin of the medial tibial condyle (doubleheaded arrow). radiographic view of the stifle is obtained with the stifle at 90◦ of flexion (neutral position). While maintaining the same stifle flexion angle, a second radiograph is performed with the tarsal joint being maximally flexed by hand (tibial compression position) (Figure 18.3). Noticeable cranial movement of the tibia relative to the distal femur between stressed and non-stressed views is considered indicative of CrCL rupture (see Figure 18.1). In a study using a subjective method of assessing for subluxation where the positions of the caudal femoral condyle relative to the tibial plateau were determined, the test was found to have 97% sensitivity and 100% specificity for detection of CR (de Rooster et al. 1998). Clinical Features VetBooks.ir 130 (A) Figure 18.3 Paired lateral radiographs (neutral and tibial compression) are obtained using positioning illustrated by the drawings. A standard lateral radiographic view is obtained with the joint at 90◦ of flexion (neutral position; A). While maintaining the angle of flexion, the tarsal joint is maximally flexed by use of manual pressure, and a second radiograph is obtained (tibial compression position, B). Source: Reproduced from de Rooster et al. 1998, with permission from the British Veterinary Association. (B) Evidence for the ability of tibial compression radiography to diagnose partial CR is conflicting. It has been suggested that performing the tibial compression test at 90◦ of flexion will be able to induce abnormal cranial tibial translation even in those cases with partial CrCL rupture, because the cranio-medial band is typically damaged and the intact caudo-lateral band is lax in flexion. In a clinical study where the change in femoro-tibial alignment between stressed and non-stressed views was quantified, significant differences in relative femoro-tibial displacement were found between normal stifles, stifles with partial CR, and stifles with complete CR (de Rooster & van Bree 1999c). In a more recent investigation, greater cranial tibial translation was also identified in palpably stable stifles with mild CrCL fiber disruption when compared to a control group (Zatloukal et al. 2000). However, an upper limit of normal laxity has not yet been defined. Indeed, a surprisingly wide range of laxity has been found for joints with completely intact CrCLs. Results of another clinical study corroborate that there is a ‘gray-zone’ of laxity that includes both normal and diseased stifles. Furthermore, differences in the degree of fiber damage to the CrCL and medial meniscus cannot be deduced from the amount of relative displacement (de Rooster & van Bree 1999c). The inability to distinguish normal laxity from subtly abnormal laxity is arguably one of the major reasons why this test has not become more widely adopted in the clinical setting. In stifles with obvious instability, tibial compression radiography is not required as drawer motion will be detected on examination. In palpably stable stifles affected by CR, the presence of stifle effusion on radiographs and orthopaedic examination are typically accurate indicators of disease, especially when appropriate efforts to rule out other diseases (e.g., immune-mediated arthritis and osteochondritis dissecans) have been performed. Thus, tibial compression radiography is typically considered as a supplemental diagnostic test, rather than a necessary one. Another limitation is radiation exposure of the handler (ionizing radiation regulations in certain countries may preclude the use of this test). Modifications of the technique where devices are used to induce tibial compression have been suggested, but not well described or validated. Stress devices Several devices for conducting stress radiography have been described. One such device was developed with the aim of precisely quantifying cranio-caudal tibial translation through the controlled application of a cranially (or caudally) directed force on the crus, while keeping the thigh region stationary (Lopez et al. VetBooks.ir Stress Imaging of the Stifle 2004). The device consisted of a radiolucent platform where the thigh and crus regions are constrained by adjustable fiberglass stays and straps. Cranially or caudally directed forces can be applied onto the mobile tibial component of the device. In an experimental study, the observed laxity on stress radiographs using the device was significantly different between stifles with intact CrCL, partially ruptured CrCL, and completely transected CrCL. The main advantages of the device include the ability to more precisely control stifle flexion angle, and consistent delivery of a known force. The device has been used in several studies to help assess the performance of novel stabilizing techniques in experimental dogs. Whereas the type of force applied by the aforementioned device applies a cranial drawer force, a more recently described device aims to induce tibial compression by positioning the limb onto a radiolucent frame and a series of adjustable pegs (Bhandal et al. 2008). The use of such a device eliminates the need for a handler to be exposed to radiation during tibial compression radiography. Unfortunately, these devices are not widely or commercially available as they lack any obvious clinical utility. Standing radiography Unlike in humans, the forces generated during standing alone are enough to consistently induce substantial tibial translation in CrCLdeficient dogs (Kim et al. 2011; Kim et al. 2012). Thus, imaging of the stifle during standing can be considered as another form of stress imaging. A horizontally aligned radiographic beam is centered over the stifle using a mobile X-ray unit, with the cassette placed between the dog’s pelvic limbs. The dog is gently restrained to limit motion and promote a comfortable posture as the image is acquired (Figure 18.4). Horizontal beam radiography has been used to quantify subluxation during standing before and after various surgical procedures. The main advantage of standing radiography is that subluxation is caused by intrinsic forces occurring naturally rather than by an externally applied force. This means that the abnormal alignment observed with standing radiography gives direct insight into the degree of in vivo 131 Figure 18.4 Photograph of the set-up used to acquire a horizontal beam radiographic view of the stifle. A horizontally aligned radiographic beam is centered over the stifle using a mobile X-ray unit, with the cassette or panel placed between the dog’s pelvic limbs. The dog is gently restrained to limit motion and promote a comfortable posture as the image is acquired. dysfunction. One previous study used standing radiography to show that persistent subluxation occurs in a subset of cases after stabilization with tibial plateau leveling osteotomy (Kim et al. 2012) and tibial tuberosity advancement (Skinner et al. 2013). The technique is labor-intensive, and generally requires a handler to restrain the dog where there is radiation exposure. The flexion angle cannot be controlled. Therefore, alternative measures of subluxation such as quantifying the distance between the proximal and distal attachment sites of the CrCL may be required to compare cranio-caudal alignment between different time points or views. This technique may also be especially prone to errors caused by oblique projections because the axial rotational position of the stifle may be variable. Stress-MRI Recently, a stress-MRI technique was described in an ex vivo study where a custom-made Clinical Features VetBooks.ir 132 a b in both the lateral and medial compartments could be quantified (Figure 18.5) (Tremolada et al. 2014). The magnitude of cranial tibial translation was shown to be greater in the lateral compartment. The main goal of the study was to demonstrate the feasibility of a stress-MRI technique to potentially improve the ability to identify meniscal tears using advanced imaging. While stress-MRI of the knee is a useful clinical test for assessing menisci in humans, further studies are required to determine if the technique has a superior diagnostic accuracy to standard MRI for characterizing meniscal pathology in dogs. Conclusions (A) a b In summary, stress imaging techniques aiming to induce cranial tibial subluxation in joints with suspected CR are well described. They have potential clinical utility, as the ability to detect instability with stress radiography is superior to physical maneuvers such as the cranial drawer test. Thus, stress imaging may be particularly valuable for clinicians with less experience and confidence with stifle palpation alone. Stress imaging is also a useful tool for providing an ability to assess stifle stability in both clinical and experimental studies. References (B) Figure 18.5 Positional changes of lateral (A) and medial (B) femoral condyles in a cranial cruciate ligament-deficient stifle using stress-MRI. The superimposed outlines of the caudal femoral condyle (solid line = neutral; dotted line = stressed) demonstrate that stress-MRI is able to induce femorotibial subluxation. Source: Tremolada et al. 2014. Reproduced with permission from the American Veterinary Medical Association. MRI-compatible jig was used for either the tibial compression test or the cranial drawer test. Both methods were equally effective in causing cranial tibial subluxation in CrCL-deficient stifles. With cross-sectional imaging, translation Bhandal J, Kuzma A, Schiller T, et al. Application of a tibial compression device to diagnose partial or complete rupture of the cranial cruciate ligament in 129 dogs. Proceedings of the Veterinary Orthopaedic Society Annual Meeting, 2008, p. 65. Carobbi B, Ness MG. Preliminary study evaluating tests used to diagnose canine cruciate ligament failure. J Small Anim Pract 2009;50:224–226. de Rooster H, van Bree H. Use of compression stress radiography for the detection of partial tears of the canine cranial cruciate ligament. J Small Anim Pract 1999a;40:573–576. de Rooster H, van Bree H. Popliteal sesamoid displacement associated with cruciate rupture in the dog. J Small Anim Pract 1999b;40:316–318. de Rooster H, van Bree H. Radiographic measurement of craniocaudal instability in stifle joints of clinically normal dogs and dogs with injury of a cranial cruciate ligament. Am J Vet Res 1999c;60: 1567–1570. VetBooks.ir Stress Imaging of the Stifle de Rooster H, Van Ryssen B, van Bree H. Diagnosis of cranial cruciate ligament injuries in dogs by tibial compression radiography. Vet Rec 1998;142:366– 368. Flo GL, DeYoung D. Meniscal injuries and medial meniscectomy in the canine stifle. J Am Anim Hosp Assoc 1978;14:683–689. Henderson RA, Milton JL. The tibial compression mechanism: a diagnostic aid in stifle injuries. J Am Anim Hosp Assoc 1978;14:474–479. Kim SE, Lewis DD, Pozzi A, et al. Radiographic quantitative assessment of cranial tibial subluxation before and after tibial plateau leveling osteotomy in dogs. Am J Vet Res 2011;72:410–416. Kim SE, Lewis DD, Pozzi A. Effect of tibial plateau leveling osteotomy on femorotibial subluxation: in vivo analysis during standing. Vet Surg 2012;41: 465–470. Lopez MJ, Hagquist W, Jeffrey SL, et al. Instrumented measurement of in vivo anterior-posterior translation in the canine knee to assess anterior 133 cruciate integrity. J Orthop Res 2004;22:949– 954. Muir P. Physical examination of lame dogs. Compend Cont Ed Pract Vet 1997;19:1149–1161. Plesman R, Sharma A, Gilbert P, et al. Radiographic landmarks for measurement of cranial tibial subluxation in the canine cruciate ligament deficient stifle. Vet Comp Orthop Traumatol 2012;25:478– 487. Skinner OT, Kim SE, Lewis DD, et al. In vivo femorotibial subluxation during weight-bearing and clinical outcome following tibial tuberosity advancement for cranial cruciate ligament insufficiency in dogs. Vet J 2013;196:86–91. Tremolada G, Winter MD, Kim SE, et al. Validation of stress magnetic resonance imaging of the canine stifle joint with and without an intact cranial cruciate ligament. Am J Vet Res 2014;75:41–47. Zatloukal J, Necas A, Dvorak M. Measuring craniocaudal instability in stifle joints of dogs using stress radiographs. Acta Vet Brno 2000;69:311–317. VetBooks.ir VetBooks.ir 19 Stifle Ultrasonography Cristi R. Cook The normal stifle joint Canine stifle joint disorders have been frequently diagnosed based on physical examination findings, radiographs, and arthrography (Reed et al. 1995; Kramer et al. 1999; Soler et al. 2007). More recently, ultrasonography, computed tomography and magnetic resonance imaging have been used to further evaluate the stifle joint (Gnudi & Bertoni 2001; Samii & Long 2002; Soler et al. 2007). Musculoskeletal ultrasound is commonly performed in humans. Canine stifle ultrasound has become a more common diagnostic modality to evaluate the intra-articular structures of the stifle joint over the last decade (Kramer et al. 1999; Gnudi & Bertoni 2001; Samii & Long 2002; Soler et al. 2007; Arnault et al. 2009; Mattoon & Nyland 2015; Cook 2016). Notably, it is useful in evaluating the intra-articular soft tissues and the supporting extra-articular structures. Stifle ultrasound examination is best performed using a 10–18 MHz high-resolution, linear transducer (Kramer et al. 1999). To minimize any artifacts, the hair along the stifle joint should be clipped and ultrasound coupling gel applied to the skin surface. The linear transducer is most appropriate for imaging superficial structures with high detail while minimizing the artifacts from anisotropy; the latter occurs when the fibers of the tendon or ligament are not perpendicular to the ultrasound beam (Figure 19.1A,B). Off-angle artifact, or anisotropy, appears as a hypoechoic area within the tendon or ligament, but when the same structure is oriented perpendicular to the ultrasound beam the fibers will reappear (Reed et al. 1995; Kramer et al. 1999). It is important to look at potential lesions in both the longitudinal and transverse planes to confirm the lesion is real or artifact, while making sure the transducer face is perpendicular to the structure of interest (Reef et al. 1998; O’Connor & Grainger 2005). The cranial joint space is imaged with the transducer interface along the patellar tendon. The patellar tendon is seen in both transverse and sagittal planes as a superficial structure with low to moderate echogenicity and linear hyperechoic interstitial fibers (Reed et al. 1995; Kramer et al. 1999; Soler et al. 2007). In the transverse imaging plane, the patellar tendon is ovoid with hyperechoic, pinpoint foci representing the interstitial fibers. The peritendinous tissue should be a thin, hyperechoic line (Kramer et al. 1999; Soler et al. 2007) (Figure 19.2). Deep to the patellar tendon is the infra-patellar fat pad, which is hypoechoic to Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 135 Clinical Features VetBooks.ir 136 (A) (B) Figure 19.1 Normal tendon anisotropy. (A) The tendon fibers ‘drop out’ when the ultrasound beam is not parallel to the tendon fibers. (B) The tendon fibers reappear when the beam is parallel. FP F T Figure 19.2 Normal cranial joint space of the stifle. The synovium is the very thin, hyperechoic line just cranial to the tibial cortex. F, femur; T, tibia; FP, fat pad. the patellar tendon and has a coarser echotexture in comparison to the tendon (Reed et al. 1995; Kramer et al. 1999; Soler et al. 2007). The collateral ligaments are similar in appearance, although smaller, to the patellar tendon in their echogenicity and echotexture; this is in contradiction to other reports which state they are not visible, and is likely due to the advancements in technology and increasing resolution capabilities (Kramer et al. 1999; Samii & Long 2002; Soler et al. 2007). The medial collateral ligament is seen along the medial joint surface, at the most distal curve of the femoral condyle. The lateral collateral ligament can be identified along the lateral joint, caudal to the long digital extensor tendon (LDE) with the tibial attachment angling caudodistally toward the fibular head (Vasseur & Arnoczky 1981). The LDE tendon is seen along the craniolateral joint space superficial to the lateral meniscus and cranial to the lateral collateral ligament. The thickness of the LDE tendon will increase as the transducer is moved distally, toward the musculotendinous junction (Reed 1995). The stifle ligaments, in general, should maintain a constant width. The femoral condyles and tibial plateau are defined as hyperechoic lines with clean distal acoustic shadowing. The cartilage is a very thin, hypoechoic line, superficial to the hyperechoic cortical bone. Deep intra-articular structures are the most difficult ligaments of the stifle joint to examine. The cranial cruciate ligament (CrCL) at its tibial attachment is best imaged from the cranial skin surface in the sagittal plane with the joint positioned in full flexion. In large dogs, the CrCL can be seen in full extension, but in small dogs the intercondylar space is too narrow, hindering visibility (Kramer et al. 1999). The CrCL appears as a hypoechoic structure compared to the patellar tendon. It is lined by the echogenic fat of the infra-patellar fat pad and synovium, which is a discrete, thin, hyperechoic line deep to the infra-patellar fat pad. The CrCL becomes hyperechoic when the transducer is perpendicular to the ligament fibers (Gnudi & Bertoni 2001; Seong et al. 2005) (Figure 19.3). In one study, the hyperechoic fibers became hypoechoic when the transducer was angled 3◦ off from the proper perpendicular orientation (i.e., drop-out or off-angle artifact) (Reed et al. 1995; O’Connor & Graninger 2005). 137 VetBooks.ir Stifle Ultrasonography Figure 19.3 Zoomed image of the normal cranial cruciate ligament in the full flexion technique with proximolateral-distomedial rotation of the transducer. The normal longitudinal fiber pattern is identified (arrows). F, femur; T, tibia. Improved viewing of the CrCL in the longitudinal axis has been shown with maximum flexion of the stifle and rotation of the ultrasound probe in a proximolateral to distomedial direction (Nayseh et al. 2015) (Figure 19.4). This allows more of the ligament to be imaged and allows an improved alignment (anisotropy) of the ligament fibers. This would also improve the likelihood of identifying subtler interstitial tears of the ligament. The caudal cruciate ligament (CaCL) is not easily visible with any cranial imaging technique due to the large muscle mass along the caudal joint (Kramer et al. 1999). The femoral attachment of the CaCL has been imaged in multiple studies with the use of Figure 19.5 Normal meniscus. Note the abaxial surface of the meniscus positioned along the femoral and tibial cortical margins (arrows). The asterisks outline the normal medial meniscus. F, femur; T, tibia. a water bath, with the stifle in extension or full flexion (Reed et al. 1995; Gnudi & Bertoni 2001; Samii & Long 2002; Seong et al. 2005). The medial and lateral menisci are best seen on sagittal plane images. Each appears as a triangular, echogenic structure that is fairly homogeneous (Reed et al. 1995; Kramer et al. 1999; Soler et al. 2007). The apex of the triangle points axially, conforming to the femoral condyle and tibial plateau (Figure 19.5). The cranial, central, and caudal regions of the medial meniscus are visible, whereas the different sections of the lateral meniscus are more difficult to identify routinely and are dependent on the individual patient. The different sections of the menisci are based on their location to the collateral ligaments (i.e., the cranial horn of the meniscus is found cranial to the collateral ligament; the caudal horn, caudal to the ligament and the central region, adjacent to the collateral ligament). Normally, there is a thin fluid line between the meniscal and osseous surfaces. The abnormal stifle joint Figure 19.4 Normal image of the cranial cruciate ligament (arrows) attachment along the tibial cortex (arrowheads). The most common abnormality of the stifle joint is cruciate ligament rupture (CR). In acute cases, the joint effusion can be mild to severe and potentially have echogenic fluid if there is a significant hemarthrosis with imaging in the early phase of the rupture. The rupture of the ligament may be identified if it is near the tibial attachment, and may not be visible if it is Clinical Features VetBooks.ir 138 F (A) T (B) Figure 19.6 (A) Hyperechoic, irregular tissue between the arrowheads is associated with synovial thickening. (B) Irregular cortex of the tibia consistent with osteophyte formation (arrows). F, femur; T, tibia. closer to the midsection or femoral attachment. In chronic CR cases, the ultrasonographic features seen are synovial hypertrophy, minimal effusion, unless complicated by a meniscal tear, and an irregular bone surface due to osteophyte formation (Figure 19.6A,B). In chronic cases, an irregular and thickened CrCL may be seen with retraction of the ends at the site of the tear (Figure 19.7). Occasionally, interstitial tears of the CrCL (i.e., intact epiligament with internal fibers disrupted) can be identified (Figure 19.8). Meniscal tears are a common primary injury in the human knee, but rarely occur as a primary Figure 19.7 Irregular cranial cruciate ligament with irregular ends (arrow) consistent with a complete rupture. T, tibia. stifle injury in dogs and are usually secondary to CR. The occurrence of secondary meniscal tears varies between studies, ranging from 10% to 77% (Mahn et al. 2005; Thieman et al. 2006; Hayes et al. 2010). The risk of medial meniscal tears increases 12.9-fold with complete CR (Hayes et al. 2010). There is an approximately 6% tear rate after surgical stabilization of the stifle (Thieman et al. 2006) The ultrasonographic findings associated with meniscal tears have been previously reported as: (i) abnormal shape of the meniscus; (ii) increased fluid adjacent to the meniscus; (iii) change in the echogenicity of the meniscus; and (iv) displacement of the meniscus. The most common abnormal appearance for a meniscal tear is the flattening of the tibial side Figure 19.8 Thickened and irregular cranial cruciate ligament (arrowheads) with synovial hypertrophy and fluid accumulation along the femoral trochlear notch consistent with partial cruciate ligament rupture and retraction of the ruptured fibers. F, femur; T, tibia. 139 VetBooks.ir Stifle Ultrasonography Figure 19.11 Bucket-handle tear of the medial meniscus. Note the abaxial displacement of the abaxial margin of the medial meniscus (arrows). F, femur; T, tibia. Figure 19.9 Meniscal tear. There is flattening of the tibial side of the meniscus with adjacent fluid (arrow). of the meniscus (Figure 19.9) (Mahn et al. 2005). Occasionally, axial splitting of the meniscus is identified in some patients with radial tears. Small radial tears or fraying of the meniscal edges may be too small to see specific changes with ultrasound, but other characteristics of meniscal tears are usually present. The complex meniscal tears and the macerated meniscus are usually seen as an irregular, hyperechoic mass of tissue with no specific shape (Figure 19.10). Fluid accumulation is often seen adjacent to the meniscal tear, and may be the only visible fluid within the joint. The normal meniscal echogenicity is relatively hyperechoic to the surrounding muscles with a fine echotexture. Figure 19.10 Macerated meniscus. The meniscal tissue has a mottled appearance with an abnormal shape (arrowhead). F, femur; T, tibia. In the presence of a meniscal tear, the meniscus may appear hypoechoic or mottled (Kramer et al. 1999). Occasionally, there may be a hyperechoic appearance adjacent to the tibial side of the meniscus. This has been confirmed with arthroscopy as hypertrophied synovium along the meniscus. Meniscal displacement may be the most difficult feature to evaluate. There is a faint, hyperechoic line between the medial meniscus and the joint capsule that is used as a reference for the meniscal position. Normally, this line is adjacent to the surface of the femoral and tibial cortices (see Figure 19.5) (Mahn et al. 2005). Caution should be used if there are large osteophytes adjacent to the joint, as the meniscus can appear falsely displaced (abaxially). With further evaluation, the osteophytes are the cause of the apparent displacement. Abaxial displacement has been associated with a displaced bucket-handle tear, following confirmation with arthroscopic evaluation (Figure 19.11). Patellar tendon abnormalities are most commonly associated with rupture (incomplete or complete) or tendonitis associated with a previous surgical treatment. In acute patellar tendon injuries, it will appear hypoechoic and thickened when compared to normal (Kramer et al. 1999). The fibers may be visible, but not parallel; disrupted with a distinct peritenon; disrupted fibers and peritenon; or complete rupture of the tendon and peritendon (Figure 19.12). Chronic patellar tendon injuries appear hyperechoic, focally narrowed, with or without dystrophic mineralization within the tendon or enthesophytes at the tibial crest. Clinical Features VetBooks.ir 140 Figure 19.12 Thickening of the distal patellar tendon with irregular margins to the tendon (arrow) and an interstitial tear (arrowhead) consistent with partial rupture, secondary to a K-wire inserted through the distal tendon during a surgical repair. Conclusions Ultrasound in general is cost-effective and readily available. However, interest and training in musculoskeletal ultrasound is much less common. An experienced musculoskeletal ultrasonographer is important to thoroughly evaluate the joint and make a knowledgeable interpretation and diagnosis that corresponds to the clinical history and examination. A thorough knowledge of the anatomy of the joint or structures is important, as well as the normal and abnormal ultrasonographic appearance of these structure. When learning the ultrasonographic appearance of a new musculoskeletal area, one is encouraged to evaluate the contralateral limb or image a normal patient for comparison. References Arnault F, Cauvin E, Viguier E, et al. Diagnostic value of ultrasonography to assess stifle lesions in dogs after cranial cruciate ligament rupture: 13 cases. Vet Comp Orthop Traumatol 2009;22:479–485. Cook CR. Ultrasound imaging of the musculoskeletal system. Vet Clin North Am Small Anim Pract 2016;46:355–371. Gnudi G, Bertoni G. Echography examination of the stifle joint affected by cranial cruciate ligament rupture in the dog. Vet Radiol Ultrasound 2001;42:266– 270. Hayes GM, Langley-Hobbs SJ, Jeffery ND. Risk factors for medial meniscal injury in association with cranial cruciate ligament rupture. J Small Anim Pract 2010;51:630–634. Kramer M, Stengel H, Gerwing M, et al. Sonography of the canine stifle. Vet Radiol Ultrasound 1999;40:282–293. Mahn MM, Cook JL, Cook CR, et al. Arthroscopic verification of ultrasonographic diagnosis of meniscal pathology in dogs. Vet Surg 2005;34:318–323. Mattoon JS, Nyland TG. Fundamentals of diagnostic ultrasound. In: Small Animal Diagnostic Ultrasound, Mattoon JS, Nyland TG, eds. Third edition. St Louis MO, Elsevier. 2015, pp. 1–49. Nayseh N, Kramer M, Ondreka N. Ultrasonographic examination of the stifle joint in the dog. Part 1: Ultrasonographic anatomy, standardized scanning protocol and common indications. Tierärztl Prax 2015;43:120–129. O’Connor PJ, Grainger AJ. Ultrasound imaging of joint disease. In: Practical Musculoskeletal Ultrasound, McNally EG, ed. First edition. Philadelphia PA, Elsevier. 2005, pp. 245–262. Reed AL, Payne JT, Constantinescu GM. Ultrasonography anatomy of the normal canine stifle. Vet Radiol Ultrasound 1995;36:315–321. Reef VB, Sertich PL, Turner RM. Musculoskeletal ultrasonography. In: Equine Diagnostic Ultrasound, Reef VB, Sertich PL, Turner RM, eds. Philadelphia PA, WB Saunders. 1998, pp. 39–186. Samii VF, Long CD. Musculoskeletal system. In: Small Animal Diagnostic Ultrasound, Nyland TG, Mattoon JS eds. Second edition. Philadelphia PA, WB Saunders, 2002, pp. 267–284. Seong Y, Eom K, Lee H, et al. Ultrasonographic evaluation of cranial cruciate ligament rupture via dynamic intra-articular saline injection. Vet Radiol Ultrasound 2005;46:80–82. Soler M, Murciano J, Latorre R, et al. Ultrasonographic, computed tomographic and magnetic resonance imaging anatomy of the normal canine stifle joint. Vet J 2007;174:351–361. Thieman KM, Tomlinson JL, Fox DB, et al. Effect of meniscal release on rate of subsequent meniscal tears and owner-assessed outcome in dogs with cruciate disease treated with tibial plateau leveling osteotomy. Vet Surg 2006;35:705–710. Vasseur PB, Arnoczky SP. Collateral ligaments of the canine stifle joint: anatomic and functional analysis. Am J Vet Res 1981;42:1133–1137. VetBooks.ir 20 Computed Tomography (CT) of the Stifle Ingrid Gielen and Henri van Bree Introduction In dogs, the stifle is a frequently injured joint. Ligamentous and meniscal damage are common and are associated with secondary degenerative changes (Vasseur 1993; Johnson et al. 1994). The diagnosis of stifle joint disorders is generally based on a history of lameness, physical examination, and radiography. For decades, radiography has been the most often-used medical imaging technique to diagnose stifle disorders and has been proven very useful in its clinical work-up (Marino & Loughin 2010). A stress radiographic technique, based on the clinical tibial compression test, has been introduced in an attempt to improve the diagnostic accuracy of clinical evaluation of craniocaudal instability. It is a valuable asset in the diagnosis of canine stifle instability due to cruciate ligament rupture (CR). It is a useful technique to prove (or disprove) a tentative diagnosis of CR, especially when there is a lack of cranial drawer sign on clinical examination, and is able to detect complete or partial CR (de Rooster et al. 1998; de Rooster & van Bree 1999). In contrast to radiography, where there is summation of the overlying structures, cross-sectional imaging such as computed tomography (CT) allows examination of the internal joint structures without superimposition. CT has proven to be extremely sensitive in demonstrating calcified or bony structures, and also allows demonstration of the soft tissues when the correct windowing has been applied (Soler et al. 2007). Indications for using CT These include: r r r r r r Developmental disorders: Osteochondrosis (OC)/osteochondritis dissecans (OCD), medial or lateral patellar subluxation or luxation. Traumatic: fractures of the tibial plateau, femoral condylar fracture, fracture of the patella, muscular hematoma, collateral ligament lesion, patellar tendon lesion, gastrocnemius avulsion, avulsion fractures of intraarticular ligaments including the CrCL and the caudal cruciate ligament (CaCL), the popliteus, the extensor digitorum longus. Degenerative: CR, osteoarthritis, enthesiopathies. Neoplastic: including synovial cell sarcoma, osteosarcoma, lipoma. Infection. Miscellaneous: including subchondral bone cysts. Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 141 Clinical Features VetBooks.ir 142 Figure 20.1 Positioning of a dog for stifle CT scanning: ventral recumbency with both stifles extended and scanned simultaneously. Technical aspects Positioning Under general anesthesia, the dogs are scanned in ventral recumbency with both stifles extended and scanned simultaneously. Care should be taken to position them symmetrically (Figure 20.1). Figure 20.2 Scout view of a stifle CT scan: transversal scans are made parallel to the joint space. The slice thickness varies between 1 mm in the joint space and 2 mm at the level of the distal femur and proximal tibia. Sagittal and dorsal reconstructions are made afterwards. The images are displayed by adjusting window width (WW) and window level (WL) and read in both a bone window (WW 3500; WL 500) and a soft-tissue window (WW 400; WL 65). Technical parameters The use of contrast medium With single-slice CT, the X-ray beam is angled parallel to the surface of the tibial plateau; the scan range should cover the whole joint, from the proximal pouches from the distal third of the femur to the proximal fifth of the length of the tibia (Figure 20.2). Multi-slice CT with isotropic resolution allows scanning of the stifle without tilting the gantry; angulation and orientation are performed during post-processing procedures. In multi-slice CT the slice thickness should be as thin as possible, 1.25 mm or thinner, with a slice increment of 50%. In single-slice devices the suspected pathology dictates the thickness, which can vary between 2 and 3 mm. Settings should be 100–120 kV and 100–200 mA, depending on the animal’s weight and size. Intravenous (IV) administration of 2 ml of iodine contrast (400 mg iodine ml–1 ) medium per kilogram body weight should be used for any stifle problem involving soft tissues; images with contrast enhancement provide most information regarding the pathology. Intra-articular (IA) administration of a diluted non-ionic, low-osmolar-type contrast medium, such as iohexol, has been reported to help with distinguishing the cruciate ligaments, evaluating the menisci and the surface of the cartilage (Sungyoung Han et al. 2008) (Figure 20.3A,B). The use of computed tomographic arthrography (CTA) has been described (Samii 2004), and although the results for CTA in identifying simulated meniscal injury are 143 VetBooks.ir Computed Tomography (CT) of the Stifle (A) Figure 20.4 Sagittal reconstruction of a CT arthrogram of a dog after partial medial meniscectomy. The cranial pole is seen to be missing (black arrow), and the caudal pole seems to be crushed (white arrows). (B) Figure 20.3 (A) Sagittal reconstruction of a CT arthrogram of the stifle of a 4-month-old mongrel dog. The articular cartilage can be seen as a radiolucent line parallel to the subchondral bone (black arrows). The silhouette of the lateral meniscus can be appreciated as well (arrowheads). (B) Transverse CT arthrogram image where the silhouettes of the cranial and caudal cruciate ligaments can be appreciated. LFC, lateral femoral condyle; a, caudal cruciate ligament; b, cranial cruciate ligament; c, menisco-femoral ligament. encouraging (Tivers et al. 2008), some clinical studies performed in dogs have reported CTA in the detection of naturally occurring meniscal damage to be of limited value (Samii et al. 2009). Although gross meniscal lesions (Figures 20.4 and 20.5B) and cruciate ligament damage (Figure 20.5A) can be evaluated, the main problem with CTA is that in inflamed stifle joints the injected contrast medium is very rapidly absorbed and diluted, making accurate interpretation of possible lesions difficult. Mixing 0.2 mg epinephrine with conventional contrast agents in order to slow down any resorption should be used (De Rycke et al. 2015). For CTA, the normal iodine concentration should be reduced to 80–100 mg ml–1 to reduce the risk of contrast obscuring intra-articular structures. The original contrast medium can be diluted with saline, and for an average stifle joint a volume of 4 ml is recommended. Care should be taken to avoid the fat pad during the intraarticular injection of contrast. Repeated gentle flexion and extension of the joint should be performed to enhance contrast dispersion. CT features of different stifle conditions Developmental disorders OC/OCD: OCD lesions have typical features, being radiolucencies surrounded by a sclerotic rim (Olstad et al. 2014). More lesions can be detected by using CT, and more intra-articular fragments can also be seen (Figure 20.6). The status of the joint cartilage can be checked using CTA (Figure 20.7). In patella luxation the location of the patella can be checked, the depth of the patellar Clinical Features VetBooks.ir 144 (A) (B) Figure 20.5 Dorsal reconstructions of a CT arthrogram of a stifle (flexed 90◦ ) with a ruptured cranial cruciate ligament (A) and associated medial meniscal damage. In the region of the cranial cruciate ligament a small accumulation of contrast medium can be seen (white arrow) filling the empty space where normally the ligament is present. (B) The damaged meniscus is visible as a small filling defect within the joint space outlined by contrast medium (white arrow). (A) (B) Figure 20.6 (A) Radiograph and corresponding CT image of the distal femur showing an obvious OCD lesion in the lateral femoral condyle not visible on the radiograph. A small fragment can also be seen (white arrow). (B) The corresponding arthroscopic pictures of the OCD lesion and the floating fragment. VetBooks.ir Computed Tomography (CT) of the Stifle Figure 20.7 CT arthrogram of a 4-month-old dog with an osteochondrosis lesion in the area of the lateral femoral condyle. The contrast medium is outlining the thickened articular cartilage but no flap can be demonstrated (black and white arrowheads). (A) Figure 20.8 (A) Transverse CT images of the left and right stifle of a 13-month-old Chesapeake Bay Retriever with bilateral lateral patellar luxation. The trochlear groove of the femur is shallow and shows bony reaction in the area of the left lateral femoral condyle (white arrow). (B) Three-dimensional reconstruction of a lateral patella luxation in a 5-month-old Flat-Coated Retriever, showing the lateralized position of the patella and the tibial tuberosity (∗ ). (B) 145 Clinical Features VetBooks.ir 146 Figure 20.9 Transverse image of a fracture of the distal femur showing displacement of one of the fragments, but no involvement of the trochlear groove. groove can be evaluated, and by using threedimensional images the rotation (curvature) of the long bones can be appreciated (Figure 20.8A,B). Traumatic lesions In case of fractures, the number and size, the orientation, and possible involvement of the articular surface can be evaluated (Figure 20.9). With avulsion fractures, the origin of the involved tendons can be determined, which is not always possible on radiographs. CT is very useful for detection of avulsion fractures of the CrCL (Figure 20.10), the CaCL (Figure 20.11), the attachment of the m. extensor digitorum longus (Figure 20.12) (Fitch et al. 1997) and the m. popliteus (Figure 20.13). By using CTA, the status of these fragments can be evaluated for surgical decision-making (Figure 20.14). Degenerative changes By using CT, degenerative changes can be detected at an earlier stage than with radiography (Figure 20.15). Neoplastic disorders The extension of neoplastic processes can be better evaluated with CT than with radiography (Figure 20.16) (synovial cell sarcoma, primary bone tumor, lipoma). By using intravenous contrast, the soft-tissue component can be better evaluated. Biopsies can be performed under CT guidance (Figure 20.17). Infection In case of infection, the extension of the process can be better evaluated than with radiographs (Figure 20.18). Miscellaneous In case of subchondral bone cysts, the communication of the cyst with the joint cavity can be checked using CTA (Figure 20.19). Conclusions CT is useful in every case where the superimposition of bony structures needs to be avoided VetBooks.ir Computed Tomography (CT) of the Stifle 147 (A) (B) Figure 20.10 (A) Radiographs of a 5-month-old Golden Retriever with an avulsion of the attachment of the cranial cruciate ligament. On the caudo-cranial view subchondral sclerosis in the area of the medial part of the lateral femoral condyle can be appreciated (black arrowheads). (B) Corresponding transversal CT image, and sagittal and dorsal reconstructed images showing clearly the avulsed proximal attachment of the cranial cruciate ligament at the medial part of the lateral condyle with associated subchondral sclerosis (black arrowheads). (Vande Berg et al. 2002). CT is useful in detecting avulsions of the different intra-articular structures including the CrCL, the CaCL, the m. extensor digitorum longus, and the m. popliteus. The detection of a bony avulsion fragment is superior with CT, compared with other types of imaging. CTA helps in evaluating the status of these fragments. Plain CT images are not very useful in evaluating the integrity of the cruciate ligaments and VetBooks.ir 148 Clinical Features (A) (B) Figure 20.11 (A) Radiographs of a 6-month-old American Staffordshire Bull Terrier with an avulsion of the attachment of the caudal cruciate ligament. On the medio-lateral and caudo-cranial views, a fragment is visible (white arrows). On the caudo-cranial view an associated radiolucency in the medial area of the distal medial femoral condyle can also be appreciated. (B) Corresponding transverse, and sagittal and dorsal reconstructed CT images showing multiple fragments (white arrows) in the area of the proximal attachment of the caudal cruciate ligament in the medial area of the medial condyle. A prominent distension of the joint capsule is present (white arrowhead). 149 VetBooks.ir Computed Tomography (CT) of the Stifle (A) (B) Figure 20.12 (A) Radiographs of a 14-month-old Great Dane with an avulsion of the origin of the long digital extensor. On the medio-lateral and caudo-cranial views a radiodense shadow (white arrows) can be identified in the lateral aspect of the stifle, the origin of which is unclear. (B) Corresponding transverse, and sagittal and dorsal reconstructed CT images showing this opacity originating from the tendon of origin of the long digital extensor (white arrow). the menisci, but the use of CTA, if performed correctly, can help in decision-making. In some patients with stifle problems, a fragment or calcified structure can be detected on radiographs. CT helps to clarify the origin of such fragments, and is very useful for diagnosing avulsions of the CrCL in young dogs. Avulsion of the CrCL is rare and is thought to be a disease primarily of skeletally immature dogs. In these animals, ligamentous attachment to bone is stronger than the immature bone itself, allowing avulsion to occur under a force that is insufficient to cause actual rupture of the ligament. This diagnosis is clinically important as the avulsed fragment may be re-attached if large enough, and consequently the CrCL can be saved in these young dogs. Clinical Features VetBooks.ir 150 (A) (B) Figure 20.13 (A) Radiographs of an 8-month-old Rottweiler with an avulsion of the popliteus tendon. On the caudo-cranial view, a rounded opacity (white arrow) can be identified in the lateral part of the stifle. Its origin is unclear from these radiographs. (B) Corresponding transverse and dorsal reconstructed CT images showing this opacity originating from the tendon of origin of the popliteus muscle (white arrows). Figure 20.14 Transverse image of a CT arthrogram through the area of the avulsed attachment of the cranial cruciate ligament. The contrast study shows that the avulsion is not surrounded by contrast medium, meaning that there is still some fibrous attachment present and that the fragment is not completely detached (arrows). The silhouette of the involved cranial cruciate ligament can also be appreciated. VetBooks.ir Computed Tomography (CT) of the Stifle Figure 20.15 Radiograph and corresponding CT image of the distal part of the femur showing new bone formation and subchondral sclerosis in the area of the medial fabella (white arrows). These lesions are hardly visible on the radiograph. (A) Figure 20.16 (A) Radiographs of a 6-year-old Bernese Mountain Dog with a synovial cell sarcoma. The radiographs show several radiolucencies in the subchondral bone (arrows). (B) Transverse images of the distal femur and proximal tibia clearly demonstrating the osteolysis caused by the tumor (arrows). One transverse image in a soft-tissue window after intravenous contrast administration shows enhancement of the severely swollen synovia (black arrowheads). These CT images better show the extent and severity of the neoplastic process. (C) Sagittal and dorsal reconstructed images giving a clear overview of the extent of the tumor. (B) 151 Clinical Features VetBooks.ir 152 (C) Figure 20.16 (A) (Continued) (B) Figure 20.17 (A) Transverse image of a primary bone tumor in the area of the proximal tibia. (B) CT guidance can be used to obtain a bone biopsy. The silhouette of the Jamshidi needle is clearly visible. 153 VetBooks.ir Computed Tomography (CT) of the Stifle (A) (B) Figure 20.18 Transverse images in soft-tissue window of the distal femur (A) and proximal tibia (B) of an infected stifle joint. The application of intravenous contrast delineates the capsule of different abscesses containing pus (white arrows). (B) (A) (C) Figure 20.19 (A) Transverse and (B) dorsal reconstruction of a bone cyst in the distal lateral femoral condyle. (C) A CT arthrogram demonstrates that there is no communication between the cyst and the joint space. VetBooks.ir 154 Clinical Features References De Rycke L, van Bree H, Van Caelenberg A, et al. Epinephrine-enhanced computed tomographic arthrography of the canine shoulder. Res Vet Sci 2015;102:15–21. de Rooster H, Van Ryssen B, van Bree H. Diagnosis of cranial cruciate ligament injuries in dogs by tibial compression radiography. Vet Rec 1998;142:366– 368. de Rooster H, van Bree H. Use of compression stress radiography for the detection of partial tears of the canine cranial cruciate ligament. J Small Anim Pract 1999:40;573–576. Fitch RB, Wilson ER, Hathcock JT, et al. Radiographic, computed tomographic and magnetic resonance imaging evaluation of a chronic long digital extensor tendon avulsion in a dog. Vet Radiol Ultrasound 1997;38:177–181. Johnson JA, Austin C, Breur GJ. Incidence of canine appendicular musculoskeletal disorders in 16 veterinary teaching hospitals from 1980 through 1989. Vet Comp Orthop Traumatol 1994;7:56–69. Marino DJ, Loughin CA. Diagnostic imaging of the canine stifle: a review. Vet Surg 2010;39:284–295. Olstad KL, Kongsro J, Grindflek E, et al. Ossification defects detected in CT scans represent early osteochondrosis in the distal femur of piglets. J Orthop Res 2014;32:1014–1023. Samii VF. Computed tomographic arthrography of the normal canine stifle. Vet Radiol Ultrasound 2004;45:402–406. Samii VF, Pozzi A, Drost WT, et al. Computed tomographic arthrography of the stifle for detection of cranial and caudal cruciate ligament and meniscal tears in dogs. Vet Radiol Ultrasound 2009;50:144– 150. Soler M, Murciano J, Latorre R, et al. Ultrasonographic, computed tomographic and magnetic resonance imaging anatomy of the normal canine stifle joint. Vet J 2007;174:351–361. Sungyoung Han, Haengbok Cheon, Hangmyo Cho, et al. Evaluation of partial cranial cruciate ligament rupture with positive contrast computed tomographic arthrography in dogs. J Vet Sci 2008;9:395– 400. Tivers MS, Mahoney P, Corr SA. Canine stifle positive contrast computed tomography arthrography for assessment of caudal horn meniscal injury: a cadaver study. Vet Surg 2008;37:269– 277. Vande Berg BC, Lecouvet FE, Poilvache P, et al. Spiral CT arthrography of the knee: technique and value in the assessment of internal derangement of the knee. Euro Radiol 2002;12:1800–1810. Vasseur P. Stifle joint. In: Textbook of Small Animal Surgery, Slatter D, ed. Second edition. Philadelphia PA, WB Saunders. 1993, pp. 1817–1865. VetBooks.ir 21 Magnetic Resonance Imaging of the Stifle Peter V. Scrivani Introduction and image acquisition Joints limit motion between bones to a particular range, and also dissipate stress during use (Dyce et al. 2002). The ability to perform these functions is based on the type of joint (synovial, cartilaginous, fibrous), bone conformation, and supporting soft tissues (Dyce et al. 2002). Therefore, a loss of function is manifested as excessive motion, restricted motion, or pain. In dogs the most common cause of joint dysfunction is osteoarthritis, a chronic degenerative disease of the articular cartilage and underlying bone that results from a combination of genetic and environmental factors. Other common arthropathies are due to inflammatory, traumatic, or neoplastic causes. Relative to this information and to the stifle joint in particular, the aims of magnetic resonance imaging (MRI) are: (i) to provide an early diagnosis of osteoarthritis; (ii) to provide a more specific diagnosis of the arthropathy; (iii) to guide therapy decisions; (iv) to offer a more detailed prognosis; and (v) to assess any response to treatment. MRI is apt to improve patient care and help achieve one of these goals. The beneficial impact of musculoskeletal MRI in humans is undisputed. However, only minimal evidence is yet available in veterinary medicine that MRI actually improves patient care relative to the cost of the examination and additional anesthesia time. Even though MRI is considered accurate for diagnosing cruciate ligament rupture (CR) in dogs (Galindo-Zamora et al. 2013), competing diagnostic modalities, such as radiography, ultrasonography, or arthroscopy, offer additional benefits such as guiding therapy without the need for anesthesia or providing the ability to treat an underlying problem during the same procedure. However, MRI has shown much promise and may have advantages in the early detection of lesions in the cranial cruciate ligament (CrCL), subchondral bone, articular cartilage or menisci, or for establishing the cause of lameness that has not been diagnosed by conventional methods. As such, MRI is being used more frequently to examine the stifle joint in dogs. The anatomy of the stifle joint has been described previously (Pujol et al. 2011). MRI recognition of joint lesions is based on alterations of signal intensity (SI) and morphologic changes (Rubin 2005). For subtle lesions, detecting these changes depends on acquiring images with high contrast and spatial resolution (Rubin 2005). It is difficult to make exact recommendations for optimal image acquisition because of different scanners (e.g., Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 155 VetBooks.ir 156 Clinical Features low-field, high-field), various manufacturer names for sequences, individual preferences, minimal evidence of efficacy of one protocol versus another, various breed conformations, and coils and algorithms that are optimized for humans. As a basic protocol, the joint should be examined using a local coil, preferably one that surrounds the joint, and the joint should be located in the magnetic isocenter. The degree of joint flexion may be dictated by coil configurations, but 90◦ flexion may improve imaging of the CrCL (Podadera et al. 2014). Proton density (PD) weighted fast spin–echo (SE) sequences should be obtained in the transverse, sagittal, and dorsal planes using a small fieldof-view centered on the area of interest and, importantly, a large matrix size. Additionally, a fat-suppressed PD-weighted sequence (e.g., short-tau inversion recovery or STIR) should be obtained in one, two, or three planes. For larger joints, a slice thickness of 3–4 mm should be used, but for smaller joints use 1–2 mm slices. Very thin slices (1 mm) may require a T2-weighted 3D gradient recall echo sequence. Additional sequences or planes may be of use in certain conditions. Intravenous or intraarticular contrast medium is not used routinely. Image orientation is accomplished by obtaining scout images in three planes. The dorsal plane is aligned parallel to the patellar tendon on the sagittal scout and parallel to the caudal aspect of the femoral condyles on the transverse scout. The transverse plane is made parallel to the distal aspect of the femoral condyles on the dorsal scout and perpendicular to the patellar tendon on the sagittal scout. The sagittal plane is made such that slices bisect the patellar tendon and intercondylar fossa of the femur on the transverse scout and parallel to the patellar tendon on the dorsal scout (Winegardner et al. 2007). High-quality images depend on the patient being still, which often requires anesthesia. Implants or metallic objects may reduce image quality (Banfield & Morrison 2000). This point may be moot when surgical implants or metal debris are far enough away from structures of interest, such as the cruciate ligaments or medial meniscus, to not interfere with interpretation (David et al. 2012a). Additionally, alterations to image acquisition parameters can reduce the severity of the susceptibility artifact to produce a diagnostic image (David et al. 2012b; Simpler et al. 2014). High-field scanners provide superior signal-to-noise ratio, but are not always available. Synovial structures Evaluation of synovial joints is one of the most important reasons for hospital visits relating to gait abnormality or lameness. Synovial joints consist of a fibrous joint capsule, synovial membrane, fluid-filled joint space, and articular cartilage (Dyce et al. 2002). The combination of the joint capsule and synovial membrane is seen as a low SI structure on MR images (Rubin 2005). The synovial membrane usually is too small to differentiate as a separate structure: it also lines joint recesses, bursas, and tendon sheaths. The normal synovial membrane does not enhance (or only minimally enhances) after intravenous contrast-medium administration (Rubin 2005). An inflamed synovial membrane is thick and may be nodular or mass-like, especially when chronic (Rubin 2005). When there is active inflammation the synovial membrane rapidly enhances with intravenous contrast-medium administration (Rubin 2005). Therefore, intravenous contrast-medium administration might be helpful when an inflammatory arthropathy (e.g., immune-mediated, infectious) is suspected. Joint effusion (Figure 21.1) that is due to increased synovial fluid production has similar signal characteristics as normal joint fluid. Joint fluid that contains proteinaceous debris or blood products has a decreased (darker) and variable SI (Rubin 2005). This different appearance may be referred to as ‘dirty’ versus ‘clean’ fluid. The appearance of normal articular cartilage reflects its chemical composition and threedimensional histological organization (Rubin 2005). For example, articular cartilage has a lowPD SI that progressively increases from deep-tosuperficial. Cartilage abnormalities appear as defects or SI changes in the smooth articular surface, which may extend to the subchondral bone plate. Traumatic articular lesions are often sharply demarcated (Rubin 2005). Meniscus Within the stifle joint, there are lateral and medial menisci, which are crescent-shaped VetBooks.ir Magnetic Resonance Imaging of the Stifle Figure 21.1 Sagittal (A) proton density MR image and sagittal (B) SE T2-weighted MR image of a 2-year-old, neutered female Mastiff with a complete rupture of the cranial cruciate ligament. There is increased fluid within the stifle joint. Compare the SI of the ‘clean’ (arrows) and ‘dirty’ synovial fluid (∗ ) on the two images. (A) fibrocartilaginous structures that partially divide the joint cavity and provide structural integrity during movement (Dyce et al. 2002). Each meniscus has unnamed cranial-tibial and caudal-tibial ligaments. The lateral meniscus also has an attachment to the femur, the meniscofemoral ligament. The transverse ligament connects the cranial-tibial ligaments of the two menisci. The normal MRI appearance of the meniscus is triangular or bow-tie shape (sagittal and dorsal planes) with uniform low SI, although some exceptions regarding SI exist (Martig et al. 2006). Meniscal tears are common in dogs secondary to CR: the medial meniscus is affected more commonly (Blond et al. 2008). Meniscal tears may be present at the time of CR diagnosis, or they may develop weeks to months after surgical treatment (Taylor-Brown et al. 2014). The MRI appearance of a meniscal tear is a primarily linear intrameniscal area of high SI that extends definitively to one or both articular surfaces, or abnormal meniscal shape (Figure 21.2) (Rubin 2005; Blond et al. 2008). Figure 21.2 Sagittal (A) SE T2-weighted MR image of a 2.5-year-old, neutered female Saint Bernard and (B) sagittal SE T2-weighted MR image of a 2.5-year-old, neutered female Rottweiler. Compare the normal appearance of the medial meniscus (A) to the abnormal (B). A full-thickness tear is present in the cranial part of the medial meniscus (arrow) and the caudal portion is absent (∗ ). (A) 157 (B) A grading system for describing meniscal injuries during MRI has been proposed in dogs, ranging from 0 (normal) to 4 (Martig et al. 2006). However, the reported accuracy of MRI signs for diagnosing meniscal tears has varied from poor to good (Blond et al. 2008; Böttcher et al. 2012; Galindo-Zamora et al. 2013). Falsepositive results for meniscal tears may be due to misinterpretation of the appearance of normal structures adjacent to the meniscus, or to artifact (Baird et al. 1998; Hashemi et al. 2004). A truncation artifact appears as alternating bright and dark bands at high-contrast interfaces such as the meniscus and synovial fluid (Figure 21.3) (Hashemi et al. 2004). It is due to an inability to approximate exactly a step-like change in the signal intensity due to a limited number of samples or sampling time, and usually occurs in the phase direction (Hashemi et al. 2004). It may be remedied by increasing the sample time to reduce the ripples, or by decreasing the pixel size by increasing the number of phase encodes or decreasing the field of view (Hashemi et al. 2004). (B) Clinical Features VetBooks.ir 158 (A) Figure 21.3 Sagittal (A) SE T2-weighted MR image of a 2-year-old, intact male Great Dane and (B) dorsal SE T1-weighted MR image of a 2.5-year-old, neutered female Rottweiler. Note the linear, high-SI band within the meniscus (arrows) that are parallel to the interface between meniscus and synovial fluid that does not extend to the articular surface. (B) Tendons, ligaments, and muscles Tendons, ligaments, and muscles of the stifle joint (Table 21.1; Figures 21.4–21.9), along with bone conformation, restrict movement primarily to a cranio-caudal plane with minimal rotation and slide. Tendons and ligaments normally appear as homogeneous, low-SI, sharply margined linear structures, and on cross-section are round, oval, or flat (Rubin 2005; Soler et al. 2007). However, the quadriceps tendon, in contrast to the patellar tendon, may normally have parallel hyperintense and hypointense linear striations due to a coarse fiber pattern. A higher SI may also be seen normally if muscle is interspersed with the fibers, or if the orientation of the fibers approaches 55◦ relative to the magnetic field (magic-angle artifact) (Spriet & McKnight 2009). During tendon degeneration or ligament sprain the structure may have an increased SI, an altered size (usually increased), irregular margins, or abnormal shape (Rubin 2005; Stahl et al. 2010). With an acute tendon or ligament tear, total discontinuity may be Table 21.1 Key for Figures 21.4–21.9. Anatomic structures 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Femur Patella Tibia Fibula Lateral collateral ligament Medial collateral ligament Meniscofemoral ligament Cranial cruciate ligament Caudal cruciate ligament Transverse ligament Quadriceps muscle a. Vastus lateralis muscle b. Vastus intermedius muscle c. Rectus femoris muscle d. Vastus medialis muscle e. Quadriceps tendon f. Patellar tendon Infrapatellar fat pad Sartorious muscle a. Cranial b. Caudal Biceps femoris muscle Abductor cruralis caudalis muscle 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. Semitendinous muscle Semimembranosus muscle Gracilis muscle Adductor muscle Aponeurosis of pectineus muscle Long digital extensor muscle a. Tendon Extensor hallucis longus muscle Fibularis longus muscle (formerly peroneus longus) Lateral digital extensor muscle Flexor hallucis longus muscle Popliteus muscle a. Tendon b. Sesamoid bone Cranial tibial muscle Caudal tibial muscle Long digital flexor muscle Gastrocnemius muscle a. Fabella (sesamoid bone) b. Lateral head c. Medial head Superficial digital flexor muscle VetBooks.ir Magnetic Resonance Imaging of the Stifle 11e Figure 21.4 Sagittal (A) proton density MR image of a 2-year-old, neutered female Chesapeake Bay Retriever and (B) dorsal SE T1-weighted MR image of a 2.5-year-old, neutered female Saint Bernard. The cranial aspect of the joint capsule and synovium (black arrow) is seen immediately caudal to the infrapatellar fat pad. For key to labels, see Table 21.1. 159 1 1 2 5 6 11f 30 12 4 3 3 (A) (B) 1 8 1 5 9 3 8 (A) 7 (B) Figure 21.5 Sagittal (A) SE T2-weighted MR image of a 10-year-old, neutered female Labrador Retriever and (B) transverse SE T1-weighted MR image of a 2.5-year-old, neutered female Saint Bernard. The proximal attachment of the cranial cruciate ligament is on the medial aspect of the lateral femoral condyle. The proximal attachments of the caudal cruciate and menisco-femoral ligaments are on the lateral aspect of the medial femoral condyle. The distal attachments of the cruciate ligaments are on the tibia. The distal attachment of the menisco-femoral ligament is on the lateral meniscus. For key to labels, see Table 21.1. extensor fossa 1 1 26b 26a 12 Figure 21.6 Sagittal SE T1-weighted MR images of a 2.5-year-old, neutered female Great Dane, depicting some normal anatomic structures. For key to labels, see Table 21.1. 3 3 (A) 21a (B) 4 160 Clinical Features VetBooks.ir 30a 30c 21a Figure 21.7 Sagittal (A) proton density MR image and (B) transverse SE T1-weighted MR image of a 2-year-old, male Great Dane, depicting some normal anatomic structures. The caudal aspect of the joint capsule and synovium (black arrow) is seen between the joint space and gastrocnemius muscle. For key to labels, see Table 21.1. 1 3 3 4 (A) (B) Figure 21.8 Dorsal (A) and transverse (B) SE T1-weighted (TR860/TE26) MR images of a 2-year-old, neutered female Chesapeake Bay Retriever, depicting some normal anatomic structures. The transverse scan is obtained through both menisci: the menisci (arrows) appear as apposing crescents with heterogeneous low SI due to slice thickness artifacts. For key to labels, see Table 21.1. 12 1 10 7 3 3 4 (A) (B) craniolateral 13a 11a 11c 11b 22 1 14 15 16 27 11d 13b 19 24 21 3 23 20 26 4 14 28 25 17 15 30b 31 29 30c 18 (A) (B) caudomedial Figure 21.9 Schematic transverse section through the thigh (A) and crus (B) depicting the anatomic relationship of muscles and bones. The positional relationship of the supporting musculature is important when assessing joints. For key to labels, see Table 21.1. Source: Evans & de Lahunta 2012. Reproduced from Miller’s Anatomy of the Dog, with permission of Elsevier. VetBooks.ir Magnetic Resonance Imaging of the Stifle Figure 21.10 Sagittal (A) SE T1-weighted MR image of a 9-year-old, intact female, mixed-breed dog and sagittal (B) SE T1-weighted MR image of a 2.5-year-old, neutered female Great Dane. Note the normal caudal cruciate ligament (CaCL, double arrow) and cranial cruciate ligament (CrCL, single arrow) (A). In the other dog (B), the CaCL (double arrow) is visible and the CrCL is completely torn. (A) detected (Rubin 2005). With a chronic ligament tear, there may be complete absence of the ligament or a low-SI scar that does not have the normal morphology of the ligament (Figure 21.10) (Rubin 2005). Bone Cortical bone has a uniform low SI on all sequences: the normal periosteum is not visible (Rubin 2005). New bone formation (periosteal, osteophytes, enthesophytes) has an intermediate-to-low SI, and is differentiated by location on the bone (Rubin 2005; D’Anjou et al. 2008). The SI of yellow bone marrow is similar to that of fat (high T1 and T2 SI), while red marrow has a slightly lower T1 SI (Rubin 2005; Armbrust et al. 2008). In dogs, the SI of the marrow in the femoral condyles on short T1 inversion recovery (STIR) images varies with age. At 4 months, the SI relative to fat is inhomogeneous and intermediate-to-low: at 8–16 months there Figure 21.11 Dorsal GE STIR MR image of a 2-year-old, neutered female Chesapeake Bay Retriever (A) and a 2-year-old, intact male Great Dane (B). Compare the normal appearance (A) to the high-SI lesions (arrows) at the proximal and distal attachments of the cranial cruciate ligament (B). (A) 161 (B) is a uniformly low SI (Armburst et al. 2008). On STIR images, high-SI lesions may be detected in the bone marrow and be due to trauma (blunt or repetitive), hyperemia, ischemia, infarction, inflammation, or neoplasia (Rubin 2005). In dogs with CR, it is common to detect varying degrees of increased SI on STIR images that are deep to the proximal and distal attachments of the CrCL (Figure 21.11) (Baird et al. 1998; Martig et al. 2007; Winegardner et al. 2007; Olive et al. 2014). Whereas these lesions develop after surgical resection of CrCL, they have also been observed in dogs with a partial CR or an intact CrCL (Winegardner et al. 2007). This observation suggests that multiple pathogeneses are possible, and questions whether the surgical model of osteoarthrosis is the best representation of CR in dogs. Additionally, the location of high-SI lesions is different compared to people with anterior cruciate ligament rupture, which further suggests a different or multiple pathogeneses. (B) VetBooks.ir 162 Clinical Features Conclusions Musculoskeletal MRI continues to be an emerging technique in veterinary medicine. For many patients there is minimal evidence to show that MRI is better than other types of examination when justified for cost and risk. However, musculoskeletal MRI is being used more frequently in veterinary medicine and is helpful, especially in patients with an elusive diagnosis or multiple joint abnormalities. Continued research also has the potential to show improved patient care through early lesion detection, to provide a better understanding of pathogenesis, and to lead to earlier, novel, or more specific treatments. References Armbrust LJ, Ostmeyer M, McMurphy R. Magnetic resonance imaging of bone marrow in the pelvis and femur of young dogs. Vet Radiol Ultrasound 2008;49:432–437. Baird DK, Hathcock JT, Kincaid SA, et al. Lowfield magnetic resonance imaging of early subchondral cyst-like lesions in induced cranial cruciate ligament deficient dogs. Vet Radiol Ultrasound 1998;39:167–173. Banfield CM, Morrison WB. Magnetic resonance arthrography of the canine stifle joint: technique and applications in eleven military dogs. Vet Radiol Ultrasound 2000;41:200–213. Böttcher P, Armbrust L, Blond L, et al. Effects of observer on the diagnostic accuracy of low-field MRI for detecting canine meniscal tears. Vet Radiol Ultrasound. 2012;53:628–635. Blond L, Thrall DE, Roe SC, et al. Diagnostic accuracy of magnetic resonance imaging for meniscal tears in dogs affected with naturally occurring cranial cruciate ligament rupture. Vet Radiol Ultrasound 2008;49:425–431. D’Anjou MA, Moreau M, Troncy E, et al. Osteophytosis, subchondral bone sclerosis, joint effusion and soft tissue thickening in canine experimental stifle osteoarthritis: comparison between 1.5T magnetic resonance imaging and computed radiography. Vet Surg 2008;37:166–177. David FH, Grierson J, Lamb CR. Effects of surgical implants on high-field magnetic resonance images of the normal canine stifle. Vet Radiol Ultrasound 2012a;53:280–288. David FH, Grierson J, Lamb CR. Reducing susceptibility artefacts in magnetic resonance images of the canine stifle following surgery for cranial cruciate ligament deficiency. Vet Comp Orthop Traumatol 2012b;25:488–497. Dyce KM, Sack WO, Wensing CJG. Textbook of Veterinary Anatomy. Third edition. Philadelphia PA, WB Saunders. 2002. Evans H, de Lahunta A. Miller’s Anatomy of the Dog. Fourth edition. Philadelphia PA, WB Saunders. 2012. Galindo-Zamora V, Dziallas P, Ludwig DC, et al. Diagnostic accuracy of a short-duration 3 Tesla magnetic resonance protocol for diagnosing stifle joint lesions in dogs with non-traumatic cranial cruciate ligament rupture. BMC Vet Res 2013;9:40. Hashemi RH, Bradley WG, Lisanti CJ. MRI The Basics. Second edition. Philadelphia PA, Lippincott Williams & Wilkins. 2004. Martig S, Konar M, Schmökel HG, et al. Low-field MRI and arthroscopy of meniscal lesions in ten dogs with experimentally induced cranial cruciate ligament insufficiency. Vet Radiol Ultrasound 2006;47:515–522. Martig S, Boisclair J, Konar M, et al. MRI characteristics and histology of bone marrow lesions in dogs with experimentally induced osteoarthritis. Vet Radiol Ultrasound 2007;48:105–112. Olive J, d’Anjou MA, Cabassu J, et al. Fast presurgical magnetic resonance imaging of meniscal tears and concurrent subchondral bone marrow lesions. Study of dogs with naturally occurring cranial cruciate ligament rupture. Vet Comp Orthop Traumatol 2014;27:1–7. Podadera J, Gavin P, Saveraid T, et al. Effects of stifle flexion angle and scan plane on visibility of the normal canine cranial cruciate ligament using low-field magnetic resonance imaging. Vet Radiol Ultrasound 2014;55:407–413. Pujol E, Van Bree H, Cauzinille L, et al. Anatomic study of the canine stifle using low-field magnetic resonance imaging (MRI) and MRI arthrography. Vet Surg 2011;40:395–401. Rubin DA. Magnetic Resonance Imaging: Practical Considerations. In: Bone and Joint Imaging, Resnick D, Kransdorf MJ, eds. Third edition. Philadelphia PA, Elsevier Saunders. 2005. Simpler RE, Kerwin SC, Eichelberger BM, et al. Evaluation of the WARP-turbo spin echo sequence for 3 Tesla magnetic resonance imaging of stifle joints in dogs with stainless steel tibial plateau leveling osteotomy implants. Vet Radiol Ultrasound 2014;55:414–419. Soler M, Murciano J, Latorre R, et al. Ultrasonographic, computed tomographic and magnetic resonance imaging anatomy of the normal canine stifle joint. Vet J 2007;174:351–361. Spriet M, McKnight A. Characterization of the magic angle effect in the equine deep digital flexor tendon using a low-field magnetic resonance system. Vet Radiol Ultrasound 2009;50:32–36. VetBooks.ir Magnetic Resonance Imaging of the Stifle Stahl C, Wacker C, Weber U, et al. MRI features of gastrocnemius musculotendinopathy in herding dogs. Vet Radiol Ultrasound 2010;51:380–385. Taylor-Brown F, Lamb CR, Tivers MS, et al. Magnetic resonance imaging for detection of late meniscal tears in dogs following tibial tuberosity advancement for treatment of cranial cruciate ligament 163 injury. Vet Comp Orthop Traumatol 2014;27:141– 146. Winegardner KR, Scrivani PV, Krotscheck U, et al. Magnetic resonance imaging of subarticular bone marrow lesions in dogs with stifle lameness. Vet Radiol Ultrasound 2007;48:312–317. VetBooks.ir VetBooks.ir 22 Risk Prediction of Cruciate Ligament Rupture using Stifle Diagnostic Imaging Peter Muir Introduction Cruciate ligament rupture (CR) is a common condition and is generally evaluated by physical examination. Over time, understanding of the disease mechanism has increased. CR is now recognized as a complex trait with genetic and environmental components that contribute to the risk of disease. As arthroscopy has been used more widely for clinical evaluation and surgical treatment during the past 15 years, it has now been established that the pathogenesis of CR is characterized by the development of subtle matrix damage, particularly in the cranial cruciate ligament (CrCL), and an associated inflammatory response within the stifle joint (Bennett et al. 1988; Bleedorn et al. 2011). Over time, progressive fiber tearing in the cruciate ligament complex, and the CrCL in particular, over a period of weeks to potentially many months; leads to the development of an unstable stifle and complete CR (Muir et al. 2011). As the disease becomes chronic, development of bilateral CR is common (Muir et al. 2011). Clinical diagnosis is centered around physical examination of the stifle. However, CR can sometimes be difficult to diagnose by the classical tests of clinical cranial drawer and cranial tibial thrust. This is particularly true in the early phase of the disease, when physical examination signs may be subtle, or in the chronic phase of the disease when stifle instability may be influenced by factors such as osteoarthritis and periarticular fibrosis. In dogs with stifle clinical signs suggestive of CR, but no cranial drawer or cranial tibial thrust, incipient CR should be suspected and confirmed by further investigation. Dogs with partial CR have a stable stifle (Grade I sprain). Clinically, a soft stop to the cranial drawer test may be identified in some dogs, suggesting very mild cranial tibial translation (Grade II sprain). Diagnostic imaging, particularly radiography, can be very useful to support the diagnosis of CR, particularly in the early phase of the disease. Recent studies have suggested that diagnostic imaging is predictive of disease progression (e.g., Chuang et al. 2014; Fuller et al. 2014). This knowledge is important as it enables refinement in patient diagnosis and management through inference from diagnostic imaging. Radiography The knowledge that subsequent contralateral rupture is a common event in dogs with Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 165 VetBooks.ir 166 Clinical Features unilateral CR has been used to investigate the predictive value of stifle radiography through the evaluation of bilateral radiographs at initial diagnosis (Bleedorn et al. 2011; Muir et al. 2011). Radiography is a more sensitive marker of disease than physical examination, and arthroscopy is a more sensitive marker than radiography, particularly with regards to the assessment of the severity of synovial effusion and associated joint inflammation (Chuang et al. 2014; Fuller et al. 2014). Even very subtle radiographic change, particularly synovial effusion, is clinically relevant to the diagnosis of partial or complete CR (Bleedorn et al. 2011; Muir et al. 2011; Chuang et al. 2014; Fuller et al. 2014). During initial epidemiological studies of CR disease progression in dogs with unilateral CR, the proportion of dogs developing subsequent contralateral rupture was investigated, and this risk was found to be about 50% at 12 months after the initial diagnosis (Doverspike et al. 1993; Moore & Read 1995; de Bruin et al. 2007; Cabrera et al. 2008; Buote et al. 2009). By using the Kaplan–Meier estimator, the time to contralateral CR in dogs with unilateral CR at diagnosis was studied in more detail in three groups of dogs (Cabrera et al. 2008; Buote et al. 2009; Muir et al. 2011). Median time to contralateral rupture was found to range from 809 to 1,227 days in the three groups (Muir et al. 2011). Subsequent contralateral rupture occurred in 54% of dogs during the study period, with an overall time to contralateral rupture of 947 days (Muir et al. 2011). Median time to contralateral rupture was reduced by neutering in both male and female dogs, and was inversely correlated to a weak degree with tibial plateau angle (Muir et al. 2011). To determine whether it is feasible to use radiographic assessment of synovial effusion and osteophytosis to make inferences regarding fiber damage in the cruciate ligament complex, more recent studies have examined the development of contralateral rupture in dogs diagnosed with unilateral complete CR and contralateral partial CR. Radiographic grading of the contralateral stifle joint for the severity of synovial effusion and osteophytosis at diagnosis is strongly predictive of the risk of CR (Chuang et al. 2014; Fuller et al. 2014), even when the contralateral stifle is deemed clinically normal by palpation (Fuller et al. 2014). If com- pression of the infrapatellar fat pad extends cranial to the cranial margin of the medial tibial condyle, or leads to bulging of the caudal joint capsule radiographically, then synovial effusion is sufficiently severe to have obvious effects on risk of disease progression over time (Chuang et al. 2014; Fuller et al. 2014). Similar inferences can be made if moderate to severe radiographic osteophytosis is present (Chuang et al. 2014; Fuller et al. 2014). At initial diagnosis, the severity of stifle synovial effusion and osteophytosis is correlated (Figure 22.1) (Chuang et al. 2014). In stifles with partial CR and moderate to severe stifle synovial effusion or stifle osteophytosis, odds of developing complete CR and an unstable stifle in the next 12 months is approximately 10-fold greater than for stifles with milder radiographic change (Chuang et al. 2014). Time to development of complete CR is significantly decreased by this severity of radiographic change (Figures 22.2 and 22.3). Breed of dog, age, body weight, gender and tibial plateau angle each have little effect on the risk of progression of disease from partial to complete CR (Chuang et al. 2014). Magnetic resonance imaging Recent work has determined that assessment of stifle radiographs in dogs with CR can enable inference to be made regarding the extent of fiber damage in the cruciate ligament complex, particularly the CrCL. A potential advantage of magnetic resonance (MR) imaging is that the cruciate ligament tissue can be assessed directly for pathological change. MR images with sufficient resolution for assessment of the cruciate ligament complex are best acquired using a 3.0 Tesla magnet and isotropic sequences, such as 3D Fast Spin Echo (FSE) Cube (Racette et al. 2016). In dogs with normal cruciate ligaments, estimation of CrCL volume using MRI is predictive of ligament structural properties (Racette et al. 2016). A fiber loss of 70–80% or more in the CrCL tissue is typically seen in stifles with complete CR. In the future, it is likely that this type of assessment will also enable inference regarding the risk of progression from partial CR to complete CR. Risk Prediction of Cruciate Ligament Rupture using Stifle Diagnostic Imaging (B) 40 22 20 35 18 16 25 14 Frequency 20 15 12 10 8 6 4 2 10 5 2 Os de gra is tifle s o ls yt ph era teo lat Os ontra c 2 e 0 0 0 1 1 e rad le n g l stif o i us era Eff ralat nt co 2 1 te op in hyt de o x sis st ifl gra e d 3 3 2 Ef fu in sio de n x gr st ad ifl e e 1 Frequency 30 0 VetBooks.ir (A) 167 Figure 22.1 Relationship of osteoarthritic changes in the index and contralateral stifles in dogs with unilateral complete cruciate ligament rupture (CR) and contralateral partial CR. (A) Bivariate histogram of radiographic synovial effusion grade in index and contralateral stifles. (B) Bivariate histogram of osteophytosis grade in index and contralateral stifles. Severity of osteophytosis (SR = 0.39, P < 0.0005), but not synovial effusion (SR = 0.17, P = 0.13) in the index and contralateral stifles were correlated (n = 85 dogs). Source: Chuang et al. 2014, http://journals.plos.org/plosone/ article?id=10.1371/journal.pone.0106389#. Used under CC BY 4.0, https://creativecommons.org/licenses/by/4.0/. Conclusions If there is any uncertainty about the diagnosis of CR, bilateral orthogonal stifle radiographs should be made in dogs with pelvic limb lameness and carefully examined for effusion and osteophyte formation. In dogs with Index effusion Index osteophytosis (B) Grade 0 Grade 1 Grade 2 100 50 Percent survival Percent survival (A) unilateral CR, bilateral films are important to fully determine the clinical status of the dog, particularly with regard to the risk of subsequent contralateral rupture (Chuang et al. 2014; Fuller et al. 2014). In stifles with partial CR, including palpably normal stifles on clinical examination, if moderate to severe radiographic Grade 0 Grade 1 Grade 2 Grade 3 100 50 0 0 0 1000 2000 Days 3000 0 1000 2000 3000 Days Figure 22.2 Time to contralateral cranial cruciate ligament rupture (CR) stratified by severity of synovial effusion and osteoarthritis in the unstable index stifle with complete CR. Kaplan-Meier plots for a population of 85 client-owned dogs with unilateral complete CR and contralateral partial CR. Time to contralateral complete CR was not significantly influenced by severity of synovial effusion (A) or osteophytosis (B) in the index stifle. Source: Chuang et al. 2014, http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106389#. Used under CC BY 4.0, https://creative commons.org/licenses/by/4.0/. Clinical Features Contralateral effusion Grade 0 Grade 1 Grade 2 100 75 50 25 0 0 1000 2000 Contralateral osteophytosis (B) 3000 Days Percent survival (A) Percent survival VetBooks.ir 168 Grade 0 Grade 1 Grade 2 Grade 3 100 50 0 0 1000 2000 3000 Days Figure 22.3 Time to contralateral cranial cruciate ligament rupture (CR) stratified by severity of synovial effusion or osteoarthritis in the contralateral stable stifle with partial CR. Kaplan-Meier plots for a population of 85 client-owned dogs with unilateral complete CR and contralateral partial CR. (A) Time to contralateral complete CR was significantly decreased in dogs with moderate to severe (Grade 2) radiographic synovial effusion of the contralateral stifle at diagnosis, when compared with the grades of 0 or 1 (P < 0.001). (B) Time to contralateral CR was significantly decreased in dogs with Grade 3 osteophytosis of the contralateral stifle at diagnosis, when compared with the grade 0 and grade 2 (P < 0.05). Source: Chuang et al. 2014, http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106389#. Used under CC BY 4.0, https://creativecommons.org/licenses/by/4.0/ synovial effusion is present, risk of disease progression to complete CR is substantially higher. This knowledge is important, particularly with regard to decision-making over surgical treatment. Tibial plateau leveling osteotomy, in particular, may be helpful in modifying disease progression in stifles with partial CR (Barger et al. 2016). References Barger B, Piazza A, Muir P. Treatment of stable partial cruciate rupture (Grade I sprain) in five dogs with tibial plateau levelling osteotomy. Vet Rec Case Rep 2016;4:e000315. Bennett D, Tennant B, Lewis DG, et al. A reappraisal of anterior cruciate ligament disease in the dog. J Small Anim Pract 1988;29:275–297. Bleedorn JA, Greuel E, Manley PA, et al. Synovitis in dogs with stable stifle joints and incipient cranial cruciate ligament rupture: A cross-sectional study. Vet Surg 2011;40:531–543. Buote N, Fusco J, Radasch R. Age, tibial plateau angle, sex, and weight as risk factors for contralateral rupture of the cranial cruciate ligament in Labradors. Vet Surg 2009;38:481–489. Cabrera SY, Owen TJ, Mueller MG, et al. Comparison of tibial plateau angles in dogs with unilateral versus bilateral cranial cruciate ligament rup- ture: 150 cases (2000–2006). J Am Vet Med Assoc 2008;232:889–892. Chuang C, Ramaker MA, Kaur S, et al. Radiographic risk factors for contralateral rupture in dogs with unilateral cranial cruciate ligament rupture. PLoS One 2014;9:e106389. de Bruin T, de Rooster H, van Bree H, et al. Radiographic assessment of the progression of osteoarthrosis in the contralateral stifle joint of dogs with a ruptured cranial cruciate ligament. Vet Rec 2007;161:745–750. Doverspike M, Vasseur PB, Harb MF, et al. Contralateral cranial cruciate ligament rupture: Incidence in 114 dogs. J Am Anim Hosp Assoc 1993;29:167–170. Fuller MC, Hayashi K, Bruecker KA, et al. Evaluation of the radiographic infrapatellar fat pad sign of the contralateral stifle joint as a risk factor for subsequent contralateral cranial cruciate ligament rupture in dogs with unilateral rupture: 96 cases (2006– 2007). J Am Vet Med Assoc 2014;244:328–338. Moore KW, Read RA. Cranial cruciate ligament rupture in the dog – a retrospective study comparing surgical techniques. Aust Vet J 1995;72:281–285. Muir P, Schwartz Z, Malek S, et al. Contralateral cruciate survival in dogs with unilateral non-contract cranial cruciate ligament rupture. PLoS One 2011;6: e25331. Racette M, Al Saleh H, Waller KR, 3rd , et al. 3D FSE Cube and VIPR-aTR 3.0 Tesla magnetic resonance imaging predicts canine cranial cruciate ligament structural properties. Vet J 2016;209:150–155. VetBooks.ir Section IV Surgical Treatment Introduction A large number of different surgical procedures have been described for the treatment of stifle instability in dogs, and decision-making regarding surgical treatment for cruciate ligament rupture (CR) remains controversial. Currently, widely used surgical procedures are aimed at the treatment of stifle instability, and not reconstruction or repair of the ruptured cranial cruciate ligament. Stabilization is accomplished either by osteotomy of the tibia or by extracapsular stabilization. Historically, by extrapolation from surgical treatment of human patients with anterior cruciate ligament rupture, intra-articular stabilization procedures have also been popular. Although initial results in experimental dogs were promising, the use of intra-articular grafting procedures has become less popular over time. Recent studies of surgical treatment have challenged the widely held belief that stifle instability is the primary reason for lameness, particularly in chronically affected dogs with meniscal damage. This section provides a detailed discussion of current surgical procedures used for the treatment of dogs affected with CR. Several new chapters have been added to this section to reflect advances in knowledge of surgical treatment of CR over the past five years. Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 169 VetBooks.ir VetBooks.ir 23 Arthroscopy and Arthrotomy of the Stifle Brian S. Beale, Donald A. Hulse, Antonio Pozzi, and Peter Muir Introduction Arthroscopy has revolutionized the treatment of joint disease in human beings and animals. Arthroscopic-assisted surgical techniques improve diagnostic accuracy, reduce postoperative pain and the duration of hospitalization, and shorten the time required for return to function (Whitney 2003; Hoelzler et al. 2004; Pozzi et al. 2008; Ertelt & Fehr 2009). Arthroscopy in animals is used primarily by veterinarians with advanced surgical training. General practitioners who routinely perform joint surgery have been slow to adopt arthroscopy due to the learning curve involved. Consideration should be given to implementing arthroscopy at the time of arthrotomy to enhance surgical observation, improve treatment and assist in arthroscopic training. The arthroscopic procedure is simplified when using arthroscopy at the time of arthrotomy. Many conditions affecting joints are best investigated arthroscopically, including osteochondritis dissecans (OCD) of the shoulder and elbow, ligamentous and tendinous injuries of the shoulder, fragmented medial coronoid process, partial cruciate ligament rupture (CR) and meniscal damage (Whitney 2003; Hoelzler et al. 2004; Pozzi et al. 2008; Ertelt & Fehr 2009). Arthroscopy via a mini-arthrotomy has been reported to be an effective method for treating CR and meniscal injury (Whitney 2003; Ertelt & Fehr 2009). Stifle arthrotomy Arthrotomy of the stifle can be performed in a traditional open or in a minimally invasive manner (Hoelzler et al. 2004; Pozzi et al. 2008; Ertelt & Fehr 2009; Johnson 2014). Traditional arthrotomy can be performed via a medial or lateral parapatellar approach depending on the surgeon’s preference (Johnson 2014). A medial parapatellar approach will typically facilitate examination of the medial femoro-tibial joint. A lateral arthrotomy may be best if lateral extracapsular stabilization is planned, as exposure of the caudolateral aspect of the joint is easier (Figure 23.1). A medial arthrotomy may be most convenient if a tibial osteotomy is to be performed due to the need to have medial exposure to the tibia. Arthrotomy should be performed meticulously. The skin is initially incised, followed by subcutaneous tissue, deep fascia, and joint capsule. Each tissue layer should be identified and incised separately. If a lateral parapatellar approach is used, the deep fascia is incised at Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 171 Surgical Treatment VetBooks.ir 172 (A) (B) (D) (E) (C) Figure 23.1 (A) A lateral parapatellar incision is most commonly used to approach the stifle joint for extracapsular treatment of cruciate ligament rupture. (B) The deep fascia is incised in a longitudinal direction cranial to the biceps femoris muscle. The fascial incision is continued distally along the lateral edge of the patellar tendon. (C) The deep fascia is incised and elevated from Gerdy’s tubercle at the lateral aspect of the proximal tibia. (D) The incision is continued caudally in a transverse manner, exposing the lateral aspect of the stifle. (E) Retraction of the fascia allows adequate access to the lateral fabella, the caudal joint capsule, lateral collateral ligament, fibular head, long digital extensor tendon, extensor groove, and the cranial joint capsule. the cranial border of the biceps femoris muscle (Figure 23.1B). The fascial incision is continued distally 5–10 mm lateral to the edge of the patellar tendon. The deep fascia should be elevated from the joint capsule and its bony attachment to Gerdy’s tubercle at the craniolateral aspect of the proximal tibia (Figure 23.1C). This allows optimal exposure to the caudal aspect of the stifle and closure of the joint capsule and deep fascia in separate layers. The fascia and attached biceps muscle is retracted caudally, giving good exposure to the lateral fabella, lateral condyle of the femur, fibular head, caudal joint capsule, long digital extensor tendon extensor groove and cranial joint capsule. This approach is particularly useful when performing extracapsular stabilization. The joint capsule is incised longitudinally just lateral to the patellar tendon along its entire length. The patella is luxated medially. The proximal aspect of the femoropatellar joint and medial and lateral gutters along the femoral condyles are evaluated for trochlear groove depth, cartilage integrity, periarticular osteophytes, and degree of synovitis. The stifle is flexed and a Gelpi retractor is used to retract the joint capsule. A Senn retractor is used to retract the patellar fat pad distally, allowing a good view of the intercondylar notch, cranial cruciate ligament (CrCL) and caudal cruciate ligament (CaCL). If torn cruciate ligament fibers obstruct viewing of the weight-bearing surfaces of the femoral condyle and tibial plateau and the menisci, they should be removed. A portion of the fat pad can also be resected if needed to improve examination of the joint. However, care should be taken to avoid damage to the intermeniscal ligament, which is hidden under the fat pad. The use of a surgical assistant will help improve joint exposure. Cranial traction on the Senn retractor or the crus can help improve exposure of the intra-articular structures by inducing cranial tibial subluxation. In stifles with substantial periarticular fibrosis this improved exposure may be limited. The use of a joint distractor will also help improve exposure. After optimizing joint exposure, the menisci should be examined, probed, and treated as indicated while maintaining joint access. Some increase in morbidity occurs with arthrotomy. The initial skin incision must be VetBooks.ir Arthroscopy and Arthrotomy of the Stifle longer and the deeper tissues must be incised. Incised tissues cause pain due to the initiation of inflammatory pathways and stimulation of sensory innervation. The surgeon should strive to minimize soft tissue trauma and surgical pain. Smaller arthrotomy incisions and meticulous surgical technique are recommended. Dessication of joint tissues should be avoided by frequent lavage to minimize tissue injury. Minimally invasive arthrotomy without luxation of the patella can help to reduce postoperative morbidity, although exposure of the intra-articular structures is limited, compared to arthrotomies with patella luxation. The arthrotomy is made just medial or lateral to the patellar tendon, extending from the distal pole of the patella to the proximal tibia. A Figure 23.2 (A) A minimally invasive arthrotomy has been used to explore the stifle. The joint capsule is retracted using a small Gelpi retractor. The fat pad and cranial joint capsule are retracted distally using a Senn retractor. (B,C) Examination of caudal parts of the menisci can be difficult using an arthrotomy. A Hohmann retractor can be used to improve the view of the menisci. The tip of the retractor is inserted just caudal to or on the caudal edge of the proximal tibia. The body of the retractor is levered against the trochlear groove of the femoral condyle. This action separates the joint surfaces, giving a better view and access to the menisci. An assistant is required when using this procedure. (D) Distraction using the Hohmann retractor provides a good view for inspection of the menisci and adequate access for partial meniscectomy or meniscal release. 173 small Gelpi retractor is used to retract the joint capsule (Figure 23.2A). Retraction or resection of the fat pad helps viewing of the joint. Care should be taken during the surgical approach to avoid injury to the cranial meniscotibial ligaments, the transverse meniscal ligament, and the cranial poles of the menisci. Joint surfaces should be distracted to facilitate meniscal evaluation and to perform meniscectomies without damaging cartilage (Figures 23.2B–D and 23.3– 23.5). Potential concerns with mini-arthrotomy are inadequate viewing and access to the femoro-tibial joint compartment. This may increase the possibility of missing a meniscal tear unless a probe and an arthroscope is used to improve meniscal examination. In addition, a partial meniscectomy performed through (A) (B) (C) (D) Surgical Treatment VetBooks.ir 174 Figure 23.3 A Leipzig stifle distractor can be used to separate the space between the femoral condyle and tibial plateau, giving an improved view and better access to the menisci. The distractor is attached to the medial femoral condyle and proximal tibia using threaded fixator pins. Distraction is achieved using the turnbuckle device on the distractor. An assistant is not required when using this device. a mini-arthrotomy may be more difficult if the meniscus does not displace cranially sufficiently. The risk of iatrogenic cartilage damage may also be higher. The view obtained through (A) a mini-arthrotomy may limit the examination of cruciate ligaments in the intercondylar notch. These potential concerns become less relevant as the surgeon becomes more experienced. A caudo-medial stifle arthrotomy can be used in selected cases, to improve exposure of the caudal pole of the medial meniscus. The arthrotomy is made along the caudal border of the medial collateral ligament. A needle is used to palpate the tibia and a 2–3 cm-long incision is made through the capsule. A small Gelpi retractor allows retraction and exposure of the medial meniscus. This arthrotomy was found to be more sensitive for meniscal diagnosis in stable stifles, such as in dogs with partial CR (Pozzi et al. 2008). This approach for medial meniscectomy can be used in combination with stifle arthroscopy, when the surgeon is not able to perform an arthroscopic meniscectomy. Arthroscopy of the stifle Arthroscopy of the stifle is the method of choice for joint exploration (Whitney 2003). The arthroscopic management of dogs with CR reduces short-term postoperative morbidity compared to arthrotomy (Hoelzler et al. 2004). The advantages of arthroscopy include magnification and (B) Figure 23.4 (A) An intra-articular stifle distractor (Arthrex Vet System) has been placed through the lateral arthroscope port to distract the joint. (B) An extra-articular human ankle distractor (Arthrex) can also be used to distract the articular surfaces. Intra-articular distractors offer the advantage of not requiring additional incisions or points of anchorage such as pins, but are technically more difficult to use because of the limited intra-articular space. 175 VetBooks.ir Arthroscopy and Arthrotomy of the Stifle (A) (B) (C) (D) Figure 23.5 Stifle distraction is recommended to improve meniscal diagnostic accuracy and to perform meniscectomy with lesser risk of iatrogenic cartilage damage. (A) At initial evaluation without joint distraction the meniscus appears normal. (B) Following joint distraction using the Arthrex Stifle Distractor the meniscus appears abnormal and a complex tear is evident. (C) A partial meniscectomy is performed. (D) Further probing of the meniscus allows detection of a horizontal tear. This example shows the importance of probing the meniscus after partial meniscectomy. Horizontal tears are common and can progress to bucket-handle or flap tears if left untreated. illumination, greater access to anatomic regions of the joint, evaluation of the joint structures in a fluid medium, and reduced morbidity. A magnified view of stifle anatomic structures allows a more accurate diagnosis and more precise treatment of pathologic conditions (Figure 23.6). Arthroscopic evaluation of the stifle enables more thorough evaluation of the patella, trochlear groove, femoral condyle, tibial plateau, CrCL, CaCL, and menisci. Arthroscopy of the stifle is often used to evaluate and treat CR and meniscal tears. Fiber rupture in both the CrCL and the CaCL can clearly be assessed with arthroscopy, but can easily be missed with arthrotomy (Figure 23.7). The identification of partial CR, early in the course of the disease, may be critical for treatment decision-making and patient management. Early surgical treatment with tibial plateau leveling osteotomy may protect against further CrCL fiber disruption and reduce the Figure 23.6 (A) The cranial and caudal cruciate ligaments are more accurately assessed when viewed with an arthroscope due to magnification and evaluation in a fluid medium. The flow of fluid improves the appearance because the tissues do not desiccate and hemorrhage is flushed away. (B) A bucket-handle tear of the medial meniscus is better viewed and more precisely removed using arthroscopy. (A) incidence of meniscal injury and articular cartilage damage. Examination of the menisci is also improved as the arthroscope can be positioned adjacent to the meniscus. Arthroscopy is superior to arthrotomy for the diagnosis of meniscal damage (Pozzi et al. 2008), especially when combined with probing. Joint distraction can improve meniscus exposure and facilitate the diagnosis and treatment of meniscal injuries. Distraction can be performed with intra- or extraarticular distractors. A joint distractor can be placed through a lateral portal into the intercondylar notch and levered against the femoral condyle to separate the joint surfaces and give better access to the menisci if needed (Figure 23.8). Bucket-handle tears of the medial meniscus are the most common type of meniscal damage associated with CR. Many of these tears are not displaced cranially at surgery and are easily missed. Examining the joint at (B) Surgical Treatment VetBooks.ir 176 (A) (B) (C) Figure 23.7 (A) The cranial cruciate ligament (CrCL) of this dog initially appears normal. (B–D) A partial tear of the cranial medial band of the CrCL was found when the proximal attachment of the ligament was carefully probed. This CrCL partial tear would be difficult to see using traditional arthrotomy. (D) different flexion angles and applying tibial thrust can displace the meniscal tear and facilitate a correct diagnosis. The magnified view from the arthroscope aids identification of meniscal damage. The femoral surface of the caudal horn of the medial meniscus may have wearing of fibers or a change in character of the surface. These changes may be difficult to detect without magnification, and are often associated with minimally displaced medial meniscal tears. Small radial and axial meniscal tears are also identified more easily with magnification. The meniscus should be carefully probed on the tibial and femoral surface to assess for MFC tears (Figures 23.5 and 23.9). Tear detection is improved with arthroscopy (Pozzi et al. 2008). Partial meniscectomy can be performed more accurately using arthroscopy whilst minimizing articular cartilage damage. Arthroscopicassisted meniscectomy through an arthrotomy incision (see below) often helps to ensure complete and efficient removal of damaged portions of the meniscus. Medial meniscal release helps to reduce development of postliminary meniscal tears after treatment of CR. Meniscal release can be performed under arthroscopic guidance by transection of the caudal meniscotibial MFC MM MM TP (A) TP (B) Figure 23.8 The view of the medial meniscus (MM) of this patient is improved using a stifle distractor. (A) The view and access to the meniscus is inadequate initially. (B) With use of a stifle distractor, meniscal evaluation and access for partial meniscectomy is improved. MFC, medial femoral condyle; TP, tibial plateau. VetBooks.ir Arthroscopy and Arthrotomy of the Stifle MFC MFC MM 177 MFC MM BHT TP TP (A) (B) (C) Figure 23.9 Meniscal tears can be difficult to see during routine arthrotomy. (A) This patient appeared to have a normal meniscus on initial arthroscopic inspection. (B) Careful probing of the medial meniscus revealed a bucket-handle tear. (C) A partial meniscectomy was performed, leaving the remaining healthy portion of the meniscus intact. MFC, medial femoral condyle; MM, medial meniscus; TP, tibial plateau; BHT, bucket-handle tear of medial meniscus. ligament, or by percutaneously incising transversely across the medial meniscus, just caudal to its attachment to the medial collateral ligament (Whitney 2003) (Figure 23.10). Magnification of intra-articular structures allows for more accurate identification of pathological changes to the articular cartilage. Early degenerative changes to articular cartilage, not MFC MM TP Figure 23.10 A mid-body medial meniscal release was performed using a #11 scalpel blade through a percutaneous stab incision made in the caudal medial aspect of the stifle joint. Meniscal release can be accurately performed and assessed using arthroscopy. MFC, medial femoral condyle; MM, medial meniscus; TP, tibial plateau. visible to the naked eye, are clearly seen arthroscopically (Figure 23.11). Fine and coarse fibrillation, superficial erosions and neovascularization of the cartilage are readily evaluated and documented (Figure 23.11). Arthroscopic-assisted arthrotomy Arthroscopy is easier to perform when combined with arthrotomy. An arthroscope can be introduced into the arthrotomy incision to enhance the observation of all intra-articular structures, which is the most important advantage of this approach. Arthroscopic-assisted arthrotomy provides the surgeon with intraarticular images that are identical to those obtained by traditional arthroscopy, and thus enables complete documentation of the changes observed and treatment provided. By combining these techniques, the arthrotomy incision can be used for triangulation of the arthroscope and instruments, as well as fluid egress. This approach not only shortens the learning curve regarding arthroscopic technique but also reduces fluid leakage into the periarticular soft tissues, a common problem with portal arthroscopy. Smaller arthrotomy incisions can be made when combined with arthroscopy. This may help reduce morbidity. The arthroscope can be quickly and easily moved in and out of the joint as needed. Ease of alignment of the arthroscope and the anatomic target is improved. The arthroscope can be positioned VetBooks.ir 178 Surgical Treatment MFC P MFC *** *** MM TP *** TG (A) *** (B) TP +++ (C) Figure 23.11 Arthroscopy improves the ability of the surgeon to assess the condition of articular cartilage. (A) A small focal area of full-thickness erosion of the femoral cartilage (∗∗∗) is seen on the underside of the patella (P) adjacent to the trochlear groove (TG) in this patient with medial patellar luxation. (B) Chondromalacia (∗∗∗) of the articular cartilage of the tibial plateau (TP) can be seen in this patient with cruciate ligament rupture. (C) Fine fibrillation (∗∗∗) of the articular cartilage of the medial femoral condyle (MFC) and fibrillation and erosion (+++) of the cartilage of the TP can be seen in this patient with cruciate ligament rupture. Changes to cartilage as seen in panels B and C are typically only visible with magnification. MM, medial meniscus. in the desired location by gross observation, while the anatomic structure of interest can be assessed more completely using the magnification and the enhanced viewing field provided by the arthroscope. Instruments are placed adjacent to the arthroscope through the same arthrotomy incision or through an adjacent stab incision used to create an instrument portal. This technique can be used to help secure the instrument to facilitate surgical operative technique. Triangulation, an arthroscopic skill that is difficult to learn, is much easier using arthroscopicassisted arthrotomy. Arthroscopic-assisted arthrotomy typically uses a mini-arthrotomy without luxation of the patella (Figure 23.12A). The arthrotomy should (A) (B) be made just medial or lateral to the patellar tendon, extending from the distal pole of the patella to the proximal tibia, preserving the femoro-patellar ligament. A small Gelpi retractor is used to retract the joint capsule (Figure 23.12B). Retraction or resection of the fat pad allows improved viewing. The proximal joint pouch and medial and lateral gutters can be examined by directing the arthroscope proximally (Figure 23.12C). Synovitis and osteophytes can be seen, assessed, and documented with images obtained using the arthroscopic camera (Figure 23.13A–C). The cruciate ligaments are inspected (Figure 23.14A). A joint distractor can be used to separate the joint surfaces of the femur and tibia, providing a better (C) Figure 23.12 (A) Arthroscopic-assisted arthrotomy can be used to evaluate the stifle with similar advantages to arthroscopy, but with the ease of arthrotomy. The arthrotomy incision is typically small, as seen in this patient, but any size arthrotomy incision can be used with arthroscopic assistance. (B) Gelpi retractors can be used to retract the joint capsule and improve exposure to the joint. (C) The arthroscope is positioned in the proximal aspect of the joint to assess the patella, trochlear groove, synovial membrane and the medial and lateral gutters for osteophytes. Fluid enters the joint through the arthroscope cannula and drains from the arthrotomy incision. VetBooks.ir Arthroscopy and Arthrotomy of the Stifle 179 SM LFC MFC *** SM *** (A) (B) (C) Figure 23.13 Arthroscopic-assisted arthrotomy facilitates assessment of intra-articular pathology at the time of arthrotomy (A). The synovium can be evaluated for hyperplasia, hyperemia, and fibrosis. Synovial biopsies can be obtained using arthroscopic assistance to ensure that optimal tissue samples are obtained. (B) Small osteophytes (∗∗∗) along the attachment of the joint capsule to the lateral femoral condyle (LFC) can be seen in this patient having an early cruciate ligament rupture. Minimal inflammation of the synovial membrane (SM) is seen. (C) Moderate-sized osteophytes (∗∗∗) are present along the medial femoral condyle (MFC) in this patient with a chronic cruciate ligament rupture. The synovial membrane (SM) appears hyperplastic in the area of the osteophytes. view of the menisci (Figures 23.3, 23.4 and 23.14B,C). The joint is then explored using the magnified view of the arthroscope. Controlling the position of the arthroscope in the joint can be more difficult with this technique, compared with portal arthroscopy. Resting the surgeon’s hand against the patient or resting the surgeon’s elbow on a Mayo stand can help avoid a shaky image and inadvertent withdrawal of the scope from the joint (Figure 23.15). The surgeon can also steady the image and prevent inadvertent withdrawal of the arthroscope by grasping the shaft of the arthroscope near the arthrotomy incision (Figure 23.15). Fluids are delivered through the arthroscope cannula, similar to portal arthroscopy. The rate of fluid flow should be lowered because of reduced resistance to flow from the arthrotomy incision. Fluid egress occurs freely from the incision and fluid collection should be performed. Fluid egress can be captured using a drainage pouch with suction attachment, floor drain, or simply placing towels or absorbent towels on the floor (Figure 23.15). A water-impervious drape should be used to avoid surgical site contamination (Figure 23.15). The tip of the arthroscope should be placed near the target tissue to provide the best view. Bubbles may obscure the view if the tip of the scope is drawn too far away from the tissue (Figure 23.16A). Surgical instruments are used with a combination of direct and arthroscopic observation. Arthroscopic treatment also helps to minimize cartilage injury. A scrubbed assistant can help to manipulate an instrument, such as a grasper or probe, during surgery (Figure 23.16B). The surgeon typically holds the arthroscope and the cutting instrument or shaver. The menisci should be carefully probed to assess for damage (Figure 23.17). Damaged meniscal tissue, such as a bucket-handle tear, should be removed by partial meniscectomy (Figure 23.18). After treatment, the affected area should be re-examined, using the arthroscope to ensure complete treatment. This is particularly important during meniscectomy, as it is common to find a second or third bucket-handle tear after removal of the first tear (Figure 23.19). The meniscus should be probed under arthroscopic viewing to ensure that additional damaged meniscal tissue is not left behind. Medial meniscal release can also be performed more accurately using arthroscopic guidance (Figure 23.20). Surgical procedures require the use of surgical instruments. Surgeons often use a variety of instruments for operative procedures in the joint, including scalpel blades, hemostats, and thumb forceps. Arthroscopic hand instruments typically used for traditional arthroscopic surgery may provide a benefit to surgeons using arthroscopic-assisted arthrotomy. Arthroscopic hand instruments are typically low profile, with 180 Surgical Treatment VetBooks.ir smooth edges to enhance access to tight regions of the joint without damaging articular cartilage. They also have been designed with more secure grasping properties to allow a stronger grasp of intra-articular structures, to apply tension, or to remove damaged structures. Hand instruments designed for arthroscopy also tend to improve joint observation due to their ergonomic design and shaft length. (A) Stifle joint distraction Distraction of the femoral and tibial joint surfaces during arthrotomy or arthroscopy is often achieved using a narrow Hohmann retractor with an appropriate contour and adequate stiffness to prevent bending. The tip of the Hohmann retractor is placed on the caudal aspect of the tibial plateau. The blade of the retractor is levered against the trochlear groove of the femoral condyle, resulting in a separation of the joint surfaces and improved viewing of the menisci and the caudal femoro-tibial joint space. Distraction must be maintained by the surgeon during the procedure. Intra-articular joint distraction (B) (C) Figure 23.14 Arthroscopy-assisted arthrotomy. (A) The cranial cruciate ligament is inspected with a probe. Diagnosis of partial cruciate ligament rupture is facilitated because of the magnified view supplied by the arthroscope. (B) A Hohmann retractor has been inserted into the mini-arthrotomy adjacent to the arthroscope allowing an improved view of the menisci. (C) The menisci are probed while viewed with an arthroscope. The magnified view and ability to position the arthroscope into an optimal position next to the meniscus increases the surgeon’s accuracy in identifying meniscal tears. This approach is useful for both arthrotomy and arthroscopic techniques. Several instruments are currently available that have an improved design relative to a Hohmann retractor. These instruments are placed in the intercondylar notch to separate the tibial and femoral joint surfaces, but distraction needs to be maintained by a surgical assistant. A self-retaining retractor is also available for joint distraction (Gemmill & Farrell 2009). This instrument is typically positioned through a medial parapatellar portal incision or through the arthrotomy. The proximal jaw is placed in the intercondylar notch and the distal jaw in the fat pad before joint distraction (see Figures 23.3 and 23.4). Extra-articular joint distraction An extra-articular pin distractor (Böttcher et al. 2009; Winkels et al. 2016) can also be used to separate the joint surfaces of the femur and tibia. Transcutaneous pins are placed in the distal 181 VetBooks.ir Arthroscopy and Arthrotomy of the Stifle (A) (B) (C) (D) Figure 23.15 During arthroscopy-assisted arthrotomy, the arthroscope can be stabilized by resting the surgeon’s hand against the patient or a sterile towel positioned on the patient to avoid a shaky image and inadvertent withdrawal of the scope from the joint (A). (B) The surgeon can steady the image and prevent inadvertent withdrawal of the arthroscope from the joint by grasping the shaft of the scope near the arthrotomy incision. (C) Fluid egress occurs freely and fluid collection should be performed. A water-impervious drape is used on patients having arthroscopy-assisted arthrotomy to avoid contamination of the surgical site. The drape used in this patient is an antimicrobial surgical incise drape with an iodophor-impregnated adhesive, designed to provide a sterile surface all the way to the wound edge and continuous antimicrobial activity throughout the procedure. (D) Fluid egress can be captured using a drainage pouch with suction attachment or a floor drain, or simply placing towels or absorbent towels on the floor. (A) (B) Figure 23.16 (A) The tip of the arthroscope should be placed near the target tissue to provide the best view. Bubbles will often obscure the view if the tip of the scope is drawn too far away from the tissue of interest. (B) A scrubbed assistant can be used to hold a grasper or probe during resection of the cranial cruciate ligament remnants or partial meniscectomy. The surgeon typically holds the scope and the cutting instrument or shaver. Surgical Treatment VetBooks.ir 182 MFC MFC MFC MM MM BHT TP TP (A) (B) (C) Figure 23.17 The meniscus should be carefully probed to assess for meniscal tears. The meniscus of this patient was examined using an arthroscopy-assisted arthrotomy technique. (A) The meniscus appears normal. (B) A probe is introduced to palpate and assess the meniscus for damage. (C) A bucket-handle tear of the medial meniscus is found and displaced cranially using the probe. MFC,-medial femoral condyle; MM, medial meniscus; TP, tibial plateau; BHT, bucket-handle tear. femur and proximal tibia. The design of this distractor allows the surgeon to use a combination of cranial tibial thrust together with distraction to optimize viewing of the femorotibial joint (Figures 23.3 and 23.4). Distraction can be maintained by the instrument after placement. Use of joint distraction is an important consideration in surgical evaluation of the stifle joint. Diagnosis of medial meniscal tearing is improved (Kim et al. 2017; Winkels et al. 2016) (Figures 23.5 and 23.8). Improved access to the caudal portion of the medial meniscus also facilitates meniscectomy or medial meniscal release in both large and small dogs (Kim et al. 2016; Winkels et al. 2016; Kim et al. 2017). Joint distraction appears a safe procedure that is unlikely to induce collateral ligament injury or joint injury from inadvertent pin penetration (Böttcher et al. 2009; Winkels et al. 2016). Patient morbidity Postoperative pain Stifle surgery is a painful procedure. Pain is generated locally by cellular mechanisms and MFC MFC HK G BHT MM BHT TP MM (A) TP (B) (C) Figure 23.18 Bucket-handle tears should be removed by partial meniscectomy. Arthroscopy-assisted arthrotomy allows the surgeon to perform a partial meniscectomy with great precision. (A) A hook knife is used to cut the abaxial attachment to the bucket-handle tear of the medial meniscus. (B) The torn portion of the meniscus is grasped and tension is applied before cutting the axial attachment of the torn fragment. (C) Appearance of the periphery of the medial meniscus and articular surfaces after partial meniscectomy. MFC, medial femoral condyle; MM, medial meniscus; TP, tibial plateau; BHT, bucket-handle tear; HK, hook knife; G, grasper. VetBooks.ir Arthroscopy and Arthrotomy of the Stifle the activation of nociceptors, particularly in the synovium and joint capsule. In dogs with CR, stifle synovitis also contributes to joint pain and lameness. Surgical pain can be decreased by applying appropriate pre-emptive analgesia, adjunctive nonsteroidal anti-inflammatory drug (NSAID) therapy, and by meticulous surgical technique. Arthroscopic-assisted surgery is minimally invasive and helps to reduce surgical morbidity. Persistent synovitis has been identified in injured joints (elbow, hip, stifle) long-term after arthrotomy or arthroscopy. This may warrant long-term anti-inflammatory therapy to decrease the insidious progression of osteoarthritis. Anti-inflammatory treatment can be provided using NSAIDs or supplements that have anti-inflammatory properties. Recent studies have demonstrated similar improvements in the ground reaction forces of dogs with osteoarthritis of the hips and stifles by treatment using an NSAID or a fatty acid supplement (Kwananocha et al. 2016). Return to function Early return to function is desirable to reduce muscle atrophy and preserve the joint range of motion after surgery. The loss of muscle mass may alter forces acting on the joint and thus influence the progression of stifle joint degeneration. Pain, tissue swelling, activity restriction Figure 23.19 It is particularly important to reassess the meniscus with a probe after performing a partial meniscectomy to treat a bucket-handle tear of the medial meniscus. It is relatively common to find a second or even a third bucket-handle tear after removal of the first. This patient had a triple bucket-handle tear of the medial meniscus. and bandaging contribute to postoperative loss of joint range of motion. Early range of motion exercise as part of a rehabilitation program (see Chapter 42) is advantageous due to the tendency for joints to become stiff after surgery. Periarticular fibrosis may lead to an irreversible loss of range of motion and morbidity, and should be minimized. Arthroscopic-assisted arthrotomy helps to preserve joint range of motion due to its effect on reducing pain and swelling after surgery. When combined with surgical stabilization of the stifle, morbidity is similar to traditional portal arthroscopy. MFC MFC *** MTL PK TP TP PK (A) 183 (B) Figure 23.20 Medial meniscal release can also be performed more accurately using arthroscopic guidance. (A) A meniscal release was performed by cutting the medial meniscotibial ligament using a meniscal push-knife. (B) The caudal horn of the medial ligament has displaced caudally after cutting the ligament. Note the gap (∗∗∗) at the site of transection of the meniscotibial ligament. MFC, medial femoral condyle; MTL, medial meniscotibial ligament; TP, tibial plateau; PK, push-knife. VetBooks.ir 184 Surgical Treatment References Böttcher P, Winkels P, Oechtering G. A novel pin distraction device for arthroscopic assessment of the medial meniscus in dogs. Vet Surg 2009;38;595– 600. Ertelt J, Fehr M. Cranial cruciate ligament repair in dogs with and without meniscal lesions treated by different minimally-invasive methods. Vet Comp Orthop Traumatol 2009;22:21–26. Gemmill TJ, Farrell M. Evaluation of a joint distractor to facilitate arthroscopy of the canine stifle. Vet Surg 2009;38:588–594. Hoelzler MG, Millis DM, Francis DA, et al. Results of arthroscopic versus open arthrotomy for surgical management of cranial cruciate ligament deficiency in dogs. Vet Surg 2004;33:146–155. Johnson KA. Piermattei’s Atlas of Surgical Approaches to the Bones and Joints of the Dog and Cat. Philadelphia, WB Saunders 2014, pp. 392–399. Kim JH, Heo SY, Lee HB. Arthroscopic detection of medial meniscal injury in small breed dogs with the use of a joint distractor. J Vet Sci 2017, epub. Kim K, Lee H, Ragetly GR. Feasibility of stifle medial meniscal release in toy breed dogs with and without a joint distractor. Vet Surg 2016;45:636–641. Kwananocha I, Vijarnsorn M, Kashemsant N, et al. Effectiveness of disease modifying osteoarthritis agents and carprofen for treatment of canine osteoarthritis. Thai K Vet Med 2016;46:363–371. Pozzi A, Hildreth BE, Rajala-Schulz PJ. Comparison of arthroscopy and arthrotomy for diagnosis of medial meniscal pathology: an ex vivo study. Vet Surg 2008;37:749–755. Whitney WO. Arthroscopically assisted surgery of the stifle joint. In: Small Animal Arthroscopy, Beale BS, Hulse DA, Schulz KS, Whitney WO, eds. Philadelphia, WB Saunders, 2003. Winkels P, Pozzi A, Cook R, et al. Prospective evaluation of the Leipzig stifle distractor. Vet Surg 2016;45:631–635. VetBooks.ir 24 Joint Lavage Peter Muir Introduction Pharmacologic treatment of arthritis often includes systemic or intra-articular administration of various types of drugs, particularly anti-inflammatory drugs. Common intra-articular therapies used for the treatment of arthritis include corticosteroids and hyaluronic acid (Jüni et al. 2007; Habib 2009). However, these treatments may be associated with adverse effects. Relief from arthritic pain after joint lavage has been noted by surgeons performing arthroscopy since 1934 (Burman et al. 1934). Subsequently, it has been suggested that large-volume lavage or irrigation of joints may facilitate the removal of cartilage degradation products, inflammatory cells, proinflammatory cytokines, and matrix-degrading enzymes. However, this remains a provocative question which has been little considered in canine orthopaedic surgery. Clinical studies To address the question of joint lavage efficacy, a number of clinical trials have been conducted in human patients, principally studying human knee osteoarthritis patients. Results of these trials have been conflicting. It has been suggested that the benefit of joint lavage is due to a placebo effect (Bradley et al. 2002). However, in at least one well-controlled trial, when arthroscopic debridement was compared with arthroscopic lavage or placebo surgery, arthroscopic procedures did not perform better than placebo surgery (Moseley et al. 2002). In other work, knee arthritis patients undergoing arthroscopic lavage have experienced persistent pain relief for up to 24 weeks (Ravaud et al. 1999). Comparison of arthroscopic lavage with lavage plus intra-articular corticosteroids suggested that little additional benefit is gained from the use of corticosteroids; benefits from intraarticular corticosteroids appear short-lived in the range of 2–4 weeks (Ravaud et al. 1999; Smith et al. 2003). In at least one study, no interaction between steroid injection and joint lavage was found (Ravaud et al. 1999), suggesting that joint lavage may have a different and more persistent mechanism of action than the injection of corticosteroids. The effects of these two treatments have also been found to be additive (Ravaud et al. 1999). In more recent studies, arthroscopic partial meniscectomy was compared with diagnostic arthroscopy (sham surgery) for patients with a degenerate meniscal tear. Outcomes after arthroscopic partial meniscectomy were no Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 185 Surgical Treatment Cartilage (A) 6 Control group * Histologic scale Treatment group * 4 better than those after sham surgery (Sihvonen et al. 2013), suggesting that joint lavage may have a role in the relief of pain in selected patients. * 2 0 Mechanism for relief of joint pain Lavage at Week 1 Lavage at Week 2 Lavage at Week 3 Synovium (B) 4 Histologic scale VetBooks.ir 186 Control group Treatment group 3 * * 2 * 1 0 Lavage at Week 1 Lavage at Week 2 Lavage at Week 3 Figure 24.1 Histologic grading of femoral condyle cartilage and synovium from stifles with osteoarthritis in a rabbit model of bilateral medial meniscectomy with medial collateral transection (n = 10 animals per time period). Bilateral joint lavage with saline was performed in 5 rabbits, with the remaining animals acting as controls. Joint lavage was performed at 1, 2, and 3 weeks after meniscectomy and euthanasia performed 1 week after lavage. (A) Histologic grading of cartilage. (B) Histologic grading of synovium. ∗ P < 0.05 versus control group, which received no lavage treatment. Source: Fu et al. 2009. Reproduced with permission from John Wiley & Sons, Inc. Few experimental data are available to provide insight into the mechanism by which joint lavage might induce relief from joint pain. However, in an experimental study using a rabbit meniscectomy model, joint lavage was found to significantly reduce joint degeneration at 1 to 3 weeks after induction of joint instability (Fu et al. 2009). Synovial inflammation and degradation of articular cartilage were both significantly reduced (Figure 24.1 and Table 24.1) (Fu et al. 2009). Joint lavage treatment also led to reduced expression of the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) in synovial fluid (Fu et al. 2009). Conclusions Collectively, these clinical trial and experimental findings suggest that joint lavage may have efficacy in the treatment of arthritis, particularly through reduction of joint inflammation. Metaanalysis of data from randomized, controlled Table 24.1 Influence of joint lavage on inflammatory markers in synovial fluid in a rabbit meniscectomy and medial collateral transection model. Period after meniscectomy before joint lavage Marker 1 week (n = 10) 2 weeks (n = 10) 3 weeks (n = 10) IL-1β (pg ml–1 ) Control (n = 5/time point) 81.35 ± 2.41 67.39 ± 2.95 53.86 ± 3.79 Saline lavage (n = 5/time point) 35.79 ± 3.50∗ 39.85 ± 4.78∗ 29.94 ± 3.99∗ 761.97 ± 17.28 446.32 ± 26.83 TNF-α (pg ml–1 ) Control (n = 5/time point) Saline lavage (n = 5/time point) 599.36 ± 25.40 313.02 ± 24.61∗ 459.15 ± 18.15∗ 309.88 ± 27.69∗ Note: Euthanasia was performed at 1 week after lavage. IL-1β and TNF-α concentrations were determined using ELISA. ∗ P < 0.05 versus control group. Reproduced from Fu et al. (2009), with permission from Wiley Blackwell. IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-alpha. VetBooks.ir Joint Lavage studies investigating joint lavage for human knee osteoarthritis suggests that at 3 months, joint lavage alone does not provide significant improvement in pain and function (Arouac et al. 2010). Since 2007, arthroscopic lavage in human knee osteoarthritis patients has been a procedure in decline (Lazic et al. 2014). In conclusion, when designing clinical trials using arthroscopy for the treatment of dogs with stifle arthritis and cruciate ligament rupture, the possibility that a significant treatment effect from arthroscopic lavage may exist should be considered in the experimental design of the trial study, although any treatment effect may be small based on human knee osteoarthritis studies. Further work is needed to more comprehensively understand the mechanistic effects of joint lavage on arthritic canine joints, particularly as any treatment effect from joint lavage appears much more durable, when compared to intra-articular corticosteroid treatment. References Arouac J, Vicaut E, Bardin T, et al. Efficacy of joint lavage in knee osteoarthritis: meta-analysis of randomized controlled studies. Rheumatology 2010;49:334–340. 187 Bradley JD, Heilman DK, Katz BP, et al. Tidal irrigation as treatment for knee osteoarthritis. A shamcontrolled, randomized, double-blinded evaluation. Arthritis Rheum 2002;46:100–108. Burman MS, Finkelstein H, Mayer L. Arthroscopy of the knee joint. J Bone Joint Surg 1934;16:255–268. Fu X, Lin L, Zhang J, et al. Assessment of the efficacy of joint lavage in rabbits with osteoarthritis of the knee. J Orthop Res 2009;27:91–96. Habib GS. Systemic effects of intra-articular corticosteroids. Clin Rheumatol 2009;28:749–756. Jüni P, Reichenbach S, Trelle S, et al. Efficacy and safety of intraarticular hylan or hyaluronic acids for osteoarthritis of the knee. Arthritis Rheum 2007;56:3610–3619. Lazic S, Boughton O, Hing C, et al. Arthroscopic washout of the knee: A procedure in decline. Knee 2014;21:631–634. Moseley JB, O’Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med 2002;347:81–88. Ravaud P, Moulinier L, Giraudeau B, et al. Effects of joint lavage and steroid injection in patients with osteoarthritis of the knee. Arthritis Rheum 1999;42:475–482. Smith MD, Wetherall M, Darby T, et al. A randomized placebo-controlled trial of arthroscopic lavage versus lavage plus intra-articular corticosteroids in the management of symptomatic osteoarthritis of the knee. Rheumatology 2003;42:1477–1485. Sihvonen R, Paavola M, Malmivaara A, et al. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. N Engl J Med 2013;369:2515–2524. VetBooks.ir VetBooks.ir 25 Extracapsular Stabilization Selena Tinga and Stanley E. Kim Introduction Extracapsular stabilization (ES) encompasses a number of different surgical techniques designed to stabilize a cranial cruciate ligament (CrCL)-deficient stifle. Biological or synthetic materials are placed superficial to the joint capsule, spanning the area lateral and/or medial to the stifle joint. From the original extracapsular repair introduced during the 1960s to the current modifications of the technique, the general theoretical goal is to counteract the translational and rotational instability that is present when the CrCL is damaged. The possible advantages of ES over other stifle stabilization procedures include the safety of the procedure, the potential for reduction of abnormal internal rotation, lower technical difficulty, minimal required inventory, and lower cost. The reported disadvantages include abnormal biomechanics such as excessive constraint, higher infection rate, and poorer long-term stability. Case selection As with any surgical treatment, correct case selection is important for optimizing success rates. Increased body weight has been associated with an increased risk of postoperative complications after ES (Casale & McCarthy 2009). Therefore, body weight and body condition score should be taken into account when considering surgical options for dogs with cruciate ligament rupture (CR). Younger age has also been associated with an increased risk of complications after ES (Casale & McCarthy 2009), and while the cause of this was not speculated, it is assumed that it may be related to a higher activity level. ES is likely at high risk of failure in dogs with a steeper tibial plateau angle (TPA). However, the TPA did not influence outcome (forceplate measures, osteoarthritis progression, and orthopaedic examination findings) at 48 weeks after surgery in 34 dogs with TPAs ranging from 19◦ to 35◦ (Havig et al. 2007), though it is notable that dogs with TPAs over 35◦ were not included. General surgical approach Before definitive stifle stabilization, intraarticular inspection should be performed using stifle arthroscopy or arthrotomy. Joint assessment is recommended to confirm the diagnosis Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 189 VetBooks.ir 190 Surgical Treatment of CR and to assess the health of the meniscus, the cranial and caudal cruciate ligaments, and cartilage surfaces. Medial meniscal tears should be debrided, or medial meniscal release may be considered to decrease the risk of late meniscal tears (see Chapters 35 and 36). An approach to the lateral distal femur and proximal tibia is then completed, including incising the fascia lata and reflecting the biceps femoris caudally. The stabilizing material is then placed in the plane between the joint capsule and fascia lata. Before closure, the stability and range of motion of the joint should be tested to ensure appropriate stability has been obtained while maintaining adequate range of motion. General care after surgery Initially, animals should be kept kenneled at all times with periodic sling walks for elimination purposes only. Starting at 2–3 weeks after surgery, focused, controlled rehabilitation activity can be initiated and should promote a recovery of function after ES procedures (Marsolais et al. 2002). Rehabilitation during the postoperative period is discussed in Chapter 42. Activity restriction is maintained for 12–16 weeks after surgery to prevent over-stressing the stabilizing structure. This is particularly important for those ES procedures that depend on the formation of implant-stimulated periarticular fibrosis for long-term success. Weight reduction should also be prescribed if appropriate. Biological extracapsular stabilization ES was first performed using biological materials; multiple techniques have been described. First introduced during the 1960s, fascial imbrication techniques rely solely on tightening the soft tissues lateral and medial to the joint to prevent cranial tibial subluxation (McCurnin et al. 1971; Pearson et al. 1971). A second technique uses a local strip of fascia lata that extends from the tibial tuberosity and is threaded around the fabella (Aiken et al. 1992) in an orientation that approximately mimics the trajectory of the native CrCL to limit cranial tibial subluxation and internal tibial rotation. A third technique, fibular head transposition, was introduced in 1985 (Smith & Torg 1985). By advancing the fibular head cranially, the lateral collateral ligament is oriented in an oblique direction similar to the native CrCL, limiting both cranial tibial subluxation and internal tibial rotation (Smith & Torg 1985; Mullen & Matthiesen 1989). Several studies using subjective outcome measures have reported reasonable success rates for these techniques (McCurnin et al. 1971; Pearson et al. 1971; Smith & Torg 1985; Mullen & Matthiesen 1989; Aiken et al. 1992). Generally, the most common complications associated with biological ES techniques in clinical cases are recurrent or persistent clinical lameness and/or stifle instability, occurring in one-fourth to one-third of cases in most reports (McCurnin et al. 1971; Pearson et al. 1971; Mullen & Matthiesen 1989; Aiken et al. 1992; Chauvet et al. 1996). Recurrent stifle instability likely results from stretching of the surgically repositioned soft tissues that are providing stability in the immediate postoperative period (Dupuis et al. 1994). Fibular head transposition has additional potential complications including fibular head fracture and softtissue irritation, seroma, or infection associated with the required metal implants (Smith & Torg 1985; Mullen & Matthiesen 1989). These biological ES techniques are now rarely used due to unacceptably low success rates and high complication rates, although fascial imbrication is often combined with other primary stifle stabilization procedures for augmentation. Extracapsular stabilization with synthetic materials The use of synthetic materials is now more common than biological techniques for ES (Korvick et al. 1994). Most commonly, a pliable linear implant (‘suture’) is passed from the caudodistal femur to the cranioproximal tibia across the lateral aspect of the joint, between the fascia lata and the joint capsule. A variety of types of ES using synthetic materials have been described, including the lateral fabello-tibial suture (Figure 25.1), TightRope CCL® (Arthrex Vet Systems, Naples, FL, USA) (Figure 25.2), various bone anchor techniques (Figure 25.3), and the Ruby Joint Stabilization System (Kyon Veterinary Surgical Products, Boston, MA) (Figure 25.4). 191 VetBooks.ir Extracapsular Stabilization Figure 25.1 Cranial and lateral illustrations of a stifle with a lateral fabello-tibial suture technique. Note that a small portion of the ‘extra-articular’ suture is within the joint. Source: Tonks et al. 2011. Reproduced with permission from Schattauer. (A) (B) (C) Figure 25.2 Medial (A), cranial (B), and lateral (C) illustrations of a stifle with the Tightrope CCL® technique. Source: Tonks et al. 2011. Reproduced with permission from Schattauer. Surgical Treatment VetBooks.ir 192 (A) (B) Figure 25.3 Cranial (A) and lateral (B) illustrations of a stifle with a femoral bone anchor technique. Source: Tonks et al. 2011. Reproduced with permission from Schattauer. The lateral fabello-tibial suture (LFTS) technique is based on Flo’s modification of the procedure described by DeAngelis and Lau (DeAngelis & Lau 1970; Flo 1975). A monofilament nylon leader line is passed from proximal to distal around the lateral fabella. Single or double tibial bone tunnels for suture passage have been described. The suture should be tunneled under the cranial tibial muscle rather than coursing over the muscle. The final suture pattern can be a box or a figure-of-eight configuration. The suture is fastened with knots or crimp clamps near the lateral fabella. The medial and lateral retinacular imbrication technique (MRIT) is similar to the LFTS except that a medial fabellotibial suture is also placed. The TightRope CCL® (TR) is a procedure in which a multifilament suture (FiberTape® ) is passed through femoral and tibial bicortical bone tunnels and secured on the medial side of each bone using endobuttons. The femoral exit site is 2 mm from the caudal edge of the lateral femoral condyle at the level of the distal fabella, and the tibial exit site is located at the caudal aspect of the extensor groove; the tunnels diverge away from the stifle joint. Multiple bone anchor systems have been described for ES, where the anchors are used to secure the suture at the femoral and/or tibial attachment sites (Figures 25.3 and 25.4), and a bone anchor at one site can be combined with a button or bone tunnel at the other site. Typically, multifilament sutures are used because the pliability of multifilament may be beneficial for use with bone anchors. The suture ends are typically joined using a knot. Anchor sites are chosen by the surgeon but should be based on isometry (see below). Examples of bone anchor products that have been used for ES include FASTak® and SwiveLock® . FASTak® anchors are pre-loaded with FiberWire® , whereas SwiveLock® anchors can be threaded with a suture of the surgeon’s preference. The Ruby Joint Stabilization System is a bone anchor system with multiple added innovations. The Ruby system uses two titanium alloy bone anchors with ceramic eyelets to secure a multifilament continuous-loop suture (Dyneema® ) to the bone. One loop of suture is associated with the femoral anchor and one loop with the tibial anchor, and the two loops are joined using a titanium link; the length of the Dyneema® loops must be pre-determined, but no knot or crimp is required. The ultralow-friction Ruby eyelet embedded in the bone 193 VetBooks.ir Extracapsular Stabilization (A) (B) Figure 25.4 The Ruby Joint Stabilization System represented in a bone model (A) and a lateral projection stifle radiograph of a clinical case (B). Source: Images courtesy of Dr. Otto Lanz. anchors is purported to minimize wear on the Dyneema® fibers. Suture material As discussed, the suture material can be either a monofilament or a multifilament line. Monofilaments may have lower infection rates (Korvick et al. 1994), while multifilaments tend to be superior in strength and stiffness, and have a greater resistance to elongation (Burgess et al. 2010; Rose et al. 2012). Nylon leader line is the most commonly used monofilament suture; it is mechanically superior to nylon fishing line (Caporn & Roe 1996; Nwadike & Roe 1998) and also to smaller-diameter polypropylene suture (Lewis et al. 1997). Nylon leader line is available in 20–80 pound test strengths; the test strength of the material should approximate the weight of the animal (Piermattei et al. 2006; Kowaleski et al. 2012), and one or two strands can be placed. When two strands are desired, many surgeons use two individual lengths tied individually, but it has been suggested that a single continuous length of suture overcomes the inevitable uneven tension on individual strands, which may lead to earlier failure (Wallace et al. 2008). Some studies have shown a weakening of the leader line after steam sterilization (Lewis et al. 1997) or ethylene oxide sterilization (Anderson et al. 1998), while others have shown no difference in mechanical properties after sterilization (Caporn & Roe 1996; Sicard et al. 2002). Generally, it is recommended to minimize the number of sterilization cycles where possible, particularly with steam sterilization. Many different multifilament products are available for extracapsular suture stabilization, which can be composed of polyethylene (e.g., Dyneema® ), polyester, polybutester, Kevlar, or a combination of materials. FiberWire® is a cylindrical multifilament composed of a core of multiple strands of high molecular weight polyethylene surrounded by a braided polyester jacket, while FiberTape® is a 2 mmwide tape with a similar material make-up to FiberWire® . Early in the development of LFTS, orthopaedic wire was used but radiographs revealed wire breakage in 26 of 33 cases (79%) by 6 weeks postoperatively (Störk et al. 2001); consequently, use of wire is not recommended. VetBooks.ir 194 Surgical Treatment Isometry Isometry refers to maintaining the same distance between the attachment sites of the stabilizing suture over a range of motion, and is a critical concept for ES as well as other types of CrCL repair. The femoral and tibial suture attachment sites should be as isometric as possible in order to minimize the impact on stifle range of flexion–extension motion and minimize stress on the suture and soft tissue or bone attachments (Figure 25.5). Suture attachment sites at the lateral caudodistal femur and the lateral cranioproximal tibia should create a suture trajectory that roughly mimics that of the CrCL in the sagittal plane. Theoretically, the use of isometric points should maximize the functional life span of the implant. However, due to the complex shapes and motions of the dog’s stifle joint, perfect isometry is not achievable with extra-articular attachment sites (Arnoczky et al. 1977; Fischer et al. 2010; Hulse et al. 2010). Numerous studies have attempted to determine the optimal tibial and femoral ES attachment points based on isometry, but resultant recommendations vary widely (Roe et al. 2008; Fischer et al. 2010; Hulse et al. 2010; Witte 2015). In two studies, measures of isometry were based on the distance between the proposed suture attachment sites on radiographs as the limb was moved through a range of flexion–extension motion (Roe et al. 2008; Witte 2015). Unsurprisingly, isometry was not achievable, but the most isometric points were determined to be: (i) caudolaterally on the femur at the level of the distal aspect of the lateral fabella; and (ii) cranial and proximal on the tibia between the tibial tuberosity and the extensor groove (Roe et al. 2008; Witte 2015). Small changes in the femoral attachment site had a greater effect on distance between attachment points than small changes in the tibial attachment site (Roe et al. 2008). Two ex vivo studies have been performed where suture tension was tested throughout a range of flexion– extension motion, where smaller changes in suture tension were interpreted as a higher degree of isometry. In one study, a circumfabellar suture was recommended that then passed through two bone tunnels just caudal to the tibial tuberosity (Fischer et al. 2010), while a second ex vivo study recommended anchoring the suture in the femoral condyle at the level of the distal aspect of the lateral fabella and in the bony prominence of the tibia just caudal to the extensor groove at the level of the tibial plateau (Hulse et al. 2010). Due to variations of conformation, the most isometric points are likely variable between breeds and individuals within a breed (Witte 2015). Methods of securing the suture to the femur and tibia Figure 25.5 Anatomic illustration showing points that are most isometric on the lateral aspect of the canine stifle, according to Hulse et al. (2010). Copyright © Samantha J. Elmhurst at www.livingart.org.uk. The suture can be secured at the femoral and tibial attachment sites in various ways. At either site, the suture can be anchored to the bone VetBooks.ir Extracapsular Stabilization either by passing it through a full-thickness bone tunnel and then through a button medially that lags up against the bone, or using a bone anchor. The femoral portion of the suture can also be anchored by passing it around the proximal fabella (fabellofemoral ligament). The tibial portion of the suture can also be anchored by passing the suture from lateral to medial under the patellar tendon and then back through a bone tunnel or medially then laterally through two bone tunnels. Few studies have been conducted to compare the various forms of anchoring, but one ex vivo study showed that the TR procedure, which uses full thickness bone tunnels anchored medially with buttons, provided more resistance to cranial tibial displacement than did LFTS (Choate et al. 2013). Methods of securing suture ends The method of securing the suture can affect the strength of the construct. In general, monofilament sutures can be joined using one or multiple knots and/or crimp clamps. When tying a monofilament suture with square knots, more throws will increase knot security (Caporn & Roe 1996) but also increases the profile of the knot, which can cause tissue irritation and necrosis of the overlying skin. Four to five total throws are typically used, starting with a square knot (rather than a surgeon’s knot). In order to avoid losing suture tension during the first knot, a hemostat is often used to grasp the first throw while throwing the second. Metal crimp clamps negate the need for a bulky knot and allow the use of a tensioning device which holds the suture taut while crimping the clamp, facilitating placement of a tight suture without assistance. The success of crimp clamp fixation is equal to or better than knots in most studies (Anderson et al. 1998; Peycke et al. 2002; Banwell et al. 2005; Vianna & Roe 2006), but using crimp clamps weakens the suture at the crimp site (Sicard et al. 2002) and slippage of the suture through the clamp is also a concern (Burgess et al. 2010). If crimp clamps are used, it has been suggested that more than one crimp clamp should be placed to lessen the risk of slippage (McCartney et al. 2007), and that a crimping system which creates multiple crimps is used (Maritato et al. 2012). 195 The strongest combination of monofilament loop configuration and securing method is not known. In a biomechanical study comparing various double-loop suture configurations that were secured using crimp clamps, the singlestrand, double-loop configuration using an interlocking knot along with a crimp clamp was mechanically superior to five other configurations (Wallace et al. 2008), while a different study found this construct to be inferior to all tested constructs, with the strongest construct being a single-strand, double-loop secured purely with crimp clamps, but no double-loop, doublestrand constructs were tested (Aisa et al. 2015). Another ex vivo study comparing various knots to crimp clamps found that single-strand constructs secured with crimp clamps were as good or better than single-strand constructs secured with knots, but a double-loop construct secured with a self-locking knot was superior to all single-strand constructs (Peycke et al. 2002). Multifilament sutures can also be joined using one or multiple knots or crimp clamps. Knot security between types of multifilament sutures is variable (Burgess et al. 2010) due to differences in base material and suture coating. Multifilament sutures may have an increased incidence of slippage through a crimp clamp (Burgess et al. 2010; Maritato et al. 2012) and, therefore, knots are commonly used. The knot profile is lower when knotting a multifilament compared to a monofilament. Stifle position while securing suture As the suture is secured, cranial tibial subluxation and internal tibial rotation should be reduced. The recommended degree of applied suture tension is controversial. The surgeon should be cognizant of over-tightening as this can limit normal range of motion and increase the contact pressure on the joint surfaces (Tonks et al. 2010). Under-tightening can predispose to inadequate stabilization and premature loosening. In order to mitigate under- and overtightening, one author recommends that the stifle should be placed in approximately 100◦ of flexion when securing the suture (Fischer et al. 2010), while the TR protocol has the stifle placed at 140◦ when tying the suture. It has been suggested that the ideal angle for tightening the VetBooks.ir 196 Surgical Treatment ES suture may be different for individual dogs, depending on conformation (Witte 2015). Clinical outcome Extracapsular stabilization techniques generally have good outcomes, particularly subjectively. The most common major complications associated with ES procedures are postoperative meniscal tear, failure of the stabilization, and implant-associated infection (Dulisch 1981; Korvick et al. 1994; Chauvet et al. 1996; Conzemius et al. 2005; Guénégo et al. 2007; Casale & McCarthy 2009; Ertelt & Fehr 2009; Cook et al. 2010; Christopher et al. 2013). After LFTS, owners are reportedly satisfied with outcomes in 82–90% of cases (Moore & Read 1995; Chauvet et al. 2009). Minimal to no lameness was reported in 78–82% by 6–20 months’ follow up in most studies (Moore & Read 1995; Chauvet et al. 1996; Ertelt & Fehr 2009), although one study reported only 40% clinical improvement by 6 months (Conzemius et al. 2005). On palpation examination, 55–76% of dogs had no drawer palpable at 6–20 months after surgery (Moore & Read 1995; Chauvet et al. 1996; Ertelt & Fehr 2009), and 73% had no pain on stifle manipulation at 20 months postoperatively in the 11 dogs that returned for follow-up (Moore & Read 1995). Force plate examination is a more objective measure of outcome, and has been used in multiple studies of clinical outcome after LFTS and has shown less satisfactory results than the previously discussed subjective outcome measures. One study reported that only 15% of dogs achieved normal ground reaction forces within 6 months (Conzemius et al. 2005), another reported that 86% returned to normal by 20 months after surgery (Chauvet et al. 1996), while a third study reported that dogs treated with LFTS remained significantly different from normal throughout the study period of one year (Nelson et al. 2013). The most recent evidence has shown tibial osteotomy procedures, particularly the tibial plateau leveling osteotomy, to have superior outcomes when compared to ES (Lazar et al. 2005; Gordon-Evans et al. 2013; Nelson et al. 2013; Bergh et al. 2014), though there are also studies showing no difference in outcome between ES and osteotomy procedures (Conzemius et al. 2005; Au et al. 2010; Cook et al. 2010; Mölsä et al. 2013). Major postoperative complications reportedly occur in 7–17% of LFTS cases and include implant infection, swelling or irritation associated with the implant, implant failure, tearing of the fabellofemoral ligament, meniscal tear, failure to control stability, and peroneal nerve damage (Dulisch 1971; Casale & McCarthy 2009; Ertelt & Fehr 2009; Au et al. 2010). In one study, the risk of development of complications after LFTS was increased in dogs that were male, had a higher body weight, or were of younger age (Casale & McCarthy 2009). When multifilament suture is used for LFTS, the risk of fabellofemoral ligament failure is increased (Lodato et al. 2013), as is the risk of infection (Korvick et al. 1994). The risk of infection when using multifilament suture may be further increased with decreased surgeon experience (Dulisch 1981). Literature reporting clinical outcomes for techniques other than the LFTS is sparse. In the largest study of long-term outcome after clinical cases of CR treated with TR, owners reported a return to full function in 76% of dogs (60/79) and a return to acceptable function in 23% (18/79), with 44% (35/79) still experiencing some degree of pain (Christopher et al. 2013). Major complications occurred in 8.9% of stifles (7/79), with the primary major complication being postoperative meniscal tear (6.3%; 5/79). Other major complications were not detailed (Christopher et al. 2013). In another clinical study, 92% of dogs (48/52) had a successful outcome more than one year after TR surgery based on follow-up via phone conversation (Ritzo et al. 2014). The outcome was more likely to be successful if a concurrent meniscal tear was diagnosed and treated at the time of initial surgery (Ritzo et al. 2014). Owner assessment of outcome after ES using bone anchors is also good, with 92–100% owner satisfaction at 10–18 months after surgery (Guénégo et al. 2007; Hulse et al. 2011). At 18 months’ follow-up, one study reported that lameness had been resolved in 91% (44/48) of dogs (Guénégo et al. 2007). Despite good subjective outcome, radiographs revealed that the bone anchors had pulled out of the femur in 21% of dogs (10/48) in this study (Guénégo VetBooks.ir Extracapsular Stabilization et al. 2007). These were large and giant breed dogs, and pull-out was found to be more likely if the anchor was placed in the less isometric mid-condylar region rather than the caudal femoral condyle (Guénégo et al. 2007), which is likely due to the difference in direction of pull (Burkhart 1995; Balara et al. 2004) and/or isometry. No clinical studies have been published using the Ruby stifle stabilization system. Conclusions A large in vivo clinical study comparing the long-term outcome of each ES technique has not been performed and, therefore, the superior method of ES has not been determined. ES techniques are generally safe for the surgical treatment of CR in dogs. Given the major benefits of ES over osteotomy techniques, such as lower costs, lower technical difficulty, and minimal requirement for specialized equipment, it is likely that ES methods will remain a popular treatment option for CR in the foreseeable future. References Aiken SW, Bauer MS, Toombs JP. Extra-articular fascial strip repair of the cranial cruciate deficient stifle: Technique and results in seven dogs. Vet Comp Orthop Traumatol 1992;5:145–150. Aisa J, Calvo I, Buckley CT, et al. Mechanical comparison of loop and crimp configurations for extracapsular stabilization of the cranial cruciate ligamentdeficient stifle. Vet Surg 2015;44:50–58. Anderson CC, Tomlinson JL, Daly WR, et al. Biomechanical evaluation of a crimp clamp system for loop fixation of monofilament nylon leader material used for stabilization of the canine stifle joint. Vet Surg 1998;27:533–539. Arnoczky SP, Torzilli PA, Marshall JL. Biomechanical evaluation of anterior cruciate ligament repair in the dog: An analysis of the instant center of motion. J Am Anim Hosp Assoc 1977;13:553–558. Au KK, Gordon-Evans WJ, Dunning D, et al. Comparison of short- and long-term function and radiographic osteoarthritis in dogs after post-operative physical rehabilitation and tibial plateau leveling osteotomy or lateral fabellar suture stabilization. Vet Surg 2010;39:173–180. Balara JM, McCarthy RJ, Boudrieau RJ, et al. Mechanical performance of a screw-type veterinary suture anchor subjected to single load to failure and cyclic loads. Vet Surg 2004;33:615–619. 197 Banwell MN, Kerwin SC, Hosgood G, et al. In vitro evaluation of the 18 and 36 kg Securos cranial cruciate ligament repair system. Vet Surg 2005;34:283– 288. Bergh MS, Sullivan C, Ferrel CL, et al. Systematic review of surgical treatments for cranial cruciate ligament disease in dogs. J Am Anim Hosp Assoc 2014;50:315–321. Burgess R, Elder S, McLaughlin R, et al. In vitro biomechanical evaluation and comparison of FiberWire, FiberTape, OrthoFiber, and nylon leader line for potential use during extraarticular stabilization of canine cruciate deficient stifles. Vet Surg 2010;39:208–215. Burkhart SS. The deadman theory of suture anchors: Observations along a south Texas fence line. Arthroscopy 1995;11:119–123. Caporn TM, Roe SC. Biomechanical evaluation of the suitability of monofilament nylon fishing and leader line for extra-articular stabilisation of the canine cruciate-deficient stifle. Vet Comp Orthop Traumatol 1996;9:126–133. Casale SA, McCarthy RJ. Complications associated with lateral fabellotibial suture surgery for cranial cruciate ligament injury in dogs: 363 cases (1997– 2005). J Am Vet Med Assoc 2009;234:229–235. Chauvet AE, Johnson AL, Pijanowski GJ, et al. Evaluation of fibular head transposition, lateral fabellar suture, and conservative treatment of cranial cruciate ligament rupture in large dogs: a retrospective study. J Am Anim Hosp Assoc 1996;32:247–255. Choate CJ, Lewis DD, Conrad BP, et al. Assessment of the craniocaudal stability of four extracapsular stabilization techniques during two cyclic loading protocols: A cadaver study. Vet Surg 2013;42:853– 859. Christopher SA, Beetem J, Cook JL. Comparison of long-term outcomes associated with three surgical techniques for treatment of cranial cruciate ligament disease in dogs. Vet Surg 2013;42:329–334. Conzemius MG, Evans RB, Besancon MF, et al. Effect of surgical technique on limb function after surgery for rupture of the cranial cruciate ligament in dogs. J Am Vet Med Assoc 2005;226:232–236. Cook JL, Luther JK, Beetem J, et al. Clinical comparison of a novel extracapsular stabilization procedure and tibial plateau leveling osteotomy for treatment of cranial cruciate ligament deficiency in dogs. Vet Surg 2010;39:315–323. DeAngelis M, Lau RE. A lateral retinacular imbrications technique for the surgical correction of anterior cruciate ligament rupture in the dog. J Am Vet Med Assoc 1970;57:79–84. Dulisch ML. Suture reaction following extra-articular stabilization in the dog. Part II: a prospective study of 66 stifles. J Am Anim Hosp Assoc 1981;17:572– 574. Dupuis J, Harari J, Blackketter D, et al. Evaluation of the lateral collateral ligament after fibular head transposition in dogs. Vet Surg 1994;23:456–465. VetBooks.ir 198 Surgical Treatment Ertelt J, Fehr M. Cranial cruciate ligament repair in dogs with and without meniscal lesions treated by different minimally invasive methods. Vet Comp Orthop Traumatol 2009;22:21–26. Fischer C, Cherres M, Grevel V, et al. Effects of attachment sites and joint angle at the time of lateral suture fixation on tension in the suture for stabilization of the cranial cruciate ligament deficient stifle in dogs. Vet Surg 2010;39:334–342. Flo GL. Modification of the lateral retinacular imbrication technique for stabilizing cruciate ligament injuries. J Am Anim Hosp Assoc 1975;11:570. Gordon-Evans WJ, Griffon DJ, Bubb C, et al. Comparison of lateral fabellar suture and tibial plateau leveling osteotomy techniques for treatment of dogs with cranial cruciate ligament disease. J Am Vet Med Assoc 2013;243:675–680. Guénégo L, Zahra A, Madelénat A, et al. Cranial cruciate ligament rupture in large and giant dogs. A retrospective evaluation of a modified lateral extracapsular stabilization. Vet Comp Orthop Traumatol 2007;20:43–50. Havig ME, Dyce J, Kowaleski MP, et al. Relationship of tibial plateau slope to limb function in dogs treated with a lateral suture technique for stabilization of cranial cruciate ligament deficient stifles. Vet Surg 2007;36:245–251. Hulse D, Hyman W, Beale B, et al. Determination of isometric points for placement of a lateral suture in treatment of the cranial cruciate ligament deficient stifle. Vet Comp Orthop Traumatol 2010;23:163– 167. Hulse D, Saunders B, Beale B, et al. Extra-articular stabilization of the cranial cruciate deficient stifle with anchor systems. Tierarztliche Praxis Kleintiere 2011;39:363–367. Kowaleski MP, Boudrieau RJ, Pozzi A. In: Veterinary Surgery: Small Animal. Stifle Joint. Karen M, Tobias SAJ, eds. 1st edn. St Louis, MO, Elsevier-Saunders, 2012, pp. 906–998. Korvick DL, Johnson AL, Schaeffer DJ. Surgeons’ preferences in treating cranial cruciate ligament ruptures in dogs. J Am Vet Med Assoc 1994;205: 1318–1324. Lazar TP, Berry CR, de Haan JJ, et al. Long-term radiographic comparison of tibial plateau leveling osteotomy versus extracapsular stabilization for cranial cruciate ligament rupture in the dog. Vet Surg 2005;34:133–141. Lewis DD, Milthorpe BK, Bellenger CR. Mechanical comparison of materials used for extra-capsular stabilisation of the stifle joint in dogs. Aust Vet J 1997;75:890–896. Lodato D, Wardlaw J, Rowe D. Retrospective study comparing two materials commonly used in the LFS technique for CCLR. J Am Anim Hosp Assoc 2013;49:108–114. Maritato KC, Barnhart MD, Kazanovicz AJ, et al. In vitro mechanical evaluation and comparison of two crimping devices for securing monofilament nylon and multifilament polyethylene for use in extracapsular stabilization of the canine stifle. Vet Comp Orthop Traumatol 2012;25:466–471. Marsolais GS, Dvorak G, Conzemius MG. Effects of postoperative rehabilitation on limb function after cranial cruciate ligament repair in dogs. J Am Vet Med Assoc 2002;220:1325–1330. McCartney WT, O’Connor JV, McCann WM. Incidence of infection and premature crimp failure after repair of cranial cruciate ligament-deficient stifles in 110 dogs. Vet Rec 2007;161:232–233. McCurnin DM, Pearson PT, Wass WM. Clinical and pathologic evaluation of ruptured cranial cruciate ligament repair in the dog. Am J Vet Res 1971;32:1517–1524. Mölsä SH, Hielm-Björkman AK, Laitinen-Vapaavuori OM. Use of an owner questionnaire to evaluate long-term surgical outcome and chronic pain after cranial cruciate ligament repair in dogs: 253 cases (2004–2006). J Am Vet Med Assoc 2013;243:689– 695. Moore KW, Read RA. Cranial cruciate ligament rupture in the dog – A retrospective study comparing surgical techniques. Aust Vet J 1995;72:281– 285. Mullen HS, Mattheisen DT. Complications of transposition of the fibular head for stabilization of the cranial cruciate-deficient stifle in dogs: 80 cases (1982–1986). J Am Vet Med Assoc 1989;195:1267– 1271. Nelson SA, Krotscheck U, Rawlinson J, et al. Longterm functional outcome of tibial plateau leveling osteotomy versus extracapsular repair in a heterogenous population of dogs. Vet Surg 2013;42: 38–50. Nwadike BS, Roe SC. Mechanical comparison of suture material and knot type used for fabello-tibial sutures. Vet Comp Orthop Traumatol 1998;11:47– 52. Pearson PT, McCurnin DM, Carter JD, et al. Lembert suture technique to surgically correct ruptured cruciate ligaments. J Am Anim Hosp Assoc 1971;7:1– 13. Peycke LE, Kerwin SC, Hosgood G, et al. Mechanical comparison of six loop fixation methods with monofilament nylon leader line. Vet Comp Orthop Traumatol 2002;15:210–214. Piermattei DL, Flo GL, DeCamp CE. Brinker, Piermattei, and Flo’s Handbook of Small Animal Orthopaedics and Fracture Repair. 4th edn. St Louis, SaundersElsevier, 2006. Ritzo ME, Ritzo BA, Siddens AD, et al. Incidence and type of meniscal injury and associated long-term clinical outcomes in dogs treated surgically for cranial cruciate ligament disease. Vet Surg 2014;43: 952–958. Roe SC, Kue J, Gemma J. Isometry of potential suture attachment sites for the cranial cruciate ligament VetBooks.ir Extracapsular Stabilization deficient canine stifle. Vet Comp Orthop Traumatol 2008;21:215–220. Rose ND, Goerke D, Evans RB, et al. Mechanical testing of orthopaedic suture material used for extraarticular stabilization of canine cruciate ligamentdeficient stifles. Vet Surg 2012;41:266–272. Sicard GK, Hayashi K, Manley PA. Evaluation of 5 types of fishing material, 2 sterilization methods, and a crimp-clamp system for extra-articular stabilization of the canine stifle joint. Vet Surg 2002;31:78–84. Störk CK, Gibson NR, Owen MR, et al. Radiographic features of a lateral extracapsular wire suture in the canine cranial cruciate deficient stifle. J Small Anim Pract 2001;42:487–490. Smith GK, Torg JS. Fibular head transposition for repair of cruciate-deficient stifle in the dog. J Am Vet Med Assoc 1985;187:375–383. 199 Tonks CA, Pozzi A, Ling HY, et al. The effects of extra-articular suture tension on contact mechanics of the lateral compartment of cadaveric stifles treated with the TightRope CCL or lateral suture technique. Vet Surg 2010;39:343–349. Vianna ML, Roe SC. Mechanical comparison of two knots and two crimp systems for securing nylon leader line used for extra-articular stabilization of the canine stifle. Vet Surg 2006;35:567–572. Wallace AM, Cutting ED, Sutcliffe MP, et al. A biomechanical comparison of six different double loop configurations for use in the lateral fabella suture technique. Vet Comp Orthop Traumatol 2008;21:391–399. Witte PG. Tibial anatomy in normal small breed dogs including anisometry of various extracapsular stabilizing suture attachment sites. Vet Comp Orthop Traumatol 2015;28:331–338. VetBooks.ir VetBooks.ir 26 Intra-Articular Repair for Cranial Cruciate Ligament Rupture in the Dog Jeffery J. Biskup and Michael G. Conzemius Introduction Cruciate ligament rupture (CR) is one of the most common orthopaedic conditions seen in small animal medicine, but an ideal repair has not yet been elucidated (Johnson et al. 1994; Bellumori et al. 2013; Krotscheck et al. 2016). Although successful treatment of CR has been achieved both medically and surgically, recent evidence suggests that outcomes are optimized in dogs after surgical treatment (Wucherer et al. 2013). This chapter first identifies some potential limitations of commonly used surgical procedures for CR, briefly explores the historic use of intra-articular repair in dogs, and then focuses on overcoming the identified limitations of both extra- and intra-articular repairs. Specifically, the limitations addressed will include graft selection, graft fixation, and graft biology. Current cruciate ligament rupture surgical treatment outcomes Surgery for CR has been shown to greatly improve lameness but may not consistently get patients back to normal (Mölsä et al. 2013; Wucherer et al. 2013). Current tibial osteotomy stabilization methods have high success rates at early and mid-range follow-up times, but outcome measures are often subjective, such as non-validated owner questionnaires (Hoffman et al. 2006; Corr & Brown 2007; Stein & Schmoekel 2008) and veterinarians’ visual assessment (Waxman et al. 2008). More objective outcomes, such as force platform analysis, pressure platform analysis, radiographic scoring and thigh circumference have been used as more sensitive ways to assess lameness after surgical treatment of CR (Jevens et al. 1996; Conzemius et al. 2005). With more objective measurements, outcomes with tibial osteotomies in certain studies have shown that operated limbs do not obtain the same function as normal limbs (Evans et al. 2005; Voss et al. 2008). A final challenge when interpreting CR surgical outcome studies is that standardized definitions of success and follow-up time have not been agreed upon, and this makes the comparison of studies difficult. For example, one study used a stringent definition of success that combined both subjective and objective outcomes, comparing medical management to tibial plateau leveling osteotomy (TPLO) (Wucherer et al. 2013). That study revealed a Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 201 VetBooks.ir 202 Surgical Treatment success rate of only 75% at one year after TPLO treatment. Although outcomes seem to be optimal for current procedures in many studies, the limitations mentioned above and the progression of more sensitive outcome measures may change the interpretations of results. One consistent finding between many studies is that most dogs will still have progressive osteoarthritis (OA) after surgical treatment, affecting long-term success (Elkins et al. 1991; Innes & Barr 1998; Lazar et al. 2005). Furthermore, although the severity of OA has not been shown to be correlated with lameness, dogs with OA have a greater chance of lameness compared to a dog with a normal stifle (Gordon et al. 2003). It is hypothesized that progressive OA develops because the most commonly performed techniques do not replace all mechanical properties of an intact cranial cruciate ligament (CrCL) (Kim et al. 2012; Skinner et al. 2013; Biskup et al. 2014a). The CrCL is known to prevent cranial translation, internal rotation, and hyperextension of the tibia (Heffron & Campbell 1978). An in-depth discussion of all current repair options is beyond the scope of this chapter, but main concepts will be briefly discussed. First, extra-articular sutures lack the material strength to eliminate drawer (Cabano et al. 2011; Rose et al. 2012; Biskup et al. 2014a), and the anchor points are not likely to be isometric (Roe et al. 2008; Fischer et al. 2010; Hulse et al. 2010b). The results of some studies that incorporated objective outcomes also suggest that suture repairs are inferior to tibial osteotomies (Gordon-Evans et al. 2013; Krotscheck et al. 2016). Similarly, tibial osteotomies have a limited ability to prevent internal rotation, and femoral-tibial subluxation is inconsistently eliminated (Kim et al. 2012; Skinner et al. 2013). Continued instability after these repairs likely contributes to a higher rate of latent meniscal tears and progressive OA that is demonstrated when follow-up is extended to a year or longer (Bennett et al. 1988; Elkins et al. 1991; Rayward et al. 2004; Kowaleski et al. 2005; Stauffer et al. 2006). Thus, is it not surprising that the veterinary surgical community has not agreed upon the ideal surgical treatment for CR. The ‘gold standard’ in humans for anterior cruciate ligament (ACL) rupture repair is intraarticular placement of a graft at the attachment sites of the ACL. Currently, there is no consensus on the ideal graft, nor on the method of fixation (Murray 2009). ACL graft repairs in human patients have a reoperation rate of 3–5%, and <20% of patients develop progressive OA (Harilainen & Sandelin 2009). In contrast, up to 30% of dogs have postoperative meniscal injury with complete CR, and close to 100% have progressive OA at 2 years after treatment (Lazar et al. 2005; Hulse et al. 2010a; DeLuke et al. 2012). Differences in pathophysiology, function, and the ability of human patients to assess their own outcome may explain some of these differences, although a fivefold difference in treatment failures might suggest that the anatomic reconstruction procedures performed in people are superior to the non-anatomic procedures commonly used in dogs. Historical use of intra-articular repairs Although the ACL was first mentioned in records dated from 3000 BC, its complex anatomy was first described by Claudis Galen between 300 and 400 BC. Although many repair methods were attempted, the first modern case series reporting an intra-articular repair was reported by Hey Groves in 1917 (Davarinos et al. 2014). Groves described a fascia lata strip placed through the joint and anchored in a tibial tunnel; this procedure is the predecessor to current repairs in humans. A modification of this technique led to the first veterinary intra-articular repair. In 1952, Paatsama described passing the lateral fascia lata through bone tunnels in the femur and tibia and suturing it to soft tissue as the graft exited the tunnel (Knecht 1976; Burnett & Fowler 1985). The original repair has gone through multiple modifications, including those by Singleton in 1957, Titemeyer and Brinker in 1958 and Rudy in 1974, leading to the intra-articular repairs most familiar to veterinarians, the ‘over-thetop’ and ’under-and-over’ techniques (Singleton 1957; Knecht 1976; Hulse et al. 1980; Shires et al. 1984). As recently as 20–30 years ago, intra-articular reconstructive techniques were the preferred CrCL repair methods in dogs, and have also been reported in cats (Korvick et al. 1994; Moore & Read 1995; Innes et al. 2000b; Garcia et al. 2012). Although the outcomes were subjective, some results were promising (Pichler et al. 1982; Denny & Barr 1987; Innes & VetBooks.ir Intra-Articular Repair for Cranial Cruciate Ligament Rupture in the Dog Barr 1998). With the development of extraarticular sutures and tibial osteotomies, intraarticular repairs fell out of favor due to their inferior outcomes, continued stifle instability, progressive cartilage degeneration, and donor site morbidity (Butler et al. 1983; Elkins et al. 1991; Innes et al. 2000a; Johnson et al. 2001; Innes et al. 2004; Conzemius et al. 2005; Snow et al. 2010; Molsa et al. 2014). These studies, as well as surgeons’ own experiences with the procedure, have led to intra-articular repairs being mostly abandoned in North America. However, a review of the literature addressing intraarticular repair in dogs identifies three common limitations: inappropriate graft selection; inappropriate fixation; and an inappropriate biological environment for graft healing. Graft selection Autografts The autograft is a natural extracellular matrix (ECM) scaffold that initially can provide biomechanical properties similar to the native ligament, as well as a biochemical and structural composition to guide cell growth. In addition, growth factors may be trapped within the natural ECM, providing a source of biological stimuli that promote ligament fibroblast differentiation. Autografts also minimize the risk of immune detection and disease transmission. The use of autografts was described in many original techniques and continues to be one of the most commonly used grafts in humans (Murray 2009). In veterinary medicine, using a portion of the straight patella tendon or a strip of the fascia lata is most commonly reported, although skin, peroneus longus, flexor digitalis pedis longus, long digital extensor, periosteum and semitendinosus/gracilis autografts have all been described (Chiroff 1975; Knecht 1976; Arnoczky et al. 1979a; Ramanaiah et al. 1990; Innes et al. 2000a; Lopez et al. 2003; Veena et al. 2003; Penha et al. 2007). Patella tendon autograft use, a technique modified from human medicine, allows for either bone or soft tissue anchor points, and was first described by Dueland in 1966 (Dueland 1966). Dueland harvested the central third of the straight patella tendon and patella, creating a tendon-bone graft. The distal end 203 of the graft maintained attachment to the tibia, while the free proximal end was passed through a femoral tunnel and sutured to the gastrocnemius. Although Dueland felt the outcomes were good, very few were reported. Subjective outcomes were promising enough that the procedure and its modifications were performed by Dueland until his retirement. A modification was described in 1979, where the lateral third of the straight patella tendon, as well as a strip of fascia lata, was passed through the joint and over the caudal aspect of the lateral condyle, often referred to as the ‘over-the-top’ technique (Arnoczky et al. 1979a; Arnoczky et al. 1979b; Denny & Barr 1984; Bennett & May 1991). Although intra-articular autografts have been described for over 50 years, there is a paucity of information on the suitability of these grafts, specifically their ability to heal, graft mechanical strength, graft attachment mechanical strength and donor site morbidity. Objective outcomes were evaluated in 1975, when healing was assessed in experimentally replaced CrCL using a third of the patella tendon (Chiroff 1975). Both the tendon and bone underwent necrosis before more rapid ingrowth occurred. Although healing progressed quickly initially, incorporation remained incomplete at one year. The modified ‘over-the-top’ technique showed there was graft revascularization where the graft contacted the fat pad and caudal joint soft tissues, suggesting vessel ingrowth into the sides of the graft rather than longitudinal revascularization (Arnoczky et al. 1979b; Arnoczky et al. 1982). In contrast, a small pilot study showed that at one year, a hamstring graft had histopathology similar to the normal CrCL. Clinically, it was reported the patients were not showing signs of lameness (Lopez et al. 2003). Subsequent studies have revealed similar results of incomplete and inconsistent revascularization and repopulation based on graft selection (Bacon et al. 1984; McFarland et al. 1986; Ng et al. 1995; Fu et al. 1999). Available data showing the initial in vitro and in vivo mechanical strength of common autografts is minimal. Given the critical role that the CrCL plays in stifle mechanics, it is believed to be of paramount importance to demonstrate that a surgical technique can reproduce the salient mechanical features of the intact CrCL. Tensile testing of the medial third, central third VetBooks.ir 204 Surgical Treatment and lateral third, in combination with the fascia lata, revealed that no graft was able to mimic the strength or stiffness of the native CrCL. Although the central and lateral thirds were stronger than the medial third, it is likely that no partial patella tendon graft has the mechanical properties necessary for recovery in the dog (Butler et al. 1983; Johnson et al. 1989). In fact, it has been reported that the entire patellar tendon is needed to reproduce the mechanical properties of the CrCL. (Biskup et al. 2014b) Mechanical properties of the patella tendon autografts at 4, 12, and 26 weeks after surgery revealed strength and stiffness increasing and elongation decreasing at each time point, although grafts never reached the full strength of the intact CrCL. Compared to extra-articular repairs, both a third of the patella tendon and a fascia lata strip showed less stiffness and greater laxity compared to fibular head transposition and lateral imbrication (Patterson et al. 1991). Clinical assessment of laxity postoperatively showed that the lateral third of the patella tendon with a fascia lata strip placed in an ‘over-the– top’ technique had increased laxity at 4 weeks after surgery before decreasing laxity out to 26 weeks. At 26 weeks, laxity of 2.5 mm was still more than the intact CrCL at 1.8 mm (Hulse et al. 1983). A limited number of clinical studies have been conducted with subjective and objective outcomes to assess the mechanical strength of common autografts. In one study, examinations were made of dogs with naturally occurring CR repaired with a fascial ‘over-the-top’ graft and assessed with an owner questionnaire and force platform analysis. With an almost 1.5 year follow-up, owner satisfaction was very high, although gait analysis revealed significantly decreased peak vertical force (Geels et al. 2000). OA also progressed in all dogs. Similar results were found in 21 dogs with patella tendon/fascia lata grafts (Vasseur & Berry 1991). All owners felt that their dog showed significant improvement, although instability and progressive OA were documented in most cases. A unique challenge to autograft collection is donor site morbidity. A mechanical study of the patella tendon after removal of its central third revealed the cross-sectional area to be dramatically increased over the control tendon, although strength was significantly less at 3 and 6 months (Linder et al. 1994). Another study revealed that the donor patella tendon decreased in failure strength by 30% compared to a control at 6 months (Burks et al. 1990). Although autografts have shown promise, an autograft with the necessary mechanical properties that minimize donor site morbidity has not been described. Further work is necessary before autografts could be commonly used for CrCL repair. Allografts Allograft benefits include a natural ECM scaffold, with the benefit of no donor site morbidity. With allografts, a whole tendon can be used, such as the entire patella tendon rather than a third of the patella tendon. The donor tendon is readily available without needing intraoperative collection, Finally, there is the option of using a ligament graft, such as the CrCL, as an allograft. Although allografts have these advantages, they raise concern of disease transmission, immunological reaction, and alteration of ingrowth characteristics. Risk of disease transmission in veterinary medicine is unlikely, especially if appropriate donor screening is performed, if grafts are collected in a timely manner with sterile technique, if post-collection monitoring is performed, and graft tracking is ensured to record any future complications. Specific protocols are often readily available from companies providing allografts commercially. The detection, reaction, and destruction of a graft is always a concern when foreign tissue is implanted in the body. The placement of a fresh allograft would increase the likelihood of an immune-directed inflammatory response, although this is not commonly performed, nor is it currently feasible for CrCL replacement. More commonly, allografts are treated with an acute deep-freeze, cyclic deep-freeze– thaw cycles, freeze-drying, gamma-irradiation or ethylene oxide. The freezing of tendons or ligaments has been shown to decrease disease transmission and immunogenic potential, although some protocols may decrease mechanical properties (Gut et al. 2016). In a dog model, central-third patella autografts were compared to similar deep-frozen allografts (Arnoczky et al. VetBooks.ir Intra-Articular Repair for Cranial Cruciate Ligament Rupture in the Dog 1986). At 1 year, both grafts had a similar appearance on histopathology. In a study of 25 dogs, central-third patella tendon deep-frozen allografts were implanted and showed evidence of revascularization at 6 weeks, and a similar histopathologic appearance to the native CrCL at 30 weeks (Shino et al. 1984). In a similar study comparing frozen CrCL allografts to CrCL autografts (Kirkpatrick et al. 1996), allografts were weaker than autografts, and appeared to have delayed revascularization at all time points up to 24 months. Gamma-irradiation is effective at decreasing negative biological reactions in the recipient, but can greatly alter mechanical properties (Fu et al. 1999); this effect seems to be dose-dependent (Fideler et al. 1995). Goertzen reported that bone-ligament-bone CrCL grafts deep-frozen and sterilized with gamma-irradiation had similar strength as non-irradiated frozen grafts. At 12 months after implantation, the grafts had 60–70% strength of the normal CrCL and a similar collagen pattern (Goertzen et al. 1995). Although 60 dogs were studied, limitations included the fact that limbs were immobilized for 5 weeks after surgery, and functional outcome was not assessed. Ethylene oxide has minimal effects of mechanical properties, but residues could be either inflammatory or carcinogenic (Silvaggio et al. 1993; Bechtold et al. 1994). 205 A final emerging technique to decrease immunogenic potential while maintaining mechanical integrity of the graft is called decellularization. This refers to the process of removing cells from the tissue while preserving the structural and functional proteins that constitute the ECM. Decellularized tissue scaffolds have the potential to provide available biocompatible graft material that can resemble native tissue structurally, biochemically, and biomechanically (Hoganson et al. 2010; Pridgen et al. 2011). Many different decellularization protocols have been described, and evaluation of the process is in its infancy. Potential negative effects include impairment of the viability of colonizing cells with chemical residues, wash-out of growth factors bound by the ECM, loss of ECM structure, and the induction of sterile inflammation (Schultze-Tanzil et al. 2012). In veterinary medicine, a described protocol reduced the mean DNA content by between 44% and 83% in an equine tendon (Youngstrom et al. 2013). In addition to verifying the removal of antigenic debris, it is also necessary to confirm that desirable components of the ECM (i.e., glycosaminoglycans, collagen, protein) are retained. A similar protocol was evaluated on the canine deep digital flexor tendon and superficial digital flexor tendon (Balogh et al. 2016) (Figure 26.1). The histological, biochemical, and mechanical results of Figure 26.1 Image of a decellularized deep digital flexor tendon being prepared for implantation as a cranial cruciate ligament allograft. VetBooks.ir 206 Surgical Treatment decellularization on deep digital flexor tendons showed a significant decrease in DNA content, preservation of the ECM, and no significant change in mechanical properties. The use of allografts has been described in veterinary medicine (Shino et al. 1984; Vasseur et al. 1991), with studies examining ideal graft size, mechanical strength, histology, and clinical outcome (Qu et al. 2015). Vasseur et al. 1985 replaced the CrCL with CrCL allografts in mixed-breed dogs in two studies. The first study resulted in unstable stifles at 9 months, with the allografts appearing immunogenic and reaching only 14% of the strength of the intact CrCL. A second study, although small and short-term, demonstrated the possibility of a successful outcome (Vasseur et al. 1987). Dogs with stable stifles immediately after surgery had a full recovery to normal gait (two dogs), but when laxity was detected after surgery, all dogs failed to have a successful outcome. Thorson et al. 1989 performed a similar study, implanting CrCL allografts in 11 patients with a 73% failure rate. Three dogs developed infections and were removed from the study, and five of the remaining eight dogs had a limp at 4 months (Thorson et al. 1989). Unfortunately, there was no description of graft size or fixation strength. The above described study found that allografts reached anywhere from 10% to 59% of the ultimate strength of an intact CrCL. A more encouraging study included 28 dogs which received CrCL allografts. Clinical assessment of the dogs was not discussed, but allografts reached 90% ultimate strength of the normal CrCL at 36 weeks (Nikolaou et al. 1986). Although the outcome measures were not clinical, these authors concluded there were only three failures during the 18-week study. Freeze-dried fascia lata strips have also served as allografts. In a study of medium-sized dogs, eight patients underwent the ‘over-thetop’ procedure, and eight dogs had graft placement through bone tunnels. At 24 weeks, both groups showed graft incorporation. Failure of the grafts occurred at 536 N, compared to 801 N for the intact CrCL (Curtis et al. 1985). Other reported allografts for CrCL repair have included the submucosa, bovine pericardium, and the deep digital flexor tendon (Figure 26.2) (Aiken et al. 1994; Biasi et al. 2005; Brendolan et al. 2007; Biskup et al. 2017). Figure 26.2 Intra-articular placement of a deep digital flexor tendon allograft to replace the cranial cruciate ligament in an ex vivo stifle. As allograft harvesting and preparation techniques continue to develop, allografts may be an inviting option for CrCL repair. Further studies are required to determine initial strength, the decrease in strength over time, cell ingrowth, and immune reaction of any newly proposed allograft. Prosthetics Prosthetic ligaments have been described as either a primary repair or as augmentation for biological grafts (Knecht 1976; Kdolsky et al. 1997; de Rooster et al. 2001; Mascarenhas & MacDonald 2008; Müller et al. 2010; Müller et al. 2011). Tissue-engineered scaffold biomaterials have been developed in attempts to improve and accelerate healing or to reconstruct tendons or ligaments altogether. They avoid donor site morbidity, eliminate the risk VetBooks.ir Intra-Articular Repair for Cranial Cruciate Ligament Rupture in the Dog of disease transmission, and the initial strength and stiffness can be selected. Braided nylon, Teflon, Supramid, GoreTex and Dacron are just some examples of materials described for ligament replacement. An early report showed good subjective outcomes when polyethylene suture was placed in an intra-articular location in 98 dogs (Singleton 1969). The limitations of these scaffolds include their diminished biocompatibility, unpredictable degradation rates, and biomechanical weakening due to degradation (Liu et al. 2008). A canine study evaluated replacement of the CrCL using Dacron. The groups included an ‘over-the-top’ placement, femoral and tibial bone tunnel placement, and the two techniques with extra-articular augmentation (Park et al. 1985). All grafts were intact at 12 weeks with no loss in strength, but at 24 weeks some grafts showed signs of wear at the origin of the tunnels, with fibrous tissue ingrowth evident. A similar study using polyester fiber placed in a similar manner produced equivalent results (Stead et al. 1991). Studies have also investigated use of prosthetic material as a short-term brace for natural grafts. In dogs with CR, stifles were more stable at 12 weeks when a fascia lata graft and poly-L-lactide implant were used compared with the fascia lata graft alone, although no differences were seen between the groups by 24 weeks (Laitinen 1994). A separate study showed that an intra-articular prosthetic graft allowed improved healing of CrCL elongation injury compared to an elongated CrCL with no protection (Lopez et al. 2006). Given the properties of the materials currently available, short-term success is often observed, followed by long-term failure due to a loss of mechanical strength before replacement with native tissue. If a material that promotes a rapid ingrowth of native cells, while maintaining mechanical strength and limiting biologic reaction, could be developed, then prosthetic ligament replacement could be the preferred technique for CrCL repair. Fixation Three main challenges arise when stabilizing an intra-articular graft: placement at an ideal location, optimal tension at the time of fixation, and 207 development of a fixation method that will provide the required strength for recovery. The CrCL has been described in detail (Arnoczky 1983), and it is not a simple band. First, there are two main components, the craniomedial and caudolateral bands, which interact intimately throughout range of motion. The craniomedial band remains taut throughout a range of motion as it twists close to 90◦ from proximally to distally. The caudolateral band is taut only in extension (Arnoczky & Marshall 1977). Intra-articular repair struggles to replicate this anatomy, and the ideal orientation of an intra-articular graft at the time of fixation is unknown. Second, the fan-like attachment to the axial aspect of the lateral femoral condyle and craniomedial tibia, underneath the intermeniscal ligament, make placement of bone tunnels challenging. One limitation of many intra-articular repairs previously reported is that the graft is not placed at the attachment sites of the CrCL (Bacon et al. 1984; Coetzee & Lubbe 1995). The ‘over-the-top’ technique does not follow the native path of the CrCL, but rather passes the graft caudally and over the top of the lateral condyle. This path also increases the working length of the graft. When bone tunnels are created, the ideal location within the CrCL attachment site is unknown. In humans, it has been shown that bone tunnel placement in the attachment sites of the ACL may not be perfectly isometric points (Austin et al. 2007). In dogs, it is suggested that the isometric location may be caudal to the femoral attachment site of the CrCL (Palmisano et al. 2000). The next challenge with graft fixation is deciding the ideal tension to be placed on the graft while it is being secured. This has been extensively explored in humans, with variation in recommendations based on the graft and technique used (Mae et al. 2008; Grunau et al. 2016). Obviously, too little tension will result in postoperative laxity, but too much tension can change the contact mechanics, decrease the range of motion and affect healing (Austin et al. 2007; Mae et al. 2008). A study exploring hamstring grafts in dogs found that, when placed under minimal tension (1 N), graft survival was superior when compared with high tension (39 N) (Yoshiya et al. 1987). Preconditioning grafts with static or cyclic tension is another highly investigated area of human VetBooks.ir 208 Surgical Treatment ligament replacement. A report describing human semitendinosus grafts assessed a single acute 80 N pull, a static 88 N pull for 20 minutes, or 20 cyclic pulls, each of 80 N. Cadaveric testing showed that either the extended load or cyclic load was superior for preventing initial elongation (Pilia et al. 2015). In contrast, a study with a similar protocol found no benefit when the secured grafts were tested in using cyclic loading (Boguszewski et al. 2015). No studies have been performed in dogs for CrCL graft placement, although it has been suggested that preconditioning a CrCL allograft would be important to eliminate initial elongation (Yahia & Drouin 1990). Stifle angle at the time of fixation could also affect tension. A study in dogs showed that the fixation angle had a greater effect on graft tension than tunnel location (Shelley et al. 1996). Although the ideal angle was unknown, the study suggested that stifles should not be flexed to 90◦ at the time of fixation. Finally, graft fixation methods are varied, and the optimal method continues to be debated. In humans, multiple techniques for securing bone–ligament and soft tissue grafts have been described, including interference screws, pinning, spiked washers, and suture (Hill et al. 2005). Interference screws are commonly used in human surgery, and when used in a repair technique they reportedly have an in vitro strength of between 463 and 1358 N (Kousa et al. 1995; Rupp et al. 1997). Possible benefits of interference screws include ease of use, and that they can be sized to accommodate grafts with different cross-sectional areas, which improves the contact between the bone tunnel and graft. When using grafts that are folded to double the graft, such as the hamstring tendon or deep digital flexor tendon (DDFT), a cross-pin technique is an alternative fixation technique (Harilainen & Sandelin 2009). In cross-pin transfixation techniques, a pin is passed through the loop created at the fold in the graft. The remaining graft ends can be secured with one of the above-mentioned techniques. A unique challenge in the dog is that the initial fixation strength has to overcome daily forces encountered by the CrCL, as a gradual increase in weight-bearing is not possible as in humans. In ex vivo canine stifles, it was shown that an entire patella tendon secured with interference screws or with bone anchors was likely not strong enough to withstand daily physiologic loads (Biskup et al. 2015). However, when DDFT was secured with a cross-pin and spikes washers, the mechanical strength was similar that of the native CrCL (Figure 26.3). Similarly, a novel graft fixation device has been shown to have equal strength to spiked washers (Lopez et al. 2007). In veterinary medicine, previous reports of commonly performed intraarticular repairs showed grafts to be secured most frequently only with suture (Bacon et al. 1984; Coetzee & Lubbe 1995). Suture stabilization of a graft undoubtedly provides insufficient strength for patient use. Fixation methods continue to progress in human and veterinary medicine. The unique challenges with management of canine patients immediately postoperatively must be considered when choosing a method. Further studies are needed to examine the effect of tunnel location and graft tension on healing and clinical outcome. Biology Although it is believed that CrCL graft and fixation mechanics must be sound, intra-articular graft placement also creates biological challenges, including the obstacle of intra-articular healing, promotion of vascular ingrowth and remodeling, and avoidance of immunemediated rejection. It is important to understand that intraarticular graft healing differs from the healing of other extra-articular ligaments. Experiments have evaluated the ability of the ACL in humans to heal compared to the healing potential of the medial collateral ligament, a ligament which is responsive to medical therapy (Murray et al. 2006; Murray et al. 2007). Cell proliferation responses were shown to be similar between the two ligaments. Therefore, the authors suggested that the differences must be in the biologic and mechanical environments. Similar to the ACL, CrCL healing occurs in a unique environment, intra-articularly but extrasynovial, due to its being completely covered by a synovial membrane. When the CrCL is damaged, the hematoma that usually forms a scaffold for healing is dissipated in the joint. Also, when VetBooks.ir Intra-Articular Repair for Cranial Cruciate Ligament Rupture in the Dog (A) (B) Figure 26.3 Lateral (A) and craniocaudal (B) radiographs of a stifle at one year after placement of an intra-articular deep digital flexor tendon allograft secured with a cross-pin on the femur and spiked washer on the tibia. 209 the synovial sheath is disrupted, the ligament is exposed to synovial fluid, which contains inflammatory mediators. The sheath contains vessels that serve as an important blood supply to the ligament (Murray et al. 2006). When a graft is initially placed, it lacks the synovial sheath, and this is suggested to deprive the graft of an early blood supply and expose it to inflammatory mediators (Arnoczky & Marshall 1981). The CrCL is exposed to constant mechanical forces during weight-bearing, and it is difficult to protect the ligament with a brace or internal repair. In a CrCL model, the ends of a transected CrCL were sutured into apposition, and the stifle was immobilized. At 10 weeks, the CrCL had shown evidence of healing but did not reach full strength (O’Donoghue et al. 1966). Lastly, an appropriate scaffold is necessary for cell migration. In one study, a 3.5mm defect was created in the CrCL, leaving peripheral bands to provide stability (Spindler et al. 2006). The defect failed to show significant healing over a 6-week period. The addition of a collagen–platelet-rich plasma scaffold promoted healing over the same time period (Murray et al. 2006; Silva et al. 2013). These studies demonstrate the importance, for any graft, of a suitable scaffold for cell migration and the necessity to mechanically protect the graft during healing. Autografts and allografts provide a natural ECM to guide cell ingrowth and, if processed appropriately, can initially maintain a similar mechanical strength. All grafts will lose strength over time if replacement with appropriate native tissue does not proceed rapidly. One possible stimulant is the proteins in the ECM of a donor autograft or allograft (Hoganson et al. 2010). Although prosthetic implant scaffold technology is improving, the threedimensional layout of the scaffold likely cannot perfectly mimic Nature. It is unknown how a different matrix affects cell ingrowth. Both natural and synthetic scaffolds can be seeded with protein, or potentially cells, to promote ingrowth (Linon et al. 2014). Many surgeons believe that intra-articular grafts historically failed due to biological breakdown, similar to the fate of the native CrCL. The exact pathogenesis of CR is not known (Comerford et al. 2011) and, therefore, there is no definitive evidence that an implanted graft VetBooks.ir 210 Surgical Treatment will undergo the same degradation as the native CrCL. The immune rejection of allografts or prosthetic materials is a concern. Processing of allografts, including deep-freezing, chemical treatment or decellularization, may decrease this potential. Prosthetic graft replacements will likely become more biocompatible as new materials are developed. With any graft, further in vivo experimental and clinical studies will be needed in dogs to demonstrate the safety and efficacy of any implanted intra-articular graft. Future developments Although extra-articular repairs continue to be the most common surgical treatment for CR, work should continue overcome the limitations of extra-articular repairs and the challenges of intra-articular repair identified in this chapter. In the search for a suitable graft, in vitro mechanical testing has revealed that the entire patella tendon and the DDFT allograft, when doubled on itself, possess similar mechanical properties to the native CrCL of a similar-sized dog (Haut et al. 1992; Biskup et al. 2014b; Biskup et al. 2015). Fixation methods have also been evaluated, placing different grafts at the proximal and distal attachment sites of the CrCL (Biskup et al. 2015). Results have shown that securing a DDFT allograft with a medial femoral cross-pin and tibial spiked washers and interference screws can mimic the mechanical properties of the native CrCL. Finally, a study evaluating the effect of decellularization on DDFTs showed significant decreases in DNA content upon histological and biochemical testing, but no decrease in mechanical strength when compared to unprocessed allografts (Balogh et al. 2016). Two recent in vivo studies have evaluated intra-articular grafts with positive outcomes. Cook et al. 2015 assessed replacement of the craniomedial band of the CrCL with a long digital extensor graft in research dogs. The outcomes were positive, including no progression of OA and continued stifle function. A small pilot prospective cohort study evaluated the feasibility of intra-articular CrCL repair in dogs with naturally occurring CR (Biskup et al. 2017). Ten client-owned dogs with unilateral CR underwent a repair using a decellularized Figure 26.4 Intraoperative picture of an intra-articular repair using a deep digital flexor allograft. A drill guide is in position to drill the femoral tunnel. DDFT allograft placed at the femoral and tibial attachment sites of the CrCL, and secured with a medial femoral cross-pin and tibial spiked washers and interference screws (Figure 26.4). Owner questionnaire results showed improvement throughout the study, with the greatest improvement over the first 6 months. Similarly, peak vertical force and vertical impulse were improved throughout all time points, with a continued upward trend at 12 months. Radiographs revealed minimal progression of OA. Mild subluxation was present in multiple dogs on both orthopaedic examination and weightbearing radiographs. Notably, caution must be taken when drawing conclusions from these studies, given the small population size and the fact that no direct treatment comparison was performed (Figure 26.5). One critical limitation was that graft integrity was not documented in the pilot project. One possibility is that periarticular fibrosis may have contributed to clinical outcome, although its contribution may be limited with intra-articular repairs (Hart et al. 2003). Conclusions Intra-articular repair in veterinary medicine continues to be inferior to extra-articular VetBooks.ir Intra-Articular Repair for Cranial Cruciate Ligament Rupture in the Dog 211 Net GRF 2 1.9 1.8 1.7 Intra-articular 1.6 1.5 TPLO 1.4 NonSX 1.3 1.2 1.1 1 PreOp 2-month 6-month 12-month Figure 26.5 Mean values of net ground reaction force (GRF) measured via force platform gait analysis of the limb with cranial cruciate ligament rupture immediately before and at various time points after surgery. Values obtained were during different time periods but data were collected by the same laboratory under identical conditions. repairs in controlled studies and in surgeon opinion. The potential mechanical benefit over current stifle stabilization surgeries makes its continued exploration justified, and likely explains why intra-articular repairs remain the ‘gold standard’ for ACL rupture treatment in human patients. As research into graft selection and processing, fixation techniques and graft healing advances, intra-articular repairs may become more common in veterinary medicine. References Aiken SW, Badylak SF, Toombs JP, et al. Small intestinal submucosa as an intra-articular ligamentous repair material: a pilot study in dogs. Vet Comp Orthop Traumatol 1994;7:124–128. Arnoczky SP. Anatomy of the anterior cruciate ligament. Clin Orthop Related Res 1983;172:19–25. Arnoczky SP, Marshall JL. Pathomechanics of cruciate and meniscal injuries. In: Pathophysiology of Small Animal Surgery, Bojrab MJ, ed. Philadelphia, PA, Lea & Febiger. 1981, pp. 590–603. Arnoczky SP, Marshall JL. The cruciate ligaments of the canine stifle: an anatomical and functional analysis. Am J Vet Res 1977;38:1807–1814. Arnoczky SP, Rubin RM, Marshall JL. Microvasculature of the cruciate ligaments and its response to injury: an experimental study in dogs. J Bone Joint Surg 1979b;61A:1221–1229. Arnoczky SP, Tarvin GP, Marshall JL. Anterior cruciate ligament replacement using patella tendon. J Bone Joint Surg 1982;64A:217–224. Arnoczky SP, Tarvin GP, Marshall JL, et al. The overthe-top procedure: a technique for anterior cruciate ligament substitution in the dog. J Am Anim Hosp Assoc 1979a;15:283–290. Arnoczky SP, Warren RF, Ashlock MA. Replacement of the anterior cruciate ligament using a patellar tendon allograft. An experimental study. J Bone Joint Surg Am 1986;68:376–385. Austin JC, Phornphutkul C, Wojtys EM. Loss of knee extension after anterior cruciate ligament reconstruction: effects of knee position and graft tensioning. J Bone Joint Surg Am 2007;89:1565–1574. Bacon JP, Pichler ME, Lynd FT, et al. Histopathological examination of two cranial cruciate ligament reconstructions. J Am Anim Hosp Assoc 1984;20:65–68. Balogh DG, Biskup JJ, O’Sullivan MG, et al. Biochemical, histologic, and biomechanical characterization of native and decellularized flexor tendons specimens harvested from the pelvic limbs of orthopedically normal dogs. Am J Vet Res 2016;77:388– 394. Bechtold JE, Eastlund DT, Butts MK, et al. The effects of freeze-drying and ethylene oxide sterilization on the mechanical properties of human patellar tendon. Am J Sports Med 1994;22:562–566. Bellumori TP, Famula TR, Bannasch DL, et al. Prevalence of inherited disorders among mixed-breed and purebred dogs: 27,254 cases (1995–2010). J Am Vet Med Assoc 2013;242:1549–1555. Bennett D, May C. An “over-the-top with tibial tunnel” technique for repair of cranial cruciate ligament rupture in the dog. J Small Anim Pract 1991;32:103–110. Bennett D, Tennant B, Lewis DG, et al. A reappraisal of anterior cruciate ligament disease in the dog. J Small Anim Pract 1988;29:275–297. VetBooks.ir 212 Surgical Treatment Biasi F, Rahal SC, Volpi RS, et al. Cranial cruciate ligament reconstruction in dogs associated or not to chondroitin sulfate. Arq Bras Med Vet Zootec 2005;57:442–447. Biskup JJ, Balogh DG, Haynes KH, et al. Mechanical strength of four allograft fixation techniques for ruptured cranial cruciate ligament repair in dogs. Am J Vet Res 2015;76:411–419. Biskup JJ, Balogh DG, Scott RM, et al. Long-term outcome of an intra-articular allograft technique for treatment of spontaneous cranial cruciate ligament rupture in the dog. Vet Surg 2017;46:691–699. Biskup J, Freeman A, Camisa W, et al. Mechanical properties of canine patella-ligament-tibia segment. Vet Surg 2014b;43:136–141. Biskup JJ, Griffon DJ, Socie M, et al. Ability of the Tightrope® and percutaneous lateral fabellar suture techniques to control cranial tibial translation. Vet Surg 2014a;43:959–965. Boguszewski DV, Joshi NB, Wang D, et al. Effect of different preconditioning protocols on anterior knee laxity after ACL reconstruction with four commonly used grafts. J Bone Joint Surg Am 2015;97:1059–1066. Brendolan AP, Rezende CMF, Melo EG, et al. Clinical and radiographic aspects of the bovine pericardium as a substitute of the canine cranial cruciate ligament. Arq Bras Med Vet Zootec 2007;59:920– 931. Burks RT, Haut RC, Lancaster RL. Biomechanical and histological observations of the dog patellar tendon after removal of its central one-third. Am J Sports Med 1990;18:146–153. Burnett QM, Fowler PJ. Reconstruction of the anterior cruciate: historical review. Orthop Clin North Am 1985;16:143–157. Butler DL, Hulse DA, Kay MD, et al. Biomechanics of cranial cruciate ligament reconstruction in the dog II. Mechanical properties. Vet Surg 1983;12:112– 118. Cabano NR, Troyer KL, Palmer RH, et al. Mechanical comparison of two suture constructs for extracapsular stifle stabilization. Vet Surg 2011;40:334– 339 Chiroff RT. Experimental replacement of the anterior cruciate ligament. J Bone Joint Surg 1975;57A:1124– 1127. Coetzee GL, Lubbe AM. A prospective study comparing two fascial reconstruction techniques to stabilise the cranial cruciate deficient stifle in the dog. Vet Comp Orthop Traumatol 1995;8:82–90. Comerford EJ, Smith K, Hayashi K. Update on the aetiopathogenesis of canine cranial cruciate ligament disease. Vet Comp Orthop Traumatol 2011;24:91–98. Conzemius MG, Evans RB, Besancon MF, et al. Effect of surgical technique on limb function after surgery for rupture of the cranial cruciate ligament in dogs. J Am Vet Med Assoc 2005;226:232–236. Cook JL, Smith PA, Stannard JP, et al. A canine hybrid double-bundle model for study of arthroscopic ACL reconstruction. J Orthop Res 2015;33:1171– 1179. Corr SA, Brown C. A comparison of outcomes following tibial plateau levelling osteotomy and cranial tibial wedge osteotomy procedures. Vet Comp Orthop Traumatol 2007;20:312–319. Curtis RJ, Delee JC, Drez DJ, Jr. Reconstruction of the anterior cruciate ligament with freeze dried fascia lata allografts in dogs. A preliminary report. Am J Sports Med. 1985;13:408–414. Davarinos N, O’Neill BJ, Curtin W. A brief history of anterior cruciate ligament reconstruction. Adv Orthop Surg 2014:706042. DeLuke AM, Allen DA, Wilson ER, et al. Comparison of radiographic osteoarthritis scores in dogs less than 24 months or greater than 24 months following tibial plateau leveling osteotomy. Can Vet J 2012;53:1095–1099. Denny HR, Barr ARS. A further evaluation of the “over-the-top” technique for anterior cruciate ligament replacement in the dog. J Small Anim Pract 1987;28:681–686. Denny HR, Barr ARS. An evaluation of two “over the top” techniques for anterior cruciate ligament replacement in the dog. J Small Anim Pract 1984;25:759–769. de Rooster H, Vangheluwe L, van Bree H, et al. Biomechanical properties of braided polyester tapes intended for use as intra-articular cranial cruciate ligament prostheses in dogs. Am J Vet Res 2001;62:48–53. Dueland TR. A recent technique for reconstruction of the anterior cruciate ligament. Anim Hosp 1966;2:1–5. Elkins AD, Pechman R, Kearney MT, et al. A retrospective study evaluating the degree of degenerative joint disease in the stifle joint of dogs following surgical repair of anterior cruciate ligament rupture. J Am Anim Hosp Assoc 1991;27:533– 540. Evans R, Horstman C, Conzemius M. Accuracy and optimization of force platform gait analysis in Labradors with cranial cruciate disease evaluated at the walking gait. Vet Surg 2005;34:445–449. Fideler BM, Vangsness CT, Jr, Lu B, et al. Gamma irradiation: effects on biomechanical properties of human bone-patellar tendon-bone allografts. Am J Sports Med 1995;23:643–646. Fischer C, Cherres M, Grevel V, et al. Effects of attachment sites and joint angle at the time of lateral suture fixation on tension in the suture for stabilization of the cranial cruciate ligament deficient stifle in dogs. Vet Surg 2010;39:334–342. Fu FH, Bennett CH, Latterman C, et al. Current trends in anterior cruciate ligament reconstruction. Part 1: biology and biomechanics of reconstruction. Am J Sports Med 1999;27:821–830. VetBooks.ir Intra-Articular Repair for Cranial Cruciate Ligament Rupture in the Dog Garcia ÉFV, Schossler JEW, Pinheiro M. Cranial cruciate ligament rupture in a cat: reconstitution with fascia lata. Ciênc Rural 2012;42:1446–1449. Geels JJ, Roush JK, Hoskinson JJ, et al. Evaluation of an intracapsular technique for the treatment of cranial cruciate ligament rupture. Vet Comp Orthop Traumatol 2000;13:197–203. Goertzen MJ, Clahsen H, Bürrig KF, et al. Sterilisation of canine anterior cruciate allografts by gamma irradiation in argon. Mechanical and neurohistological properties retained one year after transplantation. J Bone Joint Surg Br. 1995;77:205–212. Gordon WJ, Conzemius MG, Riedesel E, et al. The relationship between limb function and radiographic osteoarthrosis in dogs with stifle osteoarthrosis. Vet Surg 2003;32:451–454. Gordon-Evans WJ, Griffon DJ, Bubb C, et al. Comparison of lateral fabellar suture and tibial plateau leveling osteotomy techniques for treatment of dogs with cranial cruciate ligament disease. J Am Vet Med Assoc 2013;243:675–680. Erratum in: J Am Vet Med Assoc 2013;243:1297. Grunau PD, Arneja S, Leith JM. A randomized clinical trial to assess the clinical effectiveness of a measured objective tensioning device in hamstring anterior cruciate ligament reconstruction. Am J Sports Med 2016;44:1482-1486. Gut G, Marowska J, Jastrzebska A, et al. Structural mechanical properties of radiation-sterilized human bone-tendon-bone grafts preserved by different methods. Cell Tissue Bank 2016;17:277-287. Harilainen A, Sandelin J. A prospective comparison of 3 hamstring ACL fixation devices – Rigidfix, BioScrew, and Intrafix – randomized into 4 groups with 2 years of follow-up. Am J Sports Med 2009;37:699–706 Hart RC, Hulse D, Slater MR. Contribution of periarticular tissue to stabilization of the canine stifle joint after cranial cruciate ligament reconstruction. Vet Comp Orthop Traumatol 2003;1:21–25. Haut RC, Lancaster RL, DeCamp CE. Mechanical properties of the canine patellar tendon: some correlations with age and the content of collagen. J Biomech 1992;25:163–173. Heffron LE, Campbell JR. Morphology, histology and functional anatomy of the canine cranial cruciate ligament. Vet Rec 1978;102:280–283. Hill C, An YH, Young FA. Tendon and ligament fixation to bone. In: Repair of Ligament and Tendons, Walsh W, ed. Totowa, NJ, Humana Press. 2005, pp. 257–278. Hoffman DE, Miller JM, Ober CP, et al. Tibial tuberosity advancement in 65 canine stifles. Vet Comp Orthop Traumatol 2006:4;219–227. Hoganson DM, O’Doherty EM, Owens GE, et al. The retention of extracellular matrix proteins and angiogenic and mitogenic cytokines in a decellularized porcine dermis. Biomaterials 2010;31:6730– 6737. 213 Hulse D, Beale B, Kerwin S. Second look arthroscopic findings after tibial plateau leveling osteotomy. Vet Surg 2010a;39:350–354. Hulse D, Hyman W, Beale B, et al. Determination of isometric points for placement of a lateral suture in treatment of the cranial cruciate ligament deficient stifle. Vet Comp Orthop Traumatol 2010b;23:163– 167. Hulse DA, Butler DL, Kay MD, et al. Biomechanics of cranial cruciate ligament reconstruction in the dog I. In vitro laxity testing. Vet Surg 1983;12:109–112. Hulse DA, Michaelson F, Johnson C, et al. A technique for reconstruction of the anterior cruciate ligament in the dog: preliminary report. Vet Surg 1980;4:135– 140. Innes JF, Bacon D, Lynch C, et al. Long-term outcome of surgery for dogs with cranial cruciate ligament deficiency. Vet Rec 2000b;147:325–328. Innes JF, Barr AR. Clinical natural history of the postsurgical cruciate deficient canine stifle joint: year 1. J Small Anim Pract. 1998;39:325–332. Innes JF, Barr AR, Sharif M. Efficacy of oral calcium pentosan polysulphate for the treatment of osteoarthritis of the canine stifle joint secondary to cranial cruciate ligament deficiency. Vet Rec 2000a;146:433–437. Innes JF, Costello M, Barr FJ, et al. Radiographic progression of osteoarthritis of the canine stifle joint: a prospective study. Vet Radiol Ultrasound 2004;45:143–148. Jevens DJ, DeCamp CE, Hauptman J, et al. Use of force-plate analysis of gait to compare two surgical techniques for treatment of cranial cruciate ligament rupture in dogs. Am J Vet Res 1996;57:389– 393. Johnson JA, Austin C, Breur GJ. Incidence of canine appendicular musculoskeletal disorders in 16 veterinary teaching hospitals from 1980 to 1989. Vet Comp Orthop Traumatol 1994;7:56–59. Johnson KA, Hart RC, Chu Q, et al. Concentrations of chondroitin sulfate epitopes 3B3 and 7D4 in synovial fluid after intra-articular and extracapsular reconstruction of the cranial cruciate ligament in dogs. Am J Vet Res 2001;62:581–587. Johnson SG, Hulse DA, Hogan HA, et al. System behavior of commonly used cranial cruciate ligament reconstruction autografts. Vet Surg 1989;18:459–465. Kdolsky RK, Gibbons DF, Kwasny O, et al. Braided polypropylene augmentation device in reconstructive surgery of the anterior cruciate ligament: long-term clinical performance of 594 patients and short-term arthroscopic results, failure analysis by scanning electron microscopy and synovial histomorphology. J Orthop Res 1997;15:1–10. Kim SE, Lewis DD, Pozzi A. Effect of tibial plateau leveling osteotomy on femorotibial subluxation: in vivo analysis during standing. Vet Surg 2012;41:465–470. VetBooks.ir 214 Surgical Treatment Kirkpatrick JS, Seaber AV, Glisson RR, et al. Cryopreserved anterior cruciate ligament allografts in a canine model. J South Orthop Assoc 1996;5:20–29. Knecht CD. Evolution of surgical techniques for cruciate ligament rupture in animals. J Am Anim Hosp Assoc 1976;12:717–726. Korvick DL, Johnson AL, Schaeffer DJ. Surgeons’ preferences in treating cranial cruciate ligament ruptures in dogs. J Am Vet Med Assoc 1994;205: 1318–1324. Kousa P, Jarvinen TL, Pohjonen T, et al. Fixation strength of a biodegradable screw in anterior cruciate ligament reconstruction. J Bone Joint Surg Br 1995;77:901–905. Kowaleski MP, Apelt D, Mattoon JS, et al. The effect of tibial plateau leveling osteotomy position on cranial tibial subluxation: an in vitro study. Vet Surg 2005;34:332–336. Krotscheck U, Nelson SA, Todhunter RJ, et al. Long term functional outcome of tibial tuberosity advancement vs. tibial plateau leveling osteotomy and extracapsular repair in a heterogeneous population of dogs. Vet Surg 2016;45:261–268. Laitinen O. Prospective clinical study of biodegradable poly-1-lactide implant as an augmentation device with fascia lata in cranial cruciate ligament repair in the dog: early results. Vet Comp Orthop Traumatol 1994;7:51–55. Lazar TP, Berry CR, deHaan JJ, et al. Long-term radiographic comparison of tibial plateau leveling osteotomy versus extracapsular stabilization for cranial cruciate ligament rupture in the dog. Vet Surg 2005;34:133–141. Linder LH, Sukin DL, Burks RT, et al. Biomechanical and histological properties of the canine patellar tendon after removal of its medial third. Am J Sports Med 1994;22:136–142. Linon E, Spreng D, Rytz U, Forterre S. Engraftment of autologous bone marrow cells into the injured cranial cruciate ligament in dogs. Vet J 2014;202:448– 454. Liu Y, Ramanath HS, Wang D-A. Tendon tissue engineering using scaffold enhancing strategies. Trends Biotechnol 2008;26:201–209. Lopez MJ, Markel MM, Kalsheur VL, et al. Hamstring graft technique for stabilization of canine cranial cruciate ligament deficient stifles. Vet Surg 2003;32:390–401. Lopez MJ, Robinson SO, Quinn MM, et al. In vivo evaluation of intra-articular protection in a novel model of canine cranial cruciate ligament mid-substance elongation injury. Vet Surg 2006;35:711–720. Lopez MJ, Spencer N, Casey JP, et al. Biomechanical characteristics of an implant used to secure semitendinosus-gracilis tendon grafts in a canine model of extra-articular anterior cruciate ligament reconstruction. Vet Surg 2007;36:599–604. Mae T, Shino K, Nakata K, et al. Optimization of graft fixation at the time of anterior cruciate ligament reconstruction. Part I: effect of initial tension. Am J Sports Med 2008;36:1087–1093. Mascarenhas R, MacDonald PB. Anterior cruciate ligament reconstruction: a look at prosthetics – past, present and possible future. McGill J Med 2008;11:29–37. McFarland EG, Morrey BF, An KN, et al. The relationship of vascularity and water content to tensile strength in a patella tendon replacement of the anterior cruciate ligament in dogs. Am J Sports Med 1986;14:436–448. Mölsä SH, Hielm-Bjorkman AK, Laitinen-Vapaavuori OM. Use of an owner questionnaire to evaluate long-term outcome and chronic pain after cranial cruciate ligament repair in dogs: 253 cases (2004– 2006). J Vet Med Assoc 2013;243:689–695. Mölsä SH, Hyytiäinen HK, Hielm-Björkman AK, et al. Long-term functional outcome after surgical repair of cranial cruciate ligament disease in dogs. BMC Vet Res 2014;10:266. Moore KW, Read RA. Cranial cruciate ligament rupture in the dog – a retrospective study comparing surgical techniques. Aust Vet J 1995;72:281–285. Müller DCM, Basso PC, Serafini GMC, et al. Replacement of the cranial and caudal cruciate ligaments in dogs by double t polypropylene implant. Ciênc Rural 2011;41:487–491. Müller DCM, Pippi NL, Basso PC, et al. Synthetic implant as a stabilizer link, after desmotomy of the cruciate ligaments in dogs: proposition technique. Ciênc Rural 2010;40:1327–1334. Murray MM. Current status and potential of primary ACL repair. Clin Sports Med 2009;28:51–61. Murray MM, Spindler KP, Ballard P, et al. Enhanced histologic repair in a central wound in the anterior cruciate ligament with a collagen-plateletrich plasma scaffold. J Orthop Res 2007;25:1007– 1017. Murray MM, Spindler KP, Devin C, et al. Use of a collagen-platelet rich plasma scaffold to stimulate healing of a central defect in the canine ACL. J Orthop Res 2006;24:820–830. Ng GY, Oakes BW, Deacon OW, et al. Biomechanics of patella tendon autograft for reconstruction of the anterior cruciate ligament in the goat: three year study. J Orthop Res 1995;13:602–608. Nikolaou PK, Seaber AV, Glisson RR, et al. Anterior cruciate ligament allograft transplantation. Longterm function, histology, revascularization, and operative technique. Am J Sports Med 1986;14:348– 360. O’Donoghue DH, Rockwood CA, Frank GR, et al. Repair of the anterior cruciate ligament in dogs. Bone Joint Surg 1966;48A:503–519. Palmisano MP, Andrish JT, Olmstead ML, et al. A comparative study of the length patterns of anterior cruciate ligament reconstructions in the dog and man. Vet Comp Orthop Traumatol 2000;13:73– 77. VetBooks.ir Intra-Articular Repair for Cranial Cruciate Ligament Rupture in the Dog Park JP, Grana WA, Chitwood JS. A high-strength Dacron augmentation for cruciate ligament reconstruction. A two-year canine study. Clin Orthop Relat Res 1985;196:175–185. Patterson RH, Smith GK, Gregor TP, et al. Biomechanical stability of four cranial cruciate ligament repair techniques in the dog. Vet Surg 1991;20:85–90. Penha EM, Rezende CMF, Melo EG, et al. Late postoperative of cranial cruciate ligament replacement in dog. Arq Bras Med Vet Zootec 2007;59:1184–1193. Pichler ME, Bacon JP, Evans JA. The fascia lata as a replacement for the cranial cruciate ligament: two new surgical techniques. J Am Anim Hosp Assoc 1982;18:779. Pilia M, Murray M, Guda T, et al. Pretensioning of soft tissue grafts in anterior cruciate ligament reconstruction. Orthopedics 2015;38:e582–e587. Pridgen BC, Woon CY, Kim M, et al. Flexor tendon tissue engineering: Acellularization of human flexor tendons with preservation of biomechanical properties and biocompatibility. Tissue Eng Part C Methods 2011;17:819–828. Qu J, Thoreson AR, An K-N, et al. What is the best candidate allograft for ACL reconstruction? An in vitro mechanical and histologic study in a canine model. J Biomech 2015;48:1811–1816. Ramanaiah CV, Ramakrishna O, Sreeraman PK. Chondrogenic potential of free intra-articular periosteal autografts in dogs. Indian Vet J 1990;67: 844–847. Rayward RM, Thomson DG, Davies JV, et al. Progression of osteoarthritis following TPLO surgery: a prospective radiographic study of 40 dogs. J Small Anim Pract 2004;45:92–97. Roe SC, Kue J, Gemma J. Isometry of potential suture attachment sites for the cranial cruciate ligamentdeficient canine stifle. Vet Comp Orthop Traumatol 2008;21:215–220. Rose ND, Goerke D, Evans RB, et al. Mechanical testing of orthopedic suture material used for extraarticular stabilization of canine cruciate ligamentdeficient stifles. Vet Surg 2012;41:266–272. Rupp S, Krauss PW, Fritsch EW. Fixation strength of a biodegradable interference screw and a pressfit technique in anterior cruciate ligament reconstruction with a BPTB graft. Arthroscopy 1997;13: 61–65. Schultze-Tanzil G, Al-Sadi O, Ertel W, et al. Decellularized tendon extracellular matrix – a valuable approach for tendon reconstruction? Cells 2012;1:1010–1028. Shelley BA, Hulse DA, Slater MR, et al. Determination of graft forces for cranial cruciate ligament reconstruction in the dog. Vet Comp Orthop Traumatol 1996;9:165–171. Shino K, Kawasaki T, Hirose H, et al. Replacement of the anterior cruciate ligament by an allogeneic tendon graft. An experimental study in the dog. J Bone Joint Surg Br 1984;66:672–681. 215 Shires PK, Hulse DA, Liu W. The under-and-over fascial replacement technique for anterior cruciate ligament rupture in the dog: A retrospective study. J Am Anim Hosp Assoc 1984;20:69–77. Silva RF, Carmona JU, Rezende CM. Intra-articular injections of autologous platelet concentrates in dogs with surgical reparation of cranial cruciate ligament rupture: a pilot study. Vet Comp Orthop Traumatol 2013;26:285–290. Silvaggio VJ, Fu FH, Georgescu HI, et al. The induction of IL-1 by freeze-dried ethylene oxide-treated bone-patellar tendon-bone allograft wear particles: an in vitro study. Arthroscopy 1993;9:82–86. Singleton WB. The diagnosis and treatment of some abnormal stifle conditions in the dog. Vet Rec 1957;69:1387–1394. Singleton WB. Observations based upon the surgical repair of 106 cases of anterior cruciate ligament rupture. J Small Anim Pract 1969;10:269–278. Skinner OT, Kim SE, Lewis DD, Pozzi A. In vivo femorotibial subluxation during weight-bearing and clinical outcome following tibial tuberosity advancement for cranial cruciate ligament insufficiency in dogs. Vet J 2013;196:86–91. Snow LA, White R, Gustafson S, et al. Ex vivo comparison of three surgical techniques to stabilize canine cranial cruciate ligament deficient stifles. Vet Surg 2010;39:195–207. Spindler KP, Murray MM, Devin C, et al. The central ACL defect as a model for failure of intra-articular healing. J Orthop Res 2006;24:401–406. Stauffer KD, Tuttle TA, Elkins AD, et al. Complications associated with 696 tibial plateau leveling osteotomies (2001-2003). J Am Anim Hosp Assoc 2006;42:44–50. Stead AC, Amis AA, Campbellt JR. Use of polyester fibre as a prosthetic cranial cruciate ligament in small animals. J Small Anim Pract 1991;32:448–454. Stein S, Schmoekel H. Short-term and eight to 12 months results of a tibial tuberosity advancement as treatment of canine cranial cruciate ligament damage. J Small Anim Pract 2008;49:398–404. Thorson E, Rodrigo JJ, Vasseur P, et al. Replacement of the anterior cruciate ligament. A comparison of autografts and allografts in dogs. Acta Orthop Scand 1989;60:555–560. Vasseur PB, Berry CR. Progression of stifle osteoarthrosis following reconstruction of the cranial cruciate ligament in 21 dogs. J Am Anim Hosp Assoc 1991;28:129–136. Vasseur PB, Stevenson S, Gregory CR, et al. Anterior cruciate ligament allograft transplantation in dogs. Clin Orthop Relat Res 1991;269:295–304. Vasseur PB, Pool RR, Arnoczky SP, et al. Correlative biomechanical and histologic study of the cranial cruciate ligament in dogs. Am J Vet Res 1985;46:1842–1854. Vasseur PB, Rodrigo JJ, Stevenson S, et al. Replacement of the anterior cruciate ligament with a VetBooks.ir 216 Surgical Treatment bone-ligament-bone anterior cruciate ligament allograft in dogs. Clin Orthop Relat Res 1987;219: 268–277. Veena P, Ramakrishna O, Bharathi S, et al. Reconstruction of ruptured cranial cruciate ligament using whole thickness skin and patellar ligament as a graft in canines. Indian Vet J 2003;80:432–434. Voss K, Damur DM, Guerrero T, et al. Force plate analysis to assess limb function after tibial tuberosity advancement in dogs with cranial cruciate ligament disease. Vet Comp Orthop Traumatol 2008;21:243–249. Waxman AS, Robinson DA, Evans RB, et al. Relationship between objective and subjective assessment of limb function in normal dogs with an experimentally induced lameness. Vet Surg 2008;3:241– 246. Wucherer KL, Conzemius MG, Evans RB, et al. Shortterm and long-term outcomes for overweight dogs with cranial cruciate ligament rupture treated surgically or nonsurgically. J Am Vet Med Assoc 2013;242:1364–1372. Yahia LH, Drouin G. Study of the hysteresis phenomenon in canine anterior cruciate ligaments. J Biomed Eng 1990;12:57–62. Yoshiya S, Andrish JT, Manley MT, et al. Graft tension in anterior cruciate ligament reconstruction. An in vivo study in dogs. Am J Sports Med 1987;15:464– 470. Youngstrom DW, Barrett JG, Jose RR, et al. Functional characterization of detergent-decellularized equine tendon extracellular matrix for tissue engineering applications. PLoS One 2013;8: e64151. VetBooks.ir 27 Tibial Plateau Leveling Osteotomy Susan L. Schaefer Introduction Tibial plateau leveling osteotomy (TPLO) was first described in 1993 by Slocum to address stifle instability due to cruciate ligament rupture (CR) (Slocum & Slocum 1993). By decreasing the natural caudodistal orientation of the tibial plateau, TPLO limits the shear force generated by compression of the stifle during weightbearing, thereby abating cranial tibial thrust (Reif et al. 2002). The dynamic stability imparted to the cranial cruciate ligament (CrCL)-deficient stifle via TPLO is achieved by performing a radial osteotomy of the proximal tibia and rotating the proximal segment to decrease the tibial plateau angle (TPA) (Figure 27.1). Preoperative determination of the patient’s TPA allows calculation of the magnitude of rotation necessary to achieve a desired postoperative TPA. The minimum amount of rotation required to neutralize cranial tibial thrust results in a postoperative TPA of 6.5 ± 0.9◦ . Further rotation increases strain on the caudal cruciate ligament (CaCL); rotating from 6.5◦ to 0◦ increases CaCL strain by 37.7 ± 17.4% (Warzee et al. 2001). While convention dictates measuring and changing the TPA, more recent studies have evaluated the patella tendon angle (PTA) change seen in TPLO. After TPLO, the PTA measures around 90◦ in both ex vivo and clinical situations (Drygas et al. 2010; Sathya et al. 2014). This finding suggests that the biomechanics of TPLO may be similar to that of tibial tuberosity advancement (TTA). It is important to note that the TPLO procedure itself only addresses dynamic stifle instability. Therefore, an inspection of intra-articular structures with appropriate treatment of meniscal injuries or other abnormalities must accompany the procedure. An excellent review of the proposed mechanism of action for TPLO is available (Boudrieau 2009). TPLO technique The magnitude of rotation planned preoperatively generally correlates well with the realized postoperative TPA result (Windolf et al. 2008). However, achieving an accurate TPA measurement and executing the osteotomy and tibial rotation in a manner to accurately achieve the desired postoperative TPA without inadvertently creating angular or rotational limb deformities involves a complex interplay of factors. Intra- and interobserver variability in TPA assessment has the potential to influence preoperative planning and subsequent postoperative Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 217 Surgical Treatment VetBooks.ir 218 Pre-op Post-op (A) TPA. Interobserver variability in TPA measurement has been shown to be relatively small (standard deviation of 0.8◦ ) but significant, whereas intraobserver variability and between groups of observers was not statistically significant (Caylor et al. 2001; Fettig et al. 2003). Measurement variability in the TPA is reduced when digital radiography and computerized measurement systems are used (Unis et al. 2010). While the stifle flexion angle has been shown to not influence TPA measurement (Aulakh et al. 2011), limb position does influence radiographic TPA measurement. Cranial and proximal positioning of the limb relative to the X-ray beam results in overestimation, whereas caudal and distal positioning results in underestimation of the TPA (Reif et al. 2004). Both preoperative and intraoperative planning of the osteotomy position improves the likelihood of a more centered osteotomy, and reduces the risk of tibial tuberosity fractures (Collins et al. 2014). When planning techniques were compared, measuring the distance from the insertion point of the patella tendon to two points on the proposed osteotomy line (perpendicular to the cranial border of the tibial crest and at the joint surface) proved the most accurate (Mossman et al. 2015). An emphasis on osteotomy reduction at the expense of medial cortex alignment minimizes angular and rotational deformities due to TPLO (Wheeler et al. 2003). Distal (B) Figure 27.1 Schematic drawing depicting the reduction in tibial plateau angle following a tibial plateau leveling osteotomy and the subsequent change in individual tibiofemoral forces. (A) The tibiofemoral forces are broken down into a perpendicular and a parallel force relative to the tibial plateau (blue arrows). The force parallel to the tibial plateau represents tibial femoral shear. (B) With rotation of the tibial plateau note the elimination of tibial femoral shear. The resultant compressive force remains unchanged and is represented by the white arrow in both A and B. Source: Boudrieau 2009. Reproduced with permission from John Wiley & Sons, Inc. positioning of the osteotomy (versus centering on the proximal tibial long axis point dividing the intercondylar tubercles) results in a postoperative TPA greater than is expected. In addition, undesired craniodistal translation of the tibial plateau and tibial long axis shift is noted (Kowaleski et al. 2005). In the original surgical technique as described by Slocum, an alignment jig is secured to the tibia with the goal of maintaining a fixed plane during proximal segment rotation. The necessity for a jig for TPLO has been questioned by some authors. One study found no significant differences in postsurgical TPA, tibial crest thickness, varus–valgus malalignment, or tibial torsion between TPLOs performed with or without a jig (Bell & Ness 2007). The same authors found that the use of a jig resulted in a more distally positioned osteotomy. Another group found no significant difference in postsurgical TPA, fragment reduction, or proximodistal osteotomy orientation when a jig was not used, as long as the limb was held in 10– 15◦ of internal rotation and parallel to horizontal while performing a vertically oriented osteotomy (Schmerbach et al. 2007). A third group showed that fibular penetration by screw tip is more likely when a jig is not utilized (Flynn et al. 2014). With the recent development of a novel jig and saw guide (Mariano et al. 2016), current studies have shown improved VetBooks.ir Tibial Plateau Leveling Osteotomy accuracy of osteotomy placement over the previous jig model (Burton et al. 2013; Tan et al. 2014). TPLO reportedly eliminates the wedge effect of the medial meniscus, which may protect it from postoperative injury (Pozzi et al. 2006). Hence, the necessity for medial meniscal release during TPLO has been debated and appears to be related to the quality of intraoperative meniscal evaluation. A subsequent meniscal tear is 3.8-fold more likely to occur when meniscal evaluation is performed via an arthrotomy and no meniscal release is performed, as compared to either meniscal evaluation via an arthroscopy with no release or meniscal evaluation via arthrotomy with a release performed (Thieman et al. 2006). Importantly, although TPLO eliminates dynamic craniocaudal stifle instability and may impart protection to the medial meniscus, it fails to restore normal femorotibial contact mechanics. Postoperative femorotibial contact areas are significantly smaller than normal, with higher peak contact pressures (Kim et al. 2009). Patient selection Appropriate case selection is important to the success of TPLO. TPLO results in an increased strain on the CaCL ligament. Therefore, patients with a compromised CaCL are not candidates for the procedure (Warzee et al. 2001). While this surgery is most commonly performed on largebreed dogs (Duerr et al. 2014), patients as small as a cat (Hoots & Petersen 2005) and as large as a llama (Ray et al. 2004) have been successfully treated with TPLO. Patient size in itself is not a concern, as long as appropriately sized implants are chosen for the procedure. With the continued introduction of smaller implants, TPLO is quickly becoming more common in small-breed dogs (Witte & Scott 2014; Cosenza et al. 2015). It is important to note that the morphology of the proximal tibia differs between large- and small-breed dogs, with small-breed dogs generally having a larger TPA (Vedrine et al. 2013; Aertsens et al. 2015). Anecdotally, TPLO has been advocated in cases with a lack of cranial drawer where partial CR is suspected as a means to decrease the biomechanical strain on the CrCL and 219 theoretically protect it from further damage. Research now supports this recommendation with three studies. Haynes et al. (2015) showed that decreasing the TPA will decrease strain in the intact CrCL. Hulse et al. (2010) reported normal to near-normal intra-articular structures on second-look arthroscopic examination of stifles with stable partial CR treated with TPLO, while joints with full ruptures showed a range of pathologic changes. At long-term clinical follow-up in a small case series, progression of osteoarthritis appeared reduced with ongoing preservation of passive stability (Barger et al. 2016). TPLO implant selection A wide range of orthopaedic implant manufacturers produce commercially available TPLO implants in a growing variety of sizes. Both locking and non-locking implants are available (Figures 27.2 and 27.3). A biomechanical comparison between three different commercial manufacturer’s TPLO plates has been performed in an axially loaded gap model: Synthes TPLO plate (Synthes Vet, West Chester, PA, USA)/tibia constructs were found to be significantly stiffer than Slocum TPLO plate (Slocum Enterprises, Inc., Eugene, OR, USA)/tibia constructs, which were found to be not significantly different than Securos TPLO plate (Securos, Fiskdale, MA, USA)/tibia constructs (Kloc et al. 2009). Notably, the Synthes TPLO implant used in the above study was a locking bone plate, whereas the Slocum and Securos implants were conventional (non-locking) bone plates. The use of locking bone screws causes significantly less translational movement of the proximal tibial segment towards the bone plate compared to the use of conventional bone screws in an identical plate. However, no significant difference exists between locking and conventional screw constructs in mean stiffness or cycles to failure under load-sharing conditions (Leitner et al. 2008). Mechanical testing between non-locking and locking plates in an osteotomy gap model showed that locking plates have a higher load to failure, with the broad locking plate having both a higher load to failure and a greater mean stiffness (Bordelon et al. 2009). A retrospective evaluation of change in TPA Surgical Treatment VetBooks.ir 220 (A) (B) (C) Figure 27.2 Example of four commercial manufacturer’s tibial plateau leveling osteotomy plates. (A) Synthes 3.5 mm. (B) Arthrex 3.5 mm. (C) New Generation Devices 3.5 mm. (D) New Generation Devices 3.5 mm Broad. Plates shown in panels A and B do not require contouring. (D) (D) (C) 3.5 (B) (A) 2.7 2.4 2.0 Figure 27.3 Example of TPLO plate sizes. Synthes 2.0 mm, 2.4 mm, 2.7 mm, (A) 3.5 mm compact, (B) 3.5 mm standard, (C) 3.5 mm broad, (D) Veterinary Orthopedic Implants 3.5 mm Jumbo. VetBooks.ir Tibial Plateau Leveling Osteotomy during bone healing and radiographic osteotomy stability showed no difference between non-locking and locking plates (Krotscheck et al. 2012), while a similar prospective study concluded that locking screw fixation increases the stabilization of TPA during healing and provides improved radiographic evidence of osteotomy healing (Conkling et al. 2010). The use of a locking plate construct is also associated with a lower incidence of infection and a lower general complication rate (Kowaleski et al. 2013; Solano et al. 2015). Concerns related to the use of the original Slocum TPLO plate center around plate corrosion in vivo with the subsequent generation of chemical species that have the potential to cause disease, the presence of plate magnetism, and findings showing the plate to be a cast stainless steel implant (Boudrieau et al. 2006; Charles & Ness 2006). Furthermore, Slocum TPLO implant-associated sarcoma has been reported (Boudrieau et al. 2005). Metallurgical analysis of alternative TPLO implants by an independent, unbiased party is currently lacking. Complications after TPLO The overall postoperative complication rate of TPLO has been reported to vary from 7.2% to 28% (Pacchiana et al. 2003; Priddy et al. 2003; Stauffer et al. 2006; Fitzpatrick & Solano 2010; Gatineau et al. 2011; Oxley et al. 2013; Coletti et al. 2014). Factors associated with the development of complications include tibial plateau angle >30◦ , increased body weight, and complete versus partial CR (Fitzpatrick & Solano 2010; Coletti et al. 2014). A higher complication rate has also been reported in dogs undergoing simultaneous bilateral TPLO (Priddy et al. 2003). Notably, most complications can be resolved without surgical intervention (Pacchiana et al. 2003). Examples of complications include hemorrhage, poor incision site healing, patellar tendon enlargement, fractures involving the fibula or tibia, subsequent meniscal injury, implant failures and infection. Infection rates for TPLO average around 4.6% (Bergh & Peirone 2012), which is higher than expected for a clean surgical procedure. Theoretically, postoperative administration of antimicrobials is not indicated for clean 221 surgeries, but numerous studies have shown that postoperative antibiotic therapy does provide a protective affect against surgical site infection in TPLO (Fitzpatrick & Solano 2010; Frey et al. 2010; Nazarali et al. 2014; Nazarali et al. 2015; Solano et al. 2015). If treated appropriately, no association is seen between surgical site infection and long-term functional outcome (Brown et al. 2016). Dogs with a preoperative TPA ≥35◦ have a higher incidence of postoperative complications, with a loss of postoperative TPA or ‘rockback’ during the convalescent period being the most common. The addition of ancillary implants to TPLO significantly reduces the incidence of this problem (Duerr et al. 2008). A combination of TPLO with a closing cranial wedge ostectomy has been suggested as one possible means of addressing excessive TPA (Talaat et al. 2006). Small losses of postoperative TPA of about 1.5◦ during the convalescent period have been documented in the face of apparently stable implant fixation, and by themselves do not appear to have any deleterious effects on clinical outcome (Moeller et al. 2006; Hurley et al. 2007). Radiographic evidence of patellar tendon enlargement is a common finding after TPLO, with up to 80% of clinical cases showing evidence of moderate to severe thickening at 2 months postoperatively (Carey et al. 2005) (Figure 27.4). Despite this finding, only 7% of the dogs in this study displayed clinical signs of patellar tendinosis, with most dogs improving with medical management. Patellar femoral joint kinematics are altered by TPLO, and this may be a predisposing factor to patellar tendinosis (Pozzi et al. 2013). Patella fracture after TPLO is a rare complication (0.25–2%) that has been associated with radiographic evidence of patellar tendon thickening (Pacchiana et al. 2003; Carey et al. 2005; Gatineau et al. 2011; Rutherford et al. 2014). Non-surgical management generally provides a satisfactory outcome. Dogs that are cranial tibial thrust-negative immediately after surgery occasionally become thrust-positive after surgery. Affected dogs often have poor limb function and pivot shift on ambulation. Pivot shift is created by a combination of cranial translation of the tibia with internal rotation of the stifle. The mechanism for this Surgical Treatment VetBooks.ir 222 Figure 27.4 Lateral view radiograph of a dog 8 weeks after tibial plateau leveling osteotomy, demonstrating marked thickening of the patellar tendon (white arrows). (A) (B) complication is unclear and is more commonly identified in heavily muscled dogs with genu varum conformation. Most cases improve with aggressive physical therapy. However, a lateral fabellar imbrication suture or a femoral corrective osteotomy may be required in severe cases. Fractures of the fibula or tibia are potentially more serious complications that may be encountered during or after the TPLO procedure (Figure 27.5). Fibular fractures occurred in 5.4% of cases in a series of 168 TPLO procedures, with identified risk factors including increased body weight, greater preoperative TPA, greater change in TPA, and TPLO performed without the use of a jig (Tuttle & Manley 2009). A subsequent study by Taylor et al. (2011) of 355 TPLO cases reported a 15% fibula fracture rate, with increased body weight and an unfilled fibular drill hole identified as risk factors. Risk factors for tibial tuberosity fracture after TPLO include simultaneous bilateral TPLO, a thinner postoperative mean thickness of the tibial tuberosity, and an increase in TPA during convalescence (Kergosien et al. 2004; Bergh et al. 2008). The use of a structured postoperative physiotherapy program has been shown to result in a greater stifle range of motion (ROM) for dogs undergoing TPLO at 3 and 6 weeks postoperatively, and greater likelihood of full Figure 27.5 Cranial-caudal (A) and lateral (B) radiographic views of a dog 10 weeks after tibial plateau leveling osteotomy, showing a short oblique proximal fibular fracture (white arrows). VetBooks.ir Tibial Plateau Leveling Osteotomy function at 8 weeks, as compared to standard home-exercise-restricted dogs (Monk et al. 2006; Romano & Cook 2015). This highlights the importance of postoperative physiotherapy, as a loss of ≥10◦ ROM has been associated with significantly higher subjective clinical lameness scores than dogs with <10◦ ROM loss. Loss of extension is also correlated with osteoarthritis (OA) in the cranial femorotibial joint (Jandi & Shulman 2007). Although progression of OA occurs after TPLO (Boyd et al. 2007; Hurley et al. 2007), in general the presence of stifle OA correlates poorly with clinical function (Gordon et al. 2003). 223 TPLO evaluated via force platform gait analysis preoperatively and ≥4 months postoperatively, found no relationship between postoperative TPA (range 0–14◦ ) and postoperative ground reaction forces (Robinson et al. 2006). Client satisfaction with postoperative outcomes of TPLO in both large- and small-breed dogs has been reported as very good in multiple studies, even though such subjective assessments often do not correlate with the incidence of postoperative complications or objective measures of limb function (Priddy et al. 2003; Talaat et al. 2006; Thieman et al. 2006; Boyd et al. 2007; Waxman et al. 2008; Christopher et al. 2013; Gordon-Evans et al. 2013; Berger et al. 2015). Outcome after TPLO Despite these potential complications, outcome after TPLO has been reported as favorable in subjective and objective studies in both large- and small-breed dogs. Subjective studies employed clinical assessments such as lameness scoring, radiographic osteophyte scoring, and client questionnaires (Kergosien et al. 2004; Stauffer et al. 2006; Thiemann et al. 2006; Boyd et al. 2007; Christopher et al. 2013). The objective evaluation of limb use after TPLO via force plate and kinematic analysis has corroborated the observation that recovery after TPLO is rapid in the early stages, particularly when compared to lateral fabello-tibial suture stabilization (de Medeiros et al. 2011; Böddeker et al. 2012). Very good long-term outcome is seen in large breeds after TPLO, with improvement of ground reaction forces comparable to (Conzemius et al. 2005; Millis et al. 2008) or greater than lateral fabello-tibial suture stabilization (Gordon-Evans et al. 2013; Nelson et al. 2013). Improvement in ground reaction forces greater than lateral fabello-tibial suture stabilization is also seen in small-breed dogs with TPLO (Berger et al. 2015). A meta-analysis of the literature on surgical treatments for CR by Bergh et al. (2014) concluded that the evidence evaluated strongly supports TPLO in its ability to return dogs to normal function. While ex vivo studies (Warzee et al. 2001) have demonstrated that a postoperative TPA of 6.5 ± 0.9◦ neutralizes cranial tibial thrust, a study of 32 client-owned Labrador Retrievers with naturally occurring CR undergoing Conclusions TPLO is an important surgical stabilization technique with documented short- and longterm favorable outcomes in both large- and small-breed dogs. References Aertsens A, Rincon Alvarez J, Poncet CM, et al. Comparison of the tibia plateau angle between small and large dogs with cranial cruciate ligament disease. Vet Comp Orthop Traumatol 2015;28:385–390. Aulakh KS, Harper TA, Lanz OI, et al. Effect of stifle angle on the magnitude of the tibial plateau angle measurement in dogs with intact and transected cranial cruciate ligament. A cadaveric study. Vet Comp Orthop Traumatol 2011;24:272–278. Barger B, Piazza A, Muir P. Treatment of stable partial cruciate rupture (Grade I sprain) in five dogs with tibial plateau levelling osteotomy. Vet Rec Case Rep 2016;4:e000315. Berger B, Knebel J, Steigmeier-Raith S, et al. Longterm outcome after surgical treatment of cranial cruciate ligament rupture in small breed dogs. Comparison of tibial plateau leveling osteotomy and extra-articular stifle stabilization. Tierarztl Prax Ausg K Kleintiere Heimtiere 2015;43:373–380. Bell JC, Ness MG. Does use of a jig influence the precision of tibial plateau leveling osteotomy surgery? Vet Surg 2007;36:228–233. Bergh MS, Peirone B. Complications of tibial plateau levelling osteotomy in dogs. Vet Comp Orthop Traumatol 2012;25:349–358. Bergh MS, Rajala-Schultz P, Johnson KA. Risk factors for tibial tuberosity fracture after tibial plateau leveling osteotomy in dogs. Vet Surg 2008;37:374–382. VetBooks.ir 224 Surgical Treatment Bergh MS, Sullivan C, Ferrell CL, et al. Systematic review of surgical treatments for cranial cruciate ligament disease in dogs. J Am Anim Hosp Assoc 2014;50:315–321. Böddeker J, Drüen S, Meyer-Lindenberg A, et al. Computer-assisted gait analysis of the dog: comparison of two surgical techniques for the ruptured cranial cruciate ligament. Vet Comp Orthop Traumatol 2012;25:11–21. Bordelon J, Coker D, Payton M, et al. An in vitro mechanical comparison of tibial plateau levelling osteotomy plates. Vet Comp Orthop Traumatol 2009;22:467–472. Boudrieau RJ, McCarthy RJ, Sisson RD Jr. Sarcoma of the proximal portion of the tibia in a dog 5.5 years after tibial plateau leveling osteotomy. J Am Vet Med Assoc 2005;227:1613–1617. Boudrieau RJ, McCarthy RJ, Sprecher CM, et al. Material properties of and tissue reaction to the Slocum TPLO plate. Am J Vet Res 2006;67:1258–1265. Boudrieau RJ. Tibial plateau leveling osteotomy or tibial tuberosity advancement? Vet Surg 2009;38:1– 22. Boyd DJ, Miller CW, Etue SM, et al. Radiographic and functional evaluation of dogs at least 1 year after tibial plateau leveling osteotomy. Can Vet J 2007;48:392–396. Burton NJ, Fitzpatrick N, Wallace AM. Evaluation of cut accuracy and cis cortical damage for tibial plateau leveling osteotomy performed with and without aid of a novel saw guide: an in vitro study. Vet Surg 2013;42:28–37. Brown G, Maddox T, Baglietto Siles MM. Clientassessed long-term outcome in dogs with surgical site infection following tibial plateau levelling osteotomy. Vet Rec 2016;179:409. Carey K, Aiken SW, DiResta GR, et al. Radiographic and clinical changes of the patellar tendon after tibial plateau leveling osteotomy 94 cases (2000– 2003). Vet Comp Orthop Traumatol 2005;18:235– 242. Caylor KB, Zumpano CA, Evans LM, et al. Intraand interobserver measurement variability of tibial plateau slope from lateral radiographs in dogs. J Am Anim Hosp Assoc 2001;37:263–268. Charles AE, Ness MG. Crevice corrosion of implants recovered after tibial plateau leveling osteotomy in dogs. Vet Surg 2006;35:438–444. Christopher SA, Beetem J, Cook JL. Comparison of long-term outcomes associated with three surgical techniques for treatment of cranial cruciate ligament disease in dogs. Vet Surg 2013;42:329–334. Coletti TJ, Anderson M, Gorse MJ, et al. Complications associated with tibial plateau leveling osteotomy: a retrospective of 1519 procedures. Can Vet J 2014;55:249–254. Collins JE, Degner DA, Hauptman JG, et al. Benefits of pre- and intraoperative planning for tibial plateau leveling osteotomy. Vet Surg 2014;43:142–149. Conkling AL, Fagin B, Daye RM. Comparison of tibial plateau angle changes after tibial plateau leveling osteotomy fixation with conventional or locking screw technology. Vet Surg 2010;39:475–481. Cosenza G, Reif U, Martini FM. Tibial plateau levelling osteotomy in 69 small breed dogs using conically coupled 1.9/2.5 mm locking plates. A clinical and radiographic retrospective assessment. Vet Comp Orthop Traumatol 2015;28:347–354. Conzemius MG, Evans RB, Besancon MF, et al. Effect of surgical technique on limb function after surgery for rupture of the cranial cruciate ligament in dogs. J Am Vet Med Assoc 2005;226:232–236. de Medeiros M, Sánchez Bustinduy M, Radke H, et al. Early kinematic outcome after treatment of cranial cruciate ligament rupture by tibial plateau levelling osteotomy in the dog. Vet Comp Orthop Traumatol 2011;24:178–184. Drygas KA, Pozzi A, Goring RL, et al. Effect of tibial plateau leveling osteotomy on patellar tendon angle: a radiographic cadaveric study. Vet Surg 2010;39:418–424. Duerr FM, Duncan CG, Savicky RS, et al. Comparison of surgical treatment options for cranial cruciate ligament disease in large-breed dogs with excessive tibial plateau angle. Vet Surg 2008;37:49–62. Duerr FM, Martin KW, Rishniw M, et al. Treatment of canine cranial cruciate ligament disease. A survey of ACVS Diplomates and primary care veterinarians. Vet Comp Orthop Traumatol 2014;27:478–483. Fettig AA, Rand WM, Sato AF, et al. Observer variability of tibial plateau slope measurement in 40 dogs with cranial cruciate ligament-deficient stifle joints. Vet Surg 2003;32:471–478. Fitzpatrick N, Solano MA. Predictive variables for complications after TPLO with stifle inspection by arthrotomy in 1000 consecutive dogs. Vet Surg 2010;39:460–474. Flynn P, Duncan CG, Palmer RH, et al. In vitro incidence of fibular penetration with and without the use of a jig during tibial plateau leveling osteotomy. Vet Surg 2014;43:495–499. Frey TN, Hoelzler MG, Scavelli TD, et al. Risk factors for surgical site infection-inflammation in dogs undergoing surgery for rupture of the cranial cruciate ligament: 902 cases (2005–2006). J Am Vet Med Assoc 2010;236:88–94. Gatineau M, Dupuis J, Planté J, et al. Retrospective study of 476 tibial plateau levelling osteotomy procedures. Rate of subsequent ‘pivot shift’, meniscal tear and other complications. Vet Comp Orthop Traumatol 2011;24:333–341. Gordon WJ, Conzemius MG, Riedesel E, et al. The relationship between limb function and radiographic osteoarthrosis in dogs with stifle osteoarthrosis. Vet Surg 2003;32:451–454. Gordon-Evans WJ, Griffon DJ, Bubb C, et al. Comparison of lateral fabellar suture and tibial plateau leveling osteotomy techniques for treatment of dogs VetBooks.ir Tibial Plateau Leveling Osteotomy with cranial cruciate ligament disease. J Am Vet Med Assoc 2013;243:675–680. Haynes KH, Biskup J, Freeman A, et al. Effect of tibial plateau angle on cranial cruciate ligament strain: an ex vivo study in the dog. Vet Surg 2015;44:46–49. Hoots EA, Petersen SW. Tibial plateau leveling osteotomy and cranial closing wedge ostectomy in a cat with cranial cruciate ligament rupture. J Am Anim Hosp Assoc 2005;41:395–399. Hulse D, Beale B, Kerwin S. Second look arthroscopic findings after tibial plateau leveling osteotomy. Vet Surg 2010;39:350–354. Hurley CR, Hammer DL, Shott S. Progression of radiographic evidence of osteoarthritis following tibial plateau leveling osteotomy in dogs with cranial cruciate ligament rupture: 295 cases (2001– 2005). J Am Vet Med Assoc 2007;230:1674–1679. Jandi AS, Shulman AJ. Incidence of motion loss of the stifle joint in dogs with naturally occurring cranial cruciate ligament rupture surgically treated with tibial plateau leveling osteotomy: longitudinal clinical study of 412 cases. Vet Surg 2007;36:114– 121. Kergosien DH, Barnhart MD, Kees CE, et al. Radiographic and clinical changes of the tibial tuberosity after tibial plateau leveling osteotomy. Vet Surg 2004;33:468–474. Kim SE, Pozzi A, Banks SA, et al. Effect of tibial plateau leveling osteotomy on femorotibial contact mechanics and stifle kinematics. Vet Surg 2009;38:23–32. Kloc PA, Kowaleski MP, Litsky AS, et al. Biomechanical comparison of two alternative tibial plateau leveling osteotomy plates with the original standard in an axially loaded gap model: an in vitro study. Vet Surg 2009;38:40–48. Kowaleski MP, Apelt D, Mattoon JS, et al. The effect of tibial plateau leveling osteotomy position on cranial tibial subluxation: an in vitro study. Vet Surg 2005;34:332–326. Kowaleski MP, Boudrieau RJ, Beale BS, et al. Radiographic outcome and complications of tibial plateau leveling osteotomy stabilized with an anatomically contoured locking bone plate. Vet Surg 2013;42:847–852. Krotscheck U, Thompson MS, Ryan KK, et al. Comparison of TPA, bone healing, and intra-articular screw placement using conventional nonlocked application of surgeon-contoured versus locked application of precontoured TPLO plates in dogs. Vet Surg 2012;41:931–937. Leitner M, Pearce SG, Windolf M, et al. Comparison of locking and conventional screws for maintenance of tibial plateau positioning and biomechanical stability after locking tibial plateau leveling osteotomy plate fixation. Vet Surg 2008;37:357– 365. Mariano AD, Kowaleski MP, Boudrieau RJ. Novel TPLO alignment jig/saw guide reproduces free- 225 hand and ideal osteotomy positions. PLoS One 2016;11:e0161110. Millis D, Durant A, Headrick J, et al. Long term kinetic and kinematic comparison of cruciate-deficient dogs treated with tibial plateau leveling osteotomy or modified retinacular imbrications technique. Vet Surg 2008;37:E23. Moeller EM, Cross AR, Rapoff AJ. Change in tibial plateau angle after tibial plateau leveling osteotomy in dogs. Vet Surg 2006;35:460–464. Monk ML, Preston CA, McGowan CM. Effects of early intensive postoperative physiotherapy on limb function after tibial plateau leveling osteotomy in dogs with deficiency of the cranial cruciate ligament. Am J Vet Res 2006;67:529–536. Mossman H, von Pfeil DJ, Nicholson M, et al. Accuracy of three pre- and intra-operative measurement techniques for osteotomy positioning in the tibial plateau levelling procedure. Vet Comp Orthop Traumatol 2015;28:250–255. Nazarali A, Singh A, Moens NM, et al. Association between methicillin-resistant Staphylococcus pseudintermedius carriage and the development of surgical site infections following tibial plateau leveling osteotomy in dogs. J Am Vet Med Assoc 2015;247:909–916. Nazarali A, Singh A, Weese JS. Perioperative administration of antimicrobials during tibial plateau leveling osteotomy. Vet Surg 2014;43:966–971. Nelson SA, Krotscheck U, Rawlinson J, et al. Longterm functional outcome of tibial plateau leveling osteotomy versus extracapsular repair in a heterogeneous population of dogs. Vet Surg 2013;42:38– 50. Oxley B, Gemmill TJ, Renwick AR, et al. Comparison of complication rates and clinical outcome between tibial plateau leveling osteotomy and a modified cranial closing wedge osteotomy for treatment of cranial cruciate ligament disease in dogs. Vet Surg 2013;42:739–750. Pacchiana PD, Morris E, Gillings SL, et al. Surgical and postoperative complications associated with tibial plateau leveling osteotomy in dogs with cranial cruciate ligament rupture: 397 cases (1998–2001). J Am Vet Med Assoc 2003;222:184–193. Pozzi A, Dunbar NJ, Kim SE. Effect of tibial plateau leveling osteotomy on patellofemoral alignment: a study using canine cadavers. Vet J 2013;198:98– 102. Pozzi A, Kowaleski MP, Apelt D, et al. Effect of medial meniscal release on tibial translation after tibial plateau leveling osteotomy. Vet Surg 2006;35:486– 494. Priddy NH, Tomlinson JL, Dodam JR, et al. Complications with and owner assessment of the outcome of tibial plateau leveling osteotomy for treatment of cranial cruciate ligament rupture in dogs: 193 cases (1997–2001). J Am Vet Med Assoc 2003;222:1726– 1732. VetBooks.ir 226 Surgical Treatment Ray WM, Gustafson SB, Huber MJ. Tibial plateau leveling osteotomy in a llama with a ruptured cranial cruciate ligament. J Am Vet Med Assoc 2004;225:1739–1742. Reif U, Dejardin LM, Probst CW, et al. Influence of limb positioning and measurement method on the magnitude of the tibial plateau angle. Vet Surg 2004;33:368–375. Reif U, Hulse DA, Hauptman JG. Effect of tibial plateau leveling on stability of the canine cranial cruciate-deficient stifle joint: an in vitro study. Vet Surg 2002;31:147–154. Robinson DA, Mason DR, Evans R, et al. The effect of tibial plateau angle on ground reaction forces 4– 17 months after tibial plateau leveling osteotomy in Labrador Retrievers. Vet Surg 2006;35:294–299. Romano LS, Cook JL. Safety and functional outcomes associated with short-term rehabilitation therapy in the post-operative management of tibial plateau leveling osteotomy. Can Vet J 2015;56:942– 946. Rutherford S, Bell J, Ness M. Fracture of the patella after TPLO in dogs. Vet Surg 2014;43:523–524. Sathya S, Gilbert P, Sharma A, et al. Effect of tibial plateau levelling osteotomy on patellar tendon angle: a prospective clinical study. Vet Comp Orthop Traumatol 2014;27:346–350. Schmerbach KI, Boeltzig CK, Reif U, et al. In vitro comparison of tibial plateau leveling osteotomy with and without use of a tibial plateau leveling jig. Vet Surg 2007;36:156–163. Slocum B, Slocum TD. Tibial plateau leveling osteotomy for repair of cranial cruciate ligament rupture in the canine. Vet Clin North Am Small Anim Pract 1993;23:777–795. Solano MA, Danielski A, Kovach K, et al. Locking plate and screw fixation after tibial plateau leveling osteotomy reduces postoperative infection rate in dogs over 50 kg. Vet Surg 2015;44:59–64. Stauffer KD, Tuttle TA, Elkins AD, et al. Complications associated with 696 tibial plateau leveling osteotomies (2001–2003). J Am Anim Hosp Assoc 2006;42:44–50. Talaat MB, Kowaleski MP, Boudrieau RJ. Combination tibial plateau leveling osteotomy and cranial closing wedge osteotomy of the tibia for the treatment of cranial cruciate ligament-deficient sti- fles with excessive tibial plateau angle. Vet Surg 2006;35:729–739. Tan CJ, Bergh MS, Schembri MA, et al. Accuracy of tibial osteotomy placement using 2 different tibial plateau leveling osteotomy jigs. Vet Surg 2014;43:525–533. Taylor J, Langenbach A, Marcellin-Little DJ. Risk factors for fibular fracture after TPLO. Vet Surg 2011;40:687–693. Thieman KM, Tomlinson JL, Fox DB, et al. Effect of meniscal release on rate of subsequent meniscal tears and owner-assessed outcome in dogs with cruciate disease treated with tibial plateau leveling osteotomy. Vet Surg 2006;35:705–710. Tuttle TA, Manley PA. Risk factors associated with fibular fracture after tibial plateau leveling osteotomy. Vet Surg 2009;38:355–360. Unis MD, Johnson AL, Griffon DJ, et al. Evaluation of intra- and interobserver variability and repeatability of tibial plateau angle measurements with digital radiography using a novel digital radiographic program. Vet Surg 2010;39:187–194. Vedrine B, Guillemot A, Fontaine D, et al. Comparative anatomy of the proximal tibia in healthy Labrador Retrievers and Yorkshire Terriers. Vet Comp Orthop Traumatol 2013;26:266–70. Warzee CC, Dejardin LM, Arnoczky SP, et al. Effect of tibial plateau leveling on cranial and caudal tibial thrusts in canine cranial cruciate deficient stifles. Vet Surg 2001;30:278–286. Waxman AS, Robinson DA, Evans RB, et al. Relationship between objective and subjective assessment of limb function in normal dogs with an experimentally induced lameness. Vet Surg 2008;37:241– 246. Wheeler JL, Cross AR, Gingrich W. In vitro effects of osteotomy angle and osteotomy reduction on tibial angulation and rotation during the tibial plateau-leveling osteotomy procedure. Vet Surg 2003;32:371–377. Windolf M, Leitner M, Schwieger K, et al. Accuracy of fragment positioning after TPLO and effect on biomechanical stability. Vet Surg 2008;37:366–373. Witte PG, Scott HW. Tibial plateau leveling osteotomy in small breed dogs with high tibial plateau angles using a 4-hole 1.9/2.5 mm locking T-plate. Vet Surg 2014;43:549–557. VetBooks.ir 28 Tibial Tuberosity Advancement Randy J. Boudrieau Introduction Advancement of tibial tuberosity was first described by Maquet, where the premise of the procedure was that an increase in the efficiency of the quadriceps mechanism would subsequently decrease retropatellar pressure, thus alleviating pain associated with the patellofemoral joint in humans (Maquet 1976). Other possible effects on the biomechanics of the tibiofemoral joint included evidence that a variable tibiofemoral shear force was present in the knee joint, which was directed either anteriorly or posteriorly depending upon the angle of knee joint extension or flexion and patellar tendon angle (PTA), respectively (Nisell 1985), and that the magnitude and direction of the tibiofemoral shear force was determined by the PTA (Nisell et al. 1986) (Figure 28.1). An increase in translational knee joint instability has been demonstrated by a number of biomechanical studies in humans as a result of variations in tibial plateau slope (Giffin et al. 2004), axial loading (Li et al. 1998), and knee flexion angle (Nisell et al. 1989). A three-dimensional (3D) nonlinear finite element model of the human knee evaluating the Maquet procedure found it to be effective in decreasing the femorotibial contact forces in stifle joint extension, in addition to decreasing retropatellar pressure (Shirazi-Adl & Mesfar 2007). Similarly, changes in tibiofemoral shear forces were observed depending on the knee flexion angle, which placed either more or less stress on the anterior and posterior cruciate ligaments depending on the amount of tibial tuberosity advancement (Shirazi-Adl & Mesfar 2007). A relationship between tibial tuberosity advancement, knee joint flexion/extension, tibiofemoral shear force, retropatellar pressure, femorotibial contact forces, and patellar tendon force has been suggested and supported by a variety of experimental studies (Maquet 1976; Nakamura et al. 1985; Nisell 1985; Nisell et al. 1986; Nisell et al. 1989; Li et al. 1998; Giffin et al. 2004; Shirazi-Adl & Mesfar 2007). Stifle biomechanics Based on data published by Maquet and Nisell, Montavon and Tepic proposed that a similar situation existed in the dog, and tibial tuberosity advancement (TTA) would similarly neutralize cranial tibiofemoral shear force in a cranial cruciate ligament (CrCL)-deficient stifle joint in the dog (Maquet 1976; Nisell et al. 1986; Montavon et al. 2002; Tepic et al. 2002). A PTA of 90◦ Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 227 VetBooks.ir 228 Surgical Treatment (A) Fp Knee Angle TPS PTA PTA (B) 120° 110° 100° 60° 90° 180° 80° 150° 120° 90° Knee Angle Fs (N) (C) 600 was suggested as the crossover point at 135◦ of stifle joint extension; thus, the TTA technique was developed so as to achieve this PTA (Figure 28.2). These assumptions were supported in four experimental ex vivo models (Apelt et al. 2007; Miller et al. 2007; Kipfer et al. 2008; Hoffmann et al. 2011). These models were used to evaluate cranial tibiofemoral shear force either indirectly with cranial tibial subluxation (Apelt et al. 2007; Miller et al. 2007; Kipfer et al. 2008) or directly with cranial tibial thrust under varying loading conditions (Hoffmann et al. 2011) (Figure 28.3). A recent 3D quasi-static rigid body pelvic limb computer model simulating the stance phase of gait predicted improved joint loading in the CrCL-deficient stifle, but not restoration of normal CrCL-intact biomechanics (Brown et al. 2015). In this model, the TTA effectively reduced tibial translation, but did not stabilize tibial rotation (Brown et al. 2015). These results were similar whether using either the tibial plateau angle (TPA) or common tangent planning methods to achieve a target PTA of 90◦ (Brown et al. 2015). The findings in this model were consistent with an in vivo assessment of the TTA during weight-bearing, which demonstrated that craniotibial translation was reduced, but not eliminated (Skinner et al. 2013). A 3D nonlinear joint finite element model reconstruction, which was based on a cadaver knee joint of a human, was used to evaluate the reduction in retropatellar pressure and patellar tendon force. The analysis confirmed not only a decrease in patellofemoral contact forces after TTA, but also femorotibial contact forces with stifle joint extension (Shirazi-Adl & 400 200 90° 60° 0 180° –200 150° 120° Knee Angle Figure 28.1 (A) Anatomic landmarks of the radiographic and morphologic studies of the knee. The patellar tendon force (Fp) is shown, which is approximately of the same magnitude and direction of the tibiofemoral compressive force, and results in a variable amount of tibiofemoral shear force depending on the knee flexion angle and tibial plateau slope (TPS), both of which influence the patellar tendon angle (PTA). (B) The relationship between Figure 28.1 (Continued) the PTA (y-axis) and knee flexion angle (x-axis); note that the PTA = 90◦ at a knee flexion angle of ∼100◦ ; the 95% confidence intervals of the means are shown for men (filled circles) and women (open circles). (C) Tibiofemoral shear force (Fs; y-axis) during isometric knee extension at various knee flexion angles (x-axis) for men (filled circles) and women (open symbols). During knee extension, the application of posteriorly directed external forces of 100 N (squares and circles) and 50 N (diamonds) against the anterior tibia at 0.4 m, 0.4 m and 0.2 m distal to the tibial plateau, respectively. Positive values (Fs) indicate that the tibia tends to slide anteriorly in relation to the femur (anterior tibiofemoral shear). Source: Nisell 1985. Reproduced with permission from Taylor & Francis. VetBooks.ir Tibial Tuberosity Advancement Figure 28.2 Schematic representation of stifle joint flexion with respect to PTA. In full extension, the PTA is >90◦ and in full flexion the PTA is <90◦ . There is a point such that the PTA is 90◦ , which is termed the ‘crossover’ point (see Figure 28.1C, Fs = 0.0). At this point, there is neither cranial nor caudal tibiofemoral shear force present. The premise of the tibial tuberosity advancement (TTA), according to Tepic, is to alter the geometry of the proximal tibia such that the PTA is maintained at ≤90◦ throughout the stifle joint range of motion during weight-bearing; the TTA will change the PTA and move the crossover point such that Fs = 0.0 N when PTA = 90◦ when the stifle joint is in full extension. Further stifle joint flexion ensures that Fs is always ≤0.0 N and PTA ≤90◦ . The PTA is thus maintained at ≤90◦ throughout the stifle joint range of motion during weight-bearing. Compare with Figure 28.5. Source: Boudrieau 2009. Reproduced with permission from John Wiley & Sons, Inc. Mesfar 2007). A decrease in retropatellar pressure after TTA also has been demonstrated experimentally in the dog (Hoffmann et al. 2011). Theoretically, this diminished force can protect the articular cartilage of both the patella and the femur from subsequent damage. Femorotibial contact pressure and location have been evaluated in vitro using an experimental model of a CrCL-deficient stifle joint, which demonstrated an approximately 40% decrease in contact area with an associated 100% increase 229 in peak pressure; furthermore, the positioning of the peak pressure was found to shift caudally (Kim et al. 2009). TTA appeared to restore the normal femorotibial contact and pressure (Kim et al. 2009), which may spare the meniscus from risk of trauma after TTA (Figure 28.4). This study also suggested that because TTA did not change the geometry of the joint, and the pressure distributions essentially remained unchanged, there may be less development of osteoarthritis over time. All of these findings could support clinical studies that implied an absence of problems with the patellar tendon and the joint surfaces after TTA (Hoffmann et al. 2006; Lafaver et al. 2007; Stein & Schmoekel 2008; Kim et al. 2009). These studies have recently been challenged by more recent evaluations performed in vivo on clinical cases, where persistent instability was observed in dogs after TTA despite reportedly good postoperative function (Böttcher et al. 2013; Skinner et al. 2013). The reason for continued postoperative instability is debated, as precise assessment of the amount of advancement after surgery is lacking. A number of errors inherent in the techniques for preoperative planning and intraoperative technical failures will contribute to the final position of the tibial advancement and the resultant PTA. These include such items as the differing proximal versus distal cage width and its final position within the osteotomy and patella-based versus distal tibial tuberosity-based advancement. Furthermore, the appropriate PTA that neutralizes tibiofemoral shear has not yet been definitively documented in vivo. As the resultant PTA is crucial to the determination of the amount of TTA, it has been suggested that the PTA is more accurately determined by the method of the common tangent (PTACT ) (Dennler et al. 2006; Schwandt et al. 2006; Boudrieau 2009), as opposed to the method using the TPA (PTATPA) (Boudrieau 2009; Hoffmann et al. 2011). The former method has been proposed to be clinically more accurate as it takes into account the anatomic relationship between the femoral condyles and tibial plateau, as opposed to a static relationship of the tibial plateau with the patellar tendon (Boudrieau 2009) (Figure 28.5). Based on these suppositions, PTACT has been recommended for clinical use (2007 Veterinary Symposium – The Surgical Treatment VetBooks.ir 230 CTS-T CTS-I * * * dI * CTS-O CTS-CP * * d d * d * Figure 28.3 Lateral radiographic images of cranial tibial subluxation (CTS) in a loaded stifle joint within an experimental limb press model. Left to right: before cranial cruciate ligament (CrCL) transection (CTS-I); after CrCL transection (CTS-T); post-tibial tuberosity advancement after maximal tibial tuberosity advancement (CTS-O); and at critical point tibial tuberosity advancement (CTS-CP). The critical point for the tibial tuberosity advancement distance in this model was defined as the position one revolution before stifle joint instability occurred. The CTS was defined as ‘d’ in each figure: CTS-T/CTS-O/CTS-CP = d – dI , where dI (arrow) is the horizontal distance between the tibial marker (∗ ) and the vertical passing through the femoral marker (dotted line) in the intact CrCL (the intact CrCL was the reference position), and d is the same horizontal distance (arrows) for each respective position (CTS-T, CTS-O, and CTS-CP). In this specimen, CTS-T was positive, CTS-O was negative, and CTS-CP was slightly negative. Source: Apelt et al. 2007. Reproduced with permission from John Wiley & Sons, Inc. Normal CrCL-Deficient TTA-Treated MPa Figure 28.4 Axial view of bone models depicting three-dimensional poses of normal, cranial cruciate-deficient (CrCL-Deficient), and tibial tuberosity advancement (TTA-Treated) stifles, with corresponding contact maps representative of each testing condition. The tibia (light gray) is cranially displaced and internally rotated relative to the femur (dark gray) after CrCL transection; the femorotibial poses of normal and TTA-treated stifles are similar. CrCL transection resulted in a caudal shift, a reduced area and an increased pressure of femorotibial contact; TTA contact patterns are similar to normal. Left = lateral; top = cranial. CrCL, cranial cruciate ligament; TTA, tibial tuberosity advancement. Source: Kim et al. 2009. Reproduced with permission from John Wiley & Sons, Inc. 231 VetBooks.ir Tibial Tuberosity Advancement Post-op Pre-op (A) (B) (C) Figure 28.5 Schematic representation of the tibiofemoral forces in the stifle joint, according to Tepic, before (A) and after (B) tibial tuberosity advancement (TTA). The resultant compressive force (large white arrow) across the stifle joint is parallel to the patellar tendon. Using the common tangent at the tibiofemoral contact point as the baseline (solid red line), whereby the femur can move along this surface if the cranial cruciate ligament (CrCL) is deficient, the resultant force can be broken down into its two orthogonal components (small blue arrows), one perpendicular and one parallel to the tibial plateau. The latter represents the tibiofemoral shear force. If the angle of the tibial tuberosity is advanced cranially until the patellar tendon angle (PTA) is reduced to 90◦ , the tibiofemoral shear force vector becomes zero, and the joint compressive force and resultant force become one and the same. Note that the cranial tibiofemoral shear force is smaller than that depicted with the PTA using the tibial plateau slope (TPS), which is indicated by the green dotted line. Note that the common tangent and TPS are similar in stifle joint flexion (C). The insets clarify the force vectors depicted on the schematic bone models. Compare with Figure 28.2. Source: Boudrieau 2009. Reproduced with permission from John Wiley & Sons, Inc. Surgical Summit; Pre-Symposium Laboratories: TTA Laboratory; Chicago, IL, USA). Support for this concept has been demonstrated experimentally, whereby less variability was observed with PTACT versus PTATPA to achieve the target PTA of 90◦ (Hoffmann et al. 2011). These findings have recently been questioned in a study that found a poor agreement between PTACT and PTATPA, moderate intra-observer reliability and poor inter-observer reliability with PTACT , with good intra-observer reliability and moderate inter-observer reliability with PTATPA, thus concluding that PTACT is not recommended (Millet et al. 2013). Reconciling the differences between the different studies is problematic (Dennler 2006; Hoffmann et al. 2011; Millet et al. 2013). An agreement between PTACT and PTATPA is certainly not expected due to the complex joint anatomy that differs between dogs, including differing stifle joint extension angles and change of femoral position as the femoral condyles roll backwards with stifle joint flexion (Boudrieau 2009). The latter factors are the arguments supporting the rationale for using the PTACT in the pre-planning, as described by the originators of the surgical technique (Tepic et al. 2002). Implants and techniques Currently there are two general techniques to perform the TTA, described as the firstand second-generation methods. The firstgeneration method is the initial method as proposed by Tepic (Kyon; Boston, MA, USA), using a titanium cage to maintain the advancement and a corresponding titanium plate with forks VetBooks.ir 232 Surgical Treatment to make a stable construct. In this technique, a patella-based positioning of the tibial tuberosity is performed, with a slight proximal shift of the tibial crest segment with the advancement, so as to not change the patella position. Finally, a graft is applied within the osteotomy gap and within the cage (Lafaver et al. 2007). The need for a graft is controversial (Guerrero et al. 2011; Boudrieau 2011). The second-generation method is currently evolving. Plates are no longer used; instead, the construct is held in place by a cage only, but with varying ‘accessories’ or ‘adjunct’ methods to ensure that the cage remains in place (Brunel et al. 2013; Samoy et al. 2015; Torrington 2015). One of the major conceptual modifications is an incomplete distal osteotomy of the tibial tuberosity, so as to help stabilize the fixation. This encompasses a distal-based tuberosity advancement. This type of advancement was not recommended during development of the first-generation method, where a patellabased advancement is used. With the secondgeneration TTA, the advancement causes some distal displacement of the patella. The rationale for the incomplete osteotomy of the distal end of the tibial tuberosity is that it aids construct stability and neutralization of the distractive force of the quadriceps mechanism that were previously neutralized with a plate. A result of this modification is some distal patella displacement. The clinical ramifications, if any, of this change in patella position have yet to be investigated. First-generation implants and techniques The original implants were produced by the technique inventors (Tepic, Kyon). These titanium implants have been copied exactly, although there is controversy as to the quality of the copies. Other alternate implants that use different fixation methods to achieve the same general concept are also available. For example, stainless steel plates with standard screws instead of a fork for the tuberosity fixation (XGEN forkless TTA plates; Securos Surgical, Boise, ID, USA). Another approach is locking screw fixation for the tuberosity segment, again with a similar-appearing stainless steel plate with a PEEK spacer (DePuy Synthes Vet, West Chester, PA, USA). Many other similar copies are available from a variety of manufacturers. Second-generation implants and techniques Three basic concepts are currently marketed. These include the modified Maquet procedure1 (MMP; Orthomed, West Yorkshire, UK), TTA Rapid2 (Rita Leibinger, DE, USA) and TTA-23 (KYON Veterinary Surgical Products, Boston, MA, USA). These techniques have resulted in the development of alternative stand-alone cage designs and techniques to orient the tibial osteotomy a fixed distance along the cranial tibial shaft that corresponds to the degree of tuberosity advancement and cage width desired. The specific technical feature of these approaches, primarily pertain to the location and length of the osteotomy, and the method to spread of the incomplete osteotomy and achieve the tuberosity advancement needed. These details can be found on the manufacturer’s websites.1,2,3 TTA pre-planning and surgery There are many considerations regarding the pre-planning of TTA, particularly with regard to the measurement methods using PTACT or PTATPA. Additional alternative methods have also been proposed. Some of the other techniques, such as the MMP procedure, have been critically assessed; here, the target PTA of 90◦ is often not achieved as current planning methods may lead to underadvancement of the tibial tuberosity (Kapler et al. 2015). The planning methods for first- and secondgeneration techniques are similar and aim to achieve a PTA of 90◦ . There are a number of nuances with both the plan and its execution to ensure that the TTA does achieve a postoperative PTA of 90◦ . Unfortunately, minimal data 1 MMP see pdf downloads at http://www.orthomed .co.uk/ 2 TTA Rapid, http://tta-rapid.com/ 3 TTA-2, http://www.kyon.ch/current-products/tibialtuberosity-advancement-tta/tta-2-developmenttechnique VetBooks.ir Tibial Tuberosity Advancement are available on postoperative evaluation of the PTA in clinical cases; a single report has determined postoperative PTA in a series of cases (Wolf et al. 2012). This oversight needs to be corrected, so as to ensure that the technique is performed appropriately. Such data will help confirm clinically that TTA does result in stability of the stifle joint after surgery with neutralization of the tibiofemoral shear force in vivo. Despite the many reports of successful surgical outcomes, such evidence is not yet available. The current recommendation, as presented by the inventors of this technique (Tepic), is to use the PTACT technique. This recommendation is based on knowledge of the variations in the anatomy of the proximal tibial plateau and the distal femur, and how anatomic factors affect advancement measurements when using the common tangent between the tibial and femoral surfaces at their contact point, or PTACT (Boudrieau 2005; Boudrieau 2009). Less variation has been reported with PTACT compared with PTATPA, further supporting this recommendation (Hoffmann et al. 2011). The accuracy in planning the osteotomy and determining amount of advancement has been studied (Etchepareborde et al. 2011; Millet et al. 2013; Cadmus et al. 2014). Errors will occur because of the varied anatomy encountered, such as positioning (tibial drawer or stifle joint extension angle), patella tendon insertion point (high versus low), unrecognized effects with regard to tibial tuberosity hinge point (maintained at the distal attachment versus allowed to move proximally), variation in the pre-planning measurement method (Inauen et al. 2009; Bush et al. 2011), and loss of advancement due to the saw kerf and cage position (Botte 2013). For these reasons, virtual surgery pre-planning is currently recommended. This can be accomplished using digital software (e.g., Orthoplan Elite; Sound, Carlsbad, CA, USA) or a cut-and-paste manual method using radiographic film. Virtual pre-planning (Figure 28.6) allows the cage advancement to be measured at the appropriate point of cage placement/position to achieve the desired 90◦ PTA postoperatively. Regardless of which pre-planning method is used, accurate transfer of the plan to the bone is required to achieve the desired advancement. Factors related to saw kerf, tuberosity displacement with 233 patella-based advancement, and cage positioning all need to be recognized. TTA case selection Several factors specific to the anatomic configuration of the limb should be considered before selection of this surgical technique (Boudrieau 2009). Low versus high patellar tendon insertion point The tibial tuberosity may be at greater risk for fracture with TTA in cases with a low patellar tendon insertion point, as a smaller plate is applied to the tibial crest and the usual position of the interspersed cage is above the most proximal position of the plate, with little bone present for support. Interestingly, this conformation may be better suited for a tibial plateau leveling osteotomy as there is increased buttress support of the tibial tuberosity with greater amounts of tibial plateau rotation. In dogs with a high insertion point the TTA is preferable, as a larger TTA plate can be applied to the tibial crest, and the interspersed cage that is placed within the gap remains buttressed with adequate bone. Finally, the larger plate better disperses all the forces to the tibial crest (Figure 28.7). Currently, there are no experimental or clinical studies reported that support these assumptions. Excessive tibial plateau angle Cases where there is excessive TPA are not conducive to TTA. The target PTA is 90◦ , but achieving this angle in such cases require substantially greater advancement, sometimes beyond that obtained with currently available implants (the maximal cage width for the osteotomy gap is 15 mm). More importantly, there is a conformational deformity of the joint with excessive tibial plateau angle that places the joint in a relative angle of hyperextension, despite the limb itself not being in the extended position (Figure 28.8). The TTA does not address this malformation. The maximal TPA to perform a TTA has yet to Surgical Treatment VetBooks.ir 234 (A) (B) (C) (D) (E) (F) Figure 28.6 (A) Preoperative lateral radiograph of the stifle joint in full but not forced extension. Different breeds of dogs will have differing full extension joint angles. (B) The circles outline the femoral condyle and the tibial plateau, respectively; a line (#1) is drawn between the centers of these two circles; a second line (#2) drawn perpendicular to #1 between the circles is the common tangent of the joint surfaces; finally, a third line (#3) parallel to line #1 is drawn that passes through the cranial-most origin of the patella tendon at the distal pole. This is the planned tuberosity position in order to obtain a patellar tendon angle of 90◦ . Note that the distance to move the most proximal point of the tibial tuberosity to line #3 is NOT equivalent to the cage width (blue arrowheads, and also see panel D). A straight or distally curved osteotomy can be planned for the tibial tuberosity (dotted lines). In this case, a curved line is selected to provide more craniocaudal width due to the concave shape of the cranial border of the tibial crest (see panel C). (C) The outline (red) of the tibial tuberosity is selected to match the planned osteotomy from panel B; note the length of the patellar tendon (the orange line between the two orange arrowheads). (D) The tibial tuberosity is moved cranially so that the proximal point of the tibial tuberosity intersects with the line #3, indicating the appropriate advancement distance. Note that the position of the patella is unchanged (orange line between the two orange arrowheads). Therefore, the distal end of the osteotomized tuberosity must move proximally (yellow arrows). The appropriate cage template is selected that 235 VetBooks.ir Tibial Tuberosity Advancement Figure 28.7 Lateral radiographs of the stifle joint, demonstrating the variation between the insertion points of the patellar tendon into the tibial tuberosity. (A) Tibial tuberosity with a low insertion point. (B) Tibial tuberosity with a high insertion point. A smaller plate must be applied when a shorter tibial tuberosity distance is available. The result is an increase in the forces at each tine of the fork. Additionally, the overall plate length is shortened, potentially creating a stress riser at the distal end of the osteotomy and the screws placed to secure the distal end of the plate. The tuberosity shifts proximally with advancement in order to maintain patellar position. Furthermore, cage position (double-headed arrow) provides greater buttress support of the tuberosity, and also buttresses the proximal attachment of the plate when a high insertion point is present. be determined. No data have been published regarding the range of TPAs in dogs with TTA, although it has been presented that successful procedures have been performed in dogs with a TPA of ∼30◦ . Anecdotally, it is proposed that angles >30◦ are not well suited for a TTA (2007 Veterinary Symposium – The Surgical Summit; Pre-Symposium Laboratories: TTA Laboratory; Chicago, IL, USA). Angular and torsional limb deformities Angular and torsional limb deformities may be treated with TTA. However, a separate osteotomy is required for correction of any tibial varus, valgus, or torsion. The disadvantage of performing a separate osteotomy is that the medial side of the bone already has a plate positioned for the first-generation TTA Figure 28.6 (Continued) spans the osteotomy gap 2–3 mm distal to the tibial plateau surface (white arrows). Note the location of this cage and the corresponding location of the most proximal point of the tibial tuberosity. The width of the cage is not equal to the distance observed in panel B; rather, it is wider as the upper edge of the cage and the corresponding cage size is NOT placed at the level of the proximal point of the tibial tuberosity. (E) The appropriate plate template is selected that spans the length of the tibial crest, and its orientation is noted so as to provide appropriate positioning of both the fork and the distal screws of the plate. The large green arrowheads show the plate more caudally positioned proximally as the most cranial border cannot be followed due to the concave cranial border of the tibial crest. Note that the distal portion of the plate also overlies the tibial diaphysis, this occurs despite a slightly more caudal orientation. (F) Postoperative radiograph that has copied the virtual plan and successfully resulted in appropriate advancement to obtain a patellar tendon angle of 90◦ . The osteotomy and its position, and the cage and plate positions have been successfully duplicated on the patient. VetBooks.ir 236 Surgical Treatment (A) (B) 25° 43° Figure 28.8 Lateral stifle joint radiographs demonstrating differences in the anatomic shape of the proximal tibia such that the tibial plateau angle (TPA) is either considered excessive (A) at 43◦ , or within normal limits (B) at 25◦ . This conformational deformity of the stifle joint angle in panel (A) places the joint in a relatively hyperextended position, compared with panel (B). Advancing the tibial tuberosity does not correct this hyperextension as the TPA remains unaltered. Source: Boudrieau 2009. Reproduced with permission from John Wiley & Sons, Inc. in the proximal one-third of the medial tibial surface, which will interfere with subsequent additional medial plate fixation. Although a standard plate could be applied over the thin TTA plate, this is far from ideal and generally not recommended. With the second-generation TTA, using a wedge-only technique and no plate, this issue is ameliorated. However, a second osteotomy in the transverse plane is still required to address these deformities. Therefore, TTA is generally not recommended under these circumstances. Patellar luxation Patellar luxation requiring tibial tuberosity transposition combined with cruciate ligament rupture may be very well suited to TTA, as any desired transposition may be simultaneously performed concurrently with the advancement. In this instance, the TTA plate is slightly overbent to conform to the new laterally (or medially) transposed tibial crest. The alteration in the surgical technique occurs with cage application. For example, in a medial patellar luxation, where the tibial crest is moved laterally, either the caudal ‘ear’ of the cage is recessed into the proximal tibia, or the cranial ‘ear’ of the cage is elevated above the surface of the tibial tuberosity by interposing some washers, or both (Figure 28.9). Ancillary fixation generally is unnecessary. This technique has been briefly described (2007 Veterinary Symposium – The Surgical Summit; Pre-Symposium Laboratories: TTA Laboratory; Chicago, IL, USA) (Boudrieau 2005), and reported in a series of cases (Yeadon et al. 2011). Patient size TTA has been performed in dogs as small as 5 kg and as large as 92 kg (Hoffmann et al. 2006; Lafaver et al. 2007). Size limitation is dependent on the availability of appropriately sized implants (2- to 8-hole plates, and 3- to 15-mm cage widths, Kyon; Zürich, Switzerland). The implants are produced in a variety of sizes such that they can be used in almost any sized dog. In some instances, in very tall dogs such as Great Danes, a limitation of the TTA may be the large advancement distance (>15 mm) that is required (Burns & Boudrieau 2008). The widest cage currently available to support the osteotomy gap is 15 mm, which became available in early 2009. Whereas the cage can be moved further distally to increase VetBooks.ir Tibial Tuberosity Advancement (A) 237 (B) Figure 28.9 Craniomedial view of the proximal tibia after tibial tuberosity transposition (TTA) performed routinely (A) and after simultaneous lateral transposition (B) with the advancement for a medial patellar luxation treatment. Note that the caudal cage ‘ear’ has been recessed slightly into the caudal tibial bone fragment. This is done by bending this ‘ear’ at ∼45◦ without removing a large amount of bone. The plate also is contoured such that it meets the tuberosity more laterally. Alternatively, or additionally, the cranial cage ‘ear’ may be elevated off of the tuberosity bone by placing one to two small metal washers under this ‘ear.’ the width of the gap, this must be done judiciously because a large stress riser is created above the cage, which could result in fracture of the tibial tuberosity at that level (Burns & Boudrieau 2008) (Figure 28.10). It is possible to (A) Figure 28.10 Mediolateral radiographs of a 2.5-year-old, neutered male Labrador Retriever. (A) Immediately postoperatively a 9-mm cage is observed 1.2 cm distally within the osteotomy gap along the tibia with 2.3 cm of tibial tuberosity proximal to the cage. The granular material observed within and below the cage is the allograft of corticocancellous chips. (B) At 8 weeks postoperatively the tibial tuberosity has fractured just above the cage. Source: Burns & Boudrieau 2008. Reproduced with permission from Schattauer. buttress the tibial tuberosity above the cage with a block of cancellous bone allograft. However, adding this graft adds a considerable additional expense to the procedure (Burns & Boudrieau 2008). (B) VetBooks.ir 238 Surgical Treatment Outcome and complications with first-generation TTA The first-generation cage with plate and fork or screws has been in general use since 2006. There are many anecdotal reports of good to excellent results, and a number of early clinical results published (Hoffmann et al. 2006; Lafaver et al. 2007; Stein & Schmoekel 2008; Voss et al. 2008; Dymond et al. 2010; Kemper et al. 2011; Steinberg et al. 2011; Hirshenson et al. 2012; Wolf et al. 2012; MacDonald et al. 2013; Skinner et al. 2013; Kiefer et al. 2015). These reports comprise approximately 1600 cases, with an overall complication rate of ∼19.0% to 59%. Major complications represent 2.3% to 26.1%, and minor complications were 7.6% to 37%, with a reoperation rate of 9.8% (Hoffmann et al. 2006; Stein & Schmoekel 2008; Voss et al. 2008; Dymond et al. 2010; Kemper et al. 2011; Steinberg et al. 2011; Hirshenson et al. 2012; Wolf et al. 2012; Kiefer et al. 2015). The most common complications were postliminary meniscal tears and tibial tuberosity fractures with or without implant failure, infection, medial patella luxation and tibial fracture. It has been proposed that many of these complications are related to technical failures, particularly insufficient advancement and incorrect osteotomy placement (Botte 2013). Radiographic healing was reported to occur by 8–10 weeks postoperatively, and with reported outcomes generally from 3 to 15 months postoperatively (Hoffmann et al. 2006; Lafaver et al. 2007; Stein & Schmoekel 2008). Good to excellent overall function and clinical outcome in more than 90% of the dogs was reported by the owners. The major differences between all of the reports included the frequency of meniscal tears and the number of technical failures reported. Meniscus Whether meniscal tears are the result of a postliminary tear of an intact meniscus, or are latent tears is unclear. Postliminary tears suggest that a meniscal release might be indicated, whereas latent tears suggest that thorough joint evaluation is necessary. Controversy remains regarding the use of meniscal release. More recently, persistent instability in the joint after tibial tuberosity advancement has been suggested (Böttcher et al. 2013; Skinner et al. 2013), but whether this is a consequence of the technique itself or incorrect execution of the TTA is debated. Under-advancement because of inexperience with the technique and lack of awareness of potential pitfalls with preoperative planning may occur (Etchepareborde et al. 2011; Bush et al. 2011; Botte 2013; Boudrieau 2013; Millet et al. 2013; Cadmus et al. 2014). The problem is reduced by virtual planning. Regardless of the reason, insufficient advancement can result in persistent tibiofemoral shear instability and can be expected to result in postliminary meniscal tears. This may explain the purported value of meniscal release. Despite these assertions, it appears that the clinical results remain satisfactory in the majority of the cases (Skinner et al. 2013). Given the limited information on TTA biomechanics, debate remains as to whether or not to perform a medial meniscal release. It appears there are two opposing opinions regarding the necessity of meniscal release at this time with TTA. Further discussion of meniscal release is presented in Chapters 35 and 36. Continued postoperative instability with confirmation of the amount of advancement and postoperative PTA needs to be documented to advance any understanding of TTA clinical outcomes related to surgical planning and technique. Technical failures The most common technical failures involve an osteotomy that is too cranial with a small tibial tuberosity bone fragment, or too low adjacent to the level of distal plate screws, which can create a stress-riser and a tibial fracture. Tibial tuberosity fracture from inappropriate fork/screw placement into the tibial tuberosity bone fragment, most often due to a small size crest fragment, patellar luxation from inappropriate realignment of the tibial tuberosity in the sagittal plane; distal patella displacement because of a tuberosity-based advancement, as opposed to a patella-based advancement, are also common. Other miscellaneous complications include cage malposition (too high, too low, angled mediolaterally, upside down), intra-articular screw placement, VetBooks.ir Tibial Tuberosity Advancement (A) 239 (B) Figure 28.11 Lateral radiographs of the stifle of 41.8-kg Golden Retriever after treatment with TTA-2. (A) Immediate postoperative lateral radiograph. The saw guide was placed with four Kirschner wires to temporarily anchor it in position to guide the osteotomy; three of the four holes are visible (small white arrows). An intraoperative bridge fracture at the distal end of the tibial tuberosity occurred at the time of the tibial advancement. Note that it is no longer recommended to use the adjacent K-wire hole as the location for a restraining suture. As a result of this fracture, three K-wires (0.062") and an 18-gauge tension-band wire were placed proximally. The tension-band wire also passes through a hole used to temporarily secure the saw guide. (B) The dog fractured the tibial diaphysis one day postoperatively when rising. This shaft fracture originated at the site of the bridge fracture due to the stress-riser at this level. Recommendations for TTA-2 are evolving and have been recently updated. Currently, the saw cut is longer, with the length based on cage width/size, and applied with a revised saw guide. The tuberosity should be advanced slowly, using gradual steps to prevent any acute stress at the distal end of the tuberosity. The restraining suture at the distal end of the osteotomy is no longer used. Similarly, a distal screw placed cranio-caudal below the cage is also no longer recommended. A proximal staple is currently recommended (placed medially) to span the cage at its proximal extent to help neutralize torsional forces. All of these measures are designed to avoid the bridge fracture at the distal end of the tibial tuberosity at the termination of the osteotomy. (See also http://www.kyon.ch/current-products/tibial-tuberosity-advancement-tta/tta-2-developmenttechnique). Complications of the second-generation techniques are not unique to the TTA-2. All of the second-generation techniques continue to evolve. Images provided courtesy of Dr Robert Botte. transection or injury of the tendon of origin of the long digital extensor, and delayed union or non-union of the gap, often because no graft or osteoconductive filler material was used. Outcome and complications with second-generation cage-only TTA Second-generation TTA procedures eliminate plate fixation. These methods propose a novel cage and alternate osteotomy, but few results have been published. All of the complications noted previously with the first-generation techniques are a concern with second-generation TTA. Some technical issues have been resolved with use of a saw guide, but this approach also introduces other potential problems. The most obvious concern is the complication of tibial fractures at the distal end of the osteotomy (Figure 28.11) (Etchepareborde et al. 2011; Brunel et al. 2013; Barthélémy et al. 2014; VetBooks.ir 240 Surgical Treatment Etchepareborde et al. 2014; Bleakley 2015; Botte 2015; Hopmans 2015; Samoy et al. 2015; Torrington 2015). All second-generation TTA methods have varying techniques to decrease the stress-riser at the distal end of the axially oriented incomplete frontal plane osteotomy, such as a tensionband wire, staple, relief drill-hole at the termination of the osteotomy, or increased osteotomy length. No data are available indicating which technique, if any, is superior for preventing subsequent problems. All of these techniques use a distal tuberosity-based advancement which will result in some distal patella displacement and an underestimation of the degree of tibial advancement obtained. Whether distal patella displacement results in any clinical problems is unclear. However, inadequate advancement may result in continued instability with tibiofemoral shearing and an increased frequency of subsequent meniscal tears (Wolf et al. 2012; Boudrieau 2013). An additional and related complication is the possibility of tibial shaft fractures (Botte 2015; Hopmans 2015; Torrington 2015). Some recommendations have been proposed, along with newer saw guides, to improve the osteotomy with regard to its length, curvature, orientation in the frontal plane, width of hinge area, and the need to modify or supplement the distal aspect of the cut (Etchepareborde et al. 2011; Brunel et al. 2013; Etchepareborde et al. 2014; Bleakley 2015; Botte 2015; Hopmans 2015; Samoy et al. 2015; Torrington 2015). Further studies are needed to determine which of these strategies are most effective. Clinical studies are also needed to determine the frequency of complications with second-generation TTA. Conclusions Currently there is no peer-reviewed evidence of any substantial superiority for any one of the surgical techniques for stifle stabilization in dogs with cruciate ligament rupture over the long term, and the specific technique chosen primarily depends on individual surgeon preference (Leighton 1999). Anecdotal evidence suggests that there may be a quicker recovery and return to full mobility in a shorter period of time with TTA, similar to TPLO. The rapid return to function is one of the primary reasons that this technique is frequently performed. In addition, there is anecdotal evidence from owners that dogs treated with TTA and TPLO do better, interpreted as returning to work such as hunting or field trials, than dogs with either extra-articular lateral suture stabilization or intra-articular stabilization using an over-the-top or similar method. Long-term clinical outcomes after TTA relative to other surgical techniques need to be documented. References Apelt D, Kowaleski M, Boudrieau RJ. Effect of tibial tuberosity advancement on cranial tibial subluxation in canine cranial cruciate-deficient stifle joints: an in vitro experimental study. Vet Surg 2007;36:170–177. Barthélémy N, Ramirez JM, Noel S, et al. Modified Maquet technique for treatment of canine cranial cruciate ligament injury: Early results, complications and risk factors in 109 dogs. Vet Surg 2014;43:E129. Bleakley S. TTA-2: Research Projects, 2015 Kyon Symposium. Böttcher P, Ray J, Fisher M. In vivo stifle kinematics: The truth about TPLO and TTA. Proceedings of the 2013 ACVS Veterinary Symposium. San Antonio, TX, October 24–26, 2013, pp. 415–417. Botte R. Kyon TTA Masterclass. 2013 ACVS Veterinary Symposium. San Antonio, TX, October 23, 2013. Botte R. TTA-2 planning: Tips and tricks. 2015 Kyon Symposium. Boudrieau RJ. Tibial tuberosity advancement (TTA): Clinical results. Proceedings of the ACVS Veterinary Symposium, 2005, pp. 443–445. Boudrieau RJ. Tibial plateau leveling osteotomy or tibial tuberosity advancement? Vet Surg 2009;38:1– 22. Boudrieau RJ. Letter to the Editor; Comparison of healing of the osteotomy gap after tibial tuberosity advancement with and without use of an autogenous cancellous bone graft [Vet Surg 2011;40:27– 33]. Vet Surg 2011;40:641–643. Boudrieau RJ. Why I cut the meniscus. Kyon TTA Masterclass. 2013 ACVS Veterinary Symposium. San Antonio, TX, October 23, 2013. Brown NP, Bertocci GE, Marcellin-Little DJ. Canine stifle biomechanics associated with Tibial Tuberosity Advancement predicted using a computer model. Vet Surg 2015;44:866–873. Brunel L, Etchepareborde S, Barthélémy N, et al. Mechanical testing of a new osteotomy design for tibial tuberosity advancement using the modified Maquet technique. Vet Comp Orthop Traumatol 2013;26:47–53. VetBooks.ir Tibial Tuberosity Advancement Burns CG, Boudrieau RJ. Modified tibial tuberosity advancement procedure with tibial tuberosity advancement in excess of 12 mm in four large breed dogs with cranial cruciate ligament-deficient joints. Vet Comp Orthop Traumatol 2008;21:250–255. Bush MAZ, Bowlt K, Gines JA, et al. Effect of use of different landmark methods on determining stifle angle and on calculated tibial tuberosity advancement. Vet Comp Orthop Traumatol 2011;24:205– 210. Cadmus J, Palmer RH, Duncan C. The effect of preoperative planning method on recommended tibial tuberosity advancement cage size. Vet Surg 2014;43:995–1000. Dennler R, Kipfer NM, Tepic S, et al. Inclination of the patellar ligament in relation to flexion angle in stifle joints of dogs without degenerative joint disease. Am J Vet Res 2006;67:1849–1854. Dymond NL, Goldsmid SE, Simpson DJ. Tibial tuberosity advancement in 92 canine stifles: Initial results, clinical outcome and owner evaluation. Aust Vet J 2010;88:381–385. Etchepareborde S, Mills J, Busoni V, et al. Theoretical discrepancy between cage size and efficient tibial tuberosity advancement in dogs treated for cranial cruciate ligament rupture. Vet Comp Orthop Traumatol 2011;24:27–31. Etchepareborde S, Barthélémy N, Brunel L, et al. Biomechanical testing of a β-tricalcium phosphate wedge for advancement of the tibial tuberosity. Vet Comp Orthop Traumatol 2014;27:14–19. Giffin JR, Vogrin TM, Zantop T, et al. Effects of increasing tibial slope on the biomechanics of the knee. Am J Sports Med 2004;32:376–382. Guerrero TG, Makara MA, Katiofsky K, et al. Comparison of healing of the osteotomy gap after tibial tuberosity advancement with and without use of an autogenous cancellous bone graft. Vet Surg 2011;40:27–33. Hirshenson MS, Krotscheck U, Thompson MS, et al. Evaluation of complications and short-term outcome after unilateral or single-session bilateral tibial tuberosity advancement for cranial cruciate rupture in dogs. Vet Comp Orthop Traumatol 2012;25:402–409. Hoffmann DE, Miller JM, Ober CP, et al. Tibial tuberosity advancement in 65 canine stifles. Vet Comp Orthop Traumatol 2006;19:219–227. Hoffmann DE, Kowaleski MP, Johnson KA, et al. Ex vivo biomechanical evaluation of the canine CrCL deficient stifle with varying angles of stifle joint flexion and axial loads after TTA. Vet Surg 2011;40:311–320. Hopmans J. TTA-2 clinical experience. Kyon Symposium 2015. Inauen R, Koch D, Bass M, et al. Tibial tuberosity conformation as a risk factor for cranial cruciate ligament rupture in the dog. Vet Comp Orthop Traumatol 2009;22:16–20. 241 Kapler MW, Marcellin-Little DJ, Roe SC. Planned wedge size compared to achieved advancement in dogs undergoing the modified Maquet procedure. Vet Comp Orthop Traumatol 2015;28:379–384. Kemper M, Koch D, Bass M, et al. Revisionsoperationsrate nach 214 Tibial Tuberosity Advancements als Thbusherapie des vorderen Kreuuzbandrisses beim Hund [Major complication rate after 214 tibial tuberosity advancements as a therapy for cranial cruciate ligament rupture]. Schweiz Arch Teirheilkd 2011;153:131–133. Kiefer JE, Langenbach A, Boim J, et al. Singlestage bilateral tibial tuberosity advancement for treatment of bilateral canine cranial cruciate ligament deficiency. Vet Comp Orthop Traumatol 2015;28:215–219. Kim SE, Pozzi A, Banks SA, et al. Effect of tibial tuberosity advancement on femorotibial contact mechanics and stifle kinematics. Vet Surg 2009;38:33–39. Kipfer NM, Damur DM, Guerrero T, et al. Effect of tibial tuberosity advancement on femorotibial shear in cranial cruciate-deficient stifles: an in vitro study. Vet Comp Orthop Traumatol 2008;21:385–390. Lafaver S, Miller NA, Stubbs WP, et al. Tibial tuberosity advancement for stabilization of the canine cranial cruciate ligament-deficient stifle joint: surgical technique, early results and complication in 101 dogs. Vet Surg 2007;36:573–586. Leighton RL. Letter to the Editor, Preferred method of repair of cranial cruciate ligament rupture in dogs: A survey of ACVS diplomates specializing in canine orthopedics. Vet Surg 1999;28:194. Li G, Rudy TW, Allen C, et al. Effect of combined axial compressive and anterior tibial loads on in situ forces in the anterior cruciate ligament: a porcine model. J Orthop Res 1998;16:122–127. Maquet P. Tibial tuberosity advancement. Clin Orthop Rel Res 1976;115:225–230. MacDonald TL, Allen DA, Monteith GJ. Clinical assessment following tibial tuberosity advancement in 28 stifles at 6 months and 1 year after surgery. Can Vet J 2013;54:249–254. Miller JM, Shires PK, Lanz OI, et al. Effect of 9 mm tibial tuberosity advancement on cranial tibial translation in the canine cranial cruciate ligamentdeficient stifle. Vet Surg 2007;36:335–340. Millet M, Bismuth C, Labrunie A, et al. Measurement of the patellar tendon-tibial plateau angle and tuberosity advancement in dogs with cranial cruciate ligament rupture: Reliability of the common tangent and tibial plateau methods of measurement. Vet Comp Orthop Traumatol 2013;26:469– 478. Montavon PM, Damur DM, Tepic S. Advancement of the tibial tuberosity for the treatment of cranial cruciate deficient canine stifle. 1st World Orthopedic Veterinary Congress, Munich, Germany, 2002, p. 152. VetBooks.ir 242 Surgical Treatment Nakamura N, Ellis M, Seedhom BB. Advancement of the tibial tuberosity: a biomechanical study. J Bone Joint Surg 1985;67B:255–260. Nisell R. Mechanics of the knee. A study of joint and muscle load with clinical applications. Acta Orthop Scand Suppl 1985;56:3–42. Nisell R, Németh G, Ohlsén H. Joint forces in the extension of the knee: Analysis of a mechanical model. Acta Orthop Scand 1986;57:41–46. Nisell R, Ericson MO, Nemeth G, et al. Tibiofemoral joint forces during isokinetic knee extension. Am J Sports Med 1989;17:49–54. Samoy Y, Verhoeven G, Bosmans T, et al. TTA Rapid: Description of the technique and short term clinical trial results of the first 50 Cases. Vet Surg 2015;44:474. Schwandt CS, Bohorquez-Vanelli A, Tepic S, et al. Angle between the patellar ligament and the tibial plateau in dogs with partial rupture of the cranial cruciate ligament. Am J Vet Res 2006;67:1855–1860. Shirazi-Adl A, Mesfar W. Effect of tibial tubercle elevation on biomechanics of the entire knee joint under muscle loads. Clin Biomech 2007;22:344–351. Skinner OT, Kim SE, Pozzi A. In vivo femorotibial subluxation during weight-bearing and clinical outcome following tibial tuberosity advancement for cranial cruciate ligament insufficiency in dogs. Vet J 2013;196:86–91. Stein S, Schmoekel H. Short-term and eight to 12 months results of a tibial tuberosity advancement as treatment of canine cranial cruciate ligament damage. J Small Anim Pract 2008;49:398–404. Steinberg EJ, Prata RG, Palazzini K, et al. Tibial tuberosity advancement for treatment of CrCL injury: Complications and owner satisfaction. J Am Anim Hosp Assoc 2011;47:250–257. Tepic S, Damur D, Montavon PM. Biomechanics of the stifle joint. 1st World Orthopedic Veterinary Congress, Munich, Germany, 2002, pp. 189–190. Torrington A. TTA-2 clinical trial study data. Kyon Symposium 2015. Voss K, Damur DM, Guerrero T, et al. Force plate gait analysis to assess limb function after tibial tuberosity advancement in dogs with cranial cruciate ligament disease. Vet Comp Orthop Traumatol 2008;21:243–249. Wolf RE, Scavelli TD, Hoelzler MG, et al. Surgical and postoperative complications associated with tibial tuberosity advancement for cranial cruciate ligament rupture in dogs: 458 cases (2007–2009). J Am Vet Med Assoc 2012;240:1481–1487. Yeadon R, Fitzpatrick N, Kowaleski M. Tibial tuberosity transposition-advancement for treatment of medial patellar luxation and concomitant cranial cruciate ligament disease in the dog. Vet Comp Orthop Traumatol 2011;24:18–26. VetBooks.ir 29 Closing Cranial Wedge Ostectomy and Triple Tibial Osteotomy Simon C. Roe Closing cranial wedge ostectomy (CCWO) there are associated varus, valgus, or rotational deformities. Introduction Technique research Closing cranial wedge ostectomy (CCWO) was the first osteotomy procedure proposed to alter the forces that act around the stifle and on the cranial cruciate ligament (CrCL) (Slocum & Devine 1984). Previously, the technique had been reported for the management of five dogs with proximal tibial deformity and cruciate ligament rupture, the idea being that normalization of the tibial anatomy would improve stifle function (Read & Robins 1982). This approach was later superseded by tibial plateau leveling osteotomy (TPLO), with the potential advantages that the length of the tibia was not altered and the osteotomy did not cross the whole shaft of the bone. However, CCWO continues to be used by some surgeons, particularly in situations where TPLO may have an increased risk of complications. This applies primarily to dogs that have an excessively steep tibial plateau angle (TPA), though it may also be considered if It had been assumed that the target TPA for CCWO was similar to that proposed for TPLO (6◦ ), and therefore that the removal of a wedge that was 6◦ less than the measured tibial slope would result in the appropriate TPA. However, because the TPA is calculated from the functional tibial axis (from intercondylar eminences to center of the talus) and that, after CCWO, the intercondylar notches move cranial relative to their original position, thereby also shifting the functional axis cranially, a full correction would not be achieved using this technique (Bailey et al. 2007; Apelt et al. 2010). To minimize this cranial shift (and thus the size of the wedge that needs to be removed), the osteotomy should be located as proximally as possible (while allowing sufficient length for engaging three screws), and the cranial cortices should be aligned, rather than simply hinging the wedge on its apex (which would align the Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 243 VetBooks.ir 244 Surgical Treatment caudal cortices). If this is done, the functional axis shift will be around 5◦ for a 25◦ wedge, and 7–8◦ for a 35–40◦ wedge. Technique: planning The principles of CCWO for either managing proximal tibial deformity or reducing the TPA are similar to those used when correcting deformities in other bones, though there are certain considerations that are specific to this location. In early descriptions of the procedure, the osteotomy was located more distal because only straight plates were available for stabilization, and sufficient space was needed to ensure purchase for three bicortical screws. With the development of purpose-designed plates (TWO plates; Veterinary Instrumentation, Sheffield, UK, and TPLO plates from various manufacturers), the level of the osteotomy is now positioned more proximal, and the amount of functional axis shift is smaller. The size of the wedge to be removed is planned on the ‘90–90’ lateral view of the tibia, named after the fact that the stifle and tarsus are position at 90◦ of flexion, with the beam centered over the stifle. The TPA is measured. The optimal postoperative TPA is considered to be 6◦ . The appropriate wedge size will depend on the magnitude of the TPA, the level of the osteotomy, and whether the cranial cortices of the tibial will be aligned. If the osteotomy is proximal and the cranial cortices are aligned, wedge sizes are usually 2–3◦ less than the TPA for TPAs of 25–32◦ . For a TPA greater than 35◦ , the wedge size should be the same as the TPA. The limb and the radiographs should be assessed to determine if there is significant varus/valgus or tibial torsion that should be addressed. Varus and valgus can be corrected by adjusting the plane of one of the osteotomies relative to the other. Torsion can be corrected by rotation of the fragments at the level of the osteotomy. The stabilizing plate must be contoured appropriately to maintain the intended rotation correction. When planning corrections of large TPAs, it may be helpful to print an image of the lateral tibial radiograph, draw the planned wedge in the anticipated location, cut out the wedge, and reposition the ‘fragments’ to simulate reduction. The TPA can be measured on this paper model, and the effect of the cranial shift on the functional axis appreciated. If the final TPA is not appropriate, the size of the wedge can be adjusted accordingly and the exercise repeated. This same process can be performed digitally using some of the planning software packages that allow the ‘cutting’ and repositioning of image fragments (Figure 29.1). A recent modification described by Frederick & Cross (2017) results in less length loss for the same wedge size. The position of the proximal cut is planned similarly to that described above. The level of the distal cut is adjusted proximally such that the proximal and distal osteotomies will be of equal length (Figure 29.2). The cranial edges are aligned in the same way as usual. Technique: intraoperative The medial aspect of the proximal tibia is exposed and the muscles elevated caudally and laterally at the proposed level of the osteotomy. The joint level is identified and the planned stabilizing implant positioned on the proximal fragment to assist in identifying the most proximal level of the ostectomy. The proximal osteotomy line is scored, ensuring that it is approximately parallel to the tibial plateau and that it is 3–5 mm distal to the insertion of the patella tendon. Using a goniometer, wedge set, or custom wedge guide (sterilized radiographic film), the second osteotomy line is scored, with the apex at the caudal cortex. The two cuts are made ensuring that they are coplanar. The wedge is removed and the fragments reduced, with the cranial cortices aligned. If a large wedge was removed, the intact fibula may prevent complete reduction. It should be cut or fractured at the level of the osteotomy. A Kirschner wire placed from cranial to caudal across the osteotomy may help to maintain reduction while the plate is contoured and applied. Patient selection CCWO can be used to level the plateau of any tibia. It has been superseded by TPLO based VetBooks.ir Closing Cranial Wedge Ostectomy and Triple Tibial Osteotomy (A) 245 (B) Figure 29.1 Closing cranial wedge ostectomy planning. (A) Lateral radiograph of the tibia of a dog with cranial cruciate ligament rupture and a steep tibial slope. Lines depicting the functional axis of the tibia and the tibial plateau have been positioned. The angle between these lines indicates a tibial plateau slope of 41◦ . The planned wedge (42◦ ) is outlined on the proximal metaphysis of the tibia. (B) The radiographic image has been ‘cut’ and the proximal portion rotated to simulate the surgical correction. Note the cranial shift of the redrawn functional axis (compared to the original axis position, indicated by the light gray line). The resulting tibial plateau slope is 5◦ . on concerns that it may lead to some shortening of the tibia and that, because it is a complete osteotomy of the tibial shaft, it is potentially more susceptible to failure of fixation than a TPLO. It is, therefore, often reserved for situations where a TPLO may carry more risk. These might include a steep TPA or small patient size. VetBooks.ir 246 Surgical Treatment (A) (B) (C) (D) (E) (F) Figure 29.2 Illustration of modified cranial closing wedge ostectomy procedure steps. (A) The proximal osteotomy is scored exiting the cranial cortex ∼3 mm distal to the patella tendon insertion point. (B) The distal osteotomy is scored intersecting the proximal score at ∼2/3 the cranial-caudal point of the distal score. The intersection of these scores was the planned osteotomy angle. (C) The distal osteotomy is completed. (D) The proximal osteotomy is completed exiting through the distal osteotomy. (E) The osteotomy is reduced by rotating the segments. (F) Reduced osteotomy with alignment of cranial cortices. Implant selection There are many factors that influence implant selection, and considering all of these and their interactions is important to reduce the potential for complications. It is important to realize that there are very strong forces acting to open the osteotomy, and the chosen plate must be able to counter these forces. The primary factor is the level of the osteotomy; a low osteotomy will result in a larger proximal fragment and, therefore, more screw purchase. To reduce the shift of the functional axis, the osteotomy is moved as proximal as is feasible. T-style plates, where three or more screws are concentrated in an expanded portion of plate, are helpful for this purpose. However, plates designed specifically for TPLO have the screws clustered close to each other because of the small size of the fragment they must engage. In many of these plates VetBooks.ir Closing Cranial Wedge Ostectomy and Triple Tibial Osteotomy the screws also converge slightly on the lateral aspect. These features reduce the ability of this plate to counter the forces working to open the osteotomy, and catastrophic failure of screw purchase can occur. For this reason, a T-style or cloverleaf plate with a wider screw distribution may provide greater stability. If a plate designed for TPLO is used, it is essential to add adjunct fixation. Options for adjunct fixation include a cranial tension band wire, small plate or, with an angled osteotomy, a bone screw lagged across the osteotomy (Figure 29.3). (A) 247 Complications The primary major complication specific to CCWO is failure of fixation of the proximal fragment. This risk is reduced if an appropriately sized plate is selected and adjunct fixation is well placed. Outcome Outcome has been reported for a number of small case series, usually with some defining (B) Figure 29.3 Lateral (A) and cranio-caudal (B) postoperative radiographs after a 41◦ closing cranial wedge ostectomy (CCWO). The cranial cortices were aligned and the osteotomy stabilized with a 3.5 cloverhead plate with three locking screws in the proximal fragment applied medially (Veterinary Orthopaedic Implants, St Augustine, FL, USA). A 2.7-mm ‘L’ plate (DePuy SynthesVet, Paoli, PA, USA) has been applied cranially as a ‘tension band’ to counter the quadriceps force that tends to open the osteotomy. VetBooks.ir 248 Surgical Treatment feature such as steep slope (Read & Robins 1982) or small-sized patients (Macias et al. 2002). Outcome after CCWO is similar to that after TPLO (Corr & Brown 2007; Oxley et al. 2013). In the Corr & Brown study the complication rates were not different, but implant failure requiring revision was seen more frequently with CCWO treatment, although only a single TPLO plate with standard screws was used for stabilization. Complication rates, including late meniscal tears and wound and joint infections, were similar between procedures in the study conducted by Oxley et al. (TPLO 7.2%; CCWO 9.5%). The CCWO technique involved planning a wedge that was more proximally positioned, had equal length osteotomy surfaces, and was caudally hinged. The wedge size was adjusted for the anticipated cranial axis shift, with a larger adjustment made for larger correction angles. A pre-contoured TPLO plate with all proximal screws locked and a supporting cranial wire was used for all CCWO cases, and no implant failures were identified. A review of 300 CCWO surgeries found an overall complication rate of 31.7% (Kuan et al. 2009). Four dogs (1.3%) required additional surgery to address implant failure and osteotomy instability. The type of plate and screws was not described, but a cranially placed wire was used. Conclusions CCWO is an effective approach for leveling the tibial plateau. Planning of the wedge size must take into account the shift in the functional axis that occurs as the ostectomy is closed. This shift can be minimized by locating the osteotomy more proximally and by aligning the cranial fragment edges. Adequate fixation must be used to counter the strong forces that act on the osteotomy. A cranial ‘tension band’ of some form is recommended to minimize the risk of failure of fixation. Triple tibial osteotomy Introduction Triple tibial osteotomy (TTO) was first described by Bruce et al. in 2007. While the goal is similar to that of the TTA, namely to create a 90◦ angle between the tibial plateau slope and the patella tendon at a stifle angle of 135◦ , this is achieved by a combination of a closing wedge ostectomy (leveling of the tibial plateau) and advancement of the tibial tuberosity which is pushed by the cranio-proximal corner of the rotating proximal fragment. In the initial report a geometric analysis suggested that if the wedge were two-thirds of the correction angle, the other one-third would be achieved by the tuberosity advancement. A retrospective analysis of the amount of correction achieved indicated that this was insufficient, and the formula was later revised to: Wedge angle = Correction angle × 0.6 + 7 (TTO Technique Guide, Veterinary Instrumentation, Inc., Sheffield, UK). This adjustment is likely due to the shift in the functional tibial axis, and the fact that the tuberosity advances cranially only and not proximally, necessitating a larger correction. Technique: planning Planning is performed on a lateral radiograph of the stifle at an angle of 135◦ . The length of the patella tendon is determined and the tibial plateau–patella tendon (TP-PT) angle measured. The correction angle is the TP–PT angle minus 90◦ , and the wedge angle is calculated using the formula given above. The wedge angle may need to be adjusted in dogs with unusual tibial tuberosity morphology (Renwick et al. 2009). If the patella tendon insertion is very low, the correction may be overestimated, and if it is very high it may be underestimated. Also, if the tibia is cranially subluxated, or the stifle is more flexed than recommended when the radiograph is taken, the measured correction angle will be less. It is recommended that radiographs be critically evaluated for position, the TPA be measured, and the tuberosity morphology considered before deciding on a final wedge angle. Technique: intraoperative Specialized instrumentation is available that simplifies a number of the steps in this procedure (Veterinary Instrumentation, Inc., Sheffield, UK). First, the medial aspect of the VetBooks.ir Closing Cranial Wedge Ostectomy and Triple Tibial Osteotomy CA D WA B Figure 29.4 Triple tibial osteotomy planning. The angle between lines depicting the tibial plateau (TP) and the patella tendon (PT) with the stifle at an approximately 135◦ angle is formed. The correction angle (CA) is calculated as the TP-PT angle minus 90◦ . The length of the PT is measured. The hole at the distal end of the tibial tuberosity cut (B) is located by measuring the PT length distal from the PT insertion. The first cut, depicted by the black line extending proximad from the hole at B, separates the tibial tuberosity from the tibial shaft. The length of the cut is measured and a hole (D) is drilled level with the mid-point, approximately 3 mm in from the caudal edge of the tibia. The wedge angle (WA) is calculated from the CA: WA = CA × 0.6 + 7. The wedge is cut, and the ostectomy reduced and stabilized with a plate. tibia is exposed. Then, using the length of the patella tendon measured during planning, a point is marked distal to the insertion of the patella tendon (Figure 29.4, point B). A 2-mm hole is drilled from medial to lateral and a linear saw guide inserted and aligned parallel to the cranial edge of the tuberosity. The bone is cut, the saw guide removed, and the cut completed. 249 The tuberosity fragment is held off the caudal fragment by a spacer tool, called a wedgie. The mid-point of the osteotomy is marked and a 2-mm hole is drilled at that level from medial to lateral 2–3 mm in from the caudal edge of the tibia (Figure 29.4, point D). The pin of the combined osteometer and saw guide is placed in the hole and the guide is positioned so that the removed wedge is centered on the apex. It is held in position with a purpose-made, selfretaining forceps (a clasper) or 1.6 mm K-wire through a hole in the distal arm of the osteometer. The cuts are made in the medial cortex, the guide is removed, and the cuts are completed through the lateral cortex. The popliteal artery is retracted as the lateral cortex is cut. The bone wedge is removed and used later as a bone graft. The wedgie tool is moved distal to the ostectomy to hold the tibial crest fragment in a cranial position so that the proximal tibial fragment can be fully reduced. A large pointed reduction forceps is placed on the proximal aspect of the proximal fragment and on the base of the tibial tuberosity and is squeezed until the ostectomy is reduced. A bone plate is contoured to the medial aspect of the tibia and secured with bone screws. The bone wedge is cut into 2 mm-sized fragments and packed into the defect between the tuberosity fragment and the shaft. Patient selection TTO is more likely to develop complications if used to manage excessive slope. With a bone wedge larger than 20◦ , it is likely that one or both bone bridges will fracture. In dogs with unusual tibial tuberosity morphology, the appropriate wedge size is harder to determine and another technique may be more suitable. While TTO can be performed in small dogs, the osteotomies need to be very precise in dogs weighing <10 kg. Implant selection Because the osteotomy is slightly lower than where the TPLO osteotomy is usually located, the pre-contoured locking TPLO plate will not be suitable in all cases. Some tibias are relatively flat, and removing the pre-contour may result in screws being directed towards the osteotomy. VetBooks.ir 250 Surgical Treatment (A) (B) Figure 29.5 Lateral (A) and cranio-caudal (B) radiographs of a completed triple tibial osteotomy (TTO). A small amount of the flare of the pre-contoured locking TPLO plate was removed. The plate is secured with two standard screws and one locking screw above and below the ostectomy. Note that the tibial plateau angle has been reduced and the tibial tuberosity advanced. A very small crack is evident extending distal from the hole at the distal end of the tibial tuberosity osteotomy. A tension band was not considered necessary. The bone bridge caudal to the wedge is also cracked, but this did not impact the reduction of the ostectomy. The removed bone wedge has been cut into 2-mm pieces and packed into the defect behind the tibial tuberosity fragment. In these cases, a cloverleaf-shaped TTO plate of appropriate size or different TPLO plate (e.g., the SOPTM TPLO plate; Orthomed NA, Vero Beach, FL, USA) can be contoured and applied to stabilize the osteotomy (Figure 29.5). Complications During surgery it is possible that the bone bridges may crack or fracture. If the base of the tibial tuberosity fragment cracks, a tension band wire is placed. If it fractures completely, a Kwire is used to maintain reduction and a tension band wire (or, in large dogs, two tension band wires) is placed. If there is concurrent medial patella luxation (MPL), the tuberosity fragment can easily be lateralized. The base will usually fracture with this re-positioning, and the placement of one or two K-wires and a tension band is indicated (Figure 29.6). The caudal bone bridge also may crack during reduction. This may cause the proximal fragment to be more difficult to reduce, but the situation is usually easily managed and the plate can be applied. If the patient is too active, it is possible that the tibial tuberosity fragment may fracture. If 251 VetBooks.ir Closing Cranial Wedge Ostectomy and Triple Tibial Osteotomy (A) (B) Figure 29.6 Treatment of combined cruciate ligament rupture and medial patella luxation. Immediate postoperative radiographs of the proximal tibia after a triple tibial osteotomy (TTO) combined with lateral translation of the tibial tuberosity fragment to re-align the quadriceps mechanism and position the patella in line with the trochlear groove. The wedge ostectomy is stabilized with a pre-contoured TPLO plate. The tibial tuberosity position was maintained with two K-wires and two tension band wires were placed to counter the pull of the quadriceps mechanism. this is minimally displaced, and the patient is not lame, conservative management is usually successful. However, if it is unstable or the patient is lame, then surgical stabilization with a K-wire and tension band wire is indicated. In a review of 121 TTO procedures, fracture of the distal attachment of the tibial tuberosity fragment was observed in nine tibias, three of which were managed surgically (Moles et al. 2009). Other complications reported are similar to those evident in other osteotomy procedures (surgical site infection, late meniscal tears) (Bruce et al. 2007; Moles et al. 2009; Renwick et al. 2009). Outcome When the tuberosity fragment is stable, healing is usually adequate at 6–8 weeks after surgery. Union between the cranio-proximal corner of the plateau fragment and the tuberosity fragment likely protects the osteotomy. Subjective assessments of outcome by owners indicated a good return to normal function in the majority of cases (Bruce et al. 2007; Moles et al. 2009; Renwick et al. 2009). No studies using objective measures have been performed. Given that the endpoint of the surgery is based on similar principles to the TTA, similar outcomes would be expected. VetBooks.ir 252 Surgical Treatment Conclusions TTO represents another approach to modifying the forces around the stifle in order to achieve functional stability following cruciate ligament rupture. About two-thirds of the adjustment is achieved by leveling of the tibial plateau, and one-third by advancing the tibial tuberosity. Because of this combined approach, the overall morphology of the tibia is altered less than with a CCWO. Also, because the tibial tuberosity is separated from the plateau fragment, there is much less force acting on the osteotomy, and complications of fixation are therefore much reduced. The specialized instrumentation facilitates accurate wedge cutting. For surgeons unfamiliar with TPLO and who are unable to purchase a radial cut saw, the TTO procedure is a viable alternative. References Apelt D, Pozzi A, Marcellin-Little DM, et al. Effect of cranial tibial closing wedge angle on tibial subluxation: An ex vivo study. Vet Surg 2010;39:454–459. Bailey CJ, Smith BA, Black AP. Geometric implications of the tibial wedge osteotomy for the treatment of cranial cruciate ligament disease in dogs. Vet Comp Orthop Traumatol 2007;20:169–174. Bruce W, Rose A, Tuke J, et al. Evaluation of the triple tibial osteotomy. A new technique for the management of the canine cruciate-deficient stifle. Vet Comp Orthop Traumatol 2007;20:159–168. Corr SA, Brown C. A comparison of outcomes following tibial plateau levelling osteotomy and cranial tibial wedge osteotomy procedures. Vet Comp Orthop Traumatol 2007;20:312–319. Frederick SW, Cross AR. Modified cranial closing wedge osteotomy for treatment of cranial cruciate ligament insufficiency in dogs with excessive tibial plateau angles: Technique and complications in 19 cases. Vet Surg 2017;46:403–411. Kuan S, Smith B, Black A. Tibial wedge ostectomy: complications of 300 surgical procedures. Aust Vet J 2009;87:438–444. Macias C, McKee WM, May C. Caudal proximal tibial deformity and cranial cruciate ligament rupture in small-breed dogs. J Small Anim Pract 2002;43:433– 438. Moles AD, Hill TP, Glyde M. Triple tibial osteotomy for treatment of the canine cranial cruciate ligament-deficient stifle joint. Vet Comp Orthop Traumatol 2009;22:473–478. Oxley B, Gemmill TJ, Renwick AR, et al. Comparison of complication rates and clinical outcome between tibial plateau leveling osteotomy and a modified cranial closing wedge osteotomy for treatment of cranial cruciate ligament disease in dogs. Vet Surg 2013;42:739–750. Read RA, Robins GM. Deformity of the proximal tibia in dogs. Vet Rec 1982;111:295–298. Renwick AI, McKee WM, Emmerson TD, et al. Preliminary experiences of the triple tibial osteotomy procedure: tibial morphology and complications. J Small Anim Pract 2009;50:212–221. Slocum B, Devine T. Cranial tibial wedge osteotomy: a technique for eliminating cranial tibial thrust in cranial cruciate ligament repair. J Am Vet Med Assoc 1984;184:564–569. VetBooks.ir 30 Treatment of Excessive Tibial Plateau Angle Michael P. Kowaleski Introduction The proximal tibial articular surface is angulated distally with respect to the mechanical axis of the tibia; the magnitude of this angulation is termed the tibial plateau angle (TPA). The mean TPA in dogs has been reported to range from 23.5◦ to 28.3◦ , with individual dogs having a TPA as low as 12◦ or as high as 46◦ (Pacchiana et al. 2003; Priddy et al. 2003; Reif & Probst 2003; Moeller et al. 2006; Stauffer et al. 2006). The morphology of the proximal tibia in dogs with a steep tibial plateau slope can be distinctly different than normal dogs (Figures 30.1A and 30.2A) (Osmond et al. 2006). Affected dogs may have a steep TPA and/or a proximal tibial shaft deformity in which the cranial border of the tibia is angulated from caudal to cranial rather than the more typical proximal to distal orientation (Read & Robins 1982; Osmond et al. 2006). Slocum1 defined excessive tibial plateau angle (eTPA) as a TPA greater than 34◦ when using a 24-mm radius tibial plateau leveling osteotomy (TPLO) blade. However, this definition does not account for individual variation 1 Seminars entitled “Tibial Plateau Leveling Osteotomy for Cranial Cruciate Ligament Repair,” Slocum Enterprises, Inc. in proximal tibial anatomy. After the TPLO procedure, the tibial plateau segment acts as a buttress to support the tibial tuberosity (Talaat et al. 2006; Hamilton et al. 2015). The point of insertion of the patellar tendon on the tibial tuberosity has been suggested as a safe point (maximum) for rotation (Figure 30.2A,B) to reduce the risk of tibial tuberosity fracture (Talaat et al. 2006). This has been substantiated in a mechanical study on the effect of osteotomy position and tibial plateau rotation on the tensile force required for failure of the canine quadriceps mechanism (Hamilton et al. 2015). This ex vivo study revealed that rotation of the tibial plateau segment below the patellar tendon insertion decreased the force required for tibial tuberosity fracture, supporting the idea of a safe point, with the tibial plateau providing buttress to the tibial tuberosity (Hamilton et al. 2015). Preoperative planning Preoperative planning can be used to determine the chord length corresponding to the safe rotation distance. A tibial osteotomy guide is centered on the point dividing the intercondylar tubercles, at the intersection of the tibial mechanical axis and tibial plateau axis Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 253 VetBooks.ir 254 Surgical Treatment (A) (B) (C) (D) (E) (F) (G) Figure 30.1 Tibial plateau leveling osteotomy (TPLO) and closing cranial wedge ostectomy (CCWO) for the treatment of excessive tibial plateau angle (eTPA). Preoperative mediolateral (A) and caudocranial (B) views of a large-breed patient with cruciate ligament rupture and eTPA. Preoperative planning for TPLO/CCWO (C); Note that the safe distance S has been identified (black, double-ended arrow). Postoperative (D and E) and follow-up (F and G) radiographs taken 8 weeks postoperatively revealing osteotomy healing with stable implants. VetBooks.ir Treatment of Excessive Tibial Plateau Angle (A) (B) 255 (C) Figure 30.2 Safe and required rotation. The osteotomy is positioned (black dashed line) and a line perpendicular to the tibial crest is drawn at the level of patellar tendon insertion (white line) (A). The safe distance, S (white double-ended arrow), is the linear distance (chord) from the osteotomy exit at the cranial intercondyloid area to the intersection of the line drawn perpendicular to the tibial crest at the patellar tendon insertion, referred to as the safe point (A). The tibial plateau segment has been rotated to the safe point (safe rotation) (B). The tibial plateau segment has been rotated well below the safe point (required rotation) to achieve a tibial plateau angle of 5◦ (C). (proximal tibial joint reference line) or at any location between these two points (Figure 30.2A). The location is selected that optimizes the tibial tuberosity and tibial plateau size and shape. In cases of severe tibial deformity, alternate tibial osteotomy locations may be needed (Figures 30.1C and 30.2A). Once the tibial osteotomy is properly positioned, a line is drawn caudally from the patellar tendon insertion on the tibial tuberosity, perpendicular to the tibial crest to intersect with the osteotomy template (Figure 30.2A). The linear distance from the point at which the osteotomy exits the tibia within the cranial intercondyloid area to the intersection of the line drawn perpendicular to the tibial crest at the point of patellar tendon insertion and the osteotomy template is the safe rotation distance (S in Figure 30.2A). The safe TPA (sTPA) is the tibial plateau angle that can be treated by this magnitude of VetBooks.ir 256 Surgical Treatment rotation (Figure 30.2B), and this can be determined by identifying the safe rotation distance in the appropriate saw blade size (radius) row in the TPLO chart; the sTPA is the preoperative TPA that corresponds to this rotation distance. If the required rotation chord length (the rotation needed to achieve a TPA of 5◦ ) is significantly greater than the safe rotation cord length (Figure 30.2C), a TPLO combined with a closing cranial wedge ostectomy (TPLO/CCWO) should be considered (Talaat et al. 2006). The angle of the CCWO is the difference between the preoperative TPA and the sTPA. By utilizing the TPLO/CCWO procedure, the magnitude of both the TPLO and CCWO can be adjusted to correct the TPA and proximal tibial deformity as needed, based on individual patient anatomy. In a retrospective study evaluating treatment options for eTPA, outcome, based on owner assessment, was superior with ‘full-rotation TPLO’ (correction of the TPA to less than 14◦ ) compared to ‘under-rotated TPLO’ (leveling to >14◦ ) (Duerr et al. 2008), and supplemental fixation with additional implants was associated with a lower complication rate (Duerr et al. 2008). Additionally, this procedure can be simultaneously combined with a medial or lateral closing wedge ostectomy to address moderate to severe proximal tibial varus or valgus, and/or moderate to severe tibial torsion (Figure 30.3) (Weh et al. 2011). (A) (B) (C) (D) (E) Figure 30.3 Diagrammatic representation of a proximal tibial valgus deformity treated by tibial plateau leveling osteotomy (TPLO) and a coplanar medial wedge ostectomy. The apex of the medial closing wedge is coincident with the exit of the TPLO radial osteotomy at the caudolateral tibial cortex. Tibial torsion can be corrected at the level of the medial closing wedge (arrows) without loss of apposition at the radial osteotomy. The inset depicts various closing wedge configurations: (A) Coplanar cranial closing wedge. (B) Coplanar lateral closing wedge. (C) Coplanar medial closing wedge. (D) Biplanar medial and cranial closing wedge. (E) Biplanar lateral and cranial closing wedge. Source: Weh et al. 2011. Reproduced with permission from John Wiley & Sons, Inc. VetBooks.ir Treatment of Excessive Tibial Plateau Angle The case example illustrates a patient with a TPA of 41◦ and a safe rotation of 11 mm (S in Figure 30.1C). Referring to the TPLO chart for a 30mm saw blade, a rotation of 10.8 mm is the correction for a TPA of 26◦ . Therefore, a CCWO of 15◦ combined with a TPLO rotation of 10.8 mm (TPLO for 26◦ + 15◦ CCWO = correction for preoperative TPA of 41◦ ) would result in a postoperative TPA of approximately 5◦ with a safe rotation; thus, a CCWO of 15◦ was chosen for this patient (Figure 30.1C). The CCWO is positioned such that the apex is placed at the caudal cortical exit of the TPLO (Figure 30.1C). In cases with significant varus or valgus and eTPA, the tibial wedge ostectomy can be performed as a biplanar CCWO, rather than as a coplanar CCWO (Figure 30.3D,E) (Weh et al. 2011), to correct for the angular deformity in the frontal plane. When performing a biplanar CCWO, the angular correction is typically 257 performed by angulating the distal limb of the CCWO (rather than the proximal limb) to avoid the angled osteotomy from entering into the radial osteotomy of the TPLO. In cases with significant varus or valgus without eTPA, the tibial closing wedge ostectomy can be a coplanar medial closing wedge (valgus correction) (Figure 30.3C) or lateral closing wedge (varus correction) (Figure 30.3B) (Weh et al. 2011). The distal jig pin beyond (i.e., medial to) the jig arm can be bent to the angle of correction required, and this bent pin can be used as a reference for saw angulation while performing the osteotomy. Alternatively, a Kirschner wire can be inserted into the tibia at the desired angle, or an additional jig pin can be placed and used for a reference (Weh et al. 2011) (Figure 30.4). In cases with concurrent tibial torsion, the correction can be made at the opposing surfaces of the linear tibial osteotomy; this results in a correction of torsion (A) (B) (C) (D) (E) (F) (G) Figure 30.4 Three-jig pin technique for tibial plateau leveling osteotomy (TPLO) with correction of significant tibial valgus. The proximal and middle (articulated with distal jig arm) jig pins are placed parallel to the tibial plateau in the frontal plane, and are parallel to each other (A and B). The third jig pin (distal-most jig pin, not articulated with TPLO jig) is placed parallel to the talo-crural joint (A and B). The angle formed between the middle and distal jig pins is equal to the correction angle (B). The TPLO (C) and proximal arm of the medial closing wedge (D) are performed parallel to the proximal (and/or middle) jig pin. The distal limb of the medial closing wedge is performed parallel to the distal jig pin (E), creating the medial closing wedge (F). The TPLO jig is re-articulated with the distal jig pin, reducing the medial closing wedge ostectomy (G), and fixation is applied. VetBooks.ir 258 Surgical Treatment without any loss of bone apposition at the TPLO (arrows in Figure 30.3) (Weh et al. 2011). In cases with patella alta, the closing wedge can be used to position the patella more distally in the trochlear groove; the amount of change in patellar position is roughly equivalent to the distance of cranial tibial cortex that is removed with the CCWO (Talaat et al. 2006). Thus, the angle of the CCWO can be adjusted to provide the necessary change in patellar position, and the rotation at the TPLO can be adjusted to provide the balance of the tibial plateau leveling required achieving a postoperative TPA of 5◦ , without rotating beyond the safe point. Surgical technique Slocum & Slocum (1993) were the first to describe the TPLO/CCWO procedure utilizing two radial osteotomies.2 However, this technique was shown to result in unpredictable and inaccurate correction (Talaat et al. 2006), and consequently it was modified to use linear osteotomies at the CCWO (Talaat et al. 2006). This was found to make preoperative planning and intraoperative execution more precise. Once the radial osteotomy for the TPLO is made partially through the tibia, the proximal limb of the CCWO is scored on the medial cortex, such that it intersects the radial osteotomy of the TPLO at the caudal cortex of the tibia. The CCWO can be accurately executed intraoperatively by using a sterile angle template, a sterile goniometer, or a simple geometric method. If the geometric method is used, the proximal limb of the CCWO must be placed such that it is perpendicular to the cranial tibial cortex (Figure 30.1C). The length of the proximal limb of the CCWO (base of a right-triangle) is measured and the length of the opposite limb of the righttriangle (the limb of the triangle along cranial border of the tibia) is calculated (Figure 30.1C), determining the appropriate position of the distal limb of the CCWO (hypotenuse of the triangle), which is then scored. The TPLO is completed, the tibial plateau segment is rotated, and 2 Seminars entitled “Tibial Plateau Leveling Osteotomy for Cranial Cruciate Ligament Repair,” Slocum Enterprises, Inc. two holding Kirschner wires are placed from proximal to the patellar tendon attachment at the tibial tuberosity into the tibial plateau segment. It should be noted that the plateau is not leveled to 5◦ at this stage, and care must be taken to ensure that the Kirschner wires do not penetrate the joint surface. These Kirschner wires remain as part of the permanent fixation. The CCWO is completed, reduced, and a holding Kirschner wire is placed from craniodistal to caudoproximal, avoiding the articular surface (Figure 30.1D). Two large-gauge tension band wires are applied to achieve cranial compression and apposition of the tibial closing wedge osteotomy. The bone plate(s) are then applied in compression to complete the stabilization (Figure 30.1D,E). Application of the implants in this order seems to improve osteotomy apposition and healing (Weh et al. 2011). The CCWO wedge can be morselized and placed as autogenous corticocancellous bone graft at the osteotomy sites, particularly at the CCWO site, as this is generally the area that heals most slowly (Figure 30.1D,E). Torsional correction at the CCWO (arrows in Figure 30.3) and/or lateral translation of the tibial tuberosity segment can be accomplished before applying the fixation, facilitating limb alignment correction in complex cases, such as severe tibial torsion or medial patellar luxation with cruciate ligament rupture in which tibial tuberosity transposition is required. Rigid fixation is required in cases treated with TPLO/CCWO to mitigate the risk of implant loosening, fixation failure, or prolonged healing. In particular, fixation of the cranial tibial tuberosity segment must be rigid, since the distractive force of the patellar tendon is considerable. Therefore, in all cases, the Kirschner wires placed to stabilize the TPLO and CCWO during the procedure are maintained as permanent fixation, and two figure-of-eight tension band wires are placed to counteract this strong distractive force. The Kirschner wires and tension band wires should be of a suitably large gauge (1/16′′ or 3/32′′ Kirschner wires/pins and 18-g or 16-g cerclage wire in most patients), tightened adequately, and anchored in bone tunnels as illustrated (Figure 30.1D,E). Double plate fixation is recommended if the tibial size is sufficient to place a second bone plate. In patients weighing 30–40 kg an additional 2.4-mm or VetBooks.ir Treatment of Excessive Tibial Plateau Angle 2.7-mm straight bone plate can be added to the standard 3.5-mm TPLO plate, or a 3.5-mm broad TPLO plate can be used. In most patients weighing >40 kg an additional 3.5-mm straight bone plate can be added to the standard 3.5-mm TPLO plate. Outcome A multicenter, case-control study compared the surgical treatment options for cruciate ligament rupture in larger-breed dogs with eTPA, and found that surgical treatment had a higher complication rate but a comparable outcome to that of dogs without eTPA. In addition, ownerperceived outcome was superior for eTPA dogs when TPLO resulted in a TPA ≤14◦ , compared to dogs with postoperative TPA >14◦ . Therefore, TPLO/CCWO with a target TPA of 5◦ is the procedure of choice of the author. In a retrospective study evaluating the TPLO/CCWO procedure in 18 stifles of 15 dogs, postoperative complications included implant loosening or breakage (27.8%), seroma formation (11.1%), and local irritation due to implants (11.1%) (Talaat et al. 2006). Anecdotally, as more experience has been gained with this technique, the complication rate is considerably lower, and is now similar to that reported for TPLO alone, with the occasional need for Kirschner or tension band wire removal being the most common complication. References Duerr FM, Duncan CG, Savicky RS, et al. Comparison of surgical treatment options for cranial cruciate ligament disease in large-breed dogs with excessive tibial plateau angle. Vet Surg 2008;37:49–62. Hamilton K, Tarlton J, Parsons K, et al. Effect of osteotomy position and tibial plateau rotation on 259 the tensile force required for failure of the canine quadriceps mechanism. Vet Surg 2015;44:763–771. Moeller EM, Cross AR, Rapoff AJ. Change in tibial plateau angle after tibial plateau leveling osteotomy in dogs. Vet Surg 2006;35:460–464. Osmond CS, Marcellin-Little DJ, Harrysson OLA, et al. Morphometric assessment of the proximal portion of the tibia in dogs with and without cranial cruciate ligament rupture. Vet Radiol Ultrasound 2006;47:136–141. Pacchiana PD, Morris E, Gillings SL, et al. Surgical and postoperative complications associated with tibial plateau leveling osteotomy in dogs with cranial cruciate ligament rupture: 397 cases (1998–2001). J Am Vet Med Assoc 2003;222:184–193. Priddy NH, Tomlinson JL, Dodam JR, et al. Complications with and owner assessment of the outcome of tibial plateau leveling osteotomy for treatment of cranial cruciate ligament rupture in dogs: 193 cases (1997–2001). J Am Vet Med Assoc 2003;222:1726– 1732. Read RA, Robins GM. Deformity of the proximal tibia in dogs. Vet Record 1982;111:295–298. Reif U, Probst CW. Comparison of tibial plateau angles in normal and cranial cruciate deficient stifles of Labrador Retrievers. Vet Surg 2003;32:385– 389. Slocum B, Slocum TD. Tibial plateau leveling osteotomy for repair of cranial cruciate ligament rupture in the canine. Vet Clin North Am Small Anim Pract 1993;23:777–795. Stauffer KD, Tuttle TA, Elkins AD, et al. Complications associated with 696 tibial plateau leveling osteotomies (2001–2003). J Am Anim Hosp Assoc 2006;42:44–50. Talaat MB, Kowaleski MP, Boudrieau RJ. Combination tibial plateau leveling osteotomy and cranial closing wedge osteotomy of the tibia for the treatment of cranial cruciate ligament-deficient stifles with excessive tibial plateau angle. Vet Surg 2006;35:729–739. Weh JL, Kowaleski MP, Boudrieau RJ. Combination tibial plateau leveling osteotomy and transverse corrective osteotomy of the proximal tibia for the treatment of complex tibial deformity in 12 dogs. Vet Surg 2011;40:670–686. VetBooks.ir VetBooks.ir 31 Surgical Management of Cruciate Ligament Rupture Combined with Patella Luxation Anke Langenbach and Denis J. Marcellin-Little Pathophysiology Cruciate ligament rupture (CR) predominantly affects the cranial cruciate ligament (CrCL). CR and patellar luxation (PL) are two common causes of dysfunction and lameness in dogs that are generally independent but can coexist (Arthurs & Langley-Hobbs 2006). Medial and lateral PL have been described as risk factors for CR (Wright 1979; Willauer & Vasseur 1987). Conversely, CR can predispose dogs to patellar luxation, particularly in bow-legged dogs. The prevalence of PL in dogs with CR ranged from 6% to 20% in two reports (Willauer & Vasseur 1987; Gibbons et al. 2006). Pelvic limb lameness in dogs with combined CR and PL may be more severe than pelvic limb lameness in dogs with only CR or only PL. It has been speculated that the increase in internal rotation resulting from partial CrCL fiber rupture may increase clinical signs in dogs with Grade 1 medial PL and no previous clinical signs. Complete CR leads to stifle instability, primarily with cranial tibial thrust but also with an increase in internal rotation and extension, potentially exacerbating the clinical consequences of PL. Patellae that track in an abnormally proximal position (patella alta) are also a risk factor for medial PL. In one report, large-breed dogs with medial PL were found to have a more proximal patella than large-breed dogs with normal stifle joints (Johnson et al. 2006). However, in another report, patella alta was not identified in toy poodles with medial PL (Yasukawa et al. 2016). PL has also been reported as an unusual postoperative complication of CR stabilization surgery. The proposed mechanism for postoperative PL included a failure of incisional closure or tearing of the retinacular incision, potentially combined with muscle atrophy with a resulting lack of muscular control. Additional predisposing factors include angulation of the proximal or distal portion of the femur, a shallow trochlear sulcus with poorly developed ridges, hypoplastic femoral condyles, and torsion of the tibial tuberosity or bowing of the proximal tibia. PL after CR stabilization can be either medial or lateral and can occur after extracapsular stabilization, intra-articular stabilization, tibial plateau leveling osteotomy (TPLO), or closing cranial wedge ostectomy (Arthurs & Langley-Hobbs 2007). An incidence of PL of 1.3% was documented during the development Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 261 VetBooks.ir 262 Surgical Treatment period of the TPLO procedure (Slocum & Slocum 1993). In two large studies, the reported incidence of PL after a variety of CR stabilization methods was 0.18% and 0.3%, respectively (Arthurs & Langley-Hobbs 2007; Fitzpatrick & Solano 2010). Patient evaluation Clinical signs Patients with combined CR and PL often have no history of trauma and present with an acute unilateral pelvic limb lameness after exercise. In two studies, the mean age at presentation was 19 and 24 months, respectively (Fitzpatrick et al. 2010; Langenbach & Marcellin-Little 2010). By comparison, dogs presenting because of CR alone tend to be older: the median age at presentation for dogs with CR was 67 months in a study involving 1000 dogs (Fitzpatrick & Solano 2010). Owners may report occasional to frequent skipping and hopping on the affected leg before CR, suggesting that the PL preceded CR. The duration of lameness varies from acute to chronic lameness lasting several months. Combined CR and PL has been reported in several breeds. Labrador Retrievers are the most commonly affected dogs. In the authors’ experience, English Bulldogs and American Pit Bull Terriers are also commonly affected. These two breeds were also the most common in a study describing the management of combined medial PL and CR using TTA (Yeadon et al. 2011). Physical examination findings include cranial tibial thrust, positive cranial drawer motion and PL with varying degrees of luxation. Grades 2 and 3 are most common, but Grades 1 and 4 have also been reported. In dogs with combined CR and PL most luxations are medial, but lateral PL is possible. In one report, two lateral PL were described as a complication of CR stabilization surgery: one in a Bull Mastiff and one in a sighthound cross (Lurcher) (Arthurs & Langley-Hobbs 2007). However, in a report of 65 dogs with lateral PL, no dog had concurrent CR (Kalff et al. 2014). In that report, a breed shift from large and giant breeds to medium and large breeds was described: the most commonly affected breed was the Cocker Spaniel. Palpation The diagnosis of combined CR and PL is made by palpation. Pelvic limb radiographs are needed to provide an adequate understanding of the condition and underlying deformities, and to select treatment options. PL are graded using Putnam’s grades: Grade 1 being manual dislocation of the patella with spontaneous reduction upon release; Grade 2 being the spontaneous and frequent PL with self-reduction; Grade 3 being a near-constant luxation that can be manually reduced; and Grade 4 being a permanent luxation (Putnam 1968). Imaging For dogs with combined CR and PL, the focus of assessment is to detect malalignment of the quadriceps femoris extension apparatus. This includes angulation and torsion of the femur, tibial tuberosity malposition, and angulation and torsion of the tibia. The minimum valgus or varus femoral or tibial angles leading to medial or lateral PL are not known. Assessment of femoral and tibial geometry can be made using radiographs or computed tomography (CT) scanning. Radiographs should ideally be made under sedation or general anesthesia to allow for correct alignment and positioning. A change in distal femoral elevation influences the measurement of mediolateral angulation of the femoral shaft (Jackson & Wendelburg 2012). In that study, measurements of the anatomic lateral distal femoral angle (aLDFA) were increased when the distal aspect of the femur was elevated by >5◦ . A 10◦ elevation led to an increase in aLDFA of ∼1◦ . Radiographic views of the femurs and tibias are warranted because limb conformation is often abnormal, and because the problem is generally bilateral. For the femur and tibia, angulation in a frontal plane is assessed by use of a craniocaudal (CC) radiographic view by evaluating lateral deviation (valgus) or medial deviation (varus) of the lower extremity relative to the proximal portion of the bone. This has been done using the aLDFA and mechanical lateral distal femoral angle (mLDFA) (Palmer et al. 2011). For the tibia, angulation in a frontal plane is evaluated by measuring the relative orientation of VetBooks.ir Surgical Management of Cruciate Ligament Rupture Combined with Patella Luxation the tibial plateau and distal articular surface on a CC radiographic view (Jaeger et al. 2007). The mechanical medial proximal tibial angle (mMPTA) and mechanical medial distal tibial angle (mMDTA) can be calculated for the tibia on CC view after drawing the mechanical tibial axis from the center of the intercondylar fossa of the femur through the intertubercular eminence of the tibia and the distal intermediate ridge of the tibia (Dismukes et al. 2007; Dismukes et al. 2008a). CC radiographic views of the complete femur with coxofemoral and stifle joints and complete tibia with stifle and hock joints are recommended. This may require two radiographs, since many dogs are too large to be imaged on one large radiographic plate. The radiographic beam should be centered over the stifle joint and the femoral cortices should bisect the fabellae. However, it may be difficult to accurately assess varus angulation of the femur by use of CC radiographs (Aiken & Barnes 2014). In dogs with Grade 2, 3, or 4 medial PL, the patella may luxate during imaging, making evaluation of the shape of the femur more challenging because it is more difficult to orient the femur (Figure 31.1). Varus and valgus femoral angulation is assessed on the CC view of the femur. That assessment includes measurement of the anatomic long axis of the femur and the aLDFA (Figure 31.2) (Tomlinson et al. 2007). The mean aLDFA reportedly is 97◦ in Labrador Retrievers and 93◦ in German Shepherd dogs (Tomlinson et al. 2007). In one study, the mean aLDFA, mLDFA and femoral varus angle obtained using CT imaging in Toy Poodles with Grade 2 medial PL did not differ statistically from that of normal Toy Poodles, but they were 15◦ larger for Toy Poodles with Grade 4 medial PL (Yasukawa et al. 2016). Hip dysplasia with low femoral neck inclination (coxa vara) and low femoral head anteversion angles has been associated with medial PL (Roush 1993; Kaiser et al. 2001). However, CT-based review of femoral shape in Toy Poodles with medial PL identified no association between medial PL and hip dysplasia (Yasukawa et al. 2016). Varus orientation of the tibia is determined by measuring the mMPTA and mMDTA on a CC view and the mechanical cranial distal tibial angle and the mechanical proximal tibial angle on the sagittal or mediolateral view (Dismukes et al. 2008b). A mediolateral view of the entire femur with 263 Figure 31.1 Craniocaudal radiographic view of the femur of 1-year-old male Akita Inu with medial patellar luxation. The patella is medial to the medial trochlear ridge, and it is therefore more challenging to determine whether the view of the distal portion of the femur is truly craniocaudal. the coxofemoral joint and stifle joints included and a mediolateral view of the tibia with stifle and hock joints included are also recommended. Mediolateral views with the femoral condyles superimposed are recommended, but these may be difficult to obtain in dogs with torsional or angular deformities of the femur. A ‘condylar offset sign’ may be seen in cases of femoral torsion, in that in a mediolateral projection one of the femoral condyles is offset cranially or distally in relation to the other. Excessive femoral varus results in a distal offset, whereas femoral torsion or underdevelopment of the medial or lateral trochlear ridge results in a cranial offset (Figure 31.3). Femoral 264 Surgical Treatment VetBooks.ir torsion is assessed using an axial radiographic view of the femur (Dudley et al. 2006). This is done by placing the patient in dorsal recumbency with the radiographic plate under the hip region and by centering the radiographic beam on the femur. CT scanning allows a tridimensional assessment of the femur and tibia (Harrysson et al. 2003), and greatly enhances the repeatability of the assessment of angulation and torsion of the femur and tibia, compared to radiographs (Dudley et al. 2006; Barnes et al. 2015). The CT scan can be exported and used to produce a replica of the bone to rehearse surgery (Harrysson et al. 2003). Management Figure 31.2 Craniocaudal radiograph of a Newfoundland with combined cruciate ligament rupture and medial patella luxation. Femoral length is measured as the distance from the proximal aspect of the intercondylar fossa to the laterodistal aspect the femoral neck (open circles). The anatomic axis of the femur is drawn as the line connecting the center of two lines drawn across of the femoral shaft at one-third and one-half of femoral length. The distal joint reference line is the line connecting the distal aspect of the medial and lateral femoral condyles. The anatomic lateral distal femoral angle (aLDFA) is the angle formed by the anatomic axis of the femur (solid white line) and the distal joint reference line. The mechanical axis of the femur is drawn as the dotted line connecting the center of the femoral head and the proximal aspect of the intercondylar fossa. The mechanical lateral distal femoral angle (mLDFA) is the angle formed by the mechanical axis and the distal joint reference line. In this dog, the aLDFA is 108◦ and the mLDFA is 105◦ . Both angles are abnormally high. Management options are either non-surgical or surgical. For Grade 1 PL with partial or complete CR, focusing on quadriceps strengthening as part of a rehabilitation program could be a viable option. A stifle brace may be considered, but little is known about the benefits of braces. Braces are particularly challenging to fit in small patients and in patients with short, bulky limbs. Medium and large dogs can be fitted with a brace and can be managed with controlled activity and therapeutic exercises over a period of 8–12 weeks. Physical rehabilitation of dogs with CR is described in Chapter 42. Surgical treatment of dogs with Grade 2, 3, or 4 PL combined with complete CR with meniscal injury is generally required to regain stability of the stifle joint. Several treatment options have been reported which focus on realignment of the quadriceps mechanism while stabilizing the CrCL-deficient stifle. The surgery should prevent cranial tibial thrust and torsional instability (pivot shift) while maintaining normal range of motion of the stifle joint. Stabilization of the CrCL-deficient stifle joint combined with PL is challenging because technical steps from both surgical procedures must be combined when joint stability is surgically reestablished. The trochlear groove is often shallow, with a compromised medial or lateral trochlear ridge. This may be developmental or the result of wear caused by friction of the patella on the trochlear ridge (Figure 31.4). To restore patellar tracking, the trochlear groove may need to be deepened; this is ideally 265 VetBooks.ir Surgical Management of Cruciate Ligament Rupture Combined with Patella Luxation (A) (B) (C) Figure 31.3 In dogs with normal femoral angulation and torsion (A), the condyles are often superimposed on mediolateral radiographs of the femur. In contrast, in dogs with excessive femoral angulation or torsion and in dogs with abnormal condylar development, the femoral condyles are often offset. A distal femoral condylar offset is present in dogs with excessive femoral angulation (varus or valgus) (B). The extensor fossa at the origin of the long digital extensor muscle on the lateral condyle is visible (arrowhead), indicating that the shorter condyle is the medial condyle and that the dog has excessive varus. A cranial femoral condylar offset is present in dogs with femoral torsion (C). The extensor fossa on lateral condyle (arrowhead) is more cranial than the medial condyle, indicating the presence of excessive internal rotation of the distal portion of the femur. achieved with minimal disruption to the articular surface using trochlear block or wedge resection (Johnson et al. 2001). The groove should be wide enough to allow the patella to contact the trochlea, and deep enough for at least half of the thickness of the patella to be caudal to the medial and lateral trochlear ridges. (A) (B) The trochlear groove should also be proximally extended to accommodate the potentially proximal patella in large-breed dogs with medial PL. The cranial part of the sartorius muscle may be released near its insertion site if the muscle appears to promote internal rotation of the tibia, or prevent stifle joint extension. (C) Figure 31.4 In these intraoperative pictures of a patient with Grade 3 MPL and CR made during arthroscopy, the articular cartilage of the trochlea is slightly irregular (A, bottom). The articular cartilage of the patella is completely eroded (B). Full-thickness articular cartilage wear is also visible on the medial aspect of the medial trochlear ridge, where the patella rests in its luxated position (C). VetBooks.ir 266 Surgical Treatment Femoral torsion and angulation are routinely abnormal in dogs with CR and PL. Bow-legged dogs have varus angulation of the distal portion of the femur combined with internal torsion (genu varum) (Read & Robbins 1982). Knockkneed dogs have valgus angulation of the distal portion of the femur combined with external torsion (genu valgum) (Kalff et al. 2014). Correct patellar tracking requires realignment of the trochlear groove. Minor trochlear groove malalignment can be corrected by angling the trochlear block or wedge, while major trochlear groove malalignment is best managed with a corrective ostectomy of the distal portion of the femur (Swiderski & Palmer 2007), potentially combined with trochlear block or wedge recession. Stabilization of the CrCL-deficient stifle and the correction of deformities of proximal portion of the tibia require a combination of surgical procedures. If necessary, the quadriceps mechanism is realigned through transposition of the tibial tuberosity. In dogs with medial PL, lateralization of the tuberosity is (A) (B) often performed; conversely, in dogs with lateral luxation, the tuberosity is moved medially. The tuberosity is also displaced distally in patients with patella alta. Distal transposition can be achieved with tibial tuberosity osteotomy, angling the osteotomy and then repositioning the tuberosity and securing it using Kirschner wires or a tibial tuberosity advancement (TTA) plate. If tibial anatomy is within normal limits but rotational laxity of the stifle joint is present, the tibial position can be controlled using a fabellar-to-tibial crest suture, which will also provide extracapsular stabilization of cranial tibial translation when CR is present (see also Chapter 25). TPLO can also be used to manage dogs with combined CR and PL, particularly medial PL in large dogs (Figure 31.5) (Fitzpatrick et al. 2010; Langenbach & Marcellin-Little 2010). A medial skin incision, followed by a lateral arthrotomy of the stifle joint, is performed to allow for trochleoplasty or corrective closing wedge femoral ostectomy, and inspection of intra-articular structures including the CrCL (C) (D) Figure 31.5 Mediolateral radiographs of the tibiae of a 3-year-old Bulldog with bilateral rupture of the cranial cruciate ligament combined with medial patellar luxation. Tibial plateau leveling osteotomy (TPLO) has been performed on the right (A and B) and left (C and D) legs. A ‘right-sided’ TPLO plate has been used to stabilize the tibial plateau of the left leg (D) and synthetic bone graft is visible at the surgical site. VetBooks.ir Surgical Management of Cruciate Ligament Rupture Combined with Patella Luxation Figure 31.6 Realignment of the tibia when performing tibial plateau leveling osteotomy (TPLO) combined with patella luxation correction includes several steps performed while the patella is in its reduced position and the stifle joint is held in extension and facing cranially. First, an assistant stabilizes the tibial plateau in its leveled position while the surgeon externally rotates the distal tibia around its long axis to eliminate internal torsion of the tibia. Second, the surgeon slides the tibial plateau 3–6 mm medially, laterally translating the tibial tuberosity and the entire distal fragment. Third, to address genu varum, the distal fragment is moved abaxially against the tibial plateau, creating a medial gap of 1–3 mm (A). After the procedure is completed, a stabilizing Kirschner wire is inserted from the tibial crest into the tibial plateau (B). Source: Adapted from Langenbach & Marcellin-Little 2010. (A) and medial meniscus. A cranial sartorius muscle release and lateral retinacular imbrication are then performed. A medial approach to the proximal portion of the tibia is made and a TPLO is performed. The appropriate osteotomy position is measured on radiographs before surgery (Mossman et al. 2015). Once the tibial plateau is freed, the jig is removed to allow rotation of the plateau. An assistant stabilizes the thigh while the surgeon carefully levels the tibial plateau and realigns the proximal and distal portions of the tibia to correct tibial torsion and varus (Figure 31.6). The construct is secured with a 1.14 mm- or 1.55 mm-diameter (0.045′′ or 0.062′′ ) Kirschner wire, depending on patient size, placed from the craniolateral aspect of the tibial crest into the central tibial plateau. A stainless steel rod is used to check for correct alignment in surgery of the tibia and femur. The patella is checked for stability. Once alignment is achieved, a TPLO plate is applied. A pre-contoured locking TPLO plate can be used, but this may need to be adjusted using bending irons to fit the tibia. Plate contouring leads to 267 (B) a change in the orientation of locking screws. This may lead to an inappropriate screw orientation in the proximal bone fragment. Consequently, it may necessary to use non locking screws in the proximal portion of the plate to ensure appropriate screw orientation. In some instances, a pre-contoured TPLO plate intended for the opposite side can be used (Figure 31.5D). An alternative approach is to perform a standard TPLO and then correct the patella luxaton using a frontal plane tibial tuberosity transposition (Leonard et al. 2016). The tibial crest fragment is stabilized using pin and tension band wire fixation (Leonard et al. 2016). If a closing wedge ostectomy of the femur is performed in the same patient, the wedge can be morselized and used as graft in the medial cortical defect. Alternatively, a synthetic bone graft can be used to fill the medial defect between the distomedial aspect of the tibial plateau and the proximomedial aspect of the tibial shaft. The Kirschner wire can be left in place to enhance stability, or it can be removed. VetBooks.ir 268 Surgical Treatment TTA can also be used to manage CR combined with PL (Newman et al. 2014). The management of medial PL and CR often requires fixation of the tibial tuberosity in a more lateral and distal position. A medial approach to the stifle and proximal tibia is performed with lateral dissection and lateral arthrotomy of the stifle joint. Any CrCL remnants are removed, and a block resection sulcoplasty is performed. A tibial tuberosity osteotomy is performed as previously described (Lafaver et al. 2007). A standard TTA plate is used and the plate can be adjusted by lateral bending of the plate proximal to the screw fixation. A recession in the medial cortex of the tibia to accept the plate, and a second recession in the proximal tibia for the caudal cage screw, are made. A high-speed drill can be used to make these adjustments. To aid in the lateralized position of the TTA plate, a positional Kirschner wire can be placed from the tibial tuberosity to the principal tibial fragment. In patients with patella alta, the TTA plate can be moved distally as well as laterally. One report described the use of TTA to manage patella alta in nine dogs (Pugliese et al. 2015). The patella to patellar ligament ratio will need to be calculated from a mediolateral projection and taken into account. A mean distal translation of 14 mm was required for the nine dogs described in this case series. The outcome of surgery for the management of CR and PL is good or excellent for the majority of patients. Complications include those described for each individual procedure, with potentially an increase in the likelihood of failure of fixation and a loss for patellar reduction. In one report, the risk of loss of patellar reduction after tibial tuberosity transposition was increased in dogs with concurrent CR (Stanke et al. 2014). References Aiken M, Barnes D. Are the fabellae bisected by the femoral cortices in a true craniocaudal pelvic limb radiograph? J Small Anim Pract 2014;55:465– 470. Arthurs GI, Langley-Hobbs SJ. Complications associated with corrective surgery for patellar luxation in 109 dogs. Vet Surg 2006;35:559–566. Arthurs GI, Langley-Hobbs SJ. Patellar luxation as a complication of surgical intervention for the management of cranial cruciate ligament rupture in dogs. A retrospective study of 32 cases. Vet Comp Orthop Traumatol 2007;20:204–210. Barnes DM, Anderson AA, Frost C, et al. Repeatability and reproducibility of measurements of femoral and tibial alignment using computed tomography multiplanar reconstructions. Vet Surg 2015;44:85– 93. Dismukes DI, Tomlinson JL, Fox DB, et al. Radiographic measurement of the proximal and distal mechanical joint angles in the canine tibia. Vet Surg 2007;36:699–704. Dismukes DI, Fox DB, Tomlinson JL, et al. Determination of pelvic limb alignment in the large-breed dog: a cadaveric radiographic study in the frontal plane. Vet Surg 2008a;37:674–682. Dismukes DI, Tomlinson JL, Fox DB, et al. Radiographic measurement of canine tibial angles in the sagittal plane. Vet Surg 2008b;37:300–305. Dudley RM, Kowaleski MP, Drost WT, et al. Radiographic and computed tomographic determination of femoral varus and torsion in the dog. Vet Radiol Ultrasound 2006;47:546–552. Fitzpatrick N, Johnson J, Hayashi K, et al. Tibial plateau leveling and medial opening crescentic osteotomy for treatment of cranial cruciate ligament rupture in dogs with tibia vara. Vet Surg 2010;39:444–453. Fitzpatrick N, Solano MA. Predictive variables for complications after TPLO with stifle inspection by arthrotomy in 1000 consecutive dogs. Vet Surg 2010;39:460–474. Gibbons SE, Macias C, Tonzing MA, et al. Patellar luxation in 70 large breed dogs. J Small Anim Pract 2006;47:3–9. Harrysson OLA, Cormier DR, Marcellin-Little DJ, et al. Rapid prototyping for treatment of canine limb deformities. Rapid Prototyping J 2003;9:37–42. Jackson GM, Wendelburg KL. Evaluation of the effect of distal femoral elevation on radiographic measurement of the anatomic lateral distal femoral angle. Vet Surg 2012;41:994–1001. Jaeger GH, Marcellin-Little DJ, Ferretti A. Morphology and correction of distal tibial valgus deformities. J Small Anim Pract 2007;48:678–682. Johnson AL, Probst CW, Decamp CE, et al. Comparison of trochlear block recession and trochlear wedge recession for canine patellar luxation using a cadaver model. Vet Surg 2001;30:140–150. Johnson AL, Broaddus KD, Hauptman JG, et al. Vertical patellar position in large-breed dogs with clinically normal stifles and large-breed dogs with medial patellar luxation. Vet Surg 2006;35:78–81. Kaiser S, Cornely D, Golder W, et al. The correlation of canine patellar luxation and the anteversion angle as measured using magnetic resonance images. Vet Radiol Ultrasound 2001;42:113–118. Kalff S, Butterworth SJ, Miller A, et al. Lateral patellar luxation in dogs: a retrospective study of 65 dogs. Vet Comp Orthop Traumatol 2014;27:130–134. VetBooks.ir Surgical Management of Cruciate Ligament Rupture Combined with Patella Luxation Lafaver S, Miller NA, Stubbs WP, et al. Tibial tuberosity advancement for stabilization of the canine cranial cruciate ligament-deficient stifle joint: surgical technique, early results, and complications in 101 dogs. Vet Surg 2007;36:573–586. Langenbach A, Marcellin-Little DJ. Management of concurrent patellar luxation and cranial cruciate ligament rupture using modified tibial plateau levelling. J Small Anim Pract 2010;51:97– 103. Leonard KC, Kowaleski MP, Saunders WB, et al. Combined tibial plateau levelling osteotomy and tibial tuberosity transposition for treatment of cranial cruciate ligament insufficiency with concomitant medial patellar luxation. Vet Comp Orthop Traumatol 2016;29:546-540. Mossman H, von Pfeil DJ, Nicholson M, et al. Accuracy of three pre- and intra-operative measurement techniques for osteotomy positioning in the tibial plateau levelling procedure. Vet Comp Orthop Traumatol 2015;28:250–255. Newman M, Bertollo N, Walsh W, et al. Tibial tuberosity transposition-advancement for lateralization of the tibial tuberosity: an ex vivo canine study. Vet Comp Orthop Traumatol 2014;27:271–276. Palmer RH, Ikuta CL, Cadmus JM. Comparison of femoral angulation measurement between radiographs and anatomic specimens across a broad range of varus conformations. Vet Surg 2011;40:1023–1028. Pugliese LC, Pike FS, Aiken SW. Distal tibial tuberosity translation using TTA implants for the treatment of patella alta in large breed dogs. Surgical technique and clinical outcome. Vet Comp Orthop Traumatol 2015;28:274–281. Putnam RW. Patellar luxation in the dog. University of Guelph, 1968. 269 Read RA, Robins GM. Deformity of the proximal tibia in dogs. Vet Rec 1982;111:295–298. Roush JK. Canine patellar luxation. Vet Clin North Am Small Anim Pract 1993;23:855–868. Slocum B, Slocum TD. Tibial plateau leveling osteotomy for repair of cranial cruciate ligament rupture in the canine. Vet Clin North Am Small Anim Pract 1993;23:777–795. Stanke NJ, Stephenson N, Hayashi K. Retrospective risk factor assessment for complication following tibial tuberosity transposition in 137 canine stifles with medial patellar luxation. Can Vet J 2014;55:349–356. Swiderski JK, Palmer RH. Long-term outcome of distal femoral osteotomy for treatment of combined distal femoral varus and medial patellar luxation: 12 cases (1999–2004). J Am Vet Med Assoc 2007;231:1070–1075. Tomlinson J, Fox D, Cook JL, et al. Measurement of femoral angles in four dog breeds. Vet Surg 2007;36:593–598. Willauer CC, Vasseur PB. Clinical results of surgical correction of medial luxation of the patella in dogs. Vet Surg 1987;16:31–36. Wright JR. Combined patellar luxation-cruciate repair. J Am Anim Hosp Assoc 1979;15:85–91. Yasukawa S, Edamura K, Tanegashima K, et al. Evaluation of bone deformities of the femur, tibia, and patella in Toy Poodles with medial patellar luxation using computed tomography. Vet Comp Orthop Traumatol 2016;29:29–38. Yeadon R, Fitzpatrick N, Kowaleski MP. Tibial tuberosity transposition-advancement for treatment of medial patellar luxation and concomitant cranial cruciate ligament disease in the dog. Surgical technique, radiographic and clinical outcomes. Vet Comp Orthop Traumatol 2011;24:18–26. VetBooks.ir VetBooks.ir 32 Biomechanics of the Cranial Cruciate Ligament-Deficient Stifle Treated by Tibial Osteotomies Antonio Pozzi, Stanley E. Kim, and Selena Tinga Introduction Normal tibiofemoral motion is constrained by articular surfaces, ligaments, joint capsule and menisci. Cruciate ligament rupture (CR), particularly rupture of the cranial cruciate ligament (CrCL), alters these constraints and causes abnormal motion between the articular surfaces (Anderst & Tashman 2009). Modification in cartilage loading caused by the altered surface interaction initiates progressive osteoarthritis (Tashman et al. 2004; Anderst & Tashman 2009; Kim et al. 2009a). Thus, the goal for CrCL reconstruction should be the restoration of normal stifle mechanics, to reestablish biomechanical homeostasis, and to halt the progression of osteoarthritis. Much of the current knowledge regarding CrCL repair biomechanics in dogs has been derived from ex vivo studies evaluating normal, CrCL-deficient and surgically treated stifles under controlled conditions or theoretical analysis. However, ex vivo and theoretical studies cannot replicate functional loading, and represent only the ‘time-zero’ condition, immediately after surgical fixation (Warzee et al. 2001; Shahar & Milgram 2006; Apelt et al. 2007). More recent investigations conducted in vivo suggest that the results of ex vivo studies should be interpreted with much caution as stabilization techniques fail to provide joint stability in up to 70% of cases (Kim et al. 2012; Skinner et al. 2013; Rey et al. 2014). Most clinical and experimental studies evaluating surgical techniques for CR adopt static stability as a measure of the success of the surgical technique to reestablish normal joint mechanics (Gambardella et al. 1981; Slocum & Slocum 1993; Warzee et al. 2001). For example, a persistent positive cranial drawer test after an extracapsular technique has been traditionally considered a sign of stifle instability and an indication of failure of the procedure. A neutralized cranial tibial thrust after tibial plateau leveling osteotomy (TPLO) has generally been used as an indication of a ‘stable’ stifle after reduction of the tibial plateau slope. However, in both cases, static stability (palpable stability on orthopaedic examination) may not necessarily correlate with dynamic stability (controlled alignment of the stifle during activity in vivo). A key concept is that stifle stability is a dynamic phenomenon, describing the response of the neuromusculoskeletal system to a complex combination of body position, muscle forces, external loads and sensory inputs. The limited value of palpation tests, such as cranial drawer and tibial compression tests, for Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 271 VetBooks.ir 272 Surgical Treatment predicting clinical function is likely a reflection of the discrepancy between measures of joint laxity versus measures of dynamic stability. Laxity tests measure the maximum displacement of the joint in response to an applied external load, in the absence of muscle forces. Simple laxity elicited by palpation cannot simulate the complexity, directions and rate of application of muscular forces produced at the stifle during movement. Even the tibial compression test, which attempts to simulate weight-bearing, fails to replicate significant loads transmitted across the stifle, such as a quadriceps force. For this reason, it would be more correct to use the term ‘laxity’ when static stability is evaluated, and consider dynamic stability only if stifle kinematics can be evaluated in the whole range of motion during different gait patterns in vivo. Single-plane fluoroscopy is frequently used for the accurate non-invasive kinematic evaluation of human knees, and the technique has been validated for dog stifles (Jones et al. 2014). While biplanar fluoroscopy is considered the most accurate modality for determining joint kinematics, the lateral single plane modality was accurate to within 1.28 mm for translations and 1.58◦ for rotations (Jones et al. 2014). This technique allows for evaluation during locomotion in vivo in clinical cases, and has since been used to determine normal dog stifle kinematics during treadmill walking and trotting, stair climbing, and sitting (Kim et al. 2015). Biomechanics of tibial osteotomies In 1983 Slocum described the cranial tibial thrust as a tibiofemoral shear force occurring during weight-bearing (Slocum & Devine 1983). Slocum also presented a theoretical model which proposed that the magnitude of cranial tibial thrust was dependent on the degree of the caudal slope of the tibial plateau (Slocum & Slocum 1993). The compressive forces of weight-bearing, assumed to be parallel to the axis of the tibia, can be resolved into a cranially directed component responsible for cranial tibial translation, and a joint-compressive force (Figure 32.1). In the normal stifle the cranial shear component is opposed by the CrCL and by muscle forces. In the CrCL-deficient stifle, the uncontrolled cranial shear force results in cranial tibial subluxation. Based on his model, Slocum proposed that the tibial plateau angle (TPA) was a major factor in stifle biomechanics influencing the magnitude of cranial shear force. In an attempt to dynamically decrease the uncontrolled shear force in the CrCL-deficient stifle, Slocum described in 1984 the closing cranial wedge ostectomy (CCWO) for the treatment of CR in dogs (Slocum & Devine 1984). This technique was intended to eliminate cranial tibial thrust during the weight-bearing phase of the stride by reducing the TPA. Its mechanism has been recently investigated in an ex vivo study evaluating the size of the wedge ostectomy necessary to neutralize the tibial thrust (Apelt et al. 2010). An ostectomy with a wedge angle equal to TPA +5◦ resulted in a stable stifle at a TPA of approximately 6◦ . Other factors that influence the postoperative TPA after CCWO include the position of the ostectomy and the cortical alignment after reduction (Bailey et al. 2007). These variables may be responsible for the discrepancies in TPA reported after CCWO (Macias et al. 2002). A large CCWO can shorten the tibia cranially and alter the femoro-patellar joint, lowering the patella relative to the femur and leading to hyperextension of the stifle joint (Corr & Brown 2007). Kinematic gait analysis after the CCWO procedure has shown an increase in extension during the swing phase of the stifle and talocrural joints, and an increase in limb extension at paw contact, but no changes occurred in the stifle and talocrural joint angles at the stance phase (Lee et al. 2007). The goal of TPLO is also to neutralize cranial tibial thrust and prevent tibial subluxation (Slocum & Slocum 1993). Biomechanical studies have demonstrated that after tibial plateau rotation, the tibiofemoral shear force shifts from cranial to caudal when the limb is loaded (Warzee et al. 2001; Reif et al. 2002). Thus, it has been postulated that joint stability is dependent on the caudal cruciate ligament (CaCL) neutralizing caudal tibial translation after TPLO (Warzee et al. 2001; Reif et al. 2002). TPLO has a significant effect on CrCL strain, which decreases as the tibial plateau is rotated (Haynes et al. 2015). This protective effect of TPLO on CrCL strain is the basis for recommending TPLO in dogs 273 VetBooks.ir Biomechanics of the Cranial Cruciate Ligament-Deficient Stifle Treated by Tibial Osteotomies (A) (B) Figure 32.1 Slocum theorized that, during weight-bearing, the joint reaction force (magenta arrow) is approximately parallel the longitudinal axis of the tibia. In the cranial cruciate ligament-deficient stifle (A), the joint reaction force can be resolved into a cranially directed tibiofemoral shear component (parallel to tibial plateau) and a joint-compressive force (perpendicular to tibial plateau). By leveling the tibial plateau (B), the joint reaction force is perpendicular to the tibial plateau, and thus can only be resolved into a joint-compressive force; cranial tibial thrust is eliminated. Source: Kim et al. 2008. Reproduced with permission from John Wiley & Sons, Inc. presenting with early partial CR (Hulse et al. 2010). The integrity of the CaCL must be assessed at the time of arthrotomy or arthroscopy before performing TPLO. In the authors’ experience, CaCL abnormalities of varying severity can occur concurrently with CR (see also Chapter 17). The underlying cause of CaCL degeneration and rupture is also unknown, but it may be secondary to osteoarthritic change, or due to the same pathologic processes that causes CrCL fiber damage and rupture. TPLO increases loads on the CaCL during weight-bearing (Warzee et al. 2001), which may accelerate any pre-existing CaCL degeneration postoperatively. While rare, complete rupture of the CaCL has been documented (Slocum & Slocum 1993). This complication will result in severe stifle instability. Hence, CaCL abnormalities may preclude the use of TPLO in CrCL-deficient stifles. Another biomechanical theory argues that the tibia is not axially loaded as proposed by Slocum. Rather, Tepic suggests that the total femorotibial joint forces in vivo are directed parallel to the patellar tendon (Tepic et al. 2002). Cranial tibial thrust, according to this model, is then dependent on the angle between the tibial plateau and the patellar tendon (Figure 32.2). This model also predicts that cranial tibial translation should not occur when a CrCL-deficient stifle is flexed beyond 90◦ . The role of the flexion angle in stifle biomechanics has been investigated in ex vivo studies. As the joint approaches 90◦ of flexion, the quadriceps mechanism becomes a stabilizer and effectively unloads the CrCL by pulling the tibia caudally (Pozzi et al. 2008; Kim et al. 2009b). Likewise, tibial tuberosity advancement aims to impart functional stability by moving the patellar tendon angle to approximately 90◦ when the stifle is Surgical Treatment VetBooks.ir 274 (A) (B) Figure 32.2 An alternate theory, proposed by Tepic, suggests that the joint reaction force (magenta arrow) is approximately parallel to the patella tendon, not the tibial long axis. In the cranial cruciate ligament-deficient stifle (A), the joint reaction force can be resolved into a cranially directed tibiofemoral shear component and a joint-compressive force (yellow arrows). By advancing the tibial tuberosity cranially, the patella tendon is perpendicular to the tibial plateau during stance phase of gait (B). The joint reaction force, therefore, becomes perpendicular to the tibial plateau during weight-bearing, thus can only be resolved into a joint-compressive force; cranial tibial thrust is eliminated. Source: Kim et al. 2008. Reproduced with permission from John Wiley & Sons, Inc. positioned at a standing angle (Montavon et al. 2002). Ex vivo studies demonstrated that stifle stability after CrCL transection is attained by TTA when the patellar tendon angle is 90 ± 9◦ (Apelt et al. 2007). The proposed theoretical mechanism of action of the TTA may also explain the mechanism of action for TPLO (Tepic et al. 2002; Drygas et al. 2010; Sathya et al. 2014). The Tepic model takes into consideration both extensor mechanism anatomy and the geometry of the articulating surfaces of the stifle, and differs from Slocum’s theory in that the direction of the joint reaction force is dependent on the inclination of the patellar tendon. By changing the orientation of the tibial plateau relative to the patellar tendon, TPLO may achieve a patellar tendon angle of about 90◦ in a different way from the TTA (Drygas et al. 2010). These results were confirmed in a clinical study reporting the preoperative and postoperative TPA and patellar tendon angles after TPLO (Sathya et al. 2014). Given that craniocaudal stability is directly related to the patellar tendon angle and, therefore, the flexion angle of the stifle, it is possible that the degree of cranial tibial subluxation may vary between different activities, or even different breeds. When the stifle is loaded in deep (90◦ or greater) flexion, cranial tibial subluxation does not occur, as the patellar tendon angle also reaches 90◦ (Kim et al. 2009b). Hence, it could be argued that tibial osteotomies may not benefit dogs with crouched postures, or during activities such as stair-climbing. A recent ex vivo study demonstrated that TPLO did not improve joint mechanics when CrCL-deficient stifles were loaded in deep flexion (Kim et al. VetBooks.ir Biomechanics of the Cranial Cruciate Ligament-Deficient Stifle Treated by Tibial Osteotomies 2010). Differing stifle joint excursions over a gait cycle may also mean that the amount of tibial plateau rotation (TPLO) or advancement of the patellar tendon insertion (TTA) necessary to neutralize subluxation varies between individual dogs. Firm evidence to support specific ‘tailoring’ of postoperative TPAs or patellar tendon angles is lacking. It is unlikely that the reported optimal angles (e.g., TPA of 6◦ ) are universal for every dog with CR. Traditional surgical techniques that involve the placement of a passive stabilizing structure, such as lateral suture stabilization, have the advantage of decreasing rotational instability, but they hinder full stifle flexion and restrict normal axial rotational motion of the stifle, as placement of the implant cannot be not perfectly isometric in all three planes. Flexion– extension range of motion in stifles treated with TPLO and TTA should not be as diminished when compared to the traditional procedures (Chailleux et al. 2007). Full flexion may be slightly decreased after TPLO and CCWO when compared to normal, as they move the distal tibial segment (i.e., the longitudinal axis of the tibia) into slight extension. The biomechanical models on which TPLO and TTA are based upon are two-dimensional. Therefore, tibial osteotomies do not directly attempt to address axial rotational instability caused by CR (Kim et al. 2008). Axial rotation of the tibia relative to the femur remains unrestricted, and the control of internal–external rotational motion must then rely on muscular forces about the stifle and joint adaptation. It Figure 32.3 Representative image from shape-matching software of a stifle after tibial plateau leveling osteotomy. Three-dimensional computed tomography-derived bone models are superimposed over lateral projection fluoroscopic images that are acquired during activity, and the relative positions of the bones are calculated using custom-written software. 275 is uncertain whether this muscular compensation occurs in dogs, or whether abnormal axial rotation is a clinically significant factor in stifles treated by tibial osteotomies. Persistent axial rotational instability may be one explanation for the progression of osteoarthritis and the subsequent meniscal tears in stifles treated by tibial osteotomies (Lazar et al. 2005; Lafaver et al. 2007). When treating clinical cases with severe internal rotation, consideration should be given to combining extracapsular stabilization with osteotomies. On the other hand, extracapsular techniques create constant external rotation and abduction of the stifle over a range of motion, which may also be detrimental to joint homeostasis (Chailleux et al. 2007). The primary kinematic abnormality of CR is an increase in cranial tibial translation. Tibial osteotomies have been showed to successfully neutralize cranial tibial thrust and reestablish normal alignment of the stifle in ex vivo models. However, in vivo studies have shown that TPLO may not consistently provide stability in all dogs (Kim et al. 2012). A currently unpublished in vivo investigation of clinical dogs, using lateral fluoroscopy (Figure 32.3), has shown that TPLO resolves cranial tibial translation and internal tibial rotation in the majority of dogs, but creates a static caudal tibial displacement that is present throughout the gait cycle (Figure 32.4) (Tinga et al. 2015). When cranial tibial subluxation is resolved, internal tibial rotation is resolved, but when cranial tibial subluxation is not resolved, neither is internal tibial rotation. Presumptively, the resolution of instability 276 Surgical Treatment VetBooks.ir 15 Cranial Tibial Translation Millimeters 10 5 0 (A) –5 Swing Stance Control Post-Op TPLO - Persistent Subluxation CrCL-Deficient Post-Op TPLO - Caudal Tibial Displacement 10 Internal Tibial Rotation Degrees 5 0 –5 –10 (B) –15 Stance Swing relieves pain, although concern exists that abnormal force transmission due to this caudal tibial displacement likely continues to promote osteoarthritis development. Additional studies, particularly in vivo investigations, are required to further elucidate the mechanism by which tibial osteotomies improve clinical lameness in dogs. References Anderst WJ, Tashman S. The association between velocity of the center of closest proximity on subchondral bones and osteoarthritis progression. J Orthop Res 2009;7:71–77. Apelt D, Kowaleski MP, Boudrieau RJ. Effect of tibial tuberosity advancement on cranial tibial subluxation in canine cranial cruciate-deficient stifle joints: an in vitro experimental study. Vet Surg 2007;36:170–177. Apelt D, Pozzi A, Marcellin-Little DJ, et al. Effect of cranial tibial closing wedge on tibial subluxation: an ex vivo study. Vet Surg 2010;39;454–459. Figure 32.4 Craniocaudal tibial translation (A) and axial rotation (B) during a representative treadmill gait cycle from two dogs of equivalent size and conformation, treated by tibial plateau leveling osteotomy (TPLO). The x-axis represents progression through the gait cycle from the beginning of stance phase through to the end of swing phase. Higher values represent increased cranial tibial subluxation (A) and higher internal tibial rotation (B). The averaged curves for both dogs of the cranial cruciate ligament-deficient stifle before surgery (red) and the contralateral normal stifle (black) demonstrate marked cranial tibial subluxation and internal rotation of the affected stifle. At 6 months after TPLO, one dog developed mild caudal subluxation (blue) and mild external tibial rotation. The other dog (yellow) had mild persistent cranial tibial subluxation during stance phase, which coincided with excessive internal tibial rotation. Bailey CJ, Smith BA, Black AP. Geometric implications of the tibial wedge osteotomy for the treatment of cranial cruciate ligament disease in dogs. Vet Comp Orthop Traumatol 2007;20:169–174. Chailleux N, Lussier B, De Guise J, et al. In vitro 3dimensional kinematic evaluation of 2 corrective operations for cranial cruciate ligament-deficient stifle. Can J Vet Res 2007;71:175–180. Corr SA, Brown C. A comparison of outcomes following tibial plateau levelling osteotomy and cranial tibial wedge osteotomy procedures. Vet Comp Orthop Traumatol 2007;20:312–319. Drygas KA, Pozzi A, Goring RL, et al. Effect of tibial plateau leveling osteotomy on patellar tendon angle: a radiographic cadaveric study. Vet Surg 2010;39:428–424. Gambardella PC, Wallace LJ, Cassidy F. Lateral suture technique for management of anterior cruciate ligament rupture in dogs: a retrospective study. J Am Anim Hosp Assoc 1981;17:33–38. Haynes KH, Biskup J, Freeman A, et al. Effect of tibial plateau angle on cranial cruciate ligament strain: an ex vivo study in the dog. Vet Surg 2015;44:46–49. Hulse D, Beale B, Kerwin S. Second look arthroscopic findings after tibial plateau leveling osteotomy. Vet Surg 2010;39:350–354. VetBooks.ir Biomechanics of the Cranial Cruciate Ligament-Deficient Stifle Treated by Tibial Osteotomies Jones SC, Kim SE, Banks SA, et al. Accuracy of noninvasive, single-plane fluoroscopic analysis for measurement of three-dimensional femorotibial joint poses in dogs. Am J Vet Res 2014;75:477– 485. Kim SE, Pozzi A, Kowaleski MP, et al. Tibial osteotomies for cranial cruciate ligament insufficiency in dogs. Vet Surg 2008;37:111–125. Kim SE, Pozzi A, Banks SA, et al. Effect of tibial plateau leveling osteotomy on femorotibial contact mechanics and stifle kinematics. Vet Surg 2009a;38:33–39. Kim SE, Pozzi A, Banks SA, et al. Effect of tibial tuberosity advancement on femorotibial contact mechanics and stifle kinematics. Vet Surg 2009b;38:23–32. Kim SE, Pozzi A, Banks SA, et al. Effect of cranial cruciate ligament deficiency, tibia plateau leveling osteotomy, and tibial tuberosity advancement on contact mechanics and alignment of the stifle in flexion. Vet Surg 2010;39:363–370. Kim SE, Lewis DD, Pozzi A. Effect of tibial plateau leveling osteotomy on femorotibial subluxation: in vivo analysis during standing. Vet Surg 2012;41:465–470. Kim SE, Jones SC, Lewis DD, et al. In vivo threedimensional knee kinematics during daily activities in dogs. J Orthop Res 2015;33:1603–1610. Lafaver S, Miller NA, Stubbs WP, et al. Tibial tuberosity advancement for stabilization of the canine cranial cruciate ligament-deficient stifle joint: surgical technique, early results, and complications in 101 dogs. Vet Surg 2007;36:573–586. Lazar TP, Berry CR, de Haan JJ, et al. Long-term radiographic comparison of tibial plateau leveling osteotomy versus extracapsular stabilization for cranial cruciate ligament rupture in the dog. Vet Surg 2005;34:133–141. Lee JY, Kim G, Kim JH, et al. Kinematic gait analysis of the hind limb after tibial plateau levelling osteotomy and cranial tibial wedge osteotomy in ten dogs. J Vet Med A Physiol Pathol Clin Med 2007;54:579–584. Macias C, McKee WM, May C. Caudal proximal tibial deformity and cranial cruciate ligament rupture in small-breed dogs. J Small Anim Pract 2002;43:433– 438. Montavon PM, Damur DM, Tepic S. Advancement of the tibial tuberosity for the treatment of cranial cruciate deficient canine stifle. 1st World Orthopedic Veterinary Congress; 2002; Munich, Germany, p. 152. 277 Pozzi A, Kim SE, Banks SA, et al. Ex vivo pathomechanics of the Pond-Nuki model. Proceedings of the Veterinary Orthopedic Society Scientific Meeting, Big Sky, MT, 2008. Reif U, Hulse DA, Hauptman JG. Effect of tibial plateau leveling on stability of the canine cranial cruciate-deficient stifle joint: an in vitro study. Vet Surg 2002;31:147–154. Rey J, Fischer MS, Böttcher P. Sagittal joint instability in the cranial cruciate ligament insufficient canine stifle. Caudal slippage of the femur and not cranial tibial subluxation. Tierarztl Prax Ausg K Kleintiere Heimtiere 2014;42:151–156. Sathya S, Gilbert P, Sharma A, et al. Effect of tibial plateau levelling osteotomy on patellar tendon angle: a prospective clinical study. Vet Comp Orthop Traumatol. 2014;27:346–350. Shahar R, Milgram J. Biomechanics of tibial plateau leveling of the canine cruciate-deficient stifle joint: a theoretical model. Vet Surg 2006;35:144–149. Skinner O, Kim SE, Lewis DD, et al. In vivo femorotibial subluxation during weight-bearing after tibial tuberosity advancement. Vet J 2013;196:86–91. Slocum B, Devine T. Cranial tibial thrust: a primary force in the canine stifle. J Am Vet Med Assoc 1983;183:456–459. Slocum B, Devine T. Cranial tibial wedge osteotomy: a technique for eliminating cranial tibial thrust in cranial cruciate ligament repair. J Am Vet Med Assoc 1984;184:564–569. Slocum B, Slocum TD. Tibial plateau leveling osteotomy for repair of cranial cruciate ligament rupture in the canine. Vet Clin North Am Small Anim Pract 1993;23:777–795. Tashman S, Anderst W, Kolowich P, et al. Kinematics of the ACL-deficient canine knee during gait: serial changes over two years. J Orthop Res 2004;22:931– 941. Tepic S, Damur DM, Montavon PM. Biomechanics of the stifle joint. Proceedings, 1st World Orthopedic Veterinary Congress, Munich, Germany, 2002, pp. 189–190. Tinga S, Kim SE, Banks SA, et al. In vivo 3-dimensional kinematics of cranial cruciate ligament-deficient stifles treated with tibial plateau leveling osteotomy. Veterinary Orthopedic Society, Sun Valley, ID, 4 March, 2015. Warzee CC, Dejardin LM, Arnoczky SP, et al. Effect of tibial plateau leveling on cranial and caudal tibial thrusts in canine cranial cruciate-deficient stifles: an in vitro experimental study. Vet Surg 2001;30:278–286. VetBooks.ir VetBooks.ir 33 Arthroscopic Follow-Up after Surgical Stabilization of the Stifle Brian S. Beale and Donald A. Hulse Introduction Cruciate ligament rupture (CR) is a common cause of pelvic limb lameness in dogs (Aragon & Budsberg 2005). The majority of veterinary surgeons agree that return to optimal function is best accomplished through surgical treatment. A variety of surgical techniques have been described to stabilize the cruciate-deficient stifle, including extracapsular stabilization, intraarticular cranial cruciate ligament (CrCL) reconstruction, and techniques designed to reduce the force causing cranial tibial translation (cranial tibial thrust) during weight-bearing (Warzee et al. 2001; Reif et al. 2002; Jerram & Walker 2003). Extracapsular stabilization and tibial plateau leveling osteotomy (TPLO) are the most common techniques used by veterinary surgeons to treat CR. Although deemed clinically successful in most cases, complications associated with these techniques have been described (Pacchiana et al. 2003; Priddy et al. 2003; Stauffer et al. 2006). Follow-up arthroscopic evaluation of the stifle after surgical stabilization has provided important evidence to assess outcome after surgical treatment (Whitney 2003; Rayward et al. 2004; Hulse et al. 2010). Surgical recommendations should ideally be made by applying the principles of evidence- based medicine (Aragon & Budsberg 2005). Follow-up arthroscopic evaluation of intraarticular structures is performed as an outcome measurement in experimental studies or in client-owned dogs with clinical signs after a previous surgical procedure. Follow-up arthroscopic evaluation is also occasionally used to assess outcome in patients without clinical signs. Advocates of follow-up arthroscopy in this group of patients cite the low morbidity associated with the technique, the frequent discovery of unknown pathology, and the ability to better understand the patient’s true outcome after surgery as justification. Follow-up arthroscopy is typically only performed if the patient is having clinical problems or is undergoing general anesthesia for another reason, usually another surgical procedure. A common example would be follow-up arthroscopy performed on a stifle after previous CR stabilization at the time of treatment of the contralateral stifle for CR. Evidence of changes seen within the joint can influence treatment and activity recommendations for the patient. In addition, simultaneous implant removal can be performed, eliminating the potential necessity for implant removal in the future. Follow-up arthroscopy of the stifle has been used most commonly to assess TPLO patients, Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 279 Surgical Treatment VetBooks.ir 280 CaCL CaCL CaCL CrCL *** (A) CrCL CrCL (B) (C) Figure 33.1 (A) The insertion of the craniomedial band is torn (∗∗∗ ) in this dog with a partial tear of the cranial cruciate ligament (CrCL). This patient has a normal amount of cranial tibial translation. The caudal cruciate ligament (CaCL) is also visible. (B) The torn fibers of the ligament have been carefully debrided before performing a tibial plateau leveling osteotomy. The intact fibers of the CrCL were probed and found to have normal integrity and were left intact. (C) The CrCL appears healthy and functional at a follow-up arthroscopic examination of the same patient 2 years later. but its use has also provided valuable information in patients undergoing extracapsular or intra-articular CR stabilization and treatment of OCD of the femoral condyle. Follow-up arthroscopic examination after TPLO Follow-up arthroscopic examination of the stifle is performed using standard arthroscopic techniques (Beale et al. 2003). Typically, the same portals are used as the initial arthroscopy. Exploration of the intra-articular structures is performed, starting in the proximal aspect of the joint with the stifle held in an extended position. Periarticular osteophytes, cartilage integrity and synovial membrane appearance are evaluated. The intercondylar notch region is evaluated with the stifle positioned in flexion. The CrCL and caudal cruciate ligament (CaCL) are assessed for fiber damage, inflammation, remodeling, and vascular proliferation. The menisci are carefully observed and probed for the presence of fiber rupture or wear. A Hohmann retractor can be inserted into the joint just lateral to the proximal aspect of the patellar tendon through an accessory instrument portal to separate the joint surfaces and improve the view and access to the menisci. Alternatively, a stifle distractor can be used to improve examination (see also Chapter 23). Bucket- handle tears of the medial meniscus are the most common type of meniscal tear seen, and are typically treated by partial meniscectomy. Radial tears are also common and are treated by partial meniscectomy at the discretion of the surgeon. Large radial tears are generally treated, while small radial tears and small frays are left untreated. Small frays of the axial border of the lateral meniscus are common in normal dogs without clinical signs. Small frays may increase the susceptibility to larger radial tears in the future in stifles experiencing instability. A medial meniscal release (MR) can also be performed if deemed necessary by the surgeon. Follow-up arthroscopy was found to be valuable in assessing patients treated with TPLO (Hulse et al. 2010). Hulse et al. (2010) used a second-look arthroscopic examination to evaluate dogs with CrCL fiber rupture of varying degrees after TPLO. Intra-articular structures appeared normal or near-normal at long-term follow-up after a TPLO procedure in early partial tears of the CrCL (Hulse et al. 2010). The CrCL did not continue to rupture after the plateau was leveled to approximately 6◦ (Figure 33.1). The blocking of CrCL fiber tearing may be a consequence of decreased loading of the CrCL after rotation of the tibial plateau (Warzee et al. 2001; Reif et al. 2002; Wolf et al. 2008; Haynes et al. 2015; Barger et al. 2016). When the tibial plateau is rotated to approximately 6◦ relative to the weight-bearing VetBooks.ir Arthroscopic Follow-Up after Surgical Stabilization of the Stifle the longest interval from initial surgery to second-look arthroscopy in this group of dogs. Conversely, the majority of dogs with a partial tear with an incompetent remaining CrCL and cranial drawer or a completely ruptured CrCL ligament had significant intra-articular changes. Of interest were articular cartilage lesions involving the medial or lateral femoral condyle or tibial plateau (Figure 33.3). Lesions included chondromalacia, fibrillation, and erosion (Figure 33.4). The lesions may arise from abnormal joint contact mechanics or increased contact with cranial soft tissue after rotation of the tibial plateau to eliminate cranial tibial thrust. Some 85% of the stifles in this group (39/46) had visible cartilage lesions, with the majority (28/39 stifles) having Grade 3 or Grade 4 lesions (see Beale et al. 2003 for grading system). Cartilage lesions appeared in the medial femoral condyle (13 joints), lateral femoral condyle (12 joints), and tibial plateau (three joints) (Figure 33.5). Abaxial non-articular cartilage abrasion was most common, but axial lesions of the weight-bearing surface were also noted (Figures 33.6 and 33.7). In most dogs, mild fraying of the CaCL was noted; in three dogs there was complete rupture of the CaCL. In one of these three dogs there was over-rotation of the tibial plateau at revision surgery (initial postoperative slope 6◦ ; postoperative slope after revision 0◦ ); in the other two dogs the tibial plateau was rotated to 7◦ in one case and to 10◦ in the other case. The history and acute nature of lameness in the latter two dogs was suggestive of a traumatic episode. Eight dogs developed a bucket-handle tear in the caudal horn of the medial meniscus (postliminary meniscal MFC MM CrCL Figure 33.2 The cartilage of the medial femoral condyle (MFC) and tibial plateau and the medial meniscus (MM) appear healthy in dogs with early partial tears of the CrCL at follow-up arthroscopy. axis, cranial tibial thrust is transformed to a caudal tibial thrust (Warzee et al. 2001; Reif et al. 2002). Eliminating cranial tibial thrust would likely lower strain within the CrCL, reducing the possibility of further fiber tearing. This supports other clinical work which suggests that TPLO has a protective effect on the CrCL in dogs having an early partial CR (Wolf et al. 2008). As such, the authors do not recommend the debridement of intact functional CrCL fibers due to good functional outcome and the potential protective effect on the menisci and cartilage. The articular cartilage of the femur and tibia, the medial and lateral menisci, and synovial joint capsule all appeared normal in all joints in this group of dogs (Figure 33.2). These observations were true at 4 years after surgery, Figure 33.3 (A) The cartilage of the medial femoral condyle (MFC) and tibial plateau (TP) and the medial meniscus (MM) appear normal at the time of tibial plateau leveling osteotomy in this patient with an unstable partial CrCL tear. (B) The cartilage of the MFC and TP has fibrillation at the time of follow-up arthroscopy in this patient 12 months later. The medial meniscus also has small radial tears. MFC MFC MM TP MM TP (A) 281 (B) VetBooks.ir 282 Surgical Treatment MFC MFC MM TP MM TP *** (A) (B) LFC LFC LM LM TP *** (C) TP (D) *** femur lateral central abrasion Figure 33.5 Abrasion of the cartilage (∗∗∗ ) of the central weight-bearing region of the lateral femoral condyle can be seen in this tibial plateau leveling osteotomy patient 28 months after surgery. MFC MFC JC (A) *** *** abaxial medial condyle abrasion cranial capsule (B) Figure 33.4 (A) The cartilage of the medial femoral condyle (MFC) and tibial plateau (TP) appears healthy in this patient with a complete CrCL tear. Small radial tears of the medial meniscus (MM) are present in this patient treated with a tibial plateau leveling osteotomy. (B) The majority of the cartilage of the medial compartment continues to appear healthy in this patient 18 months later. A focal area of fibrillation is seen at the cranial aspect of the tibial plateau (∗∗∗ ). Small radial tears of the medial meniscus have progressed slightly. (C) The cartilage of the lateral femoral condyle (LFC) and tibial plateau (TP) appears healthy in this patient with a complete CrCL tear. Lateral meniscus (LM). (D) The majority of the cartilage of the lateral compartment continues to appear healthy in this patient at follow-up arthroscopy. A focal area of fibrillation is seen at the caudal aspect of the tibial plateau (∗∗∗ ). tear). Commonly, the only clinical finding was the onset of decreased limb function. Without specific intra-articular inspection, clinical findings in these cases may be mistakenly diagnosed with overuse injury or progression of osteoarthritis. Arthur et al. (2005) evaluated the synovium, CrCL, CaCL, medial meniscus, lateral meniscus, femoral trochlea, femoral condyles and tibial plateau using follow-up arthroscopy in 40 dogs (45 stifles) previously treated with TPLO. Pathologic changes were identified at the time of initial surgery and followed over time. Radiographic evidence of periarticular osteophytes was unchanged or only minimally increased at the time of follow-up in 36 stifles, and markedly increased in nine stifles. Figure 33.6 (A,B) Abrasion of the cartilage (∗∗∗ ) of the abaxial non weight-bearing region of the medial femoral condyle (MFC) adjacent to the cranial joint capsule (JC) can be seen in these tibial plateau leveling osteotomy patients at long-term follow-up arthroscopy. The joint capsule is thickened and has increased stiffness in both patients. VetBooks.ir Arthroscopic Follow-Up after Surgical Stabilization of the Stifle similar meniscal tears left untreated. The treatment of small radial tears of the lateral meniscus with radiofrequency partial meniscectomy was associated with a greater frequency of progressive cartilage wear compared to no treatment of the meniscus. Cartilage wear was evident arthroscopically in eight stifles without radiographic evidence of increased osteoarthritis. Synovitis was unchanged in 15, increased in two, and decreased in 18 stifles. Medial and lateral meniscal tears were present at follow-up in 16 and eight stifles, with increased cartilage wear in eight stifles (Figures 33.8 and 33.9). Sites of partial meniscectomies at initial arthroscopy were intact and unchanged in 12 cases, while further meniscal tearing had developed in six cases. The CaCL was initially intact in all stifles. However, lesions such as hyperemia and mild fraying were seen at this time in 13 stifles and progressed in nine cases (Figure 33.10). With the exception of one case of complete rupture, lesions at follow-up were limited to mild increases in fraying, stretching, and hyperemia (Figures 33.11–33.13). In 10 dogs, gross lesions such as fraying, remodeling, or hyperemia of the CaCL developed subsequent to a grossly normal appearance at the time of TPLO. LFC *** JC lateral femoral condyle grade 5 lesion Figure 33.7 Abrasion of the cartilage (∗∗∗ ) of the abaxial non weight-bearing region of the lateral femoral condyle (LFC) adjacent to the cranial joint capsule (JC) can be seen in this tibial plateau leveling osteotomy patient at follow-up arthroscopy. Progression of osteophytes was evident arthroscopically in 25% of stifles at follow-up. Cartilage wear was unchanged in 15 stifles and increased in 20 stifles. Stifles with small radial tears of the lateral meniscus treated by radiofrequency partial meniscectomy had increased cartilage wear in 67% of treated joints. Increased cartilage wear was evident in 50% of stifles with MFC MFC Figure 33.8 (A) The medial femoral condyle (MFC), tibial plateau (TP) and medial meniscus (MM) appear normal at the time of tibial plateau leveling osteotomy. (B) The MFC and TP appear normal, but the cranial horn of the medial meniscus has mild radial tears at follow-up arthroscopic examination (∗∗∗ ). MM MM TP TP (A) *** (B) medial condyle Figure 33.9 (A) The medial meniscus of this patient with a complete CrCL tear has a latent bucket-handle meniscal tear at follow-up arthroscopy. (B) The meniscal tear is not visible until probed. ********** probe medial meniscus (A) 283 Hohmann retraction bucket-handle tear (B) Surgical Treatment VetBooks.ir 284 CaCL CaCL *** *** (A) Figure 33.10 (A) The caudal cruciate ligament (CaCL) shows mild wear (∗∗∗ ) before tibial plateau leveling osteotomy and mild progression of wear at 20 months after surgery (B). (B) after TPLO (Figure 33.15). Synovitis was generally decreased at follow-up examination (Figure 33.16). Cases in which gross changes in the appearance of the CaCL were present lend credence to the potentially detrimental increases in caudal translation after TPLO. Small radial tears of the lateral meniscus may not require treatment, and the use of radiofrequency for partial meniscectomy should be used judiciously. Canine meniscal injuries are often found in conjunction with CR or after surgical stabilization of the CrCL-deficient stifle. Meniscal tears may be displaced and easily identified. Others Important findings in the study included the observation that arthroscopic evaluation of the stifle allowed a diagnosis of joint disease not evident radiographically. The CrCL remained intact when early partial tears were treated with TPLO in patients having no palpable instability. Partial tears of the CrCL having instability at the time of TPLO typically remained intact at follow-up, but the ligament remained stretched (Figure 33.14). Arthroscopic and radiographic evidence of increased osteophyte formation indicates the potential for progressive osteoarthritis in some cases CaCL (A) CaCL (B) CaCL CaCL *** *** (A) Figure 33.11 (A) The caudal cruciate ligament (CaCL) appears normal before tibial plateau leveling osteotomy (TPLO), and normal at 22 months after TPLO (B). (B) Figure 33.12 (A) The caudal cruciate ligament (CaCL) appears inflamed with loss of detail (∗∗∗ ) at the time of tibial plateau leveling osteotomy. Normal longitudinal fibers of the CaCL can be seen at the femoral attachment of the ligament. (B) The CaCL appears to have progressive inflammation and loss of fiber detail (∗∗∗ ) 11 months after surgery. No normal-appearing CaCL fibers are visible. VetBooks.ir Arthroscopic Follow-Up after Surgical Stabilization of the Stifle CaCL *** CrCL Figure 33.13 The caudal cruciate ligament (CaCL) has substantial tearing (∗∗∗ ) in this patient with an incompetent cranial cruciate ligament (CrCL) tear treated with a tibial plateau leveling osteotomy. This is an uncommon finding at follow-up arthroscopic examination. may be latent and require careful palpation with a probe to identify. Meniscal tears that occur subsequent to treatment of CR are termed postlimimary tears. Follow-up arthroscopy has CrCL Figure 33.14 Appearance of an incompetent partial cranial cruciate ligament (CrCL) 2 years after tibial plateau leveling osteotomy (TPLO) surgery. Instability of the stifle was present due to stretching of the CrCL before TPLO. The ligament continues to have mild laxity, but inflammation has subsided and no further damage to the ligament is seen after TPLO. The TPLO procedure appears to have protected the CrCL from progressive damage. 285 provided valuable information towards the understanding of the impact of progressive cruciate ligament fiber rupture and its treatment on the menisci over time. MR at the time of stabilization of the CrCL-deficient stifle has been recommended to prevent further injury to the caudal pole of the medial meniscus after TPLO. Conversely, MR may result in joint instability and impairment of load transmission, which may accelerate the progression of osteoarthritis (Pozzi et al. 2008). Meniscectomy, which has similar mechanical results as MR on the stifle, leads to osteoarthritis in both humans and animals. Kim et al. (2009) suggested that the risk of postliminary meniscal injury is smaller after TPLO due to the neutralization of cranial tibial thrust, and thus the need for MR is controversial. In addition, Luther et al. (2009) reported that MR alone in CrCL-intact stifles was associated with articular cartilage loss and further meniscal pathology. These studies would tend to suggest that MR is contraindicated at the time of surgical stabilization of a CR stifle. These findings, however, are based on in vitro or ex vivo studies or in dogs that had intact CrCL. Aman & Beale (2009) used follow-up arthroscopy to assess clinical patients with CR. This study compared CrCL-deficient stifles of dogs having undergone TPLO with MR to dogs having undergone TPLO with no MR. Follow-up arthroscopy was used to assess the stifles at long-term follow-up. The findings of this study suggested that there may not be a significant difference in the progression of osteoarthritis between dogs receiving TPLO with MR and dogs receiving TPLO without MR. The group found a risk of postliminary meniscal injury with or without MR, but severe meniscal injury was much more likely without MR. A higher incidence of bucket-handle tears was seen in dogs not receiving a MR. Small radial tears were the predominant type of tear seen if MR was performed. Meniscal tears were more common in the dogs having MR at the meniscotibial ligament as compared to a midbody incision. MR at the meniscotibial ligament or mid-body appeared to remain functional in all dogs having the procedure performed. The meniscotibial ligament did not appear to reattach. The mid-body MR incisions appeared to heal with great variation (Figure 33.17). Some of the mid-body MR incisions healed with a Surgical Treatment VetBooks.ir 286 MFC JC JC MFC *** *** (A) (B) (A) Figure 33.15 (A) Periosteal osteophytes typically remain the same size or become slightly larger over time after tibial plateau leveling osteotomy (TPLO). This patient with a complete CrCL tear had mild osteophyte formation (∗∗∗ ) in the medial gutter at the time of TPLO. (B) The osteophytes increased a little in size over 34 months. Joint capsule (JC), medial femoral condyle (MFC). Figure 33.16 Some degree of synovitis was typically seen at follow-up arthroscopy in patients after tibial plateau leveling osteotomy. These patients had mild (A) and moderate (B) synovitis, although both patients were subclinical. (B) MFC MFC MFC *** MR TP *** TP TP (A) (B) (C) MFC *** MFC TP *** TP (D) (E) Figure 33.17 (A) A mid-body medial meniscal release (MR) is performed under arthroscopic observation. Follow-up arthroscopic evaluation revealed inconsistent findings at the MR incision site. (B,C) The site of MR healed (∗∗∗ ) with a smooth axial border in most patients. (D) The gap at the MR incision filled with irregular fibrous tissue (∗∗∗ ) or showed no signs of healing in other patients (∗∗∗ ) (E). Interestingly, minimal signs of cartilage wear of the medial femoral condyle (MFC) and tibial plateau (TP) were seen. The MR appears to remain functional despite variation in healing patterns. Evidence of continued function of the MR includes the caudal position of the medial meniscus and the dramatic reduction in prevalence of postliminary meniscal tears. VetBooks.ir Arthroscopic Follow-Up after Surgical Stabilization of the Stifle 287 lateral femoral condyle femur lateral femoral condyle normal lateral meniscus (A) lateral meniscus (B) lateral meniscus (C) Figure 33.18 The cartilage of the femoral condyle and tibial plateau had an inconsistent appearance at the time of follow-up arthroscopic examination after extracapsular stabilization amongst patients with cruciate ligament rupture. The cartilage appeared to be normal (A), have mild wear (B), or have moderate wear (C). smooth axial border, others healed with irregular fibrous tissue, and some showed no healing response. The MR appears to remain functional despite variation in healing patterns. Evidence of continued function of the MR includes the caudal position of the medial meniscus and a dramatic reduction in the prevalence of postliminary meniscal tears. The caudal horn of the medial meniscus appeared to sit in a more caudal position, and the meniscus did not appear to shift forward during a tibial compression test or cranial drawer test while viewing the meniscus arthroscopically. Follow-up arthroscopic examination after extracapsular stabilization Follow-up arthroscopy has also been used to assess the stifle joint after extracapsular stabilization of the CrCL-deficient stifle. Most of the dogs examined in this group had undergone complete debridement of the CrCL at the Figure 33.19 Some patients show severe cartilage damage at follow-up evaluation after extracapsular stabilization. Erosion of the lateral femoral condyle (∗∗∗ ) in the region opposite the lateral tibial eminence is seen in this patient (A). This lesion is thought to occur due to excessive shear force. Full-thickness erosion (∗∗∗ ) of weight-bearing regions of the medial femoral condyle are occasionally seen (B). time of stabilization. Periarticular osteophytes typically enlarge over time. Mild to moderate synovitis is seen. Cartilage erosion is variable (Figure 33.18). Some dogs show progressive cartilage erosion of the medial and lateral compartment (Figure 33.19). Erosion primarily involves the articular cartilage of the weightbearing regions of the medial and lateral femoral condyle and tibial plateau. Cartilage damage is often more severe in the lateral compartment. Increased cartilage damage in the lateral compartment may be secondary to increased forces generated by the placement of a lateral extracapsular suture. Cartilage erosion does not appear to commonly involve non weight-bearing regions, unlike that seen after TPLO. Some dogs show very little evidence of articular cartilage damage. Meniscal tears are also common at the time of follow-up arthroscopic examination in this group of patients (Figure 33.20). Interestingly, many dogs identified as having bucket-handle tears of the medial meniscus were not observed to have significant lameness by the owners. However, physical femur *** **** shear lesion Grade 4 cartilage lesion medial femoral condyle tibial spine (A) (B) Surgical Treatment VetBooks.ir 288 medial femoral condyle ************* 2nd tear in meniscus torn medial meniscus (A) (B) Figure 33.20 Bucket-handle tears of the medial meniscus were commonly seen at follow-up arthroscopic examination of patients treated with extracapsular stabilization of cranial cruciate ligament tears in dogs with clinical signs, and in dogs thought to be without clinical signs. (A) Some meniscal tears were displaced and easily identified. Other bucket-handle tears were latent and identified only after careful probing. This patient had two bucket-handle tears of the medial meniscus. The first tear was displaced and easily identified. Partial menisectomy was performed. The second bucket-handle tear was latent and was identified after carefully probing the medial meniscus after removal of the first tear (B). examination tended to show a stiff pelvic limb gait, a reluctance to sit square, or a slight click when flexing the stifle. It appears that some dogs are quite effective in minimizing the clinical signs of pain associated with a meniscal tear. Medial patellar luxation has also been observed at the time of follow-up arthroscopic examination after extracapsular stabilization. Arthroscopic evaluation of infected joints secondary to an infected extracapsular suture provides valuable information regarding the intensity of the synovitis and the degree of cartilage damage. a high rate of failure. Follow-up arthroscopy has found ruptured ligament fibers leading to stretching, partial tear, or complete tear of the prosthetic ligament. Biological replacement ligaments have also been found to experience fiber tearing at follow-up arthroscopic examination. Fibers of the ligament are often stretched, or the ligament may have a partial or complete tear. A minority of patients have a healthy-appearing replacement ligament (Figure 33.21). Meniscal tears are also common at the time of followup arthroscopic examination in this group of patients. Intra-articular repairs are most Follow-up arthroscopic examination after intra-articular stabilization Follow-up arthroscopy after intra-articular stabilization has revealed similar findings to extracapsular stabilization. Periarticular osteophytes typically enlarge over time. Mild to moderate synovitis is seen, and cartilage erosion is variable. Some dogs show progressive cartilage erosion of the medial and lateral compartment. Erosion is seen to involve the articular cartilage of the weight-bearing regions of the medial and lateral femoral condyle and tibial plateau. On the other hand, some dogs show very little change in the appearance of the articular cartilage. Intra-articular stabilization techniques may be performed using a prosthetic or a biological ligament replacement. Prosthetic ligament replacements have CaCL CrCL graft Figure 33.21 The fascial lata graft appears healthy and functional at follow-up arthroscopic examination in this patient treated with intra-articular stabilization after cruciate ligament rupture. Caudal cruciate ligament (CaCL), cranial cruciate ligament (CrCL). VetBooks.ir Arthroscopic Follow-Up after Surgical Stabilization of the Stifle commonly performed in medium- and largebreed dogs; this group of dogs typically has persistent or intermittent lameness, and often will have a meniscal click if a bucket-handle tear of the medial meniscus is present. Conclusions Follow-up arthroscopy has provided muchneeded evidence of outcome after cruciate stabilization surgery. Follow-up arthroscopy was associated with minimal morbidity. Many changes in the intra-articular environment of the stifle have been identified, including meniscal tears, CaCL fiber wear, chronic synovitis, cartilage wear, and osteophyte formation. Many of the pathological changes were evident in dogs that were thought to be without clinical signs. Many of the arthroscopic findings are not easily assessed by imaging techniques. Followup arthroscopy is an excellent method of assessing the intra-articular condition of the canine stifle joint months to years after stifle surgery. References Aman A, Beale BS. Follow-up arthroscopic evaluation of canine stifles having undergone tibial plateau leveling osteotomy with and without meniscal release. Proceedings of the 36th Annual Conference Veterinary Orthopedic Society, 2009, p. 21. Aragon CL, Budsberg SC. Applications of evidencebased medicine: Cranial cruciate ligament injury repair in the dog. Vet Surg 2005;34:93–98. Arthur EG, Beale BS, Whitney WO. Second-look arthroscopic evaluation of the canine stifle following tibial plateau osteotomy. Proceedings of the 32nd Annual Conference Veterinary Orthopedic Society, 2005, p. 45. Barger B, Piazza A, Muir P. Treatment of stable partial cruciate rupture (Grade I sprain) in five dogs with tibial plateau levelling osteotomy. Vet Rec Case Rep 2016;4:e000315. Beale BS Hulse DA, Schulz KS, et al. Small Animal Arthroscopy. Philadelphia, WB Saunders, 2003. Haynes KH, Biskup J, Freeman A, et al. Effect of tibial plateau angle on cranial cruciate ligament strain: An ex vivo study in the dog. Vet Surg 2015;44:46–49. 289 Hulse DA, Beale BS, Kerwin S. Second look arthroscopic findings after tibial plateau leveling osteotomy. Vet Surg 2010;39:350–354. Jerram RM, Walker AM. Cranial cruciate ligament injury in the dog: pathophysiology, diagnosis and treatment. N Z Vet J 2003;51:149–158. Kim S, Pozzi A, Banks SA, et al. Effect of tibial plateau leveling osteotomy on femorotibial contact mechanics and stifle kinematics. Vet Surg 2009;38:23–32. Luther JK, Cook CR, Cook JL. Meniscal release in cruciate ligament intact stifles causes lameness and medial compartment cartilage pathology in dogs 12 weeks postoperatively. Vet Surg 2009;38:520– 529. Pacchiana PD, Morris E, Gillings SL, et al. Surgical and postoperative complications associated with tibial plateau leveling osteotomy in dogs with cranial cruciate ligament rupture: 397 cases (1998–2001). J Am Vet Med Assoc 2003;222:184–193. Pozzi A, Litsky AS, Field J, et al. Pressure distributions on the medial tibial plateau after medial meniscal surgery and tibial plateau levelling osteotomy in dogs. Vet Comp Orthop Traumatol 2008;21:8–14. Priddy NH, Tomlinson JL, Dodam JR, et al. Complications with and owner assessment of the outcome of tibial plateau leveling osteotomy for treatment of cranial cruciate ligament rupture in dogs: 193 cases (1997–2001). J Am Vet Med Assoc 2003;222:1726– 1732. Rayward RM, Thomson DG, Davies JV, et al. Progression of osteoarthritis following TPLO surgery: a prospective radiographic study of 40 dogs. J Small Anim Pract 2004;45:92–97. Reif U, Hulse DA, Hauptman JG. Effect of leveling on stability of the canine cranial cruciate-deficient stifle joint: an in vitro study. Vet Surg 2002;31:147–154. Stauffer K, Tuttle T, Elkins D. Complications associated with 696 tibial plateau leveling osteotomies (2001–2003). J Am Anim Hosp Assoc 2006;42:44–50. Warzee CC, Dejardin LM, Arnoczky SP, et al. Effect of tibial plateau leveling on cranial and caudal tibial thrusts in canine cranial cruciate-deficient stifles: an in vitro experimental study. Vet Surg 2001;30:278–286. Whitney WO. Arthroscopically assisted surgery of the stifle joint. In: Small Animal Arthroscopy, Beale BS, Hulse DA, Schulz KS, Whitney WO, eds. Philadelphia, WB Saunders, 2003. Wolf R, Beale BS, Whitney WO. Effect of debridement of the cranial cruciate ligament in dogs having early partial tears of the cranial cruciate ligament at the time of TPLO. Vet Surg 2008;37:E2. VetBooks.ir VetBooks.ir 34 Cranial Cruciate Ligament Debridement David E. Spreng Introduction Historically, total debridement of the torn ends of the cranial cruciate ligament (CrCL) was considered necessary to decrease inflammatory responses during the postoperative period. Some investigators also advocated that partially ruptured ligaments should be completely removed, again to decrease postoperative inflammation. Meanwhile, current information published on the function of the CrCL has led to new developments in the approach to ligament debridement. The CrCL has a primarily mechanical function. It is the main restraint mechanism for cranial tibial translation throughout complete stifle range of motion. It is also responsible for limitation of the internal rotation of the tibia (Vasseur 2002). Most surgeons consider ligaments only to be passive stabilizers of the joint. However, there is good evidence that the CrCL plays an important role in proprioception and neuromuscular function, and it has been shown that the residual portion of the CrCL maintains its blood flow (Bray et al. 2002), providing potential support for the healing process after joint stabilization. Mechanoreceptors within the CrCL might be responsible for signaling muscle stiffness of the pelvic limb and contribute to the proprioceptive function of the stifle (Adachi et al. 2002). Many human patients who have had an injury of the lower extremity describe vague symptoms such as unsteadiness (giving-way) of the joint (Noyes et al. 1989). It seems likely that at least some aspects of these symptoms are related to mechanoreceptors. However, this is difficult to document due to the lack of sufficiently sensitive, yet measurable, parameters. A tear or removal of the anterior cruciate ligament (ACL) in humans has been associated with neuromuscular changes such as loss of proprioception, alterations in muscle reflexes initiated by the ligament, alterations in muscle stiffness, deficits in quadriceps strength and changes in gait and electromyographic measurements (DeFranco & Bach 2009). It is not clear whether these changes are caused by the loss of mechanoreceptors in the ruptured ligament or by an altered stimulation of the remaining receptors in other articular tissue such as the joint capsule. Mechanoreceptors have been identified within the canine CrCL. The receptors are pressure-sensitive corpuscles and include Ruffini and Pacini receptors, as well as free nerve endings which are responsible for pain perception and autonomic nervous system regulation of blood flow (Cole et al. 1996). Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 291 VetBooks.ir 292 Surgical Treatment Considering the innervation of the entire stifle, the receptors in the CrCL constitute only a small minority. It seems, however, that the canine CrCL has more mechanoreceptors than other species. According to Arcand et al. (2000), more than 450 receptors could be identified in the canine CrCL compared to very few receptors in humans (<20) (Hogervost & Brand 1998) and cats (<50) (Madey et al. 1997). The comparison should be interpreted with caution due to different study designs and detection techniques. It is, however, an interesting observation, as cats and humans produce less severe osteoarthritis after CrCL rupture compared to dogs. Free nerve endings are mainly nociceptors, which react to inflammation and pain stimuli (Cole et al. 1996). Vasoactive neuropeptides, such as substance P, have been reported in free nerve endings and are thought to behave as vasoactive substances. Free nerve endings do, therefore, not only transfer information but also have effector functions such as vasodilation, vascular permeability, and effects on the immune system (Hogervost & Brand 1998). In considering this information, and the fact that the CrCL helps to maintain joint stability and is beneficial in preventing meniscal tears, it seems that total debridement of the partially ruptured CrCL should be used cautiously. Since the introduction of arthroscopy, diagnosis and surgical treatment of cruciate ligament rupture has been performed much earlier during the disease process. Early detection of anatomic partial ruptures of the CrCL has consequently increased. This is documented by the fact that before the introduction of arthroscopy in CR treatment an incidence of 8% of partially ruptured CrCL diagnosed during surgery was reported during the 1990s (Scavelli et al. 1990) compared to 21% in 2000 (Ralphs & Whitney 2002) and 41% observed during a period in which arthroscopy has become a routine procedure (Gatineau et al. 2011). With this evolution in mind, it has become very important to assess the different possibilities of CrCL debridement. Intraoperative decisions of how much to debride can be very difficult. Accurate visual grading of the percentage of torn CrCL is difficult because ligament tissue that appears to be intact may mask a substantial injury. Plastic deformation is possible and leads to a lax nonfunctional ligament. Electrothermal shrinkage of collagen fibers of a lax ligament is potentially possible, and has been used in the treatment of lax ACLs in humans (Lamar et al. 2005). After initial promising results, however, a multicenter study showed a high failure rate for thermal shrinkage, with the conclusion that this was not an appropriate treatment (Smith et al. 2008). Ligament debridement for complete CrCL rupture It is well known that ruptured cruciate ligaments do not heal spontaneously (Hefti et al. 1991), and mechanoreceptors probably do not regenerate and have a questionable function without physiologic tension (Hogervost & Brand 1998). Further, some believe that remnants of the ligament might be an inflammatory trigger and increase osteoarthritis. Experimentally, it has been shown that CrCL remnants disappear 3 months after CrCL transection in rabbits (Hefti et al. 1991). In canine clinical and experimental cases, resorption of the torn ligament is also possible. However, in contrast nodular, vascularized swellings (Figure 34.1A,B) or drumstick formations of the free (A) (B) Figure 34.1 Macroscopic view of two canine stifle joints after experimental cranial cruciate ligament (CrCL) transection 12 months earlier. Note the marked cartilage degeneration, meniscal damage and (A) CrCL resorption versus (B) CrCL vascularized proliferation. 293 VetBooks.ir Cranial Cruciate Ligament Debridement Figure 34.2 Arthroscopic view of a chronic partially ruptured cranial cruciate ligament with visible torn fibers. Note the formation of a ‘drumstick’ proliferation of the ruptured fibers. ends of the torn ligament (Figure 34.2) are also often present and might disturb normal motion. Therefore, the debridement of totally ruptured ligaments is still an appropriate and indicated therapy that is usually performed before meniscal inspection, using a motorized shaver during arthroscopy. Advances in human primary ACL repair, including stabilization of the repaired ligament with an internal dynamic femur to tibia suture, is likely to be protective and may allow healing (Kohl et al. 2013). The provision of a suitable biological environment by the addition of collagen matrix-embedded stem cells or platelet-rich plasma (PRP) to a primary repair (Joshi et al. 2009), in combination with an internal stabilizing implant, are possible future directions that will change the debridement discussion in complete CrCL rupture. Ligament debridement for partial CrCL rupture The debridement of torn fibers in partially ruptured CrCL is indicated (Figure 34.2). Shortterm negative consequences of partial debridement compared to total debridement could not be demonstrated (Wolf et al. 2008). Especially with small partial tears, it is indicated to debride visibly torn fibers using a motorized shaver (Figure 34.3). A radiofrequency energy probe can be used if shaver debridement is not satisfactory. Application using the lowest possible Figure 34.3 Arthroscopic view of a partially ruptured cranial cruciate ligament during debridement of torn fibers with a motorized shaver using a 2.0 mm full radius resector blade. The blade is positioned with the back of the shaver lying against the intact ligament part to protect viable intact fibers. energy and an appropriate application velocity is advised to reduce the risk of thermal injury in the remaining tissue (Lu et al. 2007). During debridement of the partially ruptured CrCL it is important to save the fat pad as much as possible, as this is one of the major origins of the vascular supply of the CrCL (Kobayashi et al. 2006). Dogs with partial cruciate ligament rupture have a lesser incidence of meniscal injury compared to dogs with complete rupture (Ralphs & Whitney 2002). One reason for this could be that the remaining ligament inhibits tibial translation to a certain degree, which in turn decreases the risk of meniscal injury. Clinical observations have shown that surgical interventions which dynamically stabilize the stifle joint have an influence on the remnants of the ligament (Eggli et al. 2015). Dogs with palpably stable stifle joints that have an arthroscopically diagnosed partial CrCL rupture seem to benefit from the debridement of visible torn fibers, followed by a dynamic stabilization procedure such as tibial plateau leveling osteotomy (TPLO). Subsequent meniscal injuries seem to be uncommon in this patient group, supporting the theory that CrCL remnants maintain a better stability of the joint. Second-look arthroscopies have shown an improved appearance of the intact part of the CrCL, most likely because the TPLO procedure reduces the strain on the CrCL (Hulse VetBooks.ir 294 Surgical Treatment et al. 2010). As with complete ruptures, there are novel interesting studies showing the potential of biological products such as PRP to promote CrCL healing (Cook et al. 2016). References Adachi N, Ochi M, Uchio Y, et al. Mechanoreceptors in the anterior cruciate ligament contribute to the joint position sense. Acta Orthop Scand 2002;73:330–334. Arcand MA, Rhalmi S, Rivard CH. Quantification of mechanoreceptors in the canine anterior cruciate ligament. Int Orthop 2000;24:272–275. Bray RC, Leonard CA, Salo PT. Vascular physiology and long-term healing of partial ligament tears. J Orthop Res 2002;20:984–989. Cole KJ, Daley BJ, Brand RA. The sensitivity of joint afferents to knee translation. Sportverletz Sportschaden 1996;10:27–31. Cook JL, Smith PA, Bozynski CC, et al. Multiple injections of leukoreduced platelet rich plasma reduce pain and functional impairment in a canine model of ACL and meniscal deficiency. J Orthop Res 2016;34:607–615. DeFranco MJ, Bach BR, Jr. A comprehensive review of partial anterior cruciate ligament tears. J Bone Joint Surg 2009;91A:198–208. Eggli S, Kohlhof H, Zumstein M, et al. Dynamic intraligamentary stabilization: novel technique for preserving the ruptured ACL. Knee Surg Sports Traumatol Arthrosc 2015;23:1215–1221. Gatineau M, Dupuis J, Planté J, et al. Retrospective study of 476 tibial plateau levelling osteotomy procedures. Rate of subsequent ‘pivot shift’, meniscal tear and other complications. Vet Comp Orthop Traumatol 2011;24:333–341. Hefti FL, Kress A, Fasel J, et al. Healing of the transected anterior cruciate ligament in the rabbit. J Bone Joint Surg 1991;73A:373–383. Hogervorst T, Brand RA. Mechanoreceptors in joint function. J Bone Joint Surg 1998;80A:1365– 1378. Hulse D, Beale B, Kerwin S. Second look arthroscopic findings after tibial plateau leveling osteotomy. Vet Surg 2010;39:350–354. Joshi SM, Mastrangelo AN, Magarian EM, et al. Collagen-platelet composite enhances biomechanical and histologic healing of the porcine anterior cruciate ligament. Am J Sports Med 2009;37:2401– 2410. Kobayashi S, Baba H, Uchida K, et al. Microvascular system of anterior cruciate ligament in dogs. J Orthop Res 2006;24:1509–1520. Kohl S, Evangelopoulos DS, Kohlhof H, et al. Anterior crucial ligament rupture: self-healing through dynamic intraligamentary stabilization technique. Knee Surg Sports Traumatol Arthrosc 2013;21:599– 605. Lamar DS, Bartolozzi AR, Freedman KB, et al. Thermal modification of partial tears of the anterior cruciate ligament. Arthroscopy 2005;21:809–814. Lu Y, Meyer ML, Bogdanske JJ, et al. The effects of radiofrequency energy probe speed and application force on chondrocyte viability. Vet Comp Orthop Traumatol 2007;20:34–37. Madey SM, Cole KJ, Brand RA. Sensory innervation of the cat knee articular capsule and cruciate ligament visualised using anterogradely transported wheat germ agglutinin-horseradish peroxidase. J Anat 1997;190:289–297. Noyes FR, Mooar LA, Moorman CT, 3rd, et al. Partial tears of the anterior cruciate ligament. Progression to complete ligament deficiency. J Bone Joint Surg 1989;71B:825–833. Ralphs SC, Whitney WO. Arthroscopic evaluation of menisci in dogs with cranial cruciate ligament injuries: 100 cases (1999–2000). J Am Vet Med Assoc 2002;221:1601–1604. Scavelli TD, Schrader SC, Matthiesen DT, et al. Partial rupture of the cranial cruciate ligament of the stifle in dogs: 25 cases (1982–1988). J Am Vet Med Assoc 1990;196:1135–1138. Smith DB, Carter TR, Johnson DH. High failure rate for electrothermal shrinkage of the lax anterior cruciate ligament: a multicenter follow-up past 2 years. Arthroscopy 2008;24:637–641. Vasseur PB. Stifle joint. In: Textbook of Small Animal Surgery, Slatter D, ed. Third edition. Philadelphia PA, WB Saunders, 2002, pp. 2090–2132. Wolf R, Beale B, Whitney W. Effect of debridement of the cranial cruciate ligament in dogs having early partial tears of the cranial cruciate ligament at the time of TPLO. Vet Surg 2008;37:E2. VetBooks.ir 35 Surgical Treatment of Concurrent Meniscal Injury Samuel P. Franklin, James L. Cook, and Antonio Pozzi Introduction Meniscal pathology in conjunction with cruciate ligament rupture (CR) is common and is recognized in up to 83% of cases (Ritzo et al. 2014). When CR is present in dogs, the caudal aspect of the medial meniscus is most predisposed to clinically important injury because the femoral condyle subluxates caudally in the unstable stifle (Rey et al. 2014). The types of injury commonly seen in dogs include longitudinal, bucket-handle, radial, horizontal, caudal peripheral and complex tears (Figure 35.1). It is imperative that meniscal problems are diagnosed and treated at the time of initial surgery in order to ensure optimal relief of pain, the debridement of abnormal tissue causing inflammation and degradation, patient recovery, and functional outcomes while minimizing morbidity and the potential need for additional surgeries. Diagnosis The preoperative diagnosis of meniscal pathology, including complete physical examination, joint palpation, and imaging, should be comprehensively pursued. These diagnostic approaches are addressed in Chapters 15, 18, 19, 20, 21, and 22. Arthroscopy with probing is reported to be the ‘gold standard’ for a definitive diagnosis of meniscal pathology because it allows for complete examination with magnification, manipulation of the tissue, is minimally invasive with low morbidity, and enables the identification of meniscal pathology more commonly than arthrotomy (Thieman et al. 2006; Pozzi et al. 2008a; Ritzo et al. 2014). Arthrotomy via medial, lateral, or caudomedial approaches with probing is recommended if arthroscopy of the stifle is not possible. Various instruments are available to aid in exposure and access for meniscal assessment and treatment for both arthroscopic and open approaches to stifle surgery. These instruments include probes, Hohmann retractors, micropicks, self-retaining retractors, and distraction devices. There is evidence that these instruments can improve observation and identification of meniscal tears, and so are highly recommended (Pozzi et al. 2008a; Winkels et al. 2016). In addition, assessment of the menisci with the joint in flexion and extension, with varus and valgus stress of the joint, and with internal and external rotation of the stifle can improve diagnostic accuracy. An accurate and comprehensive assessment of the menisci is the critical first Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 295 Surgical Treatment VetBooks.ir 296 (A) (B) (C) JC (D) (E) (F) Figure 35.1 Illustrations of longitudinal (A), bucket-handle (B), radial (C), horizontal (D), caudal peripheral (E), and complex (F) tears. JC, Joint capsule. Copyright © Samantha J. Elmhurst at www.livingart.org.uk. step in the appropriate surgical treatment of meniscal pathology in dogs. Indeed, at least two studies have demonstrated that dogs in which meniscal pathology is identified have a greater likelihood of a successful outcome than dogs in which meniscal pathology has not been identified (Ertelt & Fehr 2009; Ritzo et al. 2014). Treatment Once meniscal pathology is identified and characterized, three major treatment options can be considered, namely repair, resection, or release (radial transection). The repair of longitudinal, bucket-handle, and horizontal tears is technically feasible by open or arthroscopic placement of sutures, can restore normal contact mechanics in the stifle ex vivo, and may be indicated in selected cases (Cook & Fox 2007; Luther et al. 2007; Thieman et al. 2009; Thieman et al. 2010). However, the majority of meniscal pathology in dogs is still treated via resection or release because meniscal repair is perceived as being prone to failure in most dogs, based on both biologic and biomechanical factors. The primary biologic factors involved are: 1. The majority of tears occur in the axial (inner) 75% of the meniscus, which has no or poor inherent blood supply and low cell density. 2. The majority of dogs with CR and meniscal pathology have active osteoarthritis with associated inflammation and degradation processes at work. 3. Meniscal tears in dogs are typically chronic, with associated microstructural changes present in the tissue. The biomechanical issues center on an inability to restore normal joint kinematics to the cranial cruciate ligament (CrCL)-deficient stifle. Combined, these detriments to successful healing and restoration of function to damaged menisci suggest that careful decision-making regarding meniscal repair in dogs is needed, even when it is technically feasible to accomplish. As surgical techniques become more refined and developed to be more effective and consistent in stabilizing the CrCL-deficient stifle, the role of meniscal repair may become more pertinent. The resection of pathologic meniscal tissue is the most commonly recommended and performed treatment for meniscal injuries in dogs at this time. Partial meniscectomy, segmental meniscectomy (caudal hemimeniscectomy), and total meniscectomy are the three types of resection procedure typically used for dogs (Table 35.1). These can be accomplished arthroscopically or after arthrotomy. Scalpel blades (#11, #15, or Beaver blades), meniscal knives, and arthroscopic basket forceps, scissors, meniscal cutting tools designed specifically for meniscus removal in dogs, and shavers can be used to perform the resections. VetBooks.ir Surgical Treatment of Concurrent Meniscal Injury 297 Table 35.1 Meniscal resection procedures used in dogs. Procedure Illustration Indication Partial meniscectomy All meniscal tears that allow for a peripheral rim to be preserved Segmental meniscectomy (caudal hemimeniscectomy) Caudal meniscal tears where a functional rim cannot be preserved Total meniscectomy All meniscal tears involving more than caudal aspect and the rim cannot be preserved Note: Images have been reproduced from Johnson et al. (2004), with permission from the American Veterinary Medical Association. Partial meniscectomy is indicated for longitudinal, bucket-handle, radial, horizontal, and complex tears for which an intact rim (peripheral circumferential collagen fiber integrity) can be preserved after resection. Segmental meniscectomy is indicated for all types of tears in the caudal aspect of the meniscus when an intact rim cannot be preserved in conjunction with complete resection of pathologic tissue. Total meniscectomy is indicated for tears extending beyond the caudal aspect of the meniscus, and for which an intact rim cannot be maintained. There are several key factors to consider in order to optimize meniscal resection procedures. First, exposure and access must be achieved, such that adjacent structures (articular cartilage, ligaments, etc.) are not damaged during resection. Instrumentation specifically designed for meniscal surgery is recommended for minimizing iatrogenic damage to the articular cartilage during assessment and treatment. Two important goals must then be balanced in performing the resection: (i) remove all grossly damaged, displaced, and pathologic meniscal tissue; and (ii) preserve as much functional meniscal tissue as possible. Damaged, displaced, unstable, and pathologic meniscal tissue can cause mechanical dysfunction in the joint, direct articular cartilage damage, inflammation and degradation, and resultant pain, lameness, and progression of osteoarthritis. However, loss or removal of meniscal tissue, especially the peripheral rim, severely diminishes load-bearing, shock absorption, congruency, stability, lubrication, tissue nutrition, and the chondroprotection functions of the meniscus for the joint (see Chapter 4). Clearly, the two goals for treatment of meniscal injuries can be at odds to one another, and so careful evaluation and decision-making with judicious resection are critical to striking the optimal balance for the patient. The evaluation is based on preoperative imaging, in conjunction with a careful inspection of the entirety of the meniscus, probing and palpation of meniscal tissue and its attachments, and an assessment of the articular cartilage of the femoral condyle and tibial plateau. Healthy, functional meniscal Surgical Treatment VetBooks.ir 298 1 2 3 (A) (B) Figure 35.2 Illustrations of caudal (A) and central radial (B) transections of the medial meniscus for meniscal release in dogs. 1, Gerdy’s tubercle; 2, popliteal tendon; 3, caudal menisco-tibial ligament of the medial meniscus. The radial incision for the central release is made just behind the medial collateral ligament, with the blade aligned with Gerdy’s tubercle. Copyright © Samantha J. Elmhurst at www.livingart.org.uk. tissue should appear smooth, white, and glistening and not be readily displaced, folded, separated, or penetrated with a blunt arthroscopic probe. Abnormal meniscal tissue is typically soft, fibrillated, discolored and abnormal in location, architecture, and integrity, and is often associated with local articular cartilage damage. Taken together, these variables help to distinguish pathologic from functional meniscal tissue and guide the surgeon in determining what to resect and what to preserve. Meniscal release, or radial transection, is the other procedure commonly performed in dogs for the treatment or attempted prevention of meniscal injuries. The rationale behind meniscal release is that the surgeries performed to stabilize CrCL-deficient stifles do not consistently restore normal kinematics, and, therefore, the medial meniscus remains at risk of subsequent damage with intermittent or periodic caudal femoral subluxation (Kim et al. 2012). Accordingly, the meniscus can be released at the time of the stifle stabilization procedure, allowing it to displace caudally with the femoral condyle and prevent subsequent damage, tearing, and associated lameness. In this way, the need for additional surgery to treat post stifle-stabilization meniscal tears can be minimized. Importantly, it has been suggested that many meniscal injuries diagnosed after the initial surgery for CR may instead be tears that were present, but undetected, at the original surgery (Metelman et al. 1995; Thieman et al. 2006). This further highlights the importance of careful inspection and probing of the menisci during the first surgical procedure. Radial transection for medial meniscal release can be performed at the caudal meniscal horn– caudal meniscotibial ligament junction (caudal release), or at the mid-body of the meniscus (central release) via arthroscopy or arthrotomy using scalpel blades (#11, #15, or Beaver blades) or meniscal knives (Figure 35.2). While meniscal releases can be associated with a significantly lower risk for clinically apparent subsequent meniscal tears (Thieman et al. 2006; Ritzo et al. 2014), radial transection of the meniscus, regardless of location, completely disrupts the circumferential collagen fiber integrity (rim) and destroys critical meniscal functions (Pozzi et al. 2006; Pozzi et al. 2008b; Luther et al. 2009). The released menisci will not functionally heal and will remain biomechanically deficient (Cook et al. 2016). Meniscal release alone in CrCL-intact stifles in dogs results in articular cartilage loss, further meniscal pathology, osteoarthritis, and lameness within 12 weeks (Luther et al. 2009). In clinical patients with CR, however, clinically significant differences in outcome between groups receiving or not receiving meniscal release have not been noted based on subjective assessments (Thieman et al. 2006; Ritzo et al. 2014). As such, the present authors suggest that meniscal release can be justified when the meniscus cannot be full assessed for pathology, cannot be sufficiently resected safely, or the subsequent meniscal tear rate is unacceptably high to the surgeon or the client. VetBooks.ir Surgical Treatment of Concurrent Meniscal Injury 299 Table 35.2 Current best evidence for and against use of meniscal release in dogs. Evidence FOR meniscal release Evidence AGAINST meniscal release Significantly reduces the rate of subsequent meniscal tears (Thieman et al. 2006; Ritzo et al. 2014) Does not eliminate subsequent tears (Thieman et al. 2006) No clinically significant differences in subjective outcome (Thieman et al. 2006; Ritzo et al. 2014) Eliminates biomechanical functions of meniscus equivalent to total meniscectomy (Pozzi et al. 2006; Pozzi et al. 2008) Released menisci will not functionally heal (Luther et al. 2009; Cook et al. 2016) Release alone associated with full-thickness cartilage loss, radiographic osteoarthritis, and lameness (Luther et al. 2009) The authors suggest that the options, decisionmaking process, and ramifications associated with meniscal release should be discussed with the client during the preoperative consultation and consent to treatment (Table 35.2). Conclusion Meniscal injuries concurrent with CR in dogs are very common. As a good rule of thumb, if meniscal pathology is not recognized in at least 50% of patients with CR, it is very likely that tears are being missed. Preoperative assessment by palpation and imaging, combined with careful and meticulous intraoperative assessment with probing and palpation of meniscal tissue, are the keys to a comprehensive diagnosis of meniscal pathology. Once accurate and complete assessment has been performed, a treatment algorithm for meniscal injury concurrent with CR can be applied based on the location and severity of the pathology, the technical aspects of the various procedures, and Cruciate ligament rupture Preoperative Diagnostics (Palpation, Radiographs, Ultrasound, MRI) Surgical Assessment (Arthroscopy or Arthrotomy with Probing) Meniscal Pathology Present No Meniscal Pathology Seen Resection Damaged tissue accessible Document and leave intact Low subsequent tear rate Release Damaged tissue inaccessible Release Cannot fully assess High subsequent tear rate Client communication Repair In vascular zone Functional tissue Kinematics restored Technically feasible Client communication Figure 35.3 Algorithm for decision-making regarding the surgical treatment of meniscal injuries in dogs. VetBooks.ir 300 Surgical Treatment subsequent tear rates for the surgeries performed in the individual practice setting (Figure 35.3). Informing the client of the risks and benefits associated with the various options, and involving them in the decision-making process, is not only appropriate but is also imperative for optimal delivery of care in a patient- and client-based approach to small animal orthopaedic surgery. References Cook JL, Fox DB. A novel bioabsorbable conduit augments healing of avascular meniscal tears in a dog model. Am J Sports Med 2007;35:1877–1887. Cook JL, Smith PA, Bozynski CC, et al. Multiple injections of leukoreduced platelet rich plasma reduce pain and functional impairment in a canine model of ACL and meniscal deficiency. J Orthop Res 2016;34:607–615. Ertelt J, Fehr M. Cranial cruciate ligament repair in dogs with and without meniscal lesions treated by different minimally invasive methods. Vet Comp Orthop Traumatol 2009;22:21–26. Kim SE, Lewis DD, Pozzi A. Effect of tibial plateau leveling osteotomy on femorotibial subluxation: in vivo analysis during standing. Vet Surg 2012;41:465–470. Luther JK, Cook CR, Constantinescu IA, et al. Clinical and anatomical correlations of the canine meniscus. J Exp Med Surg Res 2007;14:5–14. Luther JK, Cook CR, Cook JL. Meniscal release in cruciate ligament intact stifles causes lameness and medial compartment cartilage pathology in dogs 12 weeks postoperatively. Vet Surg 2009;38:520– 529. Metelman LA, Schwarz PD, Salman M, et al. An evaluation of three different cranial cruciate ligament surgical stabilization procedures as they relate to postoperative meniscal injuries. Vet Comp Orthop Traumatol 1995;8:118–123. Pozzi A, Kowaleski MP, Apelt D, et al. Effect of medial meniscal release on tibial translation after tibial plateau leveling osteotomy. Vet Surg 2006;35:486– 494. Pozzi A, Hildreth BE, 3rd, Rajala-Schultz PJ. Comparison of arthroscopy and arthrotomy for diagnosis of medial meniscal pathology: an ex vivo study. Vet Surg 2008a;37:749–755. Pozzi A, Litsky AS, Field J, et al. Pressure distributions on the medial tibial plateau after medial meniscal surgery and tibial plateau levelling osteotomy in dogs. Vet Comp Orthop Traumatol 2008b;21:8– 14. Rey J, Fischer MS, Böttcher P. Sagittal joint instability in the cranial cruciate ligament insufficient canine stifle. Caudal slippage of the femur and not cranial tibial subluxation. Tierarztl Prax 2014;42:151– 156. Ritzo ME, Ritzo BA, Siddens AD, et al. Incidence and type of meniscal injury and associated longterm clinical outcomes in dogs treated surgically for cranial cruciate ligament disease. Vet Surg 2014;43:952–958. Thieman KM, Tomlinson JL, Fox DB, et al. Effect of meniscal release on rate of subsequent meniscal tears and owner-assessed outcome in dogs with cruciate disease treated with tibial plateau leveling osteotomy. Vet Surg 2006;35:705–710. Thieman KM, Pozzi A, Ling H, et al. Contact mechanics of simulated meniscal tears in cadaveric canine stifles. Vet Surg 2009;38:803–810. Thieman KM, Pozzi A, Ling H, et al. Comparison of contact mechanics of three meniscal repair techniques and partial meniscectomy in cadaveric dog stifles. Vet Surg 2010;39:355–362. Winkels P, Pozzi A, Cook R, et al. Prospective evaluation of the Leipzig stifle distractor. Vet Surg 2016;45:631–635. VetBooks.ir 36 Meniscal Release Antonio Pozzi and James L. Cook Introduction Meniscal pathology is commonly reported in conjunction with cruciate ligament rupture (CR) (Flo 1993; Williams et al. 1994; Ralphs & Whitney 2002; Luther et al. 2007), or at some point after surgical treatment of the cranial cruciate ligament (CrCL)-deficient stifle joint (Metelman et al. 1995; Thieman et al. 2006; Lafaver et al. 2007; Case et al. 2008). Chronic stifle instability resulting from CR causes supraphysiologic loading of the menisci, particularly shear and compression of the caudal pole of the medial meniscus, resulting in meniscal tears. When surgical treatments do not fully restore stifle kinematics, as is the case for the majority of surgical procedures, the menisci are still at risk after treatment. Meniscal pathology noted at the time of initial surgery is termed ‘concurrent’ or ‘coincident,’ and when diagnosed after surgery it is said to be ‘subsequent,’ ‘latent,’ or ‘postliminary.’ Concurrent meniscal pathology is recognized in between 20% and 77% of cases (Flo 1993; Williams et al. 1994; Ralphs & Whitney 2002; Mahn et al. 2005; Luther et al. 2007), while subsequent meniscal injury is recognized in between 3% and 100% of cases (Metelman et al. 1995; Slocum & Slocum 1998; Thieman et al. 2006; Lafaver et al. 2007; Case et al. 2008). It has been suggested that some cases diagnosed as subsequent meniscal tears may in fact have been concurrent tears that were misdiagnosed (latent tears). The rest of the subsequent tears that occur after CR surgery are called postliminary tears. Because subsequent tears are often associated with pain and lameness and necessitate a second surgery, veterinary surgeons have aimed for improved diagnostic approaches to meniscal disease in dogs (see Chapters 18, 19, 20, and 21) and strategies for prevention of subsequent meniscal pathology in a comprehensive approach to treatment of CR. One strategy designed to prevent subsequent meniscal injuries is release of the medial meniscus by radial transection at the caudal meniscotibial ligament of the medial meniscus (caudal release) or at the midbody of the medial meniscus. Medial meniscal release is theorized to free the caudal pole from exposure to the abnormal loads delivered during weight-bearing in the CrCL-deficient canine stifle joint (Slocum & Slocum 1998; Kennedy et al. 2005; Pozzi et al. 2006). The clinical goal of meniscal release is to eliminate any impingement of the meniscus between the femoral and tibial condyles, described as the ‘wedging phenomenon’ (see Chapter 4), and in doing so decrease the likelihood of subsequent Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 301 VetBooks.ir 302 Surgical Treatment meniscal pathology. The theoretical mechanism and clinical goal seem to be realized in general. However, the biomechanical and biological consequences are significant and the procedure is not always effective in accomplishing its objective. Therefore, the pros and cons of meniscal release should be carefully weighed in determining indications and communicating options and prognoses to clients. Effect of meniscal release on joint biomechanics and biology Medial meniscal release involves a complete radial transection of the tissue. Several studies have investigated the effects of release on meniscal function to determine if this procedure has detrimental effects on the joint (Pozzi et al. 2006; Pozzi et al. 2008; Luther et al. 2009; Pozzi et al. 2010). The complex material properties and functional anatomy of the meniscus allows it to absorb energy by undergoing constrained elongation, as a load is applied through the stifle (see Chapter 4). As the joint compresses, the wedge-shaped meniscus will normally slightly extrude peripherally as its circumferentially oriented collagen fibers elongate. Extrusion and elongation are limited by the large tensile hoop stress developed within the strong circumferential collagen fibers bundles of the menisci and their cranial and caudal attachments to tibial bone. This hoop stress is critical to normal meniscal functions and joint health. Meniscal release eliminates the ability of the meniscus to develop necessary hoop tension. Similar to a hammock that has lost its anchor points, a released meniscus ‘collapses’ and undergoes unconstrained extrusion under weight-bearing because of the lack of continuous circumferential fibers with cranial and caudal attachments (see also Chapter 4; Figure 4.4). The radial transection renders the meniscus functionally equivalent to a hemi- or a complete meniscectomy (Pozzi et al. 2008). Ex vivo studies have shown that radial transections at various locations redistribute and concentrate the weightbearing load to a small area in the caudal aspect of the femoro-tibial articulation (Figure 36.1) (Pozzi et al. 2008; Pozzi et al. 2010). As expected, complete radial transection, release, at any (A) (B) Figure 36.1 Illustration of contact pressures obtained from the Tekscan software in the tibial plateau leveling osteotomy-treated cranial cruciate ligament-deficient stifle with an intact meniscus (A) and after transection of the caudal menisco-tibial ligament (B). The caudal meniscal release resulted in a reduced area and increased pressure; the load across the medial compartment shifted completely to the caudal half of the compartment. The caudal meniscotibial ligament release and the mid-body release are equivalent because they eliminate the hoop tension and the ability of the meniscus to control the radially directed force developing from axial compression. Source: Pozzi et al. 2009. Reproduced with permission from John Wiley & Sons, Inc. point in the meniscus causes a 50% decrease in contact area and a 40% increase in magnitude of articular surface stress in the medial compartment of CrCL-deficient stifles treated with a TPLO (Pozzi et al. 2010). The contribution of the meniscus to joint stability is also crucial (Pozzi et al. 2006). By effectively deepening the tibial contact surface, the meniscus improves joint congruity and acts as a secondary stabilizer. This role of the intact meniscus is especially VetBooks.ir Meniscal Release important after surgical treatment of the CrCL-deficient stifle, since no current modality affords the restoration of normal stifle kinematics (Kim et al. 2012). Functional menisci may contribute to improved stifle kinematics and contact mechanics after surgery, while meniscal release effectively eliminates the stabilizing properties of the tissue. Loss of these critical functions after meniscal release has severe ramifications for the health and function of the stifle joint. Since meniscal release is functionally equivalent to meniscectomy, severe cartilage degeneration can be expected (Fairbank 1948), and an in vivo experimental study in dogs showed that meniscal release in CrCL-intact stifles resulted in severe articular cartilage pathology as early as 12 weeks after surgery (Luther et al. 2009) (Figures 36.2 and 36.3). In addition, meniscal release alone was associated with lameness, radiographic changes consistent with osteoarthritis, and further meniscal damage in these dogs (Luther et al. 2009). The effect of meniscal release in a CrCL-deficient stifle may be less evident, considering the abnormal joint biomechanics caused by CrCL rupture. However, it could be argued that for this reason the meniscus should be preserved at any cost, despite the risk of reoperation because of a subsequent meniscal tear. Surgical technique Two types of meniscal release are routinely performed. The abaxial or mid-body or central meniscal release is performed by radial transection of the meniscus immediately caudal to the medial collateral ligament. The axial or menisco-tibial ligament or caudal meniscal release is characterized by a radial transection at the junction of the menisco-tibial ligament and the caudal pole of the medial meniscus (Kennedy et al. 2005) (see Chapter 35). Meniscal release can be performed either through an open approach or arthroscopically (Slocum & Slocum 1998; Luther et al. 2009). Regardless of approach, the basic principles of meniscal surgery should be followed: (i) optimize exposure and joint distraction before performing the release; 2) use atraumatic surgical technique. Exposure and assessment of the meniscus is a crucial step in performing any meniscal 303 M (A) M (B) Figure 36.2 Photograph of right tibial plateau of disarticulated right stifle 12 weeks after experimental caudal menisco-tibial release (MR) in a stifle with an intact cranial cruciate ligament (A) and sham surgery (B). The metallic probe indicates the junction of the caudal horn and the caudal meniscal ligament of the medial meniscus, where MR was performed. Healing of the caudal horn MR site was minimal and limited to the abaxial region. Note the gross articular fibrillation on the medial aspect of the tibial plateau. Medial meniscus (M). Source: Luther et al. 2009. Reproduced with permission from John Wiley & Sons, Inc. treatment, including meniscal release. For arthrotomy and arthroscopy, the combination of joint distraction, femoro-tibial subluxation, varus and valgus stress applied to the stifle allows examination of the entire meniscus in some cases (Pozzi et al. 2008). Improved exposure can be achieved by using stifle distractors. Exposure of the meniscus is more challenging in the stable stifle with partial CR. In these cases, debridement of the entire CrCL or exposure of the caudal pole of the meniscus through a caudo-medial approach should be considered (Pozzi et al. 2008). After exposure, every region of the meniscus is accurately probed to evaluate its firmness, smoothness, and for the presence of tears (Pozzi et al. 2008). Latent tears may Surgical Treatment VetBooks.ir 304 (A) (B) (C) (D) Figure 36.3 Representative gross appearances of India ink-stained articular cartilage surfaces in meniscal release (MR) (A,B) and sham-operated (C,D) stifle joints. The photographs were taken immediately after tracings of the articular surfaces and lesions were made. The percentage area of cartilage damage was significantly greater in MR stifles than in sham stifles, as indicated here by the darkly stained regions on the medial femoral condyle and tibial plateau. Source: Luther et al. 2009. Reproduced with permission from John Wiley & Sons, Inc. occur due to misdiagnosis at the time of the initial joint evaluation (Thieman et al. 2006; Case et al. 2008). Therefore, complete and careful inspection for all types of pathology potentially present is mandatory for comprehensive management of CR in dogs. Meticulous surgical technique with an optimal view of the meniscus (arthroscopy, head-lamp, appropriate surgical lights) is also necessary to avoid iatrogenic damage to the cartilage, the medial collateral ligament and the caudal cruciate ligament (Austin et al. 2007). The mid-body release can be performed using an inside-to-outside or an outside-toinside technique. For the inside-to-outside technique, a needle is inserted into the joint from outside at the level of the caudal edge of the medial collateral ligament. The needle guides the blade inserted from inside the joint through the entire meniscus. In the outside-toinside technique, the #11 blade is inserted just caudal to the medial collateral ligament in a direction towards the Gerdy tubercle. Aiming at the Gerdy tubercle should allow the surgeon to transect the meniscus at a 30◦ cranio-medial angle, which is necessary to accomplish a complete release (Slocum & Slocum 1998). To confirm that a complete release has been performed, a probe is used to evaluate the extent of radial transection. Menisco-tibial release is used more commonly in conjunction with cranio-medial arthrotomy or arthroscopy. This is the preferred method of the present authors because of the lower risk of cartilage damage during transection. The menisco-tibial ligament can be transected with a #11, #15, or Beaver scalpel blade, meniscal knives, or arthroscopic basket forceps or scissors. Radiofrequency probes and electrosurgery devices have also been used but are not recommended by the present authors due to the potential for thermal damage to adjacent tissues. The meniscal probe can be used while releasing the meniscus to ensure that the whole ligament is transected. The tip of the probe is hooked onto the ligament and the probe is used as a guide for the blade (Figure 36.4). An incomplete release is recognized using this technique if the tip of the probe remains hooked after transection. Another technique entails using a pull-meniscal knife. This instrument allows ‘hooking’ and transecting the whole ligament VetBooks.ir Meniscal Release (A) (B) Figure 36.4 (A) Photograph of right tibial plateau illustrating the caudal menisco-tibial release using a meniscal probe as a guide for the blade. The meniscal release is completed as the tip of the probe is freed from under the meniscal ligament. (B) Photograph of right tibial plateau illustrating the caudal menisco-tibial release using a pull-meniscal-knife. After hooking the ligament with the knife, traction is applied until the ligament is transected. Care should be taken to avoid hooking the caudal cruciate ligament. The meniscal-tibial ligament should be probed to confirm that the meniscal release is complete. Both techniques can be performed via arthrotomy or arthroscopy. (Figure 36.4), and facilitates performing a complete release, potentially decreasing the risk of iatrogenic damage to the joint. Clinical decision-making The optimal treatment of meniscal injury should alleviate pain while preserving meniscal 305 function. If this principle is applied to clinical decision-making regarding an intact meniscus, meniscal release should not be performed because of its impact on meniscal function and consequently joint function (Pozzi et al. 2006; Thieman et al. 2006; Pozzi et al. 2008; Luther et al. 2009; Pozzi et al. 2010). This conservative approach is further supported by the evidence that dogs without meniscal injury and without release have a better short- and long-term outcome (Innes et al. 2000; Luther et al. 2009). The type of meniscal treatment may have a greater impact on clinical outcome than does the CrCL stabilization technique. Cases diagnosed and treated for concurrent meniscal tears were 1.3fold more likely to have a successful long-term outcome than cases in which a concurrent tear was not identified (Ritzo et al. 2014). These results would support a recommendation of meniscal release to decrease the likelihood of postoperative meniscal tears (Ritzo et al. 2014) in selected cases when some postoperative stifle laxity is to be expected. A thorough evaluation of the meniscus should be performed, especially if the meniscus is not released. Latent tears represent a failure of diagnosis at surgery and may result in persistent lameness and require additional surgical treatment. To decrease the risk of latent tears, arthroscopy and meniscal probing are recommended for their high sensitivity and specificity (Mahn et al. 2005; Pozzi et al. 2008). By improving the diagnosis of tears at the initial joint exploratory surgery, it may be possible to decrease the incidence of late injuries to a point that a release procedure may not be necessary. Subsequent meniscal tears cause discomfort to the patient and may require costly reoperation. Meniscal release decreases the rate of these tears, thus eliminating the need for revision surgeries in some dogs (Thieman et al. 2006). For this reason, meniscal release could be considered in cases of high rates of subsequent meniscal injury and when a revision surgery is not acceptable for the owner. However, in these cases consideration should be given to hemimeniscectomy in place of meniscal release because meniscal tears may still occur despite a meniscal release. The decision of releasing an intact meniscus is complex and should be made after considering several factors that include the diagnostic approach, the type of VetBooks.ir 306 Surgical Treatment CrCL stabilization technique, and client communication (see also Chapter 35; Table 35.1 and Figure 35.3). References Austin B, Montgomery RD, Wright J, et al. Evaluation of three approaches to meniscal release. Vet Comp Orthop Traumatol 2007;20:92–97. Case JB, Hulse D, Kerwin SC, et al. Meniscal injury following initial cranial cruciate ligament stabilization surgery in 26 dogs (29 stifles). Vet Comp Orthop Traumatol 2008;21:365–367. Fairbank TJ. Knee joint changes after meniscectomy. J Bone Joint Surg 1948;30B:664–670. Flo GL. Meniscal injuries. Vet Clin North Am 1993; 23:831–843. Innes JF, Bacon D, Lynch C, et al. Long-term outcome of surgery for dogs with cranial cruciate ligament deficiency. Vet Rec 2000;147:325–328. Kennedy SC, Dunning D, Bischoff MG, et al. The effect of axial and abaxial release on meniscal displacement in the dog. Vet Comp Orthop Traumatol 2005;18:227–234. Kim SE, Lewis DD, Pozzi A. Effect of tibial plateau leveling osteotomy on femorotibial subluxation: in vivo analysis during standing. Vet Surg 2012;41: 465–470. Lafaver S, Miller NA, Stubbs WP, et al. Tibial tuberosity advancement for stabilization of the canine cranial cruciate ligament-deficient stifle joint: surgical technique, early results, and complications in 101 dogs. Vet Surg 2007;36:573–586. Luther JK, Cook CR, Constantinescu IA, et al. Clinical and anatomical correlations of the canine meniscus. J Exp Med Surg Res 2007;14:5–14. Luther JK, Cook CR, Cook JL. Meniscal release in cruciate ligament intact stifles causes lameness and medial compartment cartilage pathology in dogs. Vet Surg 2009;38:520–529. Mahn MM, Cook JL, Cook CR, et al. Arthroscopic verification of ultrasonographic diagnosis of meniscal pathology in dogs. Vet Surg 2005;34:318–323. Metelman LA, Schwarz PD, Salman M, et al. An evaluation of three different cranial cruciate ligament surgical stabilization procedures as they relate to postoperative meniscal injuries. Vet Comp Orthop Traumatol 1995;8:118–123. Pozzi A, Litsky AS, Field J, et al. Pressure distributions on the medial tibial plateau after medial meniscal surgery and tibial plateau levelling osteotomy in dogs. Vet Comp Orthop Traumatol 2008;21: 8–14. Pozzi A, Kowaleski MP, Apelt D, et al. Effect of medial meniscal release on tibial translation after tibial plateau leveling osteotomy. Vet Surg 2006;35:486– 494. Pozzi A, Kim SE, Lewis DD. Effect of transection of the caudal menisco-tibial ligament on medial femorotibial contact mechanics. Vet Surg 2010;39: 489–495. Ralphs SC, Whitney WO. Arthroscopic evaluation of menisci in dogs with cranial cruciate ligament injuries: 100 cases (1999–2000). J Am Vet Med Assoc 2002;221:1601–1604. Ritzo ME, Ritzo BA, Siddens AD, et al. Incidence and type of meniscal injury and associated long-term clinical outcomes in dogs treated surgically for cranial cruciate ligament disease. Vet Surg 2014;43: 952–958. Slocum B, Slocum TD. Meniscal Release. In: Current Techniques in Small Animal Surgery, M Bojrab, ed., 4th edn. Williams & Wilkins, Baltimore, MD, 1998, pp. 1197–1199. Thieman KM, Tomlinson JL, Fox DB, et al. Effect of meniscal release on rate of subsequent meniscal tears and owner-assessed outcome in dogs with cruciate disease treated with tibial plateau leveling osteotomy. Vet Surg 2006;35:705–710. Williams J, Tomlinson J, Constantinescu GM. Diagnosing and treating meniscal injuries in the dog. Vet Med 1994;89:42–47. VetBooks.ir 37 Progression of Osteoarthritis after Stifle Stabilization Surgery Susannah J. Sample Introduction The relationship between cruciate ligament rupture (CR) and osteoarthritis (OA) is complex, dynamic, and poorly understood. Historically, development of OA in clinical patients was perceived to be a consequence of a loss of joint stability associated with cranial cruciate ligament (CrCL) fiber rupture. More recent studies have indicated that, while joint instability resulting from CrCL fiber tearing increases development of OA, initiation of OA within a diseased stifle joint actually precedes clinically detectable joint instability. This suggests that CrCL fiber disruption is, at least in part, a consequence, rather than a cause, of the disease process that leads to stifle OA. Use of cranial cruciate ligament transection as a model of osteoarthritis The historic view that OA in canine patients with naturally occurring CR is purely a consequence of stifle instability is, in part, based on dog model studies of CrCL transection. While the development of OA in patients with naturally occurring disease is likely more complex, it is important to consider the consequences of stifle joint instability on the development and progression of OA. After transection of the CrCL, changes occur throughout the tissues of the synovial joint. The articular cartilage undergoes a dramatic anabolic response, with increased cellular activity and mitosis resulting in increased matrix synthesis and an overall increase in tissue mass (Adams & Brandt 1991). However, this anabolic activity is countered by increased catabolic activity with degradation of the collagen network (Fernandes et al. 1998) and increased activity of enzymes degrading the major proteoglycan, aggrecan (Innes et al. 2005). The result of this proteolytic activity is to deplete the cartilage of aggrecan, initially in the superficial zone, and to disrupt the collagen network. Thus, the compressive stiffness and the tensile strength of the cartilage are both reduced. In a stifle affected by CR, the consequences of cartilage degradation can often be seen during arthroscopic assessment, as reflected by a decrease in cartilage stiffness and eventual fraying (Figure 37.1). Continued enzymatic activity over many months leads to loss of tissue, such that there may be full-thickness cartilage lesions within 3 to 5 years (Brandt et al. 1991). Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 307 Surgical Treatment VetBooks.ir 308 (A) (B) Osteoarthritis precedes stifle instability associated with cruciate ligament rupture Some of the most pivotal findings identified while investigating the association between development of OA and its relationship to CR have come from studies of contralateral stable stifles of dogs with unilateral complete CR. Given that the risk of contralateral CR is between 40% and 60% within 18 months of CR diagnosis (Doverspike et al. 1993; de Bruin et al. 2007), use of the contralateral stable stifle in dogs with unilateral stifle instability is advantageous in providing a model to study the natural history of CR disease progression. Based on results of investigations of clinically stable contralateral stifles in dogs with unilateral CR, it has been established that radiographically detectable OA precedes CR (Doverspike et al. 1993; de Bruin et al. 2007; Bleedorn et al. 2011; Chuang et al. 2014). This observation has led to investigations into the use of radiographic OA as a means of prediction of complete CR risk in stifles with partial CR (see also Chapter 22). Indeed, in contralateral stable stifles of dogs with unilateral CR, both the progression of OA over time (Innes et al. 2004; de Bruin et al. 2007) and the degree of OA at the time of diagnosis (Chuang et al. 2014) (see Chapter 22; Figures 22.2 and 22.3) are predictive of risk of contralateral CR. Interestingly, the presence of radiographically detectable OA in a contralateral stable stifle does not inevitability lead to complete CR, highlighting that there is incomplete understanding of the initiating factors that result in OA and cruciate ligament fiber rupture, and Figure 37.1 Arthroscopic views of medial femoral condyles in stifle joints with cranial cruciate ligament rupture. Note the cartilage pathology present in both these stifles. (A) Cartilage damage can result in minor fibrillation that does not result in full-thickness loss. (B) However, in severe cases, cartilage loss can extend to the subchondral bone. The white arrows highlight cartilage fibrillation. the factors associated with progression of disease within affected stifle joints. However, one important clue derives from studies showing that arthroscopically assessed synovitis and radiographic arthritis are correlated in both unstable and contralateral stifle joints of dogs with naturally occurring CR (Bleedorn et al. 2011), suggesting that synovitis is a key feature of early disease. Ultimately, further studies are required to understand the natural history of CR. For further information regarding the role of synovitis in cruciate ligament rupture pathology, see Chapter 12. Progression of osteoarthritis after stifle stabilization procedures It is now well established that OA progresses in the face of stifle stabilization procedures. Numerous studies have documented this progression (Table 37.1). Currently there is no standardized method by which radiographic OA is quantified in the stifle joint. In the reported literature, methods for measurement of radiographic OA, times to follow up evaluation, and use of meniscal release concurrently with stabilization, are highly variable between studies. Cause of osteoarthritis progression after stifle stabilization procedures The cause of OA progression after stifle stabilization surgery is likely multifactorial. Theories presented within the literature include continued stifle instability and altered joint contact VetBooks.ir Progression of Osteoarthritis after Stifle Stabilization Surgery 309 Table 37.1 Summary of studies reporting radiographic progression of osteoarthritis (OA) after surgical stabilization of the stifle. Author(s) Elkins et al. (1991) Number of dogs 15 17 Surgical technique Time to follow-up (mean) OA progression from time of surgery Intra-articular stabilization Extracapsular stabilization 2–96 months (26)∗ 100% of dogs with follow up >6 months had OA progression Vasseur & Berry (1992) 21 Intra-articular stabilization 1–46 months (14.8) 100% of dogs had OA progression Innes et al. (2004) 45 Intra-articular stabilization 7 months Significantly increased osteophyte score Significantly increased global OA score 13 months Rayward et al. (2004) 40 TPLO 6 months 40% of dogs had OA progression Lazar et al. (2005) 44 22 TPLO Extracapsular stabilization ≥12 months OA significantly increased with both techniques. Boyd et al. (2007) 29 TPLO ≥12 months 76% of dogs had OA progression Hurley et al. (2007) 295 TPLO 2 months OA significantly increased Cook et al. (2010) 23 24 TPLO Extracapsular (TightRope) 6 months OA progression not significant but noted to progress over time Au et al. (2010) 16 14 TPLO Extracapsular stabilization 24 months OA significantly increased for both techniques Morgan et al. (2010) 35 TTA 4–16 months (5.9) 55% of dogs had OA progression DeLuke et al. (2012) 60 TPLO 12–36 months 100% of dogs had OA progression MacDonald et al. (2013) 24 TTA Each dog evaluated at 0.5, 6, and 12 months OA significantly increased at all time points Berger et al. (2015) 15 TPLO 15 Extracapsular stabilization 14–43.3 months (29.4) 6.3–23.7 months (15) Mild OA progression for both techniques (significance not reported) ∗ Each dog had between one and four follow-up time points. TPLO, tibial plateau leveling osteotomy; TTA, tibial tuberosity advancement. mechanics resulting from both the stabilization method and potential meniscal removal or release (Kim et al. 2009a; Kim et al. 2009b; Tonks et al. 2010; Pozzi et al. 2010a; Pozzi et al. 2010b). Meniscal release, meniscal tearing, and meniscectomy are known to result in the development of OA in experimental dogs with intact cruciate ligaments (Cox & Cordell 1977; Luther et al. 2009). While these factors appear to be influential in the continued progression of OA, extrapolation of results from studies of contralateral stable stifles with early disease suggest that VetBooks.ir 310 Surgical Treatment continued synovitis is also a likely contributor to postoperative OA progression. Comparison of osteoarthritis progression between stabilization methods Currently, few studies have been reported in the veterinary literature that have compared progression of OA between various stabilization methods with a strict follow-up timeframe. Most studies have highly variable ranges from the time of surgery to follow-up. Cook et al. (2010) reported OA progression at 6 months after TPLO surgery and the TightRope extracapsular technique, noting that while OA progressed with both methods, the progression was not significantly different between stabilization methods or between time of surgery and the 6-month recheck. Lazar et al. (2005) also evaluated OA progression between TPLO and an extracapsular stabilization technique, with follow-up within 1 year of surgery. OA progression was noted with both stabilization methods, although dogs with a more severe OA progression were more likely to have undergone an extracapsular stabilization method rather than a TPLO. Conclusions Over the past few years, strong evidence regarding the relationship between OA and development of stifle instability in the stifle joint of dogs has indicated that development of radiographic OA precedes clinically detectable joint instability from CR. This suggests that OA is not only a result of stifle instability and altered contact mechanics, but is also related to the joint inflammation that contributes to cruciate ligament fiber rupture and matrix degeneration. Stabilization procedures are not diseasemodifying, as these procedures do not directly address the inflammatory environment within CR stifle joints. Stifle synovitis should be considered a contributing factor in OA progression over time, and a focus of future research. References Adams ME, Brandt KD. Hypertrophic repair of canine articular cartilage in osteoarthritis after anterior cruciate ligament transection. J Rheumatol 1991;18:428–435. Au KK, Gordon-Evans WJ, Dunning D, et al. Comparison of short- and long-term function and radiographic osteoarthrosis in dogs after postoperative physical rehabilitation and tibial plateau leveling osteotomy or lateral fabellar suture stabilization. Vet Surg 2010;39:173–180. Berger B, Knebel J, Steigmeier-Raith S, et al. Longterm outcome after surgical treatment of cranial cruciate ligament rupture in small breed dogs. Tierärztl Prax (K) 2015;43:373–380. Bleedorn JA, Greuel EN, Manley PA, et al. Synovitis in dogs with stable stifle joints and incipient cranial cruciate ligament rupture: a cross-sectional study. Vet Surg 2011;40:531–543. Boyd DJ, Miller CW, Etue SM, et al. Radiographic and functional evaluation of dogs at least 1 year after tibial plateau leveling osteotomy. Can Vet J 2007;48:392–396. Brandt KD, Myers SL, Burr D, et al. Osteoarthritic changes in canine articular cartilage, subchondral bone, and synovium fifty-four months after transection of the anterior cruciate ligament. Arthritis Rheum 1991;34:1560–1570. Chuang C, Ramaker MA, Kaur S, et al. Radiographic risk factors for contralateral rupture in dogs with unilateral cranial cruciate ligament rupture. PLoS One 2014;9:e106389. Cook JL, Luther JK, Beetem J, et al. Clinical comparison of a novel extracapsular stabilization procedure and tibial plateau leveling osteotomy for treatment of cranial cruciate ligament deficiency in dogs. Vet Surg 2010;39:315–323. Cox JS, Cordell LD. The degenerative effects of medial meniscus tears in dogs’ knees. Clin Orthop Relat Res 1977;125:236-242. de Bruin T, de Rooster H, Bosmans T, et al. Radiographic assessment of the progression of osteoarthrosis in the contralateral stifle joint of dogs with a ruptured cranial cruciate ligament. Vet Rec 2007;161:745–750. DeLuke AM, Allen DA, Wilson ER, et al. Comparison of radiographic osteoarthritis scores in dogs less than 24 months or greater than 24 months following tibial plateau leveling osteotomy. Can Vet J 2012;53:1095–1099. Doverspike M, Vasseur PB, Harb MF, et al. Contralateral cranial cruciate ligament rupture: incidence in 114 dogs. J Am Anim Hosp Assoc 1993;29:167–170. Elkins AD, Pechman R, Karney MT, et al. A retrospective study evaluating the degree of degenerative joint disease in the stifle joint of dogs following surgical repair of anterior cruciate ligament rupture. J Am Anim Hosp Assoc 1991;27:533–540. Fernandes JC, Martel-Pelletier J, Lascau-Coman V, et al. Collagenase-1 and collagenase-3 synthesis in normal and early experimental osteoarthritic canine cartilage: an immunohistochemical study. J Rheumatol 1998;25:1585–1594. VetBooks.ir Progression of Osteoarthritis after Stifle Stabilization Surgery Hurley CR, Hammer DL, Shott S. Progression of radiographic evidence of osteoarthritis following tibial plateau leveling osteotomy in dogs with cranial cruciate ligament rupture: 295 cases (2001–2005). J Am Vet Med Assoc 2007;230:1674– 1679. Innes JF, Costello M, Barr FJ, et al. Radiographic progression of osteoarthritis of the canine stifle joint: a prospective study. Vet Radiol Ultrasound 2004;45:143–148. Innes JF, Little CB, Hughes CE, et al. Products resulting from cleavage of the interglobular domain of aggrecan in samples of synovial fluid collected from dogs with early- and late-stage osteoarthritis. Am J Vet Res 2005;66:1679–1685. Kim SE, Pozzi A, Banks SA, et al. Effect of tibial plateau leveling osteotomy on femorotibial contact mechanics and stifle kinematics. Vet Surg 2009a;38: 23–32. Kim SE, Pozzi A, Banks SA, et al. Effect of tibial tuberosity advancement on femorotibial contact mechanics and stifle kinematics. Vet Surg 2009b;38: 33–39. Lazar TP, Berry CR, de Haan JJ, et al. Long-term radiographic comparison of tibial plateau leveling osteotomy versus extracapsular stabilization for cranial cruciate ligament rupture in the dog. Vet Surg 2005;34:133–141. Luther JK, Cook CR, Cook JL. Meniscal release in cruciate ligament intact stifles causes lameness and medial compartment cartilage pathology in dogs 311 12 weeks postoperatively. Vet Surg 2009;38:520– 529. MacDonald TL, Allen DA, Monteith GJ. Clinical assessment following tibial tuberosity advancement in 28 stifles at 6 months and 1 year after surgery. Can Vet J 2013;54:249–254. Morgan JP, Voss K, Damur DM, et al. Correlation of radiographic changes after tibial tuberosity advancement in dogs with cranial cruciate-deficient stifles with functional outcome. Vet Surg 2010;39:425–432. Pozzi A, Kim SE, Lewis DD. Effect of transection of the caudal menisco-tibial ligament on medial femorotibial contact mechanics. Vet Surg 2010a;39: 489–495. Pozzi A, Tonks CA, Ling HY. Femorotibial contact mechanics and meniscal strain after serial meniscectomy. Vet Surg 2010b;39:482–488. Rayward RM, Thomson DG, Davies JV, et al. Progression of osteoarthritis following TPLO surgery: a prospective radiographic study of 40 dogs. J Small Anim Pract 2004;45:92–97. Tonks CA, Pozzi A, Ling HY, et al. The effects of extraarticular suture tension on contact mechanics of the lateral compartment of cadaveric stifles treated with the TightRope CCL® or lateral suture technique. Vet Surg 2010;39:343–349. Vasseur PB, Berry CR. Progression of stifle osteoarthrosis following reconstruction of the cranial cruciate ligament in 21 dogs. J Am Anim Hosp Assoc 1992;28:129–136. VetBooks.ir VetBooks.ir 38 Clinical Outcomes after Surgical Treatment of Cruciate Ligament Rupture Mary Sarah Bergh and Steven C. Budsberg Introduction Surgical therapy has been recommended as the optimal treatment to manage pain, discomfort, and stifle instability secondary to canine cruciate ligament rupture (CR), due to the belief that it will provide a provide a more rapid return to function of the limb as compared to non-surgical management. Interestingly, relatively limited data are available to support this idea (Pond & Campbell 1972; Vasseur 1984; Wurcherer et al. 2013). Wucherer and coworkers prospectively documented that dogs undergoing tibial plateau leveling osteotomy (TPLO) had improved subjective and objective outcome scores compared to dogs undergoing nonsurgical management (weight loss, physiotherapy, and pain management with nonsteroidal anti-inflammatory drugs) at 24 and 52 weeks after surgery. Their surgical group had a higher probability of a successful outcome at the 12-, 24-, and 52-week evaluation time points. While hundreds of studies have been published describing various surgical procedures to treat CR in dogs, relatively few report clinical outcomes for naturally occurring disease, and even fewer compare surgical therapies or compare a surgical treatment to non-surgical treatment (Bergh et al. 2014). At the present time, the most commonly performed surgical procedures, including TPLO, lateral extracapsular suture stabilization (LS), and tibial tuberosity advancement (TTA), are all reported to improve clinical function in dogs postoperatively (Slocum & Slocum 1993; Lafaver et al. 2007; Voss et al. 2008; Gordon-Evans et al. 2013; Duerr et al. 2014). A clear consensus on the amount of clinical improvement with each procedure is difficult to ascertain because study designs, follow-up time frame and outcome assessment methods are highly variable between studies. From an evidence-based perspective, the most useful data are generated from prospective, randomized blinded clinical trials, utilizing objective (i.e., kinetic or kinematic gait analysis) or validated subjective outcome data. Unfortunately, these types of study are scarce in veterinary medicine. Early postoperative clinical outcomes (<6 months) Most studies report an initial decrease in limb function, followed by a progressive increase in limb function, which generally plateaus around 6 months after surgery, regardless of the surgical procedure employed (Au et al. 2010; Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 313 Surgical Treatment Gordon-Evans et al. 2013; MacDonald et al. 2013; Nelson et al. 2013; Krotscheck et al. 2016). There is conflicting evidence whether TTA results in less lameness than the TPLO or LS in the early postoperative period (<6 weeks) (Ferreira et al. 2016; Krotscheck et al. 2016). Mid- and long-term clinical outcomes (>6 months) A contemporary systematic review evaluated the scientific evidence on clinical outcomes for all surgical procedures with at least 6 months postoperative follow-up, published through September 2013, to determine if there was evidence to support whether one or more surgical procedures consistently return a dog to normal clinical function (Bergh et al. 2014). While there were relatively few studies that met the inclusion criteria, many of them offered high-quality evidence and, therefore, allowed assessments of some procedures to be made. Although the data were not homogeneous, the strength of the evidence evaluated strongly supported the ability of the TPLO to allow dogs to regain normal function postoperatively. In addition, the evidence supported a superior clinical outcome after TPLO as compared to LS (Gordon-Evans et al. 2013; Berger et al. 2015) (Figure 38.1). A recent prospective clinical trial comparing TTA, TPLO, LS, and normal dogs using force plate analysis at a walk and trot at 2 and 8 weeks, and 6 and 12 months postoperatively, was reported (Krotscheck et al. 2016). The TPLO group gained normal limb use at the 6- and 12-month time points at both a walk and trot, whereas the TTA regained normal function only at a walk at the 12-month time point. The LS group did not regain normal function at the walk or trot at any time point (Figure 38.2). Very few studies have reported clinical outcomes at greater than 1 year after surgery. However, data suggest that clinical benefits of surgery persist. Longer-term postoperative follow-up is important, as surgical procedures may have either positive or negative long-term effects on joint biology and biomechanics, and outcomes may be significantly different than in the short or intermediate postoperative period. Mölsä and colleagues (2014) found that a combined group of osteotomy techniques (TPLO, TTA, triple tibial osteotomy), but not intraarticular repair techniques, allowed a return to normal loading (peak vertical force; PVF) at a minimum of 1.5 years (mean 2.8 years) after surgery. Au et al. (2010) reported similar PVF values for the LS and TPLO at 6 and 24 months after surgery, suggesting that function does not decline. 60 PVF(%BW) 50 40 LS 30 TPLO 20 10 on th s m 12 6 m on th s ee ks w ee ks w 6 12 e- op er at iv e 0 Pr VetBooks.ir 314 Figure 38.1 Canine pelvic limb use at the trot (mean peak vertical force (PVF) × % body weight) measured by a pressure mat before and after unilateral lateral suture (LS) and tibial plateau leveling osteotomy (TPLO) in a prospective randomized blinded clinical study. Asterisks indicate significant differences between groups. Data from Gordon-Evans et al. 2013. Clinical Outcomes after Surgical Treatment of Cruciate Ligament Rupture 315 VetBooks.ir 0.8 0.7 PVF(%BW) 0.6 0.5 Normal dogs 0.4 LS 0.3 TPLO TTA 0.2 0.1 s on 12 m on m 6 th s th ks ee w 8 ks ee w 2 Pr e- op er at iv e 0 Figure 38.2 Canine pelvic limb use at the trot (mean peak vertical force (PVF) × % body weight) measured by dual force plates in normal dogs and before and after unilateral lateral suture (LS), tibial plateau leveling osteotomy (TPLO), and tibial tuberosity advancement (TTA) in prospective clinical studies. The black boxes indicate a lack of significant difference between values. Data from Nelson et al. 2013 and Krotscheck et al. 2016. Factors affecting clinical outcome Patient, owner, and surgeon factors may affect clinical outcome. Currently, the evidence supports similar clinical outcomes for small-, large-, and giant-breed dogs after LS and TPLO (Gordon-Evans et al. 2013; Nelson et al. 2013; Berger et al. 2015). Postoperative TTA complications decrease PVF, although with appropriate treatment PVF returns to a level similar to dogs without complications (Voss et al. 2008). Data suggest that the method of joint exploration (arthrotomy versus arthroscopy) and meniscal treatment do not affect the speed or extent of recovery in naturally occurring canine CR (Thieman et al. 2006; Nelson et al. 2013). However, arthroscopic evaluation does provide improved examination of the menisci, which may potentially affect outcome, as failure to identify a meniscal tear at the time of initial surgery leads to lameness in the postoperative period (Thieman et al. 2006; Pozzi et al. 2008). Stifle osteoarthritis is progressive regardless of treatment, though the severity of osteoarthritis is not reported to affect clinical function in dogs (Au et al. 2010; MacDonald et al. 2013; Berger et al. 2015). However, in the intermediate or long term, progressive osteoarthritis and periarticular fibrosis may account for the observed reduction in stifle range of motion after some techniques (MacDonald et al. 2013; Mölsä et al. 2014). Physical rehabilitation improves the speed and extent of recovery in the early postoperative time period, and some evidence suggests that there may also be long-term benefits (Au et al. 2010; Romano & Cook 2015). Conclusions Scientific evidence supports an improvement in clinical function after surgical therapy for CR in dogs. However, not all surgical procedures offer an equivalent level of recovery. At the current time, the best available evidence provides strong support that TPLO allows dogs to regain normal clinical function. The evidence suggests that the clinical outcome after TPLO is superior to the LS and TTA. Data do not support the ability of the TTA to consistently allow dogs to return to normal clinical function. Longer-term studies are necessary to evaluate clinical function following all surgical procedures. VetBooks.ir 316 Surgical Treatment References Au KK, Gordon-Evans WJ, Dunning D et al. Comparison of short- and long-term function and radiographic osteoarthrosis in dogs after postoperative physical rehabilitation and tibial plateau leveling osteotomy or lateral fabellar suture stabilization. Vet Surg 2010;39:173–180. Berger B, Knebel J, Steigmeier-Raith S, et al. Longterm outcome after surgical treatment of cranial cruciate ligament rupture in small breed dogs. Comparison of tibial plateau leveling osteotomy and extra-articular stifle stabilization. Tierarztl Prax Ausg K Kleintiere Heimtiere 2015;43:373–380. Bergh MS, Sullivan C, Ferrell CL, et al. Systematic review of surgical treatments for cranial cruciate ligament disease in dogs. J Am Anim Hosp Assoc 2014;50:315–321. Duerr FM, Martin KW, Rishniw M, et al. Treatment of canine cranial cruciate ligament disease. A survey of ACVS Diplomates and primary care veterinarians. Comp Orthop Traumatol 2014;27:478– 483. Ferreira MP, Ferrigno CR, de Souza AN, et al. Shortterm comparison of tibial tuberosity advancement and tibial plateau levelling osteotomy in dogs with cranial cruciate ligament disease using kinetic analysis. Vet Comp Orthop Traumatol 2016;29:209–213. Gordon-Evans WJ, Griffon DJ, Bubb C, et al. Comparison of lateral fabellar suture and tibial plateau leveling osteotomy techniques for treatment of dogs with cranial cruciate ligament disease. J Am Vet Med Assoc 2013;243:675–680. Krotscheck U, Nelson SA, Todhunter RJ, et al. Long term functional outcome of tibial tuberosity advancement vs. tibial plateau leveling osteotomy and extracapsular repair in a heterogeneous population of dogs. Vet Surg 2016;45:261–268. Lafaver S, Miller NA, Stubbs WP, et al. Tibial tuberosity advancement for stabilization of the canine cranial cruciate ligament-deficient stifle joint: surgical technique, early results, and complications in 101 dogs. Vet Surg 2007;36:573–586. MacDonald TL, Allen DA, Monteith GJ. Clinical assessment following tibial tuberosity advancement in 28 stifles at 6 months and 1 year after surgery. Can Vet J 2013;54:249–254. Mölsä SH, Hyytiäinen HK, Hielm-Björkman AK, et al. Long-term functional outcome after surgical repair of cranial cruciate ligament disease in dogs. BMC Vet Res 2014;10:266–276. Nelson SA, Krotscheck U, Rawlinson J, et al. Longterm functional outcome of tibial plateau leveling osteotomy versus extracapsular repair in a heterogeneous population of dogs. Vet Surg 2013;42:38– 50. Pond MJ, Campbell JR. The canine stifle joint I. Rupture of the anterior cruciate ligament: an assessment of conservative and surgical treatment. J Small Anim Pract 1972;13:1–10. Pozzi A, Hildreth BE 3rd, Rajala-Schultz PJ. Comparison of arthroscopy and arthrotomy for diagnosis of medial meniscal pathology: an ex vivo study. Vet Surg 2008;37(8):749–755. Romano LS, Cook JL. Safety and functional outcomes associated with short-term rehabilitation therapy in the post-operative management of tibial plateau leveling osteotomy. Can Vet J 2015;56:942–946. Slocum B, Slocum TD. Tibial plateau leveling osteotomy for repair of cranial cruciate ligament rupture in the canine. Vet Clin North Am Small Anim Pract 1993;23:777–795. Thieman KM, Tomlinson JL, Fox DB, et al. Effect of meniscal release on rate of subsequent meniscal tears and owner-assessed outcome in dogs with cruciate disease treated with tibial plateau leveling osteotomy. Vet Surg 2006;35:705–710. Vasseur PB. Clinical results following nonoperative management for rupture of the cranial cruciate ligament in dogs. Vet Surg 1984;13:243–246. Voss K, Damur DM, Guerrero T, et al. Force plate gait analysis to assess limb function after tibial tuberosity advancement in dogs with cranial cruciate ligament disease. Vet Comp Orthop Traumatol 2008;21:243–249. Wucherer KL, Conzemius MG, Evans R, et al. Shortterm and long-term outcomes for overweight dogs with cranial cruciate ligament rupture treated surgically or nonsurgically. J Am Vet Med Assoc 2013;242:1364–1372. VetBooks.ir 39 Success and Failure after Stifle Stabilization Surgery Michael G. Conzemius and Richard B. Evans Introduction Balanced and concurrent consideration of success and failure after stifle surgery should be used to define and explain how ‘successful’ a procedure is. To accomplish this, investigators must: (i) understand how to calculate and report the successes and failures; (ii) carefully choose the outcome measure(s) used to measure success (e.g., owner survey, gait analysis) and failure (e.g., second surgery); and (iii) evaluate and report data in a clinically meaningful manner. All of this discussion is relative to time after the intervention. Other factors, such as age, breed, surgeon experience, owner’s input, can also influence outcomes. Balancing success and failure Since surgery is a comparatively invasive intervention that has inherent risks to the patient, it is most reasonable to consider the advantages and disadvantages concurrently when discussing and reporting techniques. Although there may be disagreement regarding the exact mathematical method that should be used to report advantages and disadvantages of an intervention, the concept remains the same; benefits and risks associated with an intervention need to be evaluated together. The Number Needed to Treat (NNT) is the number of subjects that need to be treated to prevent one additional bad outcome (e.g., limping). If an intervention has a NNT of 6, it means that six patients must be treated with that intervention before one additional bad outcome (e.g., lameness) is prevented relative to the control group. A NNT of 1 would suggest that every patient treated with an intervention improves, and none in the control group improve. A NNT of 10 would suggest a high placebo effect. Absolute Risk Reduction (ARR; arithmetic difference between groups) is the change in the risk of an outcome, and is the inverse of NNT (Hutton 2009). Alternatively, the Relative Risk Reduction (RRR; proportional difference between groups) can be calculated. The likelihood of an adverse event or treatment failure is just as important to the patient and client as the probability of success. The Number Needed to Harm (NNH) is the number of patients that had an adverse event (e.g., implant removal) because of the intervention that would not have been exposed to the adverse event if there were in the control group. A NNH of 1 suggests that 100% of treated patients had an adverse event, and they would not have that Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 317 VetBooks.ir 318 Surgical Treatment adverse event if they were in the control group. Similarly, Absolute Risk Increase (ARI) can be calculated. To calculate NNT and NNH, it is necessary to choose a specific outcome measure at a specific time point. For example, if success at 1 year after surgery is defined as at least a 25% improvement from a validated owner survey and no residual lameness via visual inspection 12 months after surgery, failure will be defined as the need for a second surgery. For the control group it can be conservatively estimated that with non-surgical management of large-breed, obese dogs with cruciate ligament rupture (CR), 50% of dogs will have a successful outcome and 0% of dogs would require a second surgery (Wucherer et al. 2013). For tibial plateau leveling osteotomy (TPLO) it is estimated that 90% have a successful outcome (owner reports improvement plus no visual lameness) and 10% have failure (e.g., second surgery needed to remove bone plate). The present authors used 10% based on unpublished data from their hospital, where it was found that over a 5-year period 9% of patients that had a TPLO plate applied underwent a second surgery where the TPLO plate was removed. For comparison, only 80% of dogs that have an extracapsular suture placed have a successful outcome, and 5% require a second surgery. Using these estimates of success and failure, it can be learned that both procedures provide a good treatment advantage over non-surgical management and TPLO provides greater benefits (Table 39.1). However, if the relationship between NNT and NNH (a low number is good) is reviewed, a conclusion that TPLO is much better than a suture surgery after examining only NNT is an incomplete interpretation, as the risks of TPLO are greater than for a suture surgery. Owner questionnaires Establishing the owner’s perspective on outcome remains important since they spend the most time with their pet. Historically, manuscripts have documented that owners reported that their pet had a ‘good or excellent’ outcome 88.5–93% of the time after surgery (Hoffmann et al. 2006; Corr & Brown 2007; Stein & Schmoekel 2008). These findings, however, must be interpreted with great caution because of differences in the questions asked, the method of questionnaire delivery (mail, telephone, or personnel interview) and other biases that significantly influence owner reporting. It is also important to note the duration of follow-up after surgery, since it has been reported that outcomes worsen with increased time after surgery (Innes et al. 2000). To best interpret and compare studies, the consistent use of a validated owner questionnaire should be considered. Several validated owner questionnaires addressing patient pain, function, quality of life, and/or activity have been created. The Canine Brief Pain Inventory (CBPI) for dogs with osteoarthritis (OA) provides reasonable evidence that owner questionnaires can be effectively used in clinical research (Brown et al. 2008). The Liverpool Osteoarthritis in Dogs (LOAD) instrument has been critically evaluated and successfully used in several clinical investigations (Walton et al. 2013; Lascelles et al. 2015). The Client-Specific Outcome Measures (CSOM) has also been evaluated and used in clinical research (Rialland et al. 2012). While each of these questionnaires will effectively standardize the questions and allow for some comparison across studies, results in studies with small to modest patient enrollment numbers should be interpreted with caution Table 39.1 An example of how NNT and NNH can be used for a balanced approach to compare different interventions. Success rate (%) NNT 1/Tx-control (control = 50%) Major complication (2nd surgery) (%) NNH 1/% complication NNT/NNH TPLO 90 2.5 10 10 0.25 Extracapsular suture stabilization 80 3.33 5 20 0.167 NNT, Number Needed to Treat; NNH, Number Needed to Harm; TPLO, tibial plateau leveling osteotomy. VetBooks.ir Success and Failure after Stifle Stabilization Surgery because of low statistical power. Inconsistencies in delivery and interpretation of the questionnaire results in sizeable variabilities that can only be overcome by employing large study populations. In addition, it is necessary to be cognizant of the caregiver placebo effect that undoubtedly influences responses from owners and other caregivers (Conzemius & Evans 2012). Veterinary examination Before surgery, a clinician may assign a subjective score to limb function based on assessment of dog’s level of pain, lameness, and posture while sitting. While each clinician differs to some degree, observations when the patient is walking and/or trotting may include a dip in the patient’s hip or head, degree of limb carriage, and stride length. During physical examination the clinician may note the joint’s range of motion, the amount of muscle mass, and even if the leg is positioned ‘normally’ when sitting. All of these can contribute to a determination of the patient’s quality of limb function. Documentation of findings are generally recorded via a numeric rating score (NRS), where numbers are assigned to each finding, or via a visual analog scale (VAS) where limb function is assigned by marking a line with one end of the line representing ‘clinically normal’ (sound) and the other end representing ‘could not be more lame’ (i.e., non weight-bearing) (Waxman et al. 2008). The NRS is limited because there are a restricted number of groups (four or five) within a classification, and dogs within a group can have appreciable differences in their lameness severity (Waxman et al. 2008). A VAS does not have this limitation because it provides a continuous scale that may be easier to handle statistically. Regardless, both schemes provide only the opinion of the observer. Several manuscripts have tried to offset these limitations by including multiple, trained observers. Unfortunately, in one publication which tried to validate clinician observation of gait, neither trained nor untrained observers could reliably identify lameness. There were large disagreements between individuals. Untrained observers (first-semester veterinary students) had the same visual acuity for dog 319 lameness as boarded surgeons (Waxman et al. 2008). The only saving grace was a finding that trained clinicians provided repeatable data; that is, they consistently made the same mistake. This would allow a clinician to compare groups over time, but not necessarily to comment on the success or failure of an individual dog. Pedometers and accelerometers The greatest limitation to data collected at a veterinary hospital is that it measures a moment in time, and not the day-to-day activity of the dog at home. A pedometer or accelerometer can measure patient activity level at home over an extended period of time. In one study, pedometers were successfully used to measure physical activity in dogs over a 14-day period (Chan et al. 2005). The pedometer accuracy varied depending on the patient’s size (it overestimated walking in large dogs and underestimated walking in small dogs), but correlated well with overall reports of the dog’s activity level at home and the dog’s condition body score. Accelerometers are more sophisticated in that some can measure changes in acceleration in the x-, y-, and z- axes. Thus, body movement in any direction is measured. In one study that determined variability in accelerometer data in companion dogs, large day-to-day, and even week-to-week, variations occurred in dogs, but within dogs, a full 7-day comparison of total activity counts from one week to the next provided the least variable estimate of the dogs’ activity (Dow et al. 2009). It was also reported that accelerometers might be most useful for documenting changes in the dog’s activity over time. While pedometers and accelerometers estimate patient activity, to date, there is little information available as to whether such data can be translated to something clinically relevant, such as distance traveled and/or activity intensity. For example, it may currently be found that a patient had an increase in accelerometer counts of 20%, but what exactly does that mean? In the present authors’ opinion, if this meant that the dog was willing to travel 20% more distance or performed 20% more intense activities (e.g., stairs, jumping), it would much more beneficial. VetBooks.ir 320 Surgical Treatment Force platform gait analysis Force platform gait analysis provides an objective, sensitive method to measure gait. It has been used extensively to compare forces before and after surgical treatment of CR in clinical patients (Budsberg et al. 1988; Dupuis et al. 1994; DeCamp et al. 1996; Jevens et al. 1996; Marsolais et al. 2003; Conzemius et al. 2005), and is recognized by many as the ‘gold standard’ outcome measure for orthopaedic conditions such as CR. However, computational gait analysis is useful only if cases are carefully selected, the gait analysis is precisely performed, and the collected data are correctly analyzed (Evans et al. 2003; Evans et al. 2005). Pressure platform gait analysis can also be used and has specific advantages and disadvantages that are relevant to clinical research. Tek-scan’s Industrial Sensing pressure measurement system has been compared to traditional force platform gait analysis, and the data are comparable (Besancon et al. 2003). However, the data are not interchangeable because pressure mats consistently underestimate vertical forces; thus, studies should choose one method or the other. This system has been used successfully to evaluate limb function in dogs after surgical treatment of CR (Horstman et al. 2004). A final alternative is to use the pressure-sensing mat GAIT4Dog® . These mats do not report pad pressures or ground reaction forces, which limits validation techniques, but rather report relationships between limbs, such as asymmetry. Their long length allows for the rapid collection of data and their integration into treadmills is unique. Reporting data in a clinically meaningful manner Many investigators including the present authors have limited the usefulness of their data by only reporting group means and pvalues. If it is reported that the peak vertical force is 40.0 for group A and 38.0 for group B, and the P-value is 0.04, then clearly group A and B are different. If Group A and B have undergone different surgical procedures, then this result tells us very little clinically. What owners and veterinarians need to know is how a difference impacts the outcome for an individual dog, what is the size of the difference, and is it clinically significant? Although these topics extend beyond the scope of this chapter, investigators should consider reporting probability, such as probability of normal function (Conzemius et al. 2005), effect sizes of group differences, and then consider clinical significance from these results. Additional considerations regarding residual lameness Three additional potential contributors to residual lameness in a dog after CR stifle stabilization surgery are the development of complications, the progression of OA, and instability. While many complications are avoidable, their exclusion is impossible. Complication rates have been reported for many studies, and their relative frequency between various stabilization techniques estimated by some authors. A clear definition of the timing and severity of a complication has been described and should be used for consistency (Cook et al. 2010). As discussed above, complications need to be considered with successes. For example, Voss et al. (2008) used force platform gait analysis to determine outcome in dogs after tibial tuberosity advancement, and reported that while most dogs returned to a function that was 90% of the normal dogs studied, 25% of the cases had a complication and these dogs had ground reaction forces (GRFs) that were significantly lower than when no complication occurred (Voss et al. 2008). OA development and progression is inevitable regardless of the surgical technique used. While the severity of stifle OA is not correlated to the severity of lameness (Gordon et al. 2003), it seems likely that dogs with OA have a greater probability of lameness as compared to their counterparts. Much of this assertion could be related to the limitations of plain radiographs. Magnetic resonance imaging (MRI), using dGEMRIC or T2 mapping, can generate objective information regarding the health of the cartilage, is related to OA progression and patient prognosis (Cunningham et al. 2006; Welsch et al. 2009), and has been described in the dog (Wucherer et al. 2012). One aspect of stifle surgery that some surgeons consider routine is medial meniscus release, which aims Figure 39.1 Graph showing vertical impulse (VI; % body weight) of dogs before arthroscopic surgery and at 2 and 6 months after surgery. In a group of dogs with cruciate ligament rupture and a medial meniscal tear, dogs treated with only arthroscopic debridement of the ruptured cranial cruciate ligament and medial meniscus were compared with dogs that received arthroscopic debridement together with tibial plateau leveling osteotomy (TPLO). VI (% bw) VetBooks.ir Success and Failure after Stifle Stabilization Surgery 18 16 14 12 10 8 6 4 2 0 to reduce the risk of a medial meniscal tear after surgery. One fact that surgeons should consider is that release of the medial meniscal rapidly causes OA and lameness within 12 weeks, even in a stable stifle (Luther et al. 2009). In research hounds, evidence of cartilage loss can be seen grossly using India ink staining and via MRI T2 mapping. In addition, it should be accepted that medial meniscal tears occur more commonly in an unstable stifle as opposed to a stable stifle; thus, if the stabilization procedure performed requires a release of the medial meniscus than it should be questioned as to how effective it is at stabilizing the cruciate-deficient stifle joint. Empirically, meniscal pathology and OA are the greatest limits to outcome after surgery for CR. This suggestion is supported by a small study that evaluated dogs with chronic lameness (>3 months) from surgical treatment for CR, minimal instability, and a medial meniscal tear (Conzemius 2007). In this study, outcome was measured objectively using GRFs in dogs that had either arthroscopic debridement of the CrCL and medial meniscus or arthroscopic debridement and TPLO stabilization; no differences were found between groups (Figure 39.1). For decades, veterinary surgeons have debated which surgical procedure provides the best outcome after treatment of CR. One component of this is to establish that the procedure in question adequately stabilizes the stifle. This is based on the assumption that the degree of instability is related to the degree of lameness. The term ‘assumption’ is used because the evidence provided to date does not state that instability is good, but does suggest that it may not be all that bad. In one study (Hill et al. 1999), dogs which had undergone surgery more than 1 year previously were 321 TPLO + Scope (n = 4) Scope ( n = 4) 0 6 26 Time after Surgery (weeks) allocated to groups based on owner interview, as having either a satisfactory or unsatisfactory outcome. Surprisingly, dogs in the satisfactory outcome group had almost twice the amount of instability and less than half the stifle pain on physical examination. Conclusions Advances in understanding of how to interpret success and define outcome measures will lead to continued improvement in clinical treatments. Whilst it appears that surgical management can improve lameness in most dogs with CR, the unfortunate fact is that as yet no surgical procedure has been developed, whether it includes stabilization or not, that eliminates lameness. References Besancon MF, Conzemius MG, Derrick TR, et al. Comparison of vertical forces in normal dogs between the AMTI Model OR6-5 force platform and the Tekscan (industrial sensing pressure measurement system) pressure walkway. Vet Comp Orthop Traumatol 2003;16:153–157. Brown DC, Boston RC, Coyne JC, et al. Ability of the canine brief pain inventory to detect response to treatment in dogs with osteoarthritis. J Am Vet Med Assoc 2008;233:1278–1283. Budsberg SC, Verstraete MC, Soutas-Little RW, et al. Force plate analyses before and after stabilization of canine stifles for cruciate injury. Am J Vet Res 1988;49:1522–1524. Chan CB, Spierenburg M, Ihle SL, et al. Use of pedometers to measure physical activity in dogs. J Am Vet Med Assoc 2005;226:2010–2015. Cook JL, Evans R, Conzemius MG, et al. Proposed definitions and criteria for reporting time frame, outcome, and complications for clinical orthopaedic studies in veterinary medicine. Vet Surg 2010;39:905–908. VetBooks.ir 322 Surgical Treatment Conzemius MG, Evans RB. Care giver placebo effect in dogs with osteoarthritis. J Am Vet Med Assoc 2012;241:1314–1319. Conzemius MG. RCCL Injury: The role of stabilization. Proceedings from the American College of Veterinary Surgeons Annual Symposium, Chicago, IL, 2007, p. 332. Conzemius MG, Evans RJ, Besancon MF, et al. Effect of surgical technique on limb function after surgery for rupture of the cranial cruciate ligament in dogs. J Am Vet Med Assoc 2005;226:232–239. Corr SA, Brown C. A comparison of outcomes following tibial plateau leveling osteotomy and cranial tibial wedge osteotomy procedures. Vet Comp Orthop Traumatol 2007;20:312–319. Cunningham T, Jessel R, Zurakowski D, et al. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage to predict early failure of Bernese periacetabular osteotomy for hip dysplasia. J Bone Joint Surg 2006;88:1540–1548. DeCamp CE, Riggs CM, Olivier NB, et al. Kinematic evaluation of gait in dogs with cranial cruciate ligament rupture. Am J Vet Res 1996;57:120–126. Dow C, Michel KE, Love M, et al. Evaluation of optimal sampling interval for activity monitoring in companion dogs. Am J Vet Res 2009;70:444–448. Dupuis J, Harari J, Papageorges M, et al. Evaluation of fibular head transposition for repair of experimental cranial cruciate ligament injury in dogs. Vet Surg 1994;23:1–12. Evans RB, Gordon W, Conzemius M. The effect of velocity on ground reaction forces in dogs with lameness attributable to tearing of the cranial cruciate ligament. Am J Vet Res 2003;64:1479–1481. Evans R, Horstman C, Conzemius M. Accuracy and optimization of force platform gait analysis in Labradors with cranial cruciate disease evaluated at the walking gait. Vet Surg 2005;34:445–449. Gordon WJ, Conzemius MG, Riedesel E, et al. The relationship between limb function and radiographic osteoarthrosis in dogs with stifle osteoarthrosis. Vet Surg 2003;32:451–454. Hill CM, Conzemius MG, Smith GK, et al. Bacterial culture of the canine stifle joint following surgical repair of ruptured cranial cruciate ligament. Vet Comp Orthop Traumatol 1999;12:1–5. Hoffmann DE, Miller JM, Ober CP, et al. Tibial tuberosity advancement in 65 canine stifles. Vet Comp Orthop Traumatol 2006;19:219–227. Horstman CL, Conzemius MG, Evans R, et al. Assessing the efficacy of perioperative oral carprofen after cranial cruciate surgery using noninvasive, objective pressure platform gait analysis. Vet Surg 2004;33:286–289. Hutton JL. Number needed to treat and number needed to harm are not the best way to report and assess the results of randomized clinical trials. Br J Haematol 2009;146:27–30. Innes JF, Bacon D, Lynch C, Pollard A. Long-term outcome of surgery for dogs with cranial cruci- ate ligament deficiency. Vet Record 2000;147:325– 328. Jevens DJ, DeCamp CE, Hauptman J, et al. Use of force-plate analysis of gait to compare two surgical techniques for treatment of cranial cruciate ligament rupture in dogs. Am J Vet Res 1996;57:389– 393. Lascelles BD, Knazovicky D, Case B, et al. A caninespecific anti-nerve growth factor antibody alleviates pain and improves mobility and function in dogs with degenerative joint disease-associated pain. BMC Vet Res 2015;11:101. Luther JK, Cook CR, Cook JL. Meniscal release in cruciate ligament intact stifles causes lameness and medial compartment cartilage pathology in dogs 12 weeks postoperatively. Vet Surg 2009;38:520– 529. Marsolais GS, McLean S, Derrick T, et al. Kinematic analysis of the hind limb during swimming and walking in healthy dogs and dogs with surgically corrected cranial cruciate ligament rupture. J Am Vet Med Assoc 2003;222:739–743. Rialland P, Bichot S, Moreau M, et al. Clinical validity of outcome pain measures in naturally occurring canine osteoarthritis. BMC Vet Res 2012;8:162. Stein S, Schmoekel H. Short-term and eight to 12 months results of a tibial tuberosity advancement as treatment of canine cranial cruciate ligament damage. J Small Anim Pract 2008;49:398–404. Voss K, Damur DM, Guerrero T, et al. Force plate gait analysis to assess limb function after tibial tuberosity advancement in dogs with cranial cruciate ligament disease. Vet Comp Orthop Traumatol 2008;21:243–9. Walton MB, Cowderoy E, Lascelles D, et al. Evaluation of construct and criterion validity for the ‘Liverpool Osteoarthritis in Dogs’ (LOAD) clinical metrology instrument and comparison to two other instruments. PLoS One 2013;8:e58125. Waxman AW, Robinson DA, Evans R, et al. Relationship between objective and subjective assessment of limb function in normal dogs with an experimentally induced lameness. Vet Surg 2008;37:241– 246. Welsch GH, Mamisch TC, Marlovits S, et al. Quantitiative T2 mapping during follow-up after matrixassociated autologous chondrocyte transplantation (MCAT): Full-thickness and zonal evaluation to visualize the maturation of cartilage repair tissue. J Orthop Res 2009;27:957–963. Wucherer KL, Ober C, Conzemius MG. The use of delayed gadolinium enhanced magnetic resonance imaging of cartilage and T2 mapping to evaluate articular cartilage in the normal canine elbow. Vet Rad Ultrasound 2012; 53:57–63. Wucherer KL, Conzemius MG, Evans RB, et al. Shortterm and long-term outcomes for overweight dogs with cranial cruciate ligament rupture treated surgically or nonsurgically. J Am Vet Med Assoc 2013:242:1364–1372. VetBooks.ir 40 Diagnosis and Management of Orthopaedic Infection after Stifle Surgery Noël M.M. Moens Introduction Since ancient times, surgical infections have always been a challenge for surgeons. Although significant discoveries have been made over the past century, current understanding of surgical infections and widespread use of antibiotics have all but eliminated the risk of surgical site infection (Alexander 1985). Although the risk of developing surgical infection and the chances of dying from infection have substantially decreased, surgeons are now faced with the increasing prevalence of multi-drugresistant bacteria (Cohen 1992). Infections that are untreatable with the current range of antibiotics are becoming more frequent and cause a significant burden on the patient’s well-being and on the cost of healthcare. The overall incidence of infection in human surgery has been reported to be between 2% and 5%. However, incidence varies based on the specific surgery, specific risk factors, and wound classification (Culver et al. 1991; Anderson 2011; Eisenberg 2012). Clean elective orthopaedic procedures have the lowest infection rates, while contaminated or dirty procedures are associated with higher rates. Although slightly higher, the rate of surgical infection in veterinary surgery parallels the human surgery, with infection rates for clean procedures reported to be around 2.5% (Vasseur et al. 1992; Eugster et al. 2004). Over the past two decades, several new procedures have been developed for the treatment of various stifle conditions. Although most are clean elective procedures, higher infections rates than expected have often been reported. Definition Surgical site infections (SSI) are infectious complications that manifest at the incision site of a surgical patient, and are the result of a combination of host, pathogen, and environmental factors resulting in the establishment of infection (Mangram et al. 1999; Nelson 2011). In order to standardize the definition of SSI, the United States Centers for Disease Control and Prevention (CDC) has defined several categories of SSI and has provided criteria for its diagnosis (Table 40.1). It must be noted that although isolation and culture of the causal agent adds to the validity of the diagnosis, a positive culture is not required for the diagnosis of SSI. Some aspects of the definition can still be open to interpretation and will continue to generate variability in the results. For example, inflammation and Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 323 VetBooks.ir 324 Surgical Treatment Table 40.1 Criteria for the definition of different categories of surgical site infection. Category Superficial SSI Within 30 days of the operation. Involves only the skin and/or subcutaneous tissues. Involves one or more of the following: r Purulent discharge (with or without laboratory confirmation) r Organism isolated from aseptically collected sample of fluid or tissue r At least one of the following signs of infection: Pain or tenderness, localized swelling, r Deep SSI redness or heat and superficial incision is deliberately opened by the surgeon unless incision is culture-negative Diagnosis of superficial incisional SSI made by a surgeon or attending clinician Within 30 days of the operation if no implants or within 1 year if an implant is left in place. Involves deep soft tissues (fascial or muscle layers). Involves one or more of the following: r Purulent discharge from deep incision but not from the organ/space component of the surgical site r A deep incision spontaneously dehisces or is deliberately opened by a surgeon when r r r Organ/Space SSI the patient has at least one of the following clinical signs: Fever, localized pain or tenderness, unless site is culture-negative Organism isolated from aseptically collected sample of fluid or tissue. An abscess or other evidence of infection involving the deep incision that is found on direct examination, during reoperation, or by histopathologic or radiologic examination Diagnosis of deep incisional SSI made by a surgeon or attending clinician Within 30 days of the operation if no implants or within 1 year if an implant is left in place. Involves any organ/space, other than the incision, that was opened or manipulated during surgery. Involves one or more of the following: r Purulent drainage from a drain placed into the organ/space r Organisms isolated from an aseptically obtained culture or fluid or tissue in the organ/space r An abscess or other evidence of infection involving the organ/space that is found on direct examination, during reoperation, or by histopathologic or radiologic examination r Diagnosis of organ/space SSI made by a surgeon or attending clinician Note: Adapted from: CDC definitions for surgical site infections (Mangram et al. 1999). incisional dehiscence has always been a diagnostic challenge. Whether the animal caused the infection by opening the incision, or the infection caused the animal to open the incision, will always be a matter of debate and personal interpretation. Incidence of infection in stifle surgery Because of the high prevalence of cruciate ligament rupture, and the popularity of tibial plateau leveling osteotomy (TPLO), more studies have focused on this procedure than on any other stifle procedure. Infection rates after TPLO surgery vary greatly, and range between 2.5% and 15.8% (Pacchiana et al. 2003; Priddy et al. 2003; Corr & Brown 2007; Fitzpatrick & Solano 2010; Frey et al. 2010; Gatineau et al. 2011; Thompson et al. 2011; Gallagher & Mertens 2012; Dal-bó et al. 2013; Etter et al. 2013; Savicky et al. 2013; Nazarali et al. 2014). The actual incidence is difficult to determine because few studies use the standardized definition of infection, and even fewer are the result of active surveillance. Most studies are retrospective in nature and have not been designed to assess infection rates. One prospective, multicenter study with active surveillance for up to a year reports an overall infection rate of 6.7% over 549 VetBooks.ir Diagnosis and Management of Orthopaedic Infection after Stifle Surgery procedures (Nazarali et al. 2015). These rates seem to be fairly similar to most high tibial osteotomy procedures. Although much less has been published on the other procedures, infection rates after tibial tuberosity advancement (TTA) are very similar, and rates between 2.6% and 12.5% have been reported (Lafaver et al. 2007; Wolf et al. 2012; Dal-bó et al. 2013; Proot & Corr 2013; Yap et al. 2015). Significantly higher infection rates have been observed in a population of Boxer dogs compared to non-Boxer dogs (22% versus 3.7%), but the reasons remain unclear (de Lima Dantas et al. 2015). Closing cranial wedge ostectomy has published infection rates of between 8.3% and 16.6% (Corr & Brown 2007; Dal-bó et al. 2013). Besides the treatment of cruciate ligament rupture, reported infection rates after patellar luxation repair range from 6.4% to 10% (Gibbons et al. 2006; Clerfond et al. 2014; Kalff et al. 2014; Shaver et al. 2014). Extracapsular techniques for cruciate ligament stabilization have generally been associated with a lesser risk of infection. The largest series of 363 cases of lateral fabellar suture stabilization reports an infection rate of 3.9% (Casale & McCarthy 2009). Only infections confirmed by a positive culture were counted. Therefore, this number is likely an underestimation of the true infection rate. An additional 5% of the cases were treated with empirical antibiotics without definitive diagnosis (Casale & McCarthy 2009). This number is similar to the infection rate of 4.2% in another study (Frey et al. 2010). Extracapsular techniques using braided polyester sutures appear to have similar infection rates (Cook et al. 2010; Raske & Hulse 2013), though insufficient evidence has been published to allow any conclusion at this time. Pathogens Coagulase-positive Staphylococcus spp. such as S. pseudintermedius and S. aureus are responsible for the majority of infections, while other bacteria such as Streptococcus spp., Enterococcus spp., Escherichia coli and Pseudomonas aeruginosa and others are encountered with less frequency (Fitzpatrick & Solano 2010; Thompson et al. 2011; Gallagher & Mertens 2012; Dal-bó et al. 2013; Etter et al. 2013; Savicky et al. 2013; 325 Nazarali et al. 2015; Yap et al. 2015). The increased incidence of infection caused by multi-drug-resistant (MDR) bacteria is of particular concern for both human and veterinary surgery, as the treatment of these infections is particularly challenging. In stifle surgery, the proportion of infections caused by an MDR bacteria range between 10% and 58% (Fitzpatrick & Solano 2010; Gallagher & Mertens 2012; Etter et al. 2013; Savicky et al. 2013; Yap et al. 2015). In a multi-center study, 38% of TPLO infections were caused by a MDR bacterium. Staphylococci were particularly prone to show drug resistance, with up to 60% of S. pseudintermedius and 50% of S. aureus being methicillin-resistant (Nazarali et al. 2015). Risk factors predisposing patients to infection after stifle surgery are multiple and, for the most part, similar to the risk factors in other surgeries: Wound classification, type of procedure, American Society of Anesthesiologists (ASA) score, obesity, gender and neutering status, endocrinopathies, duration of anesthesia or surgery, number of people in the operating theater, use of skin staples, timing of clipping, and so forth have all been associated with an increased risk of infection (Beal et al. 2000; Nicholson et al. 2002; Eugster et al. 2004; Fitzpatrick & Solano 2010; Frey et al. 2010; Yap et al. 2015). Risks factors for methicillinresistant S. pseudintermedius (MRSP) infections after TPLO surgery include being an MRSP carrier and being a Bulldog (Nazarelli et al. 2015). The postoperative, prophylactic use of antibiotics is a highly debated subject in both human and veterinary surgery. Routine postoperative antibiotic treatment beyond 24 hours is not recommended in people undergoing clean surgical procedures as this practice has not been shown to reduce SSI rates and may contribute to the development of antimicrobial resistance and additional morbidity (Mangram et al. 1999; Bratzler & Houck 2005). However, several recent veterinary studies do suggest a benefit of administering postoperative antibiotics after cruciate ligament rupture surgery, in particular after TPLO (Fitzpatrick & Solano 2010; Frey et al. 2010; Gatineau et al. 2011; Nazarali et al. 2015). In those studies, the administration of antibiotics for 3 to 14 days had a significant protective effect against infections. The duration of antibiotic prophylaxis required is unknown, and none of VetBooks.ir 326 Surgical Treatment the studies was specifically designed to address this question. Prospective studies are, therefore, needed to validate these findings. Diagnosis Even though SSI can occur up to a year postoperatively, most infections are diagnosed within the first couple of months after surgery. In a study of 1000 TPLOs, the average time between surgery and diagnosis of infection was 25 days (range 7–60 days) if the dogs were treated with antibiotics postoperatively, and 18 days (range 7–30 days) for dogs that did not receive postoperative antibiotics (Fitzpatrick & Solano 2010). Similarly, for TTA, the average interval was 42 days, with 67% of infections diagnosed before 30 days (Yap et al. 2015). The infection can be localized around the surgical implants and the osteotomy site or be intra-articular, or both. Septic arthritis is relatively infrequent and is present in roughly 10– 16% of infections (Priddy et al. 2003; Yap et al. 2015). Clinical signs vary, but are typical for infection: Localized heat, redness, pain, or tenderness are usually present. The swelling and bruising may be localized around the implant or involve the entire distal limb. Excessive incisional discharge may develop soon after surgery in acute cases, while chronic cases may develop draining tracts. Dehiscence of the incision, often to the level of the bone plate, can also be observed. In some cases, systemic signs such as depression and fever may be detectable (Marchevsky & Read 1999; Thompson et al. 2011). In most cases, increased lameness is evident. Animals affected with acute septic arthritis often present with a severe lameness. However, low-level, chronic septic arthritis cases may be presented with a less severe but lingering lameness (Hill et al. 1999; Marchevsky & Read 1999; Fitch et al. 2003). Radiographic signs of infection are generally mild and non-specific unless the infection is severe and chronic. Periosteal reaction and radiolucency around surgical implants can be observed in chronic cases, but are often absent in the more acute cases (Trampuz & Zimmerli 2006; Yap et al. 2015). Joint effusion is often detected in cases with septic arthritis (Fitch et al. 2003). Arthrocentesis and analysis of synovial fluid is a quick and reliable way to rule out joint involvement. Care must be taken to avoid iatrogenic contamination of the joint when performing the arthrocentesis. Aseptic preparation of the skin is carefully performed and a puncture site away from the site of infection is selected, if possible. Septic arthritis is often associated with a markedly increased synovial cell count consisting primarily of neutrophils (Marchevsky & Read 1999). In many cases, toxic changes to synovial neutrophils are absent. Therefore, this feature should not be used to rule out a septic process (Marchevsky & Read 1999). Aerobic culture of the synovial fluid should be performed. However, only 50% of the cultures are expected to yield positive results (Montgomery et al. 1989; Marchevsky & Read 1999; Clements et al. 2005; Scharf et al. 2015). Enrichment in the blood culture medium as a way to increased sensitivity of the cultures has been recommended but has been met with mixed results (Montgomery et al. 1989; Marchevsky & Read 1999; Scharf et al. 2015). Deep aspiration of the fluid around the surgical implant before surgery or intraoperative tissue culture are the best ways of diagnosing implant-associated infection (Trampuz & Zimmerli 2006). Similar to synovial fluid, culture of fluid from around the implant can have a low sensitivity. Therefore, a negative culture should not, by itself, rule out infection (Darouiche 2004). If necessary, sonication of the implant can be used to increase sensitivity of the cultures, but is not routinely available (Trampuz & Zimmerli 2006). Because of the high incidence of MDR bacteria (Nazarali et al. 2015) it is essential to obtain culture and sensitivity panels. Extended sensitivity panels may be required for MDR bacteria. In the absence of a positive culture but clinical evidence of infection, empirical antibiotics can be administered based on the best evidence of bacterial flora and resistance patterns prevalent in each hospital. Treatment Treatment will depend on the severity of the infection, the location of infection, and the stage of healing. Infections diagnosed early without evidence of abscess formation are often initially VetBooks.ir Diagnosis and Management of Orthopaedic Infection after Stifle Surgery treated by systemic administration of an appropriate antibiotic. If bone consolidation or joint stabilization has not yet been achieved, the goal of treatment is to control the infection to prevent the development of chronic osteomyelitis until consolidation is achieved (Darouiche 2004; Trampuz & Zimmerli 2006). More severe infections, those involving the stifle joint, or those associated with the formation of an abscess or wound dehiscence, require more aggressive treatment. Due to the devastating effect of untreated septic arthritis, joint lavage, surgical drainage and debridement have been recommended over the administration of antibiotics alone for the treatment of post-surgical septic arthritis (Marchevsky & Read 1999). However, the superiority of this treatment over the administration of antibiotics alone for cases that do not involve intra-articular implants has not been clearly demonstrated (Fitch et al. 2003; Clements et al. 2005). Lavage can be performed using large ingress/egress needles or through arthrotomy and joint exploration (Marchevsky & Read 1999). The required duration of antibiotic administration for septic arthritis is unknown, but 4–6 weeks has been recommended (Marchevsky & Read 1999; Fitch et al. 2003; Clements et al. 2005). The use of intra-articular gentamicin-impregnated collagen sponges has been described for the treatment of septic arthritis in the dog and other species (Owen et al. 2004). However, this method cannot be recommended due to the short intra-articular elution times of the gentamicin and the persistent joint inflammation caused by the collagen sponge (Hayes et al. 2016). Similar to other orthopaedic infections, infections associated with abscess formation, dehiscence or chronic osteomyelitis should be treated with wound exploration, debridement, and drainage (Figure 40.1). Unstable implants are removed and, if necessary, replaced. Open wound management with delayed closure or negative pressure wound therapy should be considered for dehiscence or severe infections (Budsberg 2012; Nolff et al. 2015). The use of local antibiotic delivery systems does not replace the need for long-term systemic antibiotic administration, but can be a useful addition to treatment (Hayes et al. 2013). In severe cases 327 Figure 40.1 Intraoperative picture during debridement of a deep incisional surgical site infection after tibial plateau leveling osteotomy surgery. Although the skin incision was opened by the surgeon, the caudal sartorius muscle and fascial layer have dehisced, exposing the plate. that do not respond to traditional treatment, intravenous regional perfusion of antibiotics could be attempted. This procedure was first described by Finsterbush et al. (1970) in rabbits with experimental septic arthritis and osteomyelitis, and has been successfully used in humans and horses (Finsterbush et al. 1970; Finsterbush & Weinbergh 1972; Whithair et al. 1992; Rubio-Martı́nez & Cruz 2006). Regional perfusion results in a higher synovial concentration of antibiotics than would result from intravenous administration alone (Whithair et al. 1992; Pille et al. 2005). It has been associated with low morbidity, but has not been fully investigated in dogs. Infections associated with the implant that develop after bone consolidation are often VetBooks.ir 328 Surgical Treatment treated by implant removal, followed by a short course of antibiotics. Gram-positive aerobic bacteria have the capacity to produce polysaccharide biofilm, making eradication without removing the implant difficult (Jacques et al. 2010; Singh et al. 2013). One study highlighted the importance of implant removal by showing that implant removal alone was just as efficient as implant removal with antimicrobial use, and more effective than antimicrobial administration without implant removal (Savicky et al. 2013). In some situations, implant removal is not always easy or possible. Despite the general recommendation to remove implants after infection, a successful resolution of infection without implant removal or after partial removal has been achieved in several studies (Fitzpatrick & Solano 2010; Savicky et al. 2013; Yap et al. 2015). Risk of long-term recurrence in such cases is unknown. Prognosis and economic impact Despite the high incidence of infection and the incidence of MDR bacteria, infections of the stifle joint generally carry a favorable prognosis if treated appropriately. Resolution of infection has been achieved in 95% of cases, and lameness resolution can be observed around 38 days (range 15–45 days) after initiation of treatment (Fitzpatrick & Solano 2010; Savicky et al. 2013). In many cases, treatment requires prolonged antibiotic administration and results in additional client visits, hospitalization days, or surgeries. The economic impact of SSI has been evaluated after TPLO by Nicoll et al. (2014), and can represent a significant burden on the owner. In this Canadian study, the average postoperative cost for dogs that developed SSI was $1559, compared to an average cost of $212 for dogs that did not experience complications. Depending on the severity of the infection and treatments required, the postoperative costs varied between $145 and $5022. Presumably, the cost of treating a MDR bacterium could be higher than the cost of treating a non-resistant SSI ($2294 versus $1674). However, the difference was not significant in this publication (Nicoll et al. 2014). In addition to the financial burden, postoperative complications are also likely to decrease client satisfaction and confidence in the procedure. Conclusions Despite all the medical advances and the discovery of antibiotics more than 60 years ago, it is clear that surgical infections are here to stay. Even though infections rates have drastically decreased, the proportion of infections caused by MDR bacteria continues to increase. If the trend continues, there will soon come a post-antibiotic era in which all currently known antibiotics would be ineffective. Resistance to each and every one of the currently known antibiotic classes has already been observed (Alanis 2005). Inappropriate use of antibiotics, complacence, and the lack of discovery of new antibiotics have been largely blamed for this alarming trend (Overbye & Barrett 2005). Veterinarians are not exempt from responsibility, and the appropriate use of antibiotics is, more than ever, of the upmost importance to reduce or delay the development of bacterial resistance. It is clear that accurate data on infection rates and evidence-based guidelines for the correct use of antibiotics in veterinary surgery are lacking and must be developed. While there is a renewed push for the discovery of new antibiotics (Clardy et al. 2006; O’Connell et al. 2013), current research has been focused on understanding the mechanism of drug resistance, its epidemiology, and the role of biofilm. Understanding these may lead to new ways of disrupting the bacterial defense systems to increase the efficacy of the drugs currently available. Meanwhile, another body of research is already preparing for a post-antibiotic times, evaluating novel strategies for fighting infections without the use of antibiotics (Kaufmann 2007; de Oca 2013). What the situation will be in 5–10 years largely depends on the results of these different research avenues. References Alanis AJ. Resistance to antibiotics: are we in the postantibiotic era? Arch Med Res 2005;36:697–705. Alexander JW. The contributions of infection control to a century of surgical progress. Ann Surg 1985;201:423–428. Anderson DJ. Surgical site infections. Infect Dis Clin North Am 2011;25:135–153. Beal MW, Brown DC, Shofer FS. The effects of perioperative hypothermia and the duration of anesthesia on postoperative wound infection rate VetBooks.ir Diagnosis and Management of Orthopaedic Infection after Stifle Surgery in clean wounds: a retrospective study. Vet Surg 2000;29:123–127. Bratzler DW, Houck PM. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Am J Surg 2005;189:395–404. Budsberg SC. Osteomyelitis, In, Tobias KA, Johnston SA (eds), Veterinary Surgery: Small Animal, 1st ed., St Louis, 2012, Saunders/Elsevier, pp. 669–675. Casale SA, McCarthy RJ. Complications associated with lateral fabellotibial suture surgery for cranial cruciate ligament injury in dogs: 363 cases (1997– 2005). J Am Vet Med Assoc 2009;234:229–235. Clardy J, Fischbach MA, Walsh CT. New antibiotics from bacterial natural products. Nat Biotechnol 2006;24:1541–50. Clements DN, Owen MR, Mosley JR, et al. Retrospective study of bacterial infective arthritis in 31 dogs. J Small Anim Pract 2005;46:171–176. Clerfond P, Huneault L, Dupuis J, et al. Unilateral or single-session bilateral surgery for correction of medial patellar luxation in small dogs: short and long-term outcomes. Vet Comp Orthop Traumatol 2014;27:484–490. Cohen ML. Epidemiology of drug resistance: implications for a post-antimicrobial era. Science 1992; 257:1050–1055. Cook JL, Luther JK, Beetem J, et al. Clinical comparison of a novel extracapsular stabilization procedure and tibial plateau leveling osteotomy for treatment of cranial cruciate ligament deficiency in dogs. Vet Surg 2010;39:315–323. Corr SA, Brown C. A comparison of outcomes following tibial plateau levelling osteotomy and cranial tibial wedge osteotomy procedures. Vet Comp Orthop Traumatol 2007;20:312–319. Culver DH, Horan TC, Gaynes RP, et al. Surgical wound infection rates by wound class, operative procedure, and patient risk index National Nosocomial Infections Surveillance System. Am J Med 1991;91:152S–157S. Dal-bó Í, Ferrigno CRA, Ferreira MP, et al. Infecção óssea após osteotomia para tratamento da ruptura de ligamento cruzado em cães. Acta Sci Vet 2013; 41:1–7. Darouiche RO. Treatment of infections associated with surgical implants. N Engl J Med 2004;350: 1422–1429. de Oca E. Antimicrobial peptide elicitors: new hope for the post-antibiotic era. Innate Immun 2013;19: 227–241. de Lima Dantas B, Sul R, Parkin T, et al. Incidence of complications associated with tibial tuberosity advancement in Boxer dogs. Vet Comp Orthop Traumatol 2015;29:39–45. Eisenberg D. Surgical site infections: Time to modify the wound classification system? J Surg Res 2012; 175:54–55. Etter SW, Ragetly GR, Bennett RA, et al. Effect of using triclosan-impregnated suture for incisional closure 329 on surgical site infection and inflammation following tibial plateau leveling osteotomy in dogs. J Am Vet Med Assoc 2013;242:355–358. Eugster S, Schawalder P, Gaschen F, et al. A prospective study of postoperative surgical site infections in dogs and cats. Vet Surg 2004;33:542–550. Finsterbusch A, Argaman M, Sacks T. Bone and joint perfusion with antibiotics in the treatment of experimental staphylococcal infection in rabbits. J Bone Joint Surg Am 1970;52: 1424–32. Finsterbush A, Weinberg H. Venous perfusion of the limb with antibiotics for osteomyelitis and other chronic infections. J Bone Joint Surg Am 1972;54: 1227–34. Fitch RB, Hogan TC, Kudnig ST. Hematogenous septic arthritis in the dog: results of five patients treated nonsurgically with antibiotics. J Am Anim Hosp Assoc 2003;39:563–566. Fitzpatrick N, Solano MG. Predictive variables for complications after TPLO with stifle inspection by arthrotomy in 1000 consecutive dogs. Vet Surg 2010;39:460–474. Frey TN, Hoelzler MG, Scavelli TD, et al. Risk factors for surgical site infection-inflammation in dogs undergoing surgery for rupture of the cranial cruciate ligament: 902 cases (2005-2006). J Am Vet Med Assoc 2010;236:88–94. Gallagher AD, Mertens WD. Implant removal rate from infection after tibial plateau leveling osteotomy in dogs. Vet Surg 2012;41:705–711. Gatineau M, Dupuis J, Planté J, et al. Retrospective study of 476 tibial plateau levelling osteotomy procedures: Rate of subsequent “pivot shift”, meniscal tear and other complications. Vet Comp Orthop Traumatol 2011;24:333–341. Gibbons SE, Macias C, Tonzing MA, et al. Patellar luxation in 70 large breed dogs. J Small Anim Pract 2006;47:3–9. Hayes GM, Gibson TWG, Moens NMM, et al. Intraarticular implantation of gentamicin impregnated collagen sponge causes joint inflammation and impaired renal function in dogs. Vet Comp Orthop Traumatol 2016;29:159–163. Hayes GM, Moens NMM, Gibson TWG. A review of local antibiotic implants and applications to veterinary orthopaedic surgery. Vet Comp Orthop Traumatol 2013;26:251–259. Hill CM, Conzemius MG, Smith GK, et al. Bacterial culture of the canine stifle joint following surgical repair of ruptured cranial cruciate ligament. Vet Comp Orthop Traumatol 1999;12:1–5. Jacques M, Aragon V, Tremblay YDN. Biofilm formation in bacterial pathogens of veterinary importance. Anim Heal Res Rev 2010;11:97–121. Kalff S, Butterworth SJ, Miller A, et al. Lateral patellar luxation in dogs: a retrospective study of 65 dogs. Vet Comp Orthop Traumatol 2014;27:130–134. Kaufmann SHE. The contribution of immunology to the rational design of novel antibacterial vaccines, Nat Rev Microbiol 2007;5:491–504. VetBooks.ir 330 Surgical Treatment Lafaver S, Miller NA, Stubbs WP, et al. Tibial tuberosity advancement for stabilization of the canine cranial cruciate ligament-deficient stifle joint: surgical technique, early results, and complications in 101 dogs. Vet Surg 2007;36:573–586. Mangram Al J, Horan TC, Pearson ML, et al. Guideline for Prevention of Surgical Site Infection, 1999 Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control 1999;27:97– 132. Marchevsky AM, Read RA. Bacterial septic arthritis in 19 dogs. Aust Vet J 1999;77:233–237. Montgomery RD, Long IR, Milton JL, et al. Comparison of aerobic culturette, synovial membrane biopsy, and blood culture medium in detection of canine bacterial arthritis. Vet Surg 1989;18:300–303. Nazarali A, Singh A, Moens NMM, et al. Association between methicillin-resistant Staphylococcus pseudintermedius carriage and the development of surgical site infections following tibial plateau leveling osteotomy in dogs. J Am Vet Med Assoc 2015;247:909–916. Nazarali A, Singh A, Weese JS. Perioperative administration of antimicrobials during tibial plateau leveling osteotomy. Vet Surg 2014;43:966–971. Nelson LL. Surgical site infections in small animal surgery. Vet Clin North Am - Small Anim Pract 2011;41:1041–1056. Nicholson M, Beal M, Shofer F, et al. Epidemiologic evaluation of postoperative wound infection in clean-contaminated wounds: A retrospective study of 239 dogs and cats. Vet Surg 2002;31:577–581. Nicoll C, Singh A, Weese JS. Economic impact of tibial plateau leveling osteotomy surgical site infection in dogs. Vet Surg 2014;43:899–902. Nolff MC, Fehr M, Bolling A, et al. Negative pressure wound therapy, silver coated foam dressing and conventional bandages in open wound treatment in dogs. A retrospective comparison of 50 paired cases. Vet Comp Orthop Traumatol 2015;28:30–38. O’Connell KMG, Hodgkinson JT, Sore HF, et al. Combating multidrug-resistant bacteria: current strategies for the discovery of novel antibacterials. Angew Chem Int Ed Engl 2013;52:10706–33. Overbye KM, Barrett JF. Antibiotics: where did we go wrong? Drug Discov Today 2005;10:45–52. Owen MR, Moores AP, Coe RJ. Management of MRSA septic arthritis in a dog using a gentamicinimpregnated collagen sponge. J Small Anim Pract 2004;45:609–612. Pacchiana PD, Morris E, Gillings SL, et al. Surgical and postoperative complications associated with tibial plateau leveling osteotomy in dogs with cranial cruciate ligament rupture: 397 cases (1998-2001). J Am Vet Med Assoc 2003;222:184–193. Pille F, De Baere S, Ceelen L, et al. Synovial fluid and plasma concentrations of ceftiofur after regional intravenous perfusion in the horse. Vet Surg 2005;34:610–7. Priddy NH, Tomlinson JL, Dodam JR, et al. Complications with and owner assessment of the outcome of tibial plateau leveling osteotomy for treatment of cranial cruciate ligament rupture in dogs: 193 cases (1997-2001). J Am Vet Med Assoc 2003;222:1726– 1732. Proot JLJ, Corr SA. Clinical audit for the tibial tuberosity advancement procedure: establishing the learning curve and monitoring ongoing performance for the tibial tuberosity advancement procedure using the cumulative summation technique. Vet Comp Orthop Traumatol 2013;26:280– 284. Raske M, Hulse D. SwiveLock bone anchor stabilization of the cranial cruciate ligament deficient stifle in dogs: Clinical Outcome. Open J Vet Med 2013;03:297–301. Rubio-Martı́nez LM, Cruz AM. Antimicrobial regional limb perfusion in horses, J Am Vet Med Assoc 2006;228:706–12. Savicky R, Beale B, Murtaugh R, et al. Outcome following removal of TPLO implants with surgical site infection. Vet Comp Orthop Traumatol 2013;26: 260–265. Scharf VF, Lewis ST, Wellehan JF, et al. Retrospective evaluation of the efficacy of isolating bacteria from synovial fluid in dogs with suspected septic arthritis. Aust Vet J 2015;93:200–203. Shaver SL, Mayhew KN, Sutton JS, et al. Complications after corrective surgery for lateral patellar luxation in dogs: 36 cases (2000-2011). J Am Vet Med Assoc 2014;244:444–448. Singh A, Walker M, Rousseau J, et al. Characterization of the biofilm forming ability of Staphylococcus pseudintermedius from dogs. BMC Vet Res 2013;9:93. Thompson AM, Bergh MS, Wang C, et al. Tibial plateau levelling osteotomy implant removal: a retrospective analysis of 129 cases. Vet Comp Orthop Traumatol 2011;24:450–456. Trampuz A, Zimmerli W. Diagnosis and treatment of infections associated with fracture-fixation devices. Injury 2006;37:59–66. Vasseur PB, Levy J, Dowd E, et al. Surgical wound infection rates in dogs and cats Data from a teaching hospital. Vet Surg 1992;17:60–64. Whithair KJ, Bowersock TL, Blevins WE, et al. Regional limb perfusion for antibiotic treatment of experimentally induced septic arthritis. Vet Surg 1992;21:367–73. Wolf RE, Scavelli TD, Hoelzler MG, et al. Surgical and postoperative complications associated with tibial tuberosity advancement for cranial cruciate ligament rupture in dogs: 458 cases (2007–2009). J Am Vet Med Assoc 2012;240:1481– 1487. Yap FW, Calvo I, Smith KD, et al. Perioperative risk factors for surgical site infection in tibial tuberosity advancement: 224 stifles. Vet Comp Orthop Traumatol 2015;28:199–206. VetBooks.ir Section V Medical Management of Cruciate Ligament Rupture Introduction Although several new nonsteroidal antiinflammatory drugs have entered the veterinary market over the past several years, a limited number of different types of drug are available for the treatment of stifle osteoarthritis. In contrast, a plethora of nutritional supplements are available, although evidence of clinical efficacy for many nutritional sup- plements is limited. Physical therapy has an important role in the management of dogs with cruciate ligament rupture. There is growing evidence that appropriate rehabilitation after surgical treatment of the stifle can have important benefits to patient mobility. This section provides a detailed discussion of current medical therapies commonly used for the treatment of dogs with the cruciate ligament rupture. Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 331 VetBooks.ir VetBooks.ir 41 Medical Therapy for Stifle Osteoarthritis Steven C. Budsberg Introduction Osteoarthritis (OA) of the stifle joint is a progressive degenerative disease in dogs, which can have a profound impact on quality of life (Vasseur & Berry 1992; Lazar et al. 2005; HielmBjorkman et al. 2011). The clinical signs of stifle OA include discomfort, limited joint range of motion, loss of muscle mass and muscle tone, and decreased overall limb use. The pain can be difficult to control. One of the primary reasons hindering successful management may be the presence of central nervous system plasticity (Knazovicky et al. 2016). Additionally, while OA is considered a chronic progressive disease, the clinical picture may be quite dynamic with both intermittent periods of acute signs, or ‘flareups,’ and periods of clinical quiescence. Given all of these cofactors, it is not surprising that there is variation in the clinical impact between individual dogs. The goals of medical management are to minimize the clinical signs of OA, maintain or improve limb use and, if possible, slow the progression of the disease. Remember, OA of the joint is an end-stage process; current medical management protocols are directed at ameliorating those clinical signs. It has been proposed that multimodal therapy can yield a better response in the treatment of OA through the synergism of various therapies acting in non-competing modes of action. This allows for the administration of collectively lower doses of medication, decreasing the potential side effects of any one treatment prescribed (Altman et al. 2000). In addition to nonsteroidal anti-inflammatory drugs (NSAIDs), multimodal therapy for the treatment of OA also incorporates weight loss, exercise modification, rehabilitation, and diet supplementation (Argoff 2002; Budsberg & Bartges 2006; Aragon et al. 2007; Johnston et al. 2008; Vandeweerd et al. 2012; Monterio-Steagall et al. 2013; Comblain et al. 2016). In the last few years, a plethora of new interventions have been introduced as adjunctive therapies for OA. These include, but are not limited to, non-NSAID analgesics, purposed disease-modulating agents, biological products (e.g., autologous protein products, stem cell products, monoclonal antibodies), other oral supplements, and physical modalities such as acupuncture and light therapy. Most of these therapies have been employed without extensive clinical trials to assess efficacy. It is important to remember the need for blinded, randomized, clinical trials to assess efficacy of new treatments. A care-giver placebo effect Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 333 VetBooks.ir 334 Medical Management of Cruciate Ligament Rupture for veterinary medicine is defined when sham medical intervention causes pet care-givers, such as owners or veterinarians, to believe that the provided treatment improved the pet’s condition. A significant care-giver placebo effect has been documented in dogs with OA (Conzemius & Evans 2012). The care-giver placebo effect for owners evaluating their dog’s lameness occurred 56.9% of occasions. A caregiver placebo effect for veterinarians occurred 44.8% of the time when they examined dogs for lameness at a walk or a trot, and 43.1% of the time when veterinarians evaluated dogs for signs of pain on palpation of the joint. In all of these measurements, the owner and veterinarian, who was blinded to the treatment, believed there were improvements while the dog was on placebo treatment. Weight management The importance of weight management in the prevention and treatment of OA cannot be overestimated. A substantial portion of the patient population is obese, and it is recognized that obesity is an important medical disease in dogs (German 2006; Laflamme 2012; German 2016). Obesity, defined as exceeding ideal body weight by 15–20%, places excessive forces on joints and articular cartilage, and is exacerbated by inactivity, propagating a vicious cycle of muscle atrophy and decreased overall fitness (Impellizeri et al. 2000; Kealy et al. 2000). While there is not a clear cause and effect relationship between obesity and OA, fat is considered a metabolically active tissue promoting inflammation (Greenburg & Obin 2006). There is growing evidence that inflammatory mediators released from adipose tissue, including the cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), and the adipokines leptin, visfatin, adiponectin, adipsin and resistin, may have roles in the pathogenesis of OA (Frye et al. 2016). Levels of adipsin and leptin are associated with knee OA progression in human beings (Martel-Pelletier et al. 2016). It has also been proposed that leptin could play a role in the development of cruciate ligament rupture in dogs by the alteration of ligament fibroblast and collagenase activity. However, further research is needed to substantiate this claim (Comerford et al. 2005; Otero et al. 2006). Despite these controversies about the cause and effect of obesity and OA, weight reduction has been shown clinically to ameliorate the signs associated with OA and to have preventive effects. Burkholder et al. (2000) demonstrated, in a population of overweight dogs with clinical signs of hip dysplasia, that appropriate weight loss markedly improved ground reaction forces and joint mobility. Additionally, more recently, Marshall et al. (2010) showed decreased lameness and improved kinetic gait analysis with body weight reduction in dogs with hip and elbow OA. A series of studies have assessed the protective benefits of a calorically restricted diet for the development of OA (Kealy et al. 2000; Impellizeri et al. 2000; Kealy et al. 2002; Mlacnik et al. 2006; Smith et al. 2006). Nonsteroidal anti-inflammatory drugs NSAIDs are the most commonly prescribed class of medications to alleviate the clinical signs of OA and are the mainstay in any medical management. These drugs are effective, with relatively low adverse effects. NSAIDs reduce the formation of inflammatory prostaglandins, primarily PGE2, and thromboxane production by inhibiting cyclooxygenase (COX) enzymes in the arachadonic acid (AA) pathway. With the inhibition of COX isoenzymes, NSAIDs have a local effect at the site of injury as well as a central effect minimizing spinal nociception and central sensitization. NSAIDs may also sensitize mu receptors to the effects of opioids, explaining the synergism between these two medications. The benefit exerted by NSAIDs in the treatment of OA is indisputable. Recently, specific receptor antagonists have been developed to act on receptors activated by PGE2. Pharmacologically, these PGE2 receptors are subdivided into at least four subtypes (EP1–EP4). The distribution of these receptors is considered when explaining the multiple effects of PGE2 in various tissues (Narumiya et al. 1999; Kawabata 2011; Kawahara et al. 2015). There is increasing evidence that demonstrates the effectiveness of selective EP4 receptor antagonists as analgesics in a variety of inflammatory pain models in a variety of species (Lin et al. 2006; Nakao et al. 2007; Murase et al. 2008; Colucci et al. 2010), as well as in clinical trials in dogs (Rausch-Derra et al. 2015; Rausch-Derra et al. 2016). NSAIDs are VetBooks.ir Medical Therapy for Stifle Osteoarthritis not without adverse effects and must be used judiciously, especially in dogs with pre-existing conditions. The primary selection of an NSAID is based on individual analgesic and adverse responses. Despite similar efficacies between different NSAIDs, there can be a dramatic difference in individual response. It may be necessary to try different NSAIDs until an acceptable level of analgesia is obtained or the patient experiences an adverse response. Given that a patient may need to be medicated with different NSAIDs, there is extensive debate concerning the necessity or length of washout between the administration of sequential NSAIDs with little data to support any particular dosing protocols (Lascelles et al. 2005; Ryan et al. 2007). However, there is one situation in which a washout period can strongly be considered, which is following the use of aspirin. Aspirin use induces aspirintriggered lipoxins (ATL), which have protective effects on the stomach lining. ATLs diminish gastric mucosal injury from nitric oxide produced by traumatized vascular endothelium (Souza et al. 2003). The concurrent or immediate administration of other NSAIDs, particularly COX-2 selective or COX-1 sparing drugs, will completely block these lipoxins and their protective effects, thus increasing the risk of gastric ulceration. Additional analgesics Although NSAIDs are traditionally the first line of pharmaceuticals used to treat OA, they incompletely suppress the inflammatory process through a limited mechanism of action and, therefore, are not completely effective at obviating the clinical signs of OA. A multimodal approach incorporating additional analgesics with differing mechanisms and sites of action is often indicated for improved pain control while lowering the therapeutically effective dose, thereby minimizing the adverse effects of NSAIDs (Lascelles et al. 2008). Amantadine Amantadine, first recognized as an anti-viral agent, has gained popularity for the treatment of chronic pain disorders via the inhibition of 335 N-methyl-D-aspartate (NMDA) receptors. NMDA receptor activation, secondary to chronic stimulation of A delta and C fibers, is believed to be the primary component leading to ‘spinal windup.’ A study by Lascelles et al. (2008) compared the effects of adjunctive amantadine with meloxicam in a population of dogs with chronic OA refractory to NSAID therapy alone. Dogs treated with meloxicam in conjunction with amantadine had improved client-specific outcome measure scores and overall activity, compared with the administration of meloxicam alone. Tramadol Tramadol is an opioid analgesic acting at the mu receptor while inhibiting serotonin uptake and norepinephrine re-uptake (Raffa et al. 1992). Tramadol also inhibits central pro-inflammatory cytokines and acts as an agonist of the transient receptor potential vanilloid 1 (TRPV1) receptor, influencing various neuronal cation channels while locally decreasing IL-6 and substance P (Marincsak et al. 2008). Only one investigation has been conducted in dogs with OA to evaluate the effects of oral tramadol in a blinded study using positive and negative controls. A significant improvement was noted in the positive control group (carprofen, 2.2 mg kg–1 twice daily) and the tramadol (4 mg kg–1 three times daily) group compared with the placebo group (administered three times daily) using the canine brief pain inventory questionnaire (Malek et al. 2012). However, several other outcome measures in this study showed no improvement over placebo or baseline during the administration of tramadol. Thus, the limited data from this study is difficult to assess in terms of recommending tramadol use in dogs with OA. Gabapentin Gabapentin is structurally similar to the central inhibitory neurotransmitter gammaaminobutyric acid (GABA). The latter is synthesized from glutamate, an excitatory neurotransmitter. During periods of chronic pain, there is an upregulation of glutamate and subsequent NMDA receptor activation with a VetBooks.ir 336 Medical Management of Cruciate Ligament Rupture relative decrease in GABA concentration. This results in the loss of an endogenous feedback mechanism and an uninhibited nociceptive pathway. Although gabapentin’s mechanism of action was initially assumed to be through GABAergic transmission, the therapeutic effects are believed to be moderated through the alpha2 subunit of voltage-gated calcium channels, resulting in central analgesia (Davies et al. 2007). To the present author’s knowledge, there are no available clinical or experimental studies evaluating the role of gabapentin in treatment of OA in dogs. Anti-nerve growth factor antibody As a member of the neurotrophin family, nerve growth factor (NGF) can bind the general neurotrophin receptor p75, as well as its highaffinity cognate receptor, tropomyosin-related kinase (Trk)A (Mantyh et al. 2011). The NGFTrkA pathway in particular appears to be critical in driving acute and chronic pain. Recently, canine and feline versions of anti-NGF antibodies have been developed. Two recent studies, where dogs with OA were treated with anti-NGF antibodies, yielded promising results (Webster et al. 2014; Lascelles et al. 2015). stem cells (MSCs). MSCs have high proliferative and self-renewal capabilities, are adhesive to plastic surfaces, demonstrate specific cellsurface proteins, and have the potential to differentiate in at least three lineages including bone, cartilage, and adipose tissue. The second category is plasma-based products such as platelet-rich plasma (PRP). PRP consists of a pool of signaling proteins including growth factors, cytokines, and other adhesive proteins involved in healing mechanisms. The list is not exhaustive. The final category is conditioned culture media, which contain biologically active molecules secreted by cells in vitro; these molecules affect cell functions. Autologous and, more recently, allogenic stem cell therapies have shown some limited positive results in clinical trials when given to dogs with OA (Black et al. 2007; Black et al. 2008; Guercio et al. 2012; Vilar et al. 2013; Cuervo et al. 2014; Vilar et al. 2014; Harman et al. 2016). Additionally, studies of limited size and scope have shown initial positive results for autologous plasma/platelet treatments in dogs with OA (Fahie et al. 2013; Franklin & Cook 2013; Wanstrath et al. 2016). At present, no clinical data are available on conditioned culture media. Chondromodulating agents Botulinum toxin A Botulinum toxin A is a potent neurotoxin produced by the bacterium Clostridium botulinum. The toxin inhibits the release of neurotransmitters involved in direct pain perception. Thus, intra-articular injection of this product may have direct local anti-nociceptive properties in painful osteoarthritic joints. Two small studies have been performed in dogs to evaluate the intra-articular injection of botulinum toxin with limited positive results (Hadley et al. 2010; Heikkila et al. 2014). Biological products Current regenerative technologies for musculoskeletal injuries consist of three general categories. The first category is adult mesenchymal stromal cells, also known as mesenchymal Recently, increased interest has been shown in the alternative management of OA, not only to alleviate clinical signs associated with the disease, but also to slow the process of cartilage degradation and to promote cartilage synthesis. Polysulfated glycosaminoglycan Polysulfated glycosaminoglycan (PSGAG) is a synthetic mixture of highly sulfated GAGs, principally chondroitin sulfate, extracted from bovine lung and tracheal cartilage (Todhunter & Lust 1994). PSGAGs are beneficial in the treatment of OA by inhibiting cartilage-degradative enzymes IL-1, matrix metalloproteinases (MMPs), lysosomal elastase, cathepsin G, PGE2, the formation of oxygen radicals, and C3a and C5a complement fragments (Todhunter & Lust 1994; Sevalla et al. 2000; Mertens et al. 2003; Fujiki et al. 2007). PSGAGs stimulate VetBooks.ir Medical Therapy for Stifle Osteoarthritis cartilage repair processes by promoting protein synthesis, collagen formation, and increasing GAG and hyaluronan concentration (Glade 1990). PSGAGs also maintain chondrocyte viability and stimulate chondrocyte division, thereby slowing the process of extracellular matrix degradation (Glade 1990; Sevalla et al. 2000). Since PSGAGs are a heparin analog, their use in dogs with coagulopathies or concurrent administration of NSAIDs, particularly those with strong COX-1 (anti-thromboxane) activity, is contraindicated. Limited clinical data that supports the use of PSGAG in dogs with OA are available (Lust et al. 1992; McNamara et al. 1997; Fujiki et al. 2007). Hyaluronic acid Hyaluronic acid (HA) is a linear, non-sulfated GAG that is the primary constituent of synovial fluid. HA interacts with aggrecan monomer through non-covalent association to link proteins to produce the large aggregating polyglycosaminoglycans of articular cartilage (McNamara et al. 1997). Administered HA is speculated to increase synovial viscosity by viscosupplementation. A variety of clinical and experimental trials are available evaluating the efficacy of HA for the treatment of cruciate ligament rupture. However, these studies yield conflicting data on HA’s ability to ameliorate the progression of stifle OA (Schiavinato et al. 1989; Marshall et al. 2000; Smith et al. 2001; Hellström et al. 2003; Canapp et al. 2005; Smith et al. 2005; Franklin & Cook 2013). Dietary supplements Omega-3 fatty acids Nutritional supplementation with omega-3 (n-3) fatty acids has been proposed as an adjunctive therapy for the management of OA. The most prevalent of the polyunsaturated fatty acids (PUFAs) comprising the cell membrane are omega-6 (n-6) fatty acid and arachadonic acid (AA). When the cell membrane, and therefore AA, is metabolized by the COX enzyme, pro-inflammatory and vasoactive mediators of 2- and 4-series prostaglandins, thromboxanes, 337 and leukotrienes are produced. During the process of OA, there is an increase in serum, cartilage and synovial fluid concentrations of n-6 PUFAs that propagate an inflammatory reaction. The incorporation of n-3 PUFAs, eicosapentaenoic acid (EPA), into the cell membrane will compete with AA for COX metabolism. This results in the production of 3- and 5series prostaglandins, thromboxanes, and leukotrienes that are significantly less inflammatory and vasoactive, curtailing the inflammatory response (Bauer 2007). There are several n-3 fatty acids available, including EPA, docosahexainoid acid (DHA) and alpha-linolenic acid (ALA), although EPA is the only n-3 PUFA with selectivity for the chondrocyte cell membrane. Several studies clinically support diet supplementation, including complete diets of high dietary n-3 fatty acids, in the management of OA (Miller 1992; Bartges et al. 2001; Roush et al. 2010; Hielm-Björkman et al. 2012; Moreau et al. 2013; Rialland et al. 2013; Mehler et al. 2016). Glucosamine and chondroitin sulfate Glucosamine and chondroitin sulfate formulations encompass the majority of nutritional supplements available on the current market for the management of OA. Glucosamine is an aminomonosaccharide used in the synthesis of the disaccharide units of glycoasaminoglycan (McNamara et al. 1997; Neil et al. 2005). It can then be incorporated into the large aggregating and small-non-aggregating proteoglycans of articular cartilage, or as part of the disaccharide units of hyaluronan. Chondroitin sulfate is a longchain polymer of repeating disaccharide units of galactosamine sulfate and glucuronic acid that constitutes the majority of glucosaminoglycans within articular cartilage (McNamara et al. 1997; Neil et al. 2005). The mechanisms of action of chondroitin sulfate are synergistic with that of glucosamine, and can stimulate the synthesis of endogenous glycosaminoglycans and inhibit the synthesis of degradative enzymes, including MMPs. Additionally, chondroitin sulfate inhibits both IL-1-induced type II collagen degeneration, histamine-induced inflammation, and has the unique ability to improve synovial fluid viscosity by increasing hyaluronan concentration VetBooks.ir 338 Medical Management of Cruciate Ligament Rupture (McNamara et al. 1997; Kelly 1998; Canapp et al. 1999; Lippiello et al. 2000; Neil et al. 2005). Notably, two studies evaluating the use of glucosamine and chondroitin sulfate for the amelioration of clinical signs associated with OA yielded conflicting results. McCarthy et al. (2007) demonstrated a positive effect on pain score, weight-bearing, and severity of clinical condition in dogs with hip and elbow OA, while another study (Moreau et al. 2003) showed no effect. Two small studies suggested positive improvements when glucosamine and chondroitin sulfate are combined with glycosylated undenatured type II collagen (D’Altilio et al. 2007; Gupta et al. 2012). Avocado and soybean oil unsaponifiables Avocado and soybean oil unsaponifiables (ASUs) are biologically active lipids believed to have anti-inflammatory and anti-osteoarthritic properties. ASUs decrease the expression of inflammatory mediators and cartilage degradation (TNFα, IL-1β, COX-2, cytokine-inducible nitric oxide synthase (iNOS), and MMPs) and stimulate matrix synthesis by upregulating transforming growth factor beta (TGF-β) expression by chondroblasts and osteoblasts (Altinel et al. 2007; Au et al. 2007). A recent experimental study reported the protective effects of ASUs in a series of dogs with transected cranial cruciate ligaments (Boileau et al. 2009). Compared to the placebo group, dogs treated with ASUs had smaller macroscopic lesions on the tibial plateau. Histologically, these dogs had decreased severity of tibial and femoral cartilage lesions, synovitis, and a decreased loss of subchondral bone and calcified cartilage thickness compared with the placebo group. Conclusions The goals of multimodal medical therapy are to simultaneously maximize analgesia while minimizing the incidence and severity of adverse effects and, if possible, to slow disease progression. This can be achieved by targeting multiple sites along the nociceptive pathway, with the inclusion of medications with varying mechanisms of action. It is important when creating, maintaining, and adjusting multimodal regimens to remember that no individual responds in the same manner, and no individual disease progresses in the same way. It is imperative to continually reassess the patient’s response and adapt treatment as indicated. References Altinel L, Saritas ZK, Kose KC, et al. Treatment with unsaponifiable extracts of avocado soybean increases TGFB1 and TGFB2 levels in canine joint fluid. Tohoku J Exp Med 2007;211:181–186. Altman RD, Hochberg MC, Moskowitz RW, et al. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum 2000;43:1905–1915. Aragon CL, Hofmeister EH, Budsberg SC. Systematic review of clinical trials of treatments for osteoarthritis in dogs. J Am Vet Med Assoc 2007;15;230:514–521. Argoff CE. Pharmacologic management of chronic pain. J Am Osteopath Assoc 2002;102:S21–S27. Au RY, Al-Talib TK, Au AY, et al. Avocado soybean unsaponifiables (ASU) suppress TNFalpha, IL-1beta, COX-2, iNOS gene expression, and prostaglandin E2 and nitric oxide production in articular chondrocytes and monocytes/ macrophages. Osteoarthritis Cartilage 2007;15: 1249–1255. Bartges JW, Budsberg SC, Pazak HE, et al. Effects of different n6:n3 fatty acid ratio diets on canine stifle osteoarthritis. Proc Orthop Res Soc Annual Meeting 2001;47:462. Bauer JE. Responses of dogs to dietary omega-3 fatty acids. J Am Vet Med Assoc 2007;231:1657–1661. Black L, Gaynor J, Gahring D, et al. Effect of adiposederived mesenchymal stem and regenerative cells on lameness in dogs with chronic osteoarthritis of the coxofemoral joints: a randomized, doubleblinded, multicenter, controlled trial. Vet Ther 2007;8:272–284. Black L, Gaynor J, Adams C, et al. Effect of intraarticular injection of autologous adipose-derived mesenchymal stem and regenerative cells on clinical signs of chronic osteoarthritis of the elbow joint in dogs. Vet Ther 2008;9:192–200. Boileau C, Martel-Pelletier J, Caron J, et al. Protective effects of total fraction of avocado/soybean unsaponifiables on the structural changes in experimental dog osteoarthritis: inhibition of nitric oxide synthase and matrix metalloproteinase-13. Arthritis Res Ther 2009;11:R41. VetBooks.ir Medical Therapy for Stifle Osteoarthritis Budsberg SC, Bartges JW. Nutrition and osteoarthritis in dogs: does it help? Vet Clin North Am Small Anim Pract 2006;36:1307–1323. Burkholder WJ, Taylor L, Hulse DA. Weight loss to optimal body condition increases ground reactive force in dogs with osteoarthritis. Compend Cont Educ Pract Vet 2000;23:74. Canapp SO, McLaughlin RM, Hoskinson JJ, et al. Scintigraphic evaluation of dogs with acute synovitis after treatment with glucosamine hydrochloride and chondroitin sulfate. Am J Vet Res 1999;60:1552– 1557. Canapp SO, Cross AR, Brown MP, et al. Examination of synovial fluid and serum following intravenous injections of hyaluronan for the treatment of osteoarthritis in dogs. Vet Comp Orthop Traumatol 2005;18:169–174. Colucci J, Boyd M, Berthelette C, et al. Discovery of 4-{1-[({1-[4-(trifluoromethyl)benzyl]-1H-indol7-yl}carbonyl)amino]cyclopropyl}benzoic acid (MF-766), a highly potent and selective EP4 antagonist for treating inflammatory pain. Bioorg Med Chem Lett 2010;20:3760–3763. Comblain F, Serisier S, Barthelemy N, et al. Review of dietary supplements for the management of osteoarthritis in dogs in studies from 2004 to 2014. J Vet Pharmacol Ther 2016;39:1–15. Comerford EJ, Tarlton JF, Innes JF et al. Metabolism and composition of the canine anterior cruciate ligament relate to difference in knee joint mechanics and predisposition to ligament rupture. J Orthop Res 2005;23:61–66. Conzemius MG, Evans RB. Caregiver placebo effect for dogs with lameness from osteoarthritis. J Am Vet Med Assoc 2012;241:1314–1319. Cuervo M, Rubio M, Sopena J, et al. Osteoarthritis in dogs: a randomized study using mesenchymal stem cells from adipose tissue and plasma rich in growth factors. Int J Mol Sci 2014;15:13437–13460. D’Altilio M, Peal A, Alvey M, et al. Therapeutic efficacy and safety of undenatured type II collagen singly or in combination with glucosamine and chondroitin in arthritic dogs. Toxicol Mech Methods 2007;17:189–196. Davies A, Hendrich J, Van Minh AT, et al. Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends Pharmacol Sci 2007;28:220–228. Fahie MA, Ortolano GA, Guercio V, et al. A randomized controlled trial of the efficacy of autologous platelet therapy for the treatment of osteoarthritis in dogs. J Am Vet Med Assoc 2013;243:1291–1297. Franklin SP, Cook JL. Prospective trial of autologous conditioned plasma versus hyaluronan plus corticosteroid for elbow osteoarthritis in dogs. Can Vet J 2013;54:881–884. Frye CW, Shmalberg JW, Wakshlag JJ. Obesity, exercise and orthopedic disease. Vet Clin North Am Small Anim Pract 2016;46:831–841 339 Fujiki M, Shineha J, Yamanokucki K, et al. Effects of treatment of polysulfated glycosaominoglycan on serum cartilage olgomeric matrix protein and C-reactive protein concentrations, serum matrix metalloproteinase-2 and -9 activities, and lameness in dogs with osteoarthritis. Am J Vet Res 2007;68:827–833. German AJ. The growing problem of obesity in dogs and cats. J Nutr 2006;136:1940S–1946S. German AJ. Weight management in obese pets: the tailoring concept and how it can improve results. Acta Vet Scand. 2016;20:57. Glade MJ. Polysulfated glycosaminoglycan accelerates net synthesis of collagen and glycosaminoglycans by arthritic equine cartilage tissues and chondrocytes. Am J Vet Res 1990;51:779–785. Greenberg AS, Obin MS. Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 2006;83:S461–S465. Guercio A, Di Marco P, Casella S, et al. Production of canine mesenchymal stem cells from adipose tissue and their application in dogs with chronic osteoarthritis of the humeroradial joints. Cell Biol Int 2012;36:189–194. Gupta RC, Canerdy TD, Lindley J, et al. Comparative therapeutic efficacy and safety of type-II collagen (UC-II), glucosamine and chondroitin in arthritic dogs: pain evaluation by ground force plate. J Anim Physiol Anim Nutr (Berl) 2012;96:770–777. Hadley HS, Wheeler JL, Petersen SW. Effects of intraarticular botulinum toxin type A (Botox) in dogs with chronic osteoarthritis. Vet Comp Orthop Traumatol 2010;23:254–258. Harman R, Carlson K, Gaynor J, et al. A prospective, randomized, masked, and placebo-controlled efficacy study of intraarticular allogeneic adipose stem cells for the treatment of osteoarthritis in dogs. Front Vet Sci 2016;3:81. Heikkila HM, Hielm-Björkman AK, Morelius M, et al. Intra-articular botulinum toxin A for the treatment of osteoarthritic joint pain in dogs: a randomized, double-blinded, placebo-controlled clinical trial. Vet J 2014;200:162–169. Hellström LE, Carlsson C, Boucher JF, et al. Intraarticular injections with high molecular weight sodium hyaluronate as a therapy for canine arthritis. Vet Rec 2003;153:89–90. Hielm-Björkman AK, Kapatkin AS, Rita HJ. Reliability and validity of a visual analogue scale used by owners to measure chronic pain attributable to osteoarthritis in their dogs. Am J Vet Res 2011;72:601–607. Hielm-Björkman A, Roine J, Elo K, et al. An un-commissioned randomized, placebo-controlled double-blind study to test the effect of deep sea fish oil as a pain reliever for dogs suffering from canine OA. BMC Vet Res 2012;8:157. Impellizeri JA, Tetrick MA, Muir P. Effect of weight reduction on clinical signs of lameness in dogs VetBooks.ir 340 Medical Management of Cruciate Ligament Rupture with hip osteoarthritis. J Am Vet Med Assoc 2000;216:1089–1091. Johnston SA, McLaughlin RM, Budsberg SC. Nonsurgical management of osteoarthritis in dogs. Vet Clin North Am Small Anim Pract 2008;38:1449– 1470. Kawabata A. Prostaglandin E2 and pain – an update. Biol Pharm Bull 2011;34:1170–1073. Kawahara K, Hohjoh H, Inazumi T, et al. Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors. Biochim Biophys Acta 2015;1851:414–421. Kealy RD, Lawler DF, Ballam JM, et al. Evaluation of the effect of limited food consumption on radiographic evidence of osteoarthritis in dogs. J Am Vet Med Assoc 2000;217:1678–1680. Kealy RD, Lawler DF, Ballam JM, et al. Effects of diet restriction on life span and age-related changes in dogs. J Am Vet Med Assoc 2002;220:1315–1320. Kelly GS. The role of glucosamine sulfate and chondroitin sulfates in the treatment of degenerative joint disease. Altern Med Rev 1998;3:27–39. Knazovicky D, Helgeson ES, Case B, et al. Widespread somatosensory sensitivity in naturally occurring canine model of osteoarthritis. Pain 2016;157:1325– 1332 Laflamme DP. Companion Animals Symposium: Obesity in dogs and cats: What is wrong with being fat? J Anim Sci 2012;90:1653–1662. Lascelles BD, McFarland JM, Swann H. Guidelines for safe and effective use of NSAIDs in dogs. Vet Ther 2005;6:237–251. Lascelles BDX, Gaynor JS, Smith ES, et al. Amantidine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs. J Vet Intern Med 2008;22:53–59. Lascelles BD, Knazovicky D, Case B, et al. A caninespecific anti-nerve growth factor antibody alleviates pain and improves mobility and function in dogs with degenerative joint disease-associated pain. BMC Vet Res 2015;11:101 Lazar TP, Berry CR, de Haan JJ, et al. Long-term radiographic comparison of tibial plateau leveling osteotomy versus extracapsular stabilization for cranial cruciate ligament rupture in the dog. Vet Surg 2005;34:133–141. Lin CR, Amaya F, Barrett L, et al. Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity. J Pharmacol Exp Ther 2006;319:1096–1103. Lippiello L, Woodward J, Karpman R, et al. In vivo chondroprotection and metabolic synergy of glucosamine and chondroitin sulfate. Clin Orthop Rel Res 2000;381:229–240. Lust G, Williams AJ, Burton-Wurster N, et al. Effects of intramuscular administration of glycosaminoglycan polysulfates on signs of incipient hip dysplasia in growing pups. Am J Vet Res 1992;53:1836– 1843. Malek S, Sample SJ, Schwartz Z, et al. Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using clientowned dogs with hip osteoarthirits. BMC Vet Res 2012;8:185. Mantyh PW, Koltzenburg M, Mendell LM, et al. Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology 2011;115:189– 204. Marincsak R, Toth BI, Czifra G, et al. The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1. Anesth Analg 2008;106:1890–1896. Marshall KW, Manolopoulos V, Mancer K, et al. Amelioration of disease severity by intraarticular hylan therapy in bilateral canine osteoarthritis. J Orthop Res 2000;18:416–425. Marshall WG, Hazewinkel HA, Mullen D, et al. The effect of weight loss on lameness in obese dogs with osteoarthritis. Vet Res Commun 2010;34:241–253 Martel-Pelletier J, Raynauld JP, Dorais M, et al. The levels of the adipokines adipsin and leptin are associated with knee osteoarthritis progression as assessed by MRI and incidence of total knee replacement in symptomatic osteoarthritis patients: a post hoc analysis. Rheumatology (Oxford) 2016;55:680–688. McCarthy G, O’Donovan J, Jones B, et al. Randomised double-blind, positive-controlled trial to assess the efficacy of glucosamine/chondroitin sulfate for the treatment of dogs with osteoarthritis. Vet J 2007;174:54–61. McNamara PS, Johnston SA, Todhunter RJ. Slowacting disease-modifying osteoarthritis agents. Vet Clin North Am Small Anim Pract 1997;27:863– 881. Mehler SJ, May LR, King C, et al. A prospective, randomized, double blind, placebo-controlled evaluation of the effects of eicosapentaenoic acid and docosahexaenoic acid on the clinical signs and erythrocyte membrane polyunsaturated fatty acid concentrations in dogs with osteoarthritis. Prostaglandins Leukot Essent Fatty Acids 2016;109:1–7. Mertens WD, MacLead JN, Fubini L, et al. Polysulphated glycosaminoglycans modulate transcription of interleukin-1B treated chondrocytes in monolayer culture. Vet Comp Orthop Traumatol 2003;2:93–98. Miller WH, Scott DW, Wellington JR. Treatment of dogs with hip arthritis with a fatty acid supplement. Canine Pract 1992;17:6–8. Mlacnik E, Bockstahler BA, Muller M, et al. Effects of caloric restriction and a moderate or intense physiotherapy program for treatment of lameness in overweight dogs with osteoarthritis. J Am Vet Med Assoc 2006;229:1756–1760. Monteiro-Steagall BP, Steagall PV, Lascelles BD. Systematic review of nonsteroidal anti-inflammatory VetBooks.ir Medical Therapy for Stifle Osteoarthritis drug-induced adverse effects in dogs. J Vet Intern Med 2013;27:1011–1019. Moreau M, Dupuis J, Bonneau NH, et al. Clinical evaluation of a nutraceutical, carprofen and meloxicam for the treatment of dogs with osteoarthritis. Vet Rec 2003;152:323–329. Moreau M, Troncy E, Del Castillo JR, et al. Effects of feeding a high omega-3 fatty acids diet in dogs with naturally occurring osteoarthritis. J Anim Physiol Anim Nutr (Berl) 2013;97:830–837. Murase A, Okumura T, Sakakibara A, et al. Effect of prostanoid EP4 receptor antagonist, CJ-042,794, in rat models of pain and inflammation. Eur J Pharmacol 2008;580:116–121. Nakao K, Murase A, Ohshiro H, et al. CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties. J Pharmacol Exp Ther 2007;322: 686–694. Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structure, properties and functions. Physiol Rev 1999;79:1193–1226. Neil KM, Caron JP, Orth MW. The role of glucosamine and chondroitin sulfate in treatment for and prevention of osteoarthritis in animals. J Am Vet Med Assoc 2005;226:1079–1088. Otero M, Lago R, Gomez R, et al. Leptin: a metabolic hormone that functions like a proinflammatory adipokine. Drug News Perspect 2006;19:21–26. Raffa RB, Friderichs E, Reimann W, et al. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J Pharmacol Exp Ther 1992;260:275–285. Rausch-Derra L, Huebner M, Wofford J, et al. Prospective, randomized, masked, placebocontrolled multisite clinical study of grapiprant, an EP4 prostaglandin receptor antagonist (PRA), in dogs with osteoarthritis. J Vet Intern Med 2016;30:756–763. Rausch-Derra LC, Huebner M, Rhodes L. Evaluation of the safety of long-term, daily oral administration of grapiprant, a novel drug for treatment of osteoarthritic pain and inflammation, in healthy dogs. Am J Vet Res 2015;76:853–859. Rialland P, Bichot S, Lussier B, et al. Effect of a diet enriched with green-lipped mussel on pain behavior and functioning in dogs with clinical osteoarthritis. Can J Vet Res 2013;77:66–74. Roush JK, Cross AR, Renberg WC, et al. Evaluation of the effects of dietary supplementation with fish oil omega-3 fatty acids on weight bearing in dogs with osteoarthritis. J Am Vet Med Assoc 2010;236:67–73. Ryan WG, Moldave K, Carithers D. Switching NSAIDs in practice: insights from the Previcox (firocoxib) experience trial. Vet Ther 2007;8:263– 271. Schiavinato A, Lini E, Guidolin D, et al. Intraarticular sodium hyaluronate injections in the 341 Pond-Nuki experimental model of osteoarthritis in dogs. II. Morphological findings. Clin Orthop Relat Res 1989;241:286–299. Sevalla K, Todhunter RJ, Verneir-Singer M, et al. Effect of polysulfated glycosaminoglycan on DNA content and proteoglycan metabolism in normal and osteoarthritic canine articular cartilage explants. Vet Surg 2000;29:407–414. Smith G, Jr, Myers SL, Brandt KD, et al. Effect of intraarticular hyaluronan injection on vertical ground reaction force and progression of osteoarthritis after anterior cruciate ligament transection. J Rheumatol 2005;32:325–334. Smith GK, Paster ER, Powers MY, et al. Lifelong diet restriction and radiographic evidence of osteoarthritis of the hip joint in dogs. J Am Vet Med Assoc 2006;229:690–693. Smith GN, Jr, Mickler EA, Myers SL, et al. Effect of intraarticular hyaluronan injection on synovial fluid hyaluronan in the early stage of canine posttraumatic osteoarthritis. J Rheumatol 2001;28:1341– 1346. Souza MH, de Lima OM, Jr, Zamuner SR, et al. Gastritis increases resistance to aspirin-induced mucosal injury via COX-2-mediated lipoxin synthesis. Am J Physiol Gastrointest Liver Physiol 2003;285:54– 61. Todhunter RJ, Lust G. Polysulfated glycosaminoglycan in the treatment of osteoarthritis. J Am Vet Med Assoc 1994;8:1245–1251. Vandeweerd JM, Coisnon C, Clegg P, et al. Systematic review of efficacy of nutraceuticals to alleviate clinical signs of osteoarthritis. J Vet Intern Med 2012;26:448–456. Vasseur PB, Berry CR. Progression of stifle osteoarthrosis following reconstruction of the cranial cruciate ligament in 21 dogs. J Am Anim Hosp Assoc 1992;28:129–136. Vilar JM, Morales M, Santana A, et al. Controlled, blinded force platform analysis of the effect of intraarticular injection of autologous adiposederived mesenchymal stem cells associated to PRGF-Endoret in osteoarthritic dogs. BMC Vet Res 2013;9:131. Vilar JM, Batista M, Morales M, et al. Assessment of the effect of intra-articular injection of autologous adipose-derived mesenchymal stem cells in osteoarthritic dogs using a double blinded force platform analysis. BMC Vet Res 2014;10:143. Wanstrath AW, Hettlich BF, Su L, et al. Evaluation of a single intra-articular injection of autologous protein solution for treatment of osteoarthritis in a canine population. Vet Surg 2016;45:764–774. Webster RP, Anderson GI, Gearing DP. Canine Brief Pain Inventory scores for dogs with osteoarthritis before and after administration of a monoclonal antibody against nerve growth factor. Am J Vet Res 2014;75:532–535. VetBooks.ir VetBooks.ir 42 Rehabilitation for Dogs with Cruciate Ligament Rupture Denis J. Marcellin-Little and Courtney J. Arnoldy Introduction Physical rehabilitation is routinely incorporated into a plan for the care of dogs with cruciate ligament rupture (CR). Rehabilitation is often performed during the early postoperative period after surgical stabilization, but is also part of the conservative management of dogs where surgery is not performed, or part of the long-term management of dogs that fail to thrive after surgery. The aim of this chapter is to review rehabilitation goals and treatment options for dogs with CR, to review the scientific evidence supporting rehabilitation, and to discuss the selection of rehabilitation plans for specific patients. The goals of rehabilitation for dogs with cruciate ligament rupture The goals of rehabilitation for dogs recovering from surgery to stabilize stifle joints with CR include providing pain relief throughout recovery, eliminating postoperative edema, maintaining or recovering stifle joint motion, promoting controlled limb use, preventing and recovering from a loss of muscle mass and from changes in posture resulting from chronic pain and limb disuse, preventing abnormal movement strategies, and preventing mechanical complications after surgery. The goals of rehabilitation in dogs with CR before surgery and in dogs with CR that are managed without surgery are similar to the goals listed above, with emphasis on providing pain management, promoting controlled limb use, preventing abnormal movement strategies, preventing and recovering from a loss of muscle mass, and from changes in posture resulting from chronic pain and limb disuse. Re-evaluations during recovery are used to monitor progress towards rehabilitation goals and adjust rehabilitation priorities. Pain relief Little is known about the pain resulting from CR in dogs. While all agree that dogs with CR experience pain, there is no specific information regarding the neuropathology associated with cruciate ligament fiber damage or rupture. In dogs with hip dysplasia, cyclooxygenase-1 (COX-1), COX-2, and lipooxygenase concentrations in the femoral head are increased, as is the concentration of COX-2 in the hip joint capsule (Lascelles et al. 2009). Similar assessment in Advances in the Canine Cranial Cruciate Ligament, Second Edition. Edited by Peter Muir. © 2018 ACVS Foundation. This Work is a co-publication between the American College of Veterinary Surgeons Foundation and Wiley-Blackwell. 343 VetBooks.ir 344 Medical Management of Cruciate Ligament Rupture the dog stifle and human knee is lacking. Clinically, the signs of CR vary widely in dogs. Subjectively, dogs that are affected bilaterally shift their weight cranially more than dogs that are unilaterally affected. While dogs with a large amount of cranial tibial thrust during weightbearing are most often very lame, the presence of dysfunction in dogs with CR does not correlate highly with the amount of stifle instability. Other than instability, the presence of a tear or fold in the caudal horn of the meniscus, the presence of severe synovitis, and the presence of osteoarthritis may be other factors causing pain and dysfunction. Dogs may also perceive acuteon-chronic pain after surgery. In one report, 30% of dogs had chronic pain after surgical treatment of CR (Mölsa et al. 2013). Eliminating postoperative edema Limb edema is a source of postoperative pain and a potential factor promoting limb disuse during the early postoperative period. Edema typically subsides within 10 days; simple strategies, such as cold therapy, minimize its severity and accelerate its resolution. A decrease in the invasiveness of surgery decreases the severity of edema. Edema resorption is promoted by elevation of the limb extremity, gentle tissue massage, passive range of motion and stretching, cold therapy, and by the use of electrical stimulation (Rexing et al. 2010; Drygas et al. 2011). Maintaining or recovering stifle joint motion Stifle extension is more critical to correct limb use than stifle flexion because the functional range of motion of the stifle requires near full extension but occurs far from full flexion. Stifle joint extension may be negatively impacted by capsular or periarticular fibrosis that developed before surgery (Figure 42.1). Extension may be further impacted by the suboptimal placement of an extracapsular stabilization suture. Subjectively, the most common surgical error leading to a loss of stifle extension is the excessively distal placement of the tibial tunnel. This problem may subside over time due to loss of stiffness of the extracapsular stabilization suture as a result of cyclic loading and the potential Figure 42.1 This 4-year-old Great Dane had a cruciate ligament rupture that was managed conservatively, leading to joint fibrosis and a loss of stifle joint extension. At the time of presentation, he was non weight-bearing on his left pelvic limb and stifle extension was limited to 134◦ , corresponding to a ∼30◦ loss of extension. Therapy initially focused on preheating the joint and stretching the joint manually. enlargement of bone tunnels. Surgical procedures that alter the tibial plateau slope or displace the tibial crest do not alter stifle joint motion since they do not include a femorotibial tether (Jandi & Schulman 2007). Stifle joint motion should be measured with a goniometer before surgery whenever possible, particularly before extracapsular stabilization to differentiate a chronic loss of joint motion from acute loss of joint motion caused by the surgical procedure. Promoting controlled limb use Limb use after CR stabilization surgery ranges from good (mild weight-bearing lameness) to poor (non weight-bearing lameness; Figure 42.2). Factors that are likely to lead to a decrease in limb use include chronicity of the problem including osteoarthritis, limb weakness and quadriceps inhibition, neuropathological changes, surgical technique (residual instability, medial meniscal injuries), and suboptimal pain management (peripheral sensitization, allodynia). Rehabilitation strategies to facilitate limb use include pain management, client education regarding controlled walking, sling use (proximal stability to promote distal mobility), and active exercises to promote weight shifting. Rehabilitation for Dogs with Cruciate Ligament Rupture 345 VetBooks.ir Marsolais et al. 2002; Jerre 2009). Strengthening exercises and a focus on normalizing muscle activation/control via proprioceptive retraining may assist in reducing abnormal gait strategies and optimize recovery in patients with CR (Adrian et al. 2013). Preventing and recovering from changes in posture resulting from chronic pain and limb disuse Preventing and recovering from a loss of muscle mass and motor control Muscle mass and neuromuscular control are impaired in patients with CR, leading to a loss of strength and dynamic joint stability (Risberg et al. 2007). Controlled exercises promote limb use, prevent loss of muscle mass, and accelerate recovery of muscle mass after CR stabilization (Figures 42.3 and 42.4) (Johnson et al. 1997; Limb function (PVF % BW) 43 Preventing mechanical complications after surgery Mechanical failure can occur after all forms of CR stabilization, and its likelihood is increased by falls and by owners’ unwillingness or inability to control physical activity (Langenbach & Marcellin-Little 2010). Physical rehabilitation *# *# 41 14 13 39 * 37 12 * 35 11 33 10 31 29 9 27 Limb function (VI % BW) Figure 42.2 A dog is standing with a non weight-bearing stance on his operated pelvic limb 14 days after extracapsular stabilization of his cruciate ligament-deficient stifle joint. A non weight-bearing stance during the subacute postoperative period is generally the consequence of chronic pain from a biological or mechanical problem. Dogs with CR develop changes in posture that include moving their center of gravity cranially so that the loads resisted by their pelvic limbs decrease (Figure 42.5). With time, these changes in posture become deeply rooted. Therapeutic exercises promote strategies to increase pelvic limb muscle recruitment, improve motor control and proximal strength to help improve posture. 8 25 0 6 0 Time (months after surgery) 6 Figure 42.3 Peak vertical forces (PVF) and vertical impulse (VI) relative to body weight (BW) before and 6 months after extracapsular stabilization of the stifle joint for dogs that were exercise-restricted (dotted lines) and dogs that underwent rehabilitation (solid lines). PVF and VI were larger 6 months after surgery compared to before s