Veterinary Ophthalmology Two-Volume Set [6 ed.] 1119441838, 9781119441830

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About the pagination of this eBook This eBook contains a multi-volume set. To navigate the front matter of this eBook by page number, you will need to use the volume number and the page number, separated by a hyphen. For example, to go to page v of volume 1, type “1-v” in the Go box at the bottom of the screen and click "Go." To go to page v of volume 2, type “2-v”… and so forth.

Veterinary Ophthalmology

Veterinary Ophthalmology Volume I and Volume II Editor

Kirk N. Gelatt Associate Editors Gil Ben-Shlomo Brian C. Gilger Diane V.H. Hendrix Thomas J. Kern Caryn E. Plummer Sixth Edition

This edition first published 2021 © 2021 by John Wiley & Sons, Inc. Fifth Edition © 2013 John Wiley & Sons, Inc. Fourth Edition © 2007 Blackwell Publishing. Third Edition © 1999 Lippincott Williams & Wilkins. Second Edition © 1991 Lea & Febiger. First Edition © 1981 Lea & Febiger. Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley‐Blackwell. The right of Kirk N. Gelatt 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. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging‐in‐Publication Data Names: Gelatt, Kirk N., editor. Title: Veterinary ophthalmology / editor, Kirk N. Gelatt ; associate editors, Gil Ben‐Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, Caryn E. Plummer. Other titles: Textbook of veterinary ophthalmology Description: Sixth edition. | Hoboken, NJ : Wiley‐Blackwell, 2020. | Includes bibliographical references and index. Identifiers: LCCN 2020010772 (print) | LCCN 2020010773 (ebook) | ISBN 9781119441830 (hardback) | ISBN 9781119441823 (adobe pdf) | ISBN 9781119441816 (epub) Subjects: MESH: Eye Diseases–veterinary | Diagnostic Techniques, Ophthalmological–veterinary | Ophthalmologic Surgical Procedures–veterinary Classification: LCC SF891 (print) | LCC SF891 (ebook) | NLM SF 891 | DDC 636.089/77–dc23 LC record available at https://lccn.loc.gov/2020010772 LC ebook record available at https://lccn.loc.gov/2020010773 Cover image: Eye of a black horse © happylights / Shutterstock, Closeup of cat face. Fauna background © darkbird77 / Getty Images, Inquisitive Beagle Hound © bpretorius / Getty Images, Inset images courtesy of Kirk N. Gelatt. Cover design by Wiley Set in 9.5/12pt STIX TwoText by SPi Global, Pondicherry, India 10  9  8  7  6  5  4  3  2  1

This book is dedicated to the memory of Dr. Gil Ben-Shlomo, an exceptional scholar, teacher, father and friend. The veterinary ophthalmology community has lost a gentle doctor and a gentleman.

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Contents Contributors  xi Preface  xvii About the Companion Website  xix Volume 1 Section I  Basic Vision Sciences  1 Edited by Diane V.H. Hendrix 1 Ocular Embryology and Congenital Malformations  3 Cynthia S. Cook 2 Ophthalmic Anatomy  41 Jessica M. Meekins, Amy J. Rankin, and Don A. Samuelson 3 Physiology of the Eye  124 Diane V.H. Hendrix, Sara M. Thomasy, and Glenwood G. Gum 4 Optics and Physiology of Vision  168 Ron Ofri and Björn Ekesten 5 Fundamentals of Animal Vision  225 Björn Ekesten and Ron Ofri Section II  Foundations of Clinical Ophthalmology  261 Edited by Diane V.H. Hendrix, Gil Ben-Shlomo, and Brian C. Gilger 6 Ocular Immunology  263 Robert English and Brian C. Gilger 7 Clinical Microbiology and Parasitology  293 David Gould, Emma Dewhurst, and Kostas Papasouliotis 8 Clinical Pharmacology and Therapeutics Part 1  Ocular Drug Delivery  349 Alain Regnier

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Part 2  Antibacterial Agents, Antifungal Agents, and Antiviral Agents  385 Alison Clode and Erin M. Scott Part 3  Anti-Inflammatory and Immunosuppressant Drugs  417 Amy J. Rankin Part 4  Mydriatics/Cycloplegics, Anesthetics, and Tear Substitutes and Stimulators  435 Ian P. Herring Part 5  Medical Therapy for Glaucoma  451 Caryn E. Plummer 9 Veterinary Ophthalmic Pathology  479 Bruce H. Grahn and Robert L. Peiffer 10 Ophthalmic Examination and Diagnostics Part 1  The Eye Examination and Diagnostic Procedures  564 Heidi J. Featherstone and Christine L. Heinrich Part 2  Ocular Imaging  662 David Donaldson and Claudia Hartley Part 3  Diagnostic Ophthalmic Ultrasound  733 Ellison Bentley, Stefano Pizzirani, and Kenneth R. Waller, III Part 4  Clinical Electrodiagnostic Evaluation of the Visual System  757 Gil Ben-Shlomo 11 Ophthalmic Genetics and DNA Testing  778 Simon M. Petersen-Jones 12 Fundamentals of Ophthalmic Microsurgery  787 David A. Wilkie 13 Digital Ophthalmic Photography  815 Richard J. McMullen, Jr., Nicholas J. Millichamp, and Christopher G. Pirie Section IIIA  Canine Ophthalmology  877 Edited by Gil Ben-Shlomo, Brian C. Gilger, Kirk N. Gelatt, and Caryn E. Plummer 14 Diseases and Surgery of the Canine Orbit  879 Simon A. Pot, Katrin Voelter, and Patrick R. Kircher 15 Diseases and Surgery of the Canine Eyelid  923 Frans C. Stades and Alexandra van der Woerdt 16 Diseases and Surgery of the Canine Nasolacrimal System  988 Lynne S. Sandmeyer and Bruce H. Grahn

Contents

17 Diseases and Surgery of the Canine Lacrimal Secretory System  1008 Elizabeth A. Giuliano 18 Diseases and Surgery of the Canine Conjunctiva and Nictitating Membrane  1045 Claudia Hartley and Diane V.H. Hendrix 19 Diseases and Surgery of the Canine Cornea and Sclera  1082 R. David Whitley and Ralph E. Hamor 20 The Canine Glaucomas  1173 Caryn E. Plummer, András M. Komáromy, and Kirk N. Gelatt Index  i1 Volume 2 Section IIIB  Canine Ophthalmology  1257 Edited by Gil Ben-Shlomo, Brian C. Gilger, Kirk N. Gelatt, Caryn E. Plummer, and Thomas J. Kern 21 Diseases and Surgery of the Canine Anterior Uvea  1259 Diane V.H. Hendrix 22 Diseases of the Lens and Cataract Formation  1317 Marta Leiva and Teresa Peña 23 Surgery of the Lens  1371 Tammy Miller Michau 24 Diseases and Surgery of the Canine Vitreous  1459 Michael H. Boevé and Frans C. Stades 25 Diseases of the Canine Ocular Fundus  1477 Simon M. Petersen-Jones and Freya Mowat 26 Surgery of the Canine Posterior Segment  1575 Allison R. Hoffman, Joseph C. Wolfer, Samuel J. Vainisi, and András M. Komáromy 27 Diseases of the Canine Optic Nerve  1622 Gillian J. McLellan Section IV  Special Ophthalmology  1663 Edited by Caryn E. Plummer and Thomas J. Kern 28 Feline Ophthalmology  1665 Mary Belle Glaze, David J. Maggs, and Caryn E. Plummer 29 Equine Ophthalmology  1841 Caryn E. Plummer 30 Food and Fiber Animal Ophthalmology  1983 Bianca C. Martins

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31 Avian Ophthalmology  2055 Lucien V. Vallone and Thomas J. Kern 32 Ophthalmology of New World Camelids  2085 Juliet R. Gionfriddo and Ralph E. Hamor 33 Laboratory Animal Ophthalmology  2109 Seth Eaton 34 Small Mammal Ophthalmology  2179 David L. Williams 35 Exotic Animal Ophthalmology  2200 Thomas J. Kern 36 Neuro-Ophthalmology 2237 Aubrey A. Webb and Cheryl L. Cullen 37 Ocular Manifestations of Systemic Disease Part 1  The Dog  2329 Aubrey A. Webb and Cheryl L. Cullen Part 2  The Cat  2421 Aubrey A. Webb and Cheryl L. Cullen Part 3  The Horse  2495 Aubrey A. Webb and Cheryl L. Cullen Part 4  Food Animals  2535 Aubrey A. Webb and Cheryl L. Cullen Index  i1

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Contributors Gil Ben-Shlomo, DVM, PhD Diplomate ACVO, Diplomate ECVO Associate Professor of Ophthalmology Departments of Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, NY, USA Ellison Bentley, DVM Diplomate ACVO Clinical Professor, Comparative Ophthalmology Department of Surgical Sciences School of Veterinary Medicine University of Wisconsin‐Madison Madison, WI, USA Michael H. Boevé, DVM, PhD Diplomate ECVO Staff Ophthalmologist Department of Clinical Sciences of Companion Animals Faculty of Veterinary Medicine Utrecht University, The Netherlands Alison Clode, DVM Diplomate ACVO Port City Veterinary Referral Hospital Portsmouth, NH, USA Cynthia S. Cook, DVM, PhD Diplomate ACVO Veterinary Vision San Carlos and San Francisco, CA, USA

Cheryl L. Cullen, DVM Diplomate ACVO CullenWebb Animal Eye Specialists Riverview, NB, Canada Emma Dewhurst, MA, VetMB, MRCVS Diplomate ECVCP, FRCPath IDEXX Laboratories Wetherby, West Yorkshire, UK David Donaldson, BVSc(Hons), MRCVS, MANZCVS Diplomate ECVO European Specialist in Veterinary Ophthalmology Senior Clinician in Ophthalmology Langford Vets University of Bristol Veterinary School Langford, Bristol, UK Seth Eaton, VMD Diplomate ACVO Clinical Assistant Professor, Comparative Ophthalmology Department of Surgical Sciences School of Veterinary Medicine University of Wisconsin – Madison Madison, WI, USA Björn Ekesten, DVM, PhD Diplomate ECVO Professor of Ophthalmology Department of Clinical Sciences Faculty of Veterinary Medicine Swedish University of Agricultural Science Uppsala, Sweden

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Contributors

Robert English, DVM, PhD Diplomate ACVO Animal Eye Care of Cary Cary, NC, USA Heidi J. Featherstone, BVetMed, DVOphthal, MRCVS Diplomate ECVO, Diplomate RCVS Head of Ophthalmology The Ralph Veterinary Referral Centre; Honorary Associate Professor Nottingham Veterinary School Marlow, Buckinghamshire, UK Kirk N. Gelatt, VMD Diplomate ACVO Emeritus Distinguished Professor of Comparative Ophthalmology Department of Small and Large Animal Clinical Sciences College of Veterinary Medicine University of Florida Gainesville, FL, USA

David Gould, BSc (Hons), BVM&S, PhD, DVOphthal, FRCVS Diplomate ECVO RCVS and European Specialist in Veterinary Ophthalmology Head of Ophthalmology Davies Veterinary Specialists Manor Farm Business Park Higham Gobion, Hertfordshire, UK Bruce H. Grahn, DVM Diplomate ACVO Professor Emeritus of Veterinary Ophthalmology Western College of Veterinary Medicine and Prairie Ocular Pathology of Prairie Diagnostic Laboratories University of Saskatchewan Saskatoon, SK, Canada Glenwood G. Gum, MS, PhD Director of Ophthalmology Absorption Systems San Diego, CA, USA

Brian C. Gilger, DVM, MS Diplomate ACVO, Diplomate ACT Professor of Ophthalmology Department of Clinical Sciences College of Veterinary Medicine North Carolina State University Raleigh, NC, USA

Ralph E. Hamor, DVM, MS Diplomate ACVO Clinical Professor of Comparative Ophthalmology Departments of Small and Large Animal Clinical Sciences College of Veterinary Medicine University of Florida Gainesville, FL, USA

Juliet R. Gionfriddo, DVM Diplomate ACVO Professor Emeritus of Ophthalmology Department of Clinical Sciences College of Veterinary Medicine Colorado State University Fort Collins, CO, USA

Claudia Hartley, BVSc, CertVOphthal, MRCVS Diplomate ECVO European Specialist in Veterinary Ophthalmology Head of Ophthalmology Langford Vets University of Bristol Veterinary School Langford, Bristol, UK

Elizabeth A. Giuliano, DVM, MS Diplomate ACVO Associate Professor of Ophthalmology Department of Veterinary Medicine and Surgery College of Veterinary Medicine University of Missouri Columbia, MO, USA Mary Belle Glaze, DVM Diplomate ACVO Gulf Coast Animal Eye Clinic Houston, TX, USA

Christine L. Heinrich, DVOphthal, MRCVS Diplomate ECVO RCVS and European Specialist in Veterinary Ophthalmology Eye Veterinary Clinic Leominster, Herefordshire, UK Diane V.H. Hendrix, DVM Diplomate ACVO Professor of Ophthalmology Department of Small Animal Clinical Sciences College of Veterinary Medicine University of Tennessee Knoxville, TN, USA

Contributors

Ian P. Herring, DVM, MS Diplomate ACVO Associate Professor of Ophthalmology Department of Small Animal Clinical Sciences Virginia‐Maryland College of Veterinary Medicine Virginia Tech Blacksburg, VA, USA

Bianca C. Martins, DVM, MSc, PhD Diplomate ACVO Clinical Associate Professor of Ophthalmology Department of Surgical and Radiological Sciences School of Veterinary Medicine University of California - Davis Davis, CA, USA

Allison R. Hoffman, DVM Diplomate ACVO Eye Care for Animals Pasadena, CA, USA

Gillian J. McLellan, BVMS, PhD, DVOphthal, MRCVS Diplomate ECVO, Diplomate ACVO Associate Professor of Comparative Ophthalmology Department of Surgical Sciences School of Veterinary Medicine and Department of Ophthalmology and Visual Sciences School of Medicine and Public Health University of Wisconsin‐Madison Madison, WI, USA

Thomas J. Kern, DVM Diplomate ACVO Associate Professor of Ophthalmology Department of Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, NY, USA Patrick R. Kircher, Dr.Med.Vet., PhD Diplomate ECVDI, Exec. MBA, UZH Professor of Veterinary Diagnostic Imaging Clinic for Diagnostic Imaging Department of Clinical Diagnostics and Services Vetsuisse Faculty, University of Zurich Zurich, Switzerland András M. Komáromy, DrMedVet, PhD Diplomate ACVO, Diplomate ECVO Professor of Ophthalmology Department of Small Animal Clinical Science College of Veterinary Medicine Michigan State University East Lansing, MI, USA Marta Leiva, DVM, PhD Diplomate ECVO Professor Associate Hospital Clinic Veterinari Fundació Universitat Autònoma de Barcelona; Departament de Medicina i Cirurgia Animal Facultat de Veterinària Universitat Autònoma de Barcelona Bellaterra, Barcelona, Spain David J. Maggs, BVSc Diplomate ACVO Professor of Ophthalmology Department of Surgical and Radiological Sciences School of Veterinary Medicine University of California – Davis Davis, CA, USA

Richard J. McMullen, Jr., Dr.Med.Vet, CertEqOphth (Germany) Diplomate ACVO, Diplomate ECVO Associate Professor of Equine Ophthalmology Department of Clinical Sciences Auburn University JT Vaughan Large Animal Teaching Hospital Auburn, AL, USA Jessica M. Meekins, DVM, MS Diplomate ACVO Associate Professor of Ophthalmology Department of Clinical Sciences Veterinary Health Center College of Veterinary Medicine Kansas State University Manhattan, KS, USA Tammy Miller Michau, DVM, MS, MSpVM Diplomate ACVO Vice President, Medical Affairs Operations Mars Veterinary Health Vancouver, WA, USA Nicholas J. Millichamp, BVetMed, PhD, DVOphthal, MRCVS Diplomate ACVO, Diplomate ECVO Eye Care for Animals‐Houston Houston, TX, USA Freya Mowat, BVSc, PhD Diplomate ECVO, Diplomate ACVO Assistant Professor of Ophthalmology Department of Surgical Sciences School of Veterinary Medicine University of Wisconsin‐Madison Madison, WI, USA

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Contributors

Ron Ofri, DVM, PhD Diplomate ECVO Professor, Veterinary Ophthalmology Koret School of Veterinary Medicine Hebrew University of Jersualem Rehovot, Israel Kostas Papasouliotis, DVM, PhD, MRCVS Diplomate RCPath (Vet.Clin.Path.), Diplomate ECVCP EBVS® European Specialist in Veterinary Clinical Pathology Senior Clinical Pathologist IDEXX Laboratories Wetherby, West Yorkshire, UK Robert L. Peiffer, Jr., DVM, PhD Diplomate ACVO Professor Emeritus of Ophthalmology and Pathology School of Medicine University of North Carolina Chapel Hill, NC, USA Teresa Peña, DVM, PhD Diplomate ECVO Professor Hospital Clinic Veterinari Fundació Universitat Autònoma de Barcelona; Departament de Medicina i Cirurgia Animal Facultat de Veterinària Universitat Autònoma de Barcelona Bellaterra, Barcelona, Spain Simon M. Petersen-Jones, DVetMed, PhD, DVOphthal, MRCVS Diplomate ECVO Myers‐Dunlap Endowed Chair in Canine Health Professor of Comparative Ophthalmology Department of Small Animal Clinical Sciences College of Veterinary Medicine Michigan State University East Lansing, MI, USA Christopher G. Pirie, DVM Diplomate ACVO Associate Professor of Ophthalmology Department of Small Animal Clinical Sciences College of Veterinary Medicine Michigan State University East Lansing, MI, USA Stefano Pizzirani, DVM, PhD Diplomate ACVO, Diplomate ECVS‐inactive Associate Professor of Ophthalmology Department of Clinical Science Tufts Cummings School of Veterinary Medicine North Grafton, MA, USA

Caryn E. Plummer, DVM Diplomate ACVO Professor of Comparative Ophthalmology Departments of Small and Large Animal Clinical Sciences College of Veterinary Medicine University of Florida Gainesville, FL, USA Simon A. Pot, DVM Diplomate ACVO, Diplomate ECVO Ophthalmology Section Equine Department Vetsuisse Faculty, University of Zurich Zurich, Switzerland Amy J. Rankin, DVM, MS Diplomate ACVO Associate Professor of Ophthalmology Department of Clinical Sciences Veterinary Health Center College of Veterinary Medicine Kansas State University Manhattan, KS, USA Alain Regnier, Dr.Med.Vet, PhD Emeritus Professor of Ophthalmology Department of Clinical Sciences School of Veterinary Medicine Toulouse, France Don A. Samuelson, PhD, MS Professor of Comparative Ophthalmology (Retired) Department of Small Animal Clinical Sciences College of Veterinary Medicine University of Florida Gainesville, FL, USA Lynne S. Sandmeyer, DVM, DVSc Diplomate ACVO Associate Professor of Ophthalmology (Retired) Department of Small Animal Clinical Sciences Western College of Veterinary Medicine University of Saskatchewan Saskatoon, SK, Canada Erin M. Scott, VMD Diplomate ACVO Assistant Professor of Ophthalmology Department of Small Animal Clinical Sciences College of Veterinary Medicine and Biomedical Sciences Texas A&M University College Station, TX, USA

Contributors

Frans C. Stades, DVM, PhD Diplomate ECVO Emeritus Professor of Veterinary Ophthalmology Department of Clinical Sciences of Companion Animals Faculty of Veterinary Medicine Utrecht University Utrecht, The Netherlands

Kenneth R. Waller III, DVM, MS Diplomate ACVR Clinical Associate Professor of Diagnostic Imaging Department of Surgical Sciences School of Veterinary Medicine University of Wisconsin-Madison Madison, WI, USA

Sara M. Thomasy, DVM, PhD Diplomate ACVO Professor of Comparative Ophthalmology Department of Surgical and Radiological Sciences School of Veterinary Medicine; Department of Ophthalmology & Vision Science School of Medicine University of California Davis, CA, USA

Aubrey A. Webb, DVM, PhD CullenWebb Animal Eye Specialists Riverview, NB, Canada

Samuel J. Vainisi, DVM Diplomate ACVO Animal Eye Clinic Denmark, WI, USA Lucien V. Vallone, DVM Diplomate ACVO Assistant Clinical Professor of Comparative Ophthalmology Department of Small Animal Clinical Sciences College of Veterinary Medicine Texas A&M University College Station, TX, USA Alexandra van der Woerdt, DVM, MS Diplomate ACVO, Diplomate ECVO The Animal Medical Center New York, NY, USA Katrin Voelter, DVM, Dr.Med.Vet., PhD Diplomate ECVO Equine Department Vetsuisse Faculty, University of Zurich Zurich, Switzerland

R. David Whitley, DVM, MS Diplomate ACVO Gulf Coast Veterinary Specialists Houston, TX; Departments of Small and Large Animal Clinical Sciences College of Veterinary Medicine University of Florida Gainesville, FL, USA David A. Wilkie, DVM, MS Diplomate ACVO Professor of Comparative Ophthalmology Department of Veterinary Clinical Sciences College of Veterinary Medicine The Ohio State University Columbus, OH, USA David L. Williams, MA, VetMB, PhD, CertVOphthal, MRCVS Senior Lecturer, Veterinary Ophthalmology Department of Clinical Veterinary Medicine University of Cambridge Cambridge, UK Joseph C. Wolfer, DVM Diplomate ACVO Toronto Animal Eye Clinic Toronto, ON, Canada

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Preface In 1965 when I entered veterinary ophthalmology, it became very quickly apparent that there was a very limited information base or knowledge in veterinary ophthalmology. If this new clinical discipline was to grow and develop into a respected clinical specialty, we would need to develop our own scientific base, and compete with the other emerging clinical specialties in veterinary medicine. And we have! With our limited English‐language books of Veterinary Ophthalmology by R.H. Smythe (1956), W.G. Magrane’s first edition of Canine Ophthalmology (1965; Lea and Febiger), and Diseases of the Canine Eye by F.G. Startup (1969; Williams and Wilkins), and the chapter in Advances in Veterinary Science called ‘Examination of the Eye’ and ‘Eye Operations in Animals’ by Otto Überreiter (1959; Academic Press), we needed to “roll up our sleeves” and get to work big time! We have available now (2021) a large number of veterinary ophthalmology books concentrating on the dog, cat, exotic animals, horses, ophthalmic pathology, and ophthalmic surgery. Two veterinary ophthalmology journals have proven invaluable to our success as a discipline. The first journal, Veterinary and Comparative Ophthalmology, was published by Fidia Research Foundation and Veterinary Practice Publishing (1991–1998), and our second journal was Veterinary Ophthalmology (published by Blackwell and Wiley‐Blackwell, 1998 to present); they greatly assisted our development and proved critical for the distribution of new scientific information. In fact, the current journal provides more than 90% of animal ophthalmic literature annually worldwide. In the late 1950s and extending into the 1970s, professional groups of budding veterinary ophthalmologists organized scientific societies to gather and exchange their knowledge and clinical experiences, which rapidly evolved to Colleges of Veterinary Ophthalmologists whose primary missions were to train new veterinary ophthalmologists (termed residents), and foster (and fund) research to “grow” the clinical discipline long term and worldwide. Nowadays these significant changes have greatly enriched veterinary ophthalmology, and markedly improved the quality of our ophthalmic animal patients.

The advances in this text, Veterinary Ophthalmology, have paralleled and documented the changes in veterinary ophthalmology, and has become our symbol of where we are today. In 1981, the first edition was released, consisting of 21 chapters (788 pages) by 22 authors, and was well received. As a result, subsequent editions followed: second edition (1991; 765 pages and 19 authors), and then in 1999 our last single‐volume release (1544 pages, 37 chapters, and 44 authors). The third edition was markedly expanded and had color illustrations throughout the text. The last two editions were two‐volume sets: for 2007, volume one 535 pages, 9 chapters, and 45 authors, and for the second larger volume 1672 pages, 20 chapters, and 36 authors; and in 2012 for volume one 789 pages, 12 chapters, and 26 authors, and for the second volume 1479 pages, 22 chapters, and 39 authors. All editions were well referenced; in fact, a great value of this text is that it documents the advances in veterinary ophthalmology during the past half of the twentieth century, and the first two decades of the twenty‐first century! The sixth edition again consists of two volumes, 37 ­chapters, and 64 contributors. Like the last two editions, the first volume contains the basic science and foundations of clinical ophthalmology chapters and the first part of the third section on canine ophthalmology. Basic vision science courses in veterinary medical colleges are often an afterthought, and our veterinary ophthalmic basic sciences are frequently documented by veterinary ophthalmologists (rather than anatomists, physiologists, pharmacologists, etc.). The first volume of the basic sciences and foundations of veterinary ophthalmology is designed to provide the base of those subjects that underpin the clinical sciences. They include embryology, anatomy, ophthalmology physiology, optics and physiology of vision, and fundamentals of vision in animals. In the foundations of clinical ophthalmology section, the chapters include immunity, microbiology, clinical pharmacology and therapeutics, ophthalmic pathology, ophthalmic examination and diagnostics, ophthalmic genetics and DNA testing, fundamentals of microsurgery, and photography. The third section starts with the chapters for

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Preface

the first part of the canine ophthalmology including orbit, eyelids, nasolacrimal system, lacrimal secretory system, conjunctiva and nictitating membrane, cornea and sclera, and glaucoma. The second volume focuses on clinical ophthalmology in the different species, and starts with the second part of canine ophthalmology (chapters- anterior uvea, lens and cataract formation, surgery of the lens, vitreous, ocular fundus, surgery of the posterior segment, and optic nerve), and continues with feline, equine, food and fiber‐producing animals, avian, New World camelids, laboratory animals, pocket pet animals, and exotics, and concludes with comparative neuro‐ophthalmology, ophthalmic manifestations of systemic diseases, and the index. The sixth edition more or less has devoted space relative to the amount of time based on different animal species encountered in veterinary ophthalmology practice. Now, in 2021, the sixth edition of Veterinary Ophthalmology continues to document this discipline’s advances. The magnitude of this edition has now required five associate editors, who devoted their time and expertise to make it happen. Like for me, I’m certain it was a learning experience! They are Drs. Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, Caryn E. Plummer, and Gil Ben‐Shlomo. Each editor chose their authors and respective chapters, based on their

expertise and preferences. A book like this is a huge undertaking, and all of us have devoted hundreds of hours to make it a successful product for the profession. Our 64 authors contributed hundreds of hours to this edition, taking time away from family and practice, and we thank them. When all the chapters had been submitted and production had started, the COVID‐19 pandemic spread across the world like a massive hurricane. Terms like “face masks,” “social distancing,” “isolation,” and “quarantine or shelter at home” became common terms, and our daily personal and professional routines were markedly disrupted. But progress in the production of the sixth edition continued uninterrupted. We thank Erica Judisch, Executive Editor, Veterinary Medicine and Dentistry, and Purvi Patel, Project Editor, of Wiley‐Blackwell for their expertise and assistance in making the sixth edition of Veterinary Ophthalmology a reality. Our copyeditors, Jane Grisdale and Sally Osborn, and project manager Mirjana Misina were superb. And lastly, we thank and appreciate the continued support and encouragement of our spouses and family members who bear with us as we struggle to meet our time schedules and other life priorities. Distinguished Kirk N. Gelatt, VMD, Diplomate, Professor of Comparative American College of Veterinary Ophthalmology, Emeritus Ophthalmologists

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About the Companion Website This book is accompanied by a companion website: www.wiley.com/go/gelatt/veterinary The website includes: ●● ●●

PowerPoints of all figures from the book for downloading References linked to CrossRef

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Section I Basic Vision Sciences

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1 Ocular Embryology and Congenital Malformations Cynthia S. Cook Veterinary Vision, San Carlos and San Francisco, CA, USA

An understanding of normal and abnormal ocular develop­ ment is essential to the broader subjects of anatomy, physiol­ ogy, and pathology. Embryology provides both insight into the development of structures such as the cornea, iridoc­ orneal angle, and retina and their normal and pathologic functions, as well as a means of understanding how congeni­ tal malformations occur. Investigations of ocular development have often used rodents as animal models. Comparison with studies of humans and other animals demonstrates that the sequence of developmental events is very similar across species (Cook, 1995; Cook & Sulik, 1986; Hilfer, 1983; O’Rahilly, 1983). Factors that must be considered when making interspecies comparisons include duration of gestation, differences in anatomic end point (e.g., presence of a tapetum, macula, or Schlemm’s canal), and when eyelid fusion breaks (during the sixth month of gestation in the human versus 2 weeks postnatal in the dog; Table 1.1). This chapter describes normal events and abnormalities in this developmental sequence that can lead to malforma­ tions. Bearing in mind the species differences alluded to ear­ lier, the mouse is a valuable model in the study of normal and abnormal ocular morphogenesis. In particular, studying the effects of acute exposure to teratogens during develop­ ment has provided valuable information about the specific timing of events that lead to malformations.

Gastrulation and Neurulation Cellular mitosis following fertilization results in transforma­ tion of the single‐cell zygote into a cluster of 12–16 cells. With continued cellular proliferation, this morula becomes a blastocyst, containing a fluid‐filled cavity. The cells of the blastocyst will form both the embryo proper and the extraem­ bryonic tissues (i.e., amnion and chorion). At this early stage, the embryo is a bilaminar disc, consisting of hypoblast

and epiblast. This embryonic tissue divides the blastocyst space into the amniotic cavity (adjacent to epiblast) and the yolk sac (adjacent to hypoblast; Fig. 1.1). Gastrulation (formation of the mesodermal germ layer) begins during day 10 of gestation in the dog (day 7 in the mouse; days 15–20 in the human). The primitive streak forms as a longitudinal groove within the epiblast (i.e., future ectoderm). Epiblast cells migrate toward the primitive streak, where they invaginate to form the mesoderm. This forms the three classic germ layers: ectoderm, mesoderm, and endoderm. Gastrulation proceeds in a cranial‐to‐caudal progression; simultaneously, the cranial surface ectoderm proliferates, forming bilateral elevations called the neural folds (i.e., the future brain). The columnar surface ectoderm in this area now becomes known as the neural ectoderm (Fig. 1.2). As the neural folds elevate and approach each other, a spe­ cialized population of mesenchymal cells, the neural crest, emigrates from the neural ectoderm at its junction with the surface ectoderm (Fig. 1.3). Migration and differentiation of the neural crest cells are influenced by the hyaluronic acid‐ rich extracellular matrix. This acellular matrix is secreted by the surface epithelium as well as by the crest cells, and it forms a space through which the crest cells migrate. Fibronectin secreted by the noncrest cells forms the limits of this mesenchymal migration (LeDouarin & Teillet, 1974). Interactions between the migrating neural crest and the associated mesoderm appear to be essential for normal crest differentiation (LeDouarin & Teillet, 1974; Noden, 1993). The neural crest cells migrate peripherally beneath the sur­ face ectoderm to spread throughout the embryo, populating the region around the optic vesicle and ultimately giving rise to nearly all the connective tissue structures of the eye (Table  1.2; Hilfer & Randolph, 1993; Johnston et  al., 1979; Noden, 1993). The patterns of neural crest emergence and migration correlate with the segmental disposition of the developing brain.

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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Section I: Basic Vision Sciences

SECTION I

Table 1.1  Sequence of ocular development (Cook, 1995; O’Rahilly, 1983). Human (Approximate Postfertilization Age)

Dog (Day Postfertilization)

Month

Week

Mouse (Day Day Postfertilization)

Postnatal (P)

Developmental Events

1

3

22

8

13

Optic sulci present in forebrain

4

24

9

15

Optic sulci convert into optic vesicles

10

17

Optic vesicle contacts surface ectoderm Lens placode begins to thicken

26 2

5

28

Optic vesicle surrounded by neural crest mesenchyme 10.5

Optic vesicle begins to invaginate, forming optic cup Lens pit forms as lens placode invaginates Retinal primordium thickens, marginal zone present

32

11

19

Optic vesicle invaginated to form optic cup Optic fissure delineated Retinal primordium consists of external limiting membrane, proliferative zone, primitive zone, marginal zone, and internal limiting membrane Oculomotor nerve present

33

11.5

25

Pigment in outer layer of optic cup Hyaloid artery enters through the optic cup Lens vesicle separated from surface ectoderm Retina: inner marginal and outer nuclear zones

11.5

29

Basement membrane of surface ectoderm intact Primary lens fibers form Trochlear and abducens nerves appear Lid folds present

6

37

12 12

Edges of optic fissure in contact 30

Tunica vasculosa lentis present Lens vesicle cavity obliterated Ciliary ganglion present

41

12

32

Posterior retina consists of nerve fiber layer, inner neuroblastic layer, transient fiber layer of Chievitz, proliferative zone, outer neuroblastic layer, and external limiting membrane

17

32

Eyelids fuse (dog)

12.5

40

Secondary lens fibers present

14

32

Corneal endothelium differentiated

7

Anterior chamber beginning to form 48

8

51

Optic nerve fibers reach the brain Optic stalk cavity is obliterated Lens sutures appear Acellular corneal stroma present

54 9

57

17

30–35

Scleral condensation present

40

First indication of ciliary processes and iris Extraocular muscles visible

1: Ocular Embryology and Congenital Malformations

Human (Approximate Postfertilization Age)

Month

Week

10

Mouse (Day Day Postfertilization)

SECTION I

Table 1.1  (Continued) Dog (Day Postfertilization)

Postnatal (P)

Developmental Events

—

Eyelids fuse (occurs earlier in the dog)

45

Pigment visible in iris stroma Ciliary processes touch lens equator Rudimentary rods and cones appear

3 4

12

45–1 P

Hyaloid artery begins to atrophy to the disc

—

Branches of the central retinal artery form

51

Pupillary sphincter differentiates Retinal vessels present

—

56

Ciliary muscle appears

—

Eye axis forward (human)

56

Tapetum present (dog)

2–14 P

Tunica vasculosa lentis atrophies Short eyelashes appear

5

40

Layers of the choroid are complete with pigmentation

6

—

Eyelids begin to open, light perception

1P

Pupillary dilator muscle present

1–14 P

Pupillary membrane atrophies

1–16 P

Rod and cone inner and outer segments present in posterior retina

10–13 P

Pars plana distinct

16–40 P

Retinal layers developed

14 P

Regression of pupillary membrane, tunica vasculosa lentis, and hyaloid artery nearly complete

7

9

5

Lacrimal duct canalized Data from Aguirre et al. (1972), Akiya et al. (1986), Cook (1995), and van der Linde‐Sipman et al. (2003).

It is important to note that mesenchyme is a general term for any embryonic connective tissue. Mesenchymal cells generally appear stellate and are actively migrating popu­ lations surrounded by extensive extracellular space. In con­ trast, the term mesoderm refers specifically to the middle embryonic germ layer. In other parts of the body (e.g., the axial skeletal system), mesenchyme develops primarily from mesoderm, with a lesser contribution from the neural crest. In the craniofacial region, however, mesoderm plays a rela­ tively small role in the development of connective tissue structures. In the eye, mesoderm probably gives rise only to the striated myocytes of the extraocular muscles and vascu­ lar endothelium. Most of the craniofacial mesenchymal tis­ sue comes from neural crest cells (Johnston et al., 1979). The neural tube closes initially in the craniocervical region with closure proceeding cranially and caudally. Once closure is complete, the exterior of the embryo is fully covered by

surface ectoderm, and the neural tube is lined by neural ectoderm. Neural segmentation then occurs to form the specific parts of the brain: forebrain (i.e., prosencepha­ lon), midbrain (i.e., mesencephalon), and hindbrain (i.e., rhombencephalon; see Fig. 1.3 and Fig. 1.4). The optic vesi­ cles develop from neural ectoderm within the forebrain, with the ocular connective tissue derivatives originating from the midbrain neural crest.

Formation of the Optic Vesicle and Optic Cup The optic sulci are visible as paired evaginations of the forebrain neural ectoderm on day 13 of gestation in the dog (see Fig.  1.3, Fig.  1.4, Fig.  1.5, Fig.  1.6, and Fig.  1.7). The transformation from optic sulcus to optic vesicle occurs

Section I: Basic Vision Sciences

Maternal sinusoid

SECTION I

Endometrial stroma

Amnioblast cavity

Bilaminar embryo

6

Epiblast Hypoblast

Endoderm Extra-embryonic coelom

Extra-embryonic somatopleuric mesoderm

Exocoelomic membrane

Figure 1.1  A blastocyst that has penetrated the maternal endometrium. An embryoblast has formed and consists of two cell layers: the epiblast above, and the hypoblast below. (Reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.) Amniotic cavity Primitive streak

Primitive streak

Hypoblast

Primitive node Yolk sac

A

Surface ectoderm

Yolk sac

Amnion Epiblast

Invaginating epiblast cells

B Neural ectoderm

Mesoderm

Endoderm

C

Figure 1.2  A. Dorsal view of an embryo in the gastrulation stage with the amnion removed. B. Cross-section through the primitive streak, representing invagination of epiblast cells between the epiblast and hypoblast layers. Note that the epiblast cells filling the middle area form the mesodermal layer. C. Cross-section through the neural plate. Note that the ectoderm in the area of the neural groove (shaded cells) has differentiated into neural ectoderm, whereas the ectoderm on each side of the neural groove is surface ectoderm (clear water cells). (Reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.)

Table 1.2  Embryonic origins of ocular tissues (Johnston et al., 1979; Noden, 1993; Yamashita & Sohal, 1987).

Optic sulci Neural crest cells

Pericardial bulge

Brain regions: Forebrain Midbrain

Hindbrain

Somite

Neural Ectoderm

Neural Crest

Neural retina

Stroma of iris, ciliary body, choroid, and sclera

Retinal pigment epithelium Ciliary muscles Posterior iris epithelium

Corneal stroma and endothelium

Pupillary sphincter and dilator muscle (except in avian species)

Perivascular connective tissue and smooth muscle cells

Bilayered ciliary epithelium

Meninges of optic nerve

Striated muscles of iris (avian species only) Orbital cartilage and bone Connective tissue of the extrinsic ocular muscles Endothelium of trabecular meshwork

Surface Ectoderm

Mesoderm

Lens

Extraocular myoblasts

Corneal and conjunctival epithelium

Vascular endothelium

Lacrimal gland

Schlemm’s canal (human) Posterior sclera (?)

Figure 1.3  Dorsal view showing partial fusion of the neural folds to form the neural tube. Brain vesicles have divided into three regions: forebrain, midbrain, and hindbrain. The neural tube, groove, and facing surfaces of the large neural folds are lined with neural ectoderm (shaded cells), whereas surface ectoderm covers the rest of the embryo. Neural crest cells are found at the junction of the neural ectoderm and surface ectoderm. Neural crest cells migrate beneath the surface ectoderm, spreading throughout the embryo and specifically to the area of the optic sulci. Somites have formed along the lateral aspect of the closed cephalic neural tube. On the inside of both forebrain vesicles is the optic sulci. (Reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.)

Data from Ashton (1966), Cook et al. (1991a), and Cook and Sulik (1986, 1988). Anterior neuropore Optic sulci

Future lens placode Midbrain 1st and 2nd pharyngeal pouches

Pericardial bulge

concurrent with the closure of the neural tube (day 15 in the dog). Intracellular filaments and microtubules within the cytoskeleton alter cell shape and allow for cell movement. In addition to the mechanical influences of the cytoskeleton and the extracellular matrix, localized proliferation and cell growth contribute to expansion of the optic vesicle (Fig. 1.5; Hilfer & Randolph, 1993; Hilfer et al., 1981). The optic vesicle enlarges and, covered by its own basal lamina, approaches the basal lamina underlying the surface ectoderm (Fig. 1.5). The optic vesicle appears to play a sig­ nificant role in the induction and size determination of the palpebral fissure and of the orbital and periocular structures (Jones et  al., 1980). An external bulge indicating the pres­ ence of the enlarging optic vesicle can be seen at approxi­ mately day 17 in the dog.

Forebrain

Hindbrain Somite

Cut edge of amnion

Yolk sac

Figure 1.4  Development of the optic sulci, which are the first sign of eye development. Optic sulci on the inside of the forebrain vesicles consisting of neural ectoderm (shaded cells). The optic sulci evaginate toward the surface ectoderm as the forebrain vesicles simultaneously rotate inward to fuse. (Reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.)

7

SECTION I

1: Ocular Embryology and Congenital Malformations

Section I: Basic Vision Sciences

SECTION I

8

Figure 1.5  A. Scanning electron micrograph of a mouse embryo (six somite pairs) on day 8 of gestation, equivalent to day 13 of canine gestation. The amnion has been removed, and the neural folds have segmented into a forebrain region containing the optic sulci (arrowhead), which are evaginations of neural ectoderm (NE). The close proximity to the developing heart (H) can be seen. The area where the NE meets the surface ectoderm (SE) is where the neural fold will meet and fuse; this area also gives rise to the neural crest cells. The entrance to the foregut is indicated by the arrow. B. Scanning electron micrograph of the optic vesicle on day 9 of gestation in the mouse (day 15 in the dog). Expansion of the optic sulcus results in an optic vesicle (OV) that approaches the surface ectoderm (SE). A thin layer of mesenchyme is still present between the NE and the SE. The optic stalk (OS) is continuous with the ventricle of the forebrain. C. The bulge of the enlarging OV (arrows) can be seen externally. MN, mandibular prominence of the first visceral arch; MX, maxillary prominence of the first visceral arch; II, second visceral arch. D. Partial removal of the SE from an embryo of 25 somite pairs (day 17 in the dog; day 19 in the mouse) reveals the exposed basal lamina of the OV (arrows). Enlargement of the optic vesicle has displaced the adjacent mesenchyme (M) so that the basal lamina of the SE is in direct contact with that of the OV. (Reprinted with permission from Cook, C.S. & Sulik, K.K. (1986) Sequential scanning electron microscopic analyses of normal and spontaneously occurring abnormal ocular development in C57B1/6J mice. Scanning Electron Microscopy, 3, 1215–1227.)

The optic vesicle and optic stalk invaginate through ­ ifferential growth and infolding (Fig.  1.6 and Fig. 1.7). d Local apical contraction (Wrenn & Wessells, 1969) and physiologic cell death (Schook, 1978) have been identified during invagination. The surface ectoderm in contact with the optic vesicle thickens to form the lens placode (Fig. 1.6, Fig. 1.7, and Fig. 1.8A, B), which then invaginates with the underlying neural ectoderm. The invaginating neural ecto­ derm folds onto itself as the space within the optic vesicle collapses, thus creating a double layer of neural ectoderm, the optic cup.

This process of optic vesicle/lens placode invagination progresses from inferior to superior, so the sides of the optic cup and stalk meet inferiorly in an area called the optic (cho­ roid) fissure (Fig.  1.8F). Mesenchymal tissue (of primarily neural crest origin) surrounds and fills the optic cup, and by day 25 in the dog, the hyaloid artery develops from mesen­ chyme in the optic fissure. This artery courses from the optic stalk (i.e., the region of the future optic nerve) to the devel­ oping lens (Fig. 1.9 and Fig. 1.10). The two edges of the optic fissure meet and initially fuse anterior to the optic stalk, with fusion then progressing anteriorly and posteriorly.

Surface ectoderm

Neural ectoderm Surface ectoderm

Lens placode

Optic sulci

Neural ectoderm Optic stalk

Figure 1.6  Cross-section at the level of the optic vesicle. Note that the neural tube is closed. The surface ectoderm now covers the surface of the forebrain, and the neural ectoderm is completely internalized. The surface ectoderm cells overlying the optic vesicles enlarge to form the early lens placode. (Reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.)

Forebrain

Lens placode

protein in the embryonic vitreous humor (13% of plasma protein) is derived from plasma proteins entering the eye by diffusion out of permeable vessels in the anterior segment. After day 15, protein content in the vitreous decreases, pos­ sibly through dilution with aqueous humor produced by developing ciliary epithelium (Beebe et al., 1986).

Lens Formation

Neural ectoderm

Optic vesicle Surface ectoderm

Figure 1.7  Transection showing invaginating lens placode and optic vesicle (arrows), thus creating the lens vesicle within the optic cup. Note the orientation of the eyes 180° from each other. (Reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.)

This process is mediated by glycosaminoglycan‐induced adhesion between the two edges of the fissure (Ikeda et al., 1995). Apoptosis has been identified in the inferior optic cup prior to formation of the optic fissure and, transiently, associated with its closure (Ozeki et al., 2000). Failure of this fissure to close normally may result in inferiorly located defects (i.e., colobomas) in the iris, choroid, or optic nerve. Colobomas other than those in the “typical” six o’clock location may occur through a different mechanism and are discussed later. Closure of the optic cup through fusion of the optic fissure allows intraocular pressure (IOP) to be established. The

Before contact with the optic vesicle, the surface ectoderm first becomes competent to respond to lens inducers. Inductive signals from the anterior neural plate give this area of ectoderm a “lens‐forming bias.” Signals from the optic vesicle are required for complete lens differentiation, and inhibitory signals from the cranial neural crest may sup­ press any residual lens‐forming bias in head ectoderm adja­ cent to the lens (Grainger et  al., 1988, 1992). Adhesion between the optic vesicle and surface ectoderm exists, but there is no direct cell contact (Cohen, 1961; Hunt, 1961; Weiss & Jackson, 1961). The basement membranes of the optic vesicle and the surface ectoderm remain separate and intact throughout the contact period. Thickening of the lens placode can be seen on day 17 in the dog. A tight, extracellular matrix‐mediated adhesion between the optic vesicle and the surface ectoderm has been described (Aso et  al., 1995; Cook & Sulik, 1988; Garcia‐ Porrero et al., 1979). This anchoring effect on the mitotically active ectoderm results in cell crowding and elongation and in formation of a thickened placode. This adhesion between the optic vesicle and lens placode also assures alignment of the lens and retina in the visual axis (Beebe, 1985). Abnormal orientation of the optic vesicle as it approaches the surface ectoderm may result in induction of a smaller lens vesicle,

9

SECTION I

1: Ocular Embryology and Congenital Malformations

Section I: Basic Vision Sciences

SECTION I

10

Figure 1.8  A. Mouse embryo on day 10 of gestation (29 somite pairs, equivalent to day 17 in the dog). On external examination, the invaginating lens placode can be seen (arrow). Note its position relative to the maxillary prominence (Mx) and mandibular (Mn) prominence of the first visceral arch. B. Frontal fracture through the lens placode (arrow) illustrates the associated thickening of the surface ectoderm (E). Mesenchyme (M) of neural crest origin is adjacent to the lens placode. As the precursor to the neural retina (NR), the distal portion of the optic vesicle concurrently thickens, whereas the proximal optic vesicle becomes a shorter, cuboidal layer that is the anlage of the retinal pigment epithelium (PE). The cavity of the optic vesicle (V) becomes progressively smaller. C. Light micrograph of the epithelium of the invagination lens placode (L). There is an abrupt transition between the thicker epithelium of the placode and the adjacent surface ectoderm, which is not unlike the transition between the future NR and PE. D. As the lens vesicle enlarges, the external opening of lens pore (arrow) becomes progressively smaller. The lens epithelial cells at the posterior pole of the lens elongate to form the primary lens fibers (L). NR, anlage of the neural retina; PE, anlage of the pigment epithelium (now a short cuboidal layer). E. External view of the lens pore (arrow) and its relationship to the Mx. F. Frontal fracture reveals the optic fissure (*) where the two sides of the invaginating optic cup meet. This forms an opening in the cup, allowing access to the hyaloid artery (H), which ramifies around the invaginating lens vesicle (L). The former cavity of the optic vesicle is obliterated except in the marginal sinus (S), at the transition between the NR and the PE. E, surface ectoderm. (Panels B and F reprinted with permission from Cook, C.S. & Sulik, K.K. (1986) Sequential scanning electron microscopic analyses of normal and spontaneously occurring abnormal ocular development in C57B1/6J mice. Scanning Electron Microscopy, 3, 1215–1227; panels C, D, and E reprinted with permission from Cook, C. (1995) Embryogenesis of congenital eye malformations. Veterinary and Comparative Ophthalmology, 5, 109–123.)

1: Ocular Embryology and Congenital Malformations

11

Optic cup

Collapsing optic vesicle Neurosensory retina RPE

Optic stalk

Lens placode

Lens vesicle

Optic (choroidal) fissure A

B

Figure 1.9  Formation of the lens vesicle and optic cup. Note that the optic fissure is present, because the optic cup is not yet fused inferiorly. A. Formation of lens vesicle and optic cup with inferior choroidal or optic fissure. Mesenchyme (M) surrounds the invaginating lens vesicle. B. Surface ectoderm forms the lens vesicle with a hollow interior. Note that the optic cup and optic stalk are of surface ectoderm origin. (Reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.) Figure 1.10  Cross-section through optic cup and optic fissure. The lens vesicle is separated from the surface ectoderm. Mesenchyme (M) surrounds the developing lens vesicle, and the hyaloid artery is seen within the optic fissure. (Reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.)

Optic cup

Intraretinal space Neurosensory retina

Surface ectoderm

RPE Neural ectoderm

Lens vesicle

Primary vitreous

which may assume an abnormal location within the optic cup (Cook & Sulik, 1988). The lens placode invaginates, forming a hollow sphere, now referred to as a lens vesicle (Fig. 1.8C, D, Fig. 1.9, and Fig. 1.10). The size of the lens vesicle is determined by the contact area of the optic vesicle with the surface ectoderm and by the ability of the latter tissue to respond to induction. Aplasia may result from failure of lens induction or through later involutions of the lens vesicle, either before or after separation from the surface ectoderm (Aso et al., 1995). Lens vesicle detachment is the initial event leading to for­ mation of the chambers of the ocular anterior segment. This process is accompanied by active migration of epithelial cells out of the keratolenticular stalk, cellular necrosis, apop­ tosis, and basement membrane breakdown (Garcia‐Porrero

Hyaloid vessels

Optic stalk Optic fissure

et al., 1979; Ozeki et al., 2001). Induction of a small lens vesi­ cle that fails to undergo normal separation from the surface ectoderm is one of the characteristics of the teratogen‐ induced anterior segment dysgenesis described in animal models (Cook & Sulik, 1988). Anterior lenticonus and ante­ rior capsular cataracts as well as anterior segment dysgene­ sis may result from faulty keratolenticular separation. Additional discussion of anterior segment dysgenesis occurs later in this chapter. Following detachment from the surface ectoderm (day 25 in the dog), the lens vesicle is lined by a monolayer of cuboidal cells surrounded by a basal lamina, the future lens capsule. The primitive retina promotes primary lens fiber formation in the adjacent lens epithelial cells. Surgical rotation of the chick lens vesicle by 180° results in elongation of the lens epithelial

SECTION I

Surface ectoderm

Section I: Basic Vision Sciences

SECTION I

12

Figure 1.11  A. Following detachment of the lens vesicle from the surface ectoderm (SE), the posterior lens epithelial cells–primary lens fibers (L) elongate, obliterating the lens vesicle lumen (equivalent to day 29 of gestation in the dog). Invagination of the optic cup forms the inner neural retina (R) and the outer pigmented epithelium (PE). Mesenchyme of neural crest origin (M) surrounds the optic cup. B. Lens bow illustrating elongation of secondary lens fibers. C and D. Longitudinal view (C) and cross-section (D) of secondary lens fibers, illustrating the extensive interdigitations and the relative absence of extracellular space. (Reprinted with permission from Sulik, K.K. & Schoenwolf, G.C. (1985) Highlights of craniofacial morphogenesis in mammalian embryos, as revealed by scanning electron microscopy. Scanning Electron Microscopy, 4, 1735–1752.)

cells nearest the presumptive retina, regardless of the orienta­ tion of the transplanted lens (Coulombre & Coulombre, 1969). Thus, while the retina develops independently of the lens, the lens appears to be dependent on the retinal primordium for its differentiation. The primitive lens filled with primary lens fib­ ers is the embryonic lens nucleus. In the adult, the embryonic nucleus is the central sphere inside the “Y” sutures; there are no sutures within the embryonal nucleus (Fig. 1.11A, Fig. 1.12, and Fig. 1.13). At birth, the lens consists almost entirely of lens nucleus, with minimal lens cortex. Lens cortex continues to develop from the anterior cuboidal epithelial cells, which remain mitotic throughout life. Differentiation of epithelial cells into secondary lens fibers occurs at the lens equator (i.e., lens bow; Fig. 1.11B). Lens fiber elongation is accompanied by a corresponding increase in cell volume and a decrease in intercellular space within the lens (Beebe et al., 1982). The

lens fibers exhibit a hexagonal cross‐sectional shape and extensive surface interdigitations (Fig.  1.11C, D). The sec­ ondary lens fibers course anteriorly and posteriorly around the embryonal nucleus to meet at the “Y” sutures (Fig. 1.13). The zonule fibers are termed the tertiary vitreous, but their origin remains uncertain. The zonules may form from the developing ciliary epithelium or the endothelium of the posterior tunica vasculosa lentis (TVL). The embry­ onic TVL may produce fibrillin‐2 and ‐3, providing a scaffold for zonule formation (Hubmacher et al., 2014). Abnormalities could result in congenital ectopia lentis. Congenitally dis­ placed lenses are often small and are abnormally shaped (i.e., spherophakia), indicating a possible relationship between zonule traction and lens shape. Localized absence of zonules may result in a flattened lens equator; although not a true lens defect, this is often described inaccurately as a lens coloboma (see later Fig. 1.32).

1: Ocular Embryology and Congenital Malformations

13

Embryonal nucleus

Muscle Secondary vitreous RPE

Anterior chamber Lens fibers Cornea

Anterior lens epithelium

Neurosensory retina Hyaloid artery

Anterior lens epithelium

Posterior “Y” suture

Anterior “Y” suture Fetal nucleus Secondary lens fibers

Optic nerve Lid bud Mesenchyme

Muscle

Figure 1.12  Overview of the developing eye surrounded by mesenchyme (M), which is mostly of neural crest origin. The hyaloid vasculature enters the optic cup through the optic fissure and surrounds the lens with capillaries that anastomose with the tunica vasculosa lentis. Axial migration of mesenchyme forms the corneal stroma and endothelium. RPE, retinal pigment epithelium. (Reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.)

Vascular Development The hyaloid artery is the termination of the primitive oph­ thalmic artery, a branch of the internal ophthalmic artery, and it remains within the optic cup following closure of the optic fissure. The hyaloid artery branches around the poste­ rior lens capsule and continues anteriorly to anastomose with the network of vessels in the pupillary membrane Figure 1.14  The hyaloid vascular system and tunica vasculosa lentis. (Reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.)

Figure 1.13  Secondary lens fibers and Y sutures. Secondary lens fibers elongate at the equator to span the entire lens, from the anterior to the posterior Y suture. The anterior Y suture is upright; the posterior Y suture is inverted. (Reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.)

(Fig. 1.14 and Fig. 1.15A, B; Schaepdrijver et al., 1989). The pupillary membrane consists of vessels and mesenchyme overlying the anterior lens capsule. This hyaloid vascular network that forms around the lens is called the anterior and posterior TVL. The hyaloid artery and associated TVL pro­ vide nutrition to the lens and anterior segment during its period of rapid differentiation. Venous drainage occurs via a network near the equatorial lens, in the area where the cili­ ary body will eventually develop. There is no discrete hyaloid vein (Schaepdrijver et al., 1989). Once the ciliary body begins actively producing aqueous humor, which circulates and nourishes the lens, the hyaloid system is no longer needed. The hyaloid vasculature and Primary vitreous

Lid bud

Secondary vitreous

Cornea Hyaloid artery Anterior chamber lens

Optic nerve Pupillary membrane Muscle Tunica vasculosa lentis

SECTION I

Primary vitreous

Section I: Basic Vision Sciences

SECTION I

14

A

B

C

D

Figure 1.15  A. Scanning electron micrograph of a mouse embryo at 14 days of gestation (equivalent to day 32 in the dog). The hyaloid vasculature enters the optic cup through the optic stalk, and it surrounds the lens (L) with capillaries that anastomose with the tunica vasculosa lentis. Axial migration of mesenchyme forms the corneal stroma and endothelium (C). The retina (R) is becoming stratified, whereas the pigment epithelium (PE) remains cuboidal. B. The retina becomes stratified into an inner marginal zone and an outer nuclear zone. Note that the inner marginal zone is most prominent in the posterior pole. C, cornea; H, hyaloid artery; L, lens; R, retina. C. Segregation of the retina into inner (IN) and outer (ON) neuroblastic layers. The ganglion cells are the first to differentiate, giving rise to the nerve fiber layer (arrowhead). The PE has become artifactually separated in this specimen. D. Differentiation of the retina progresses from the central to the peripheral regions. Centrally, the inner (IN) and outer (ON) neuroblastic layers are apparent, with early formation of the nerve fiber layer (arrowhead). Peripherally, however, the retina consists of a single nuclear zone. Between the inner and outer neuroblastic layers is a clear zone, the transient fiber layer of Chievitz. This stage is equivalent to day 32 in the dog. (Panel A reprinted with permission from Sulik, K.K. & Schoenwold, G.C. (1985) Highlights of craniofacial morphogenesis in mammalian embryos, as revealed by scanning electron microscopy. Scanning Electron Microscopy, 4, 1735–1752; panel B reprinted with permission from Cook, C.S. & Sulik K.K. (1986) Sequential scanning electron microscopic analyses of normal and spontaneously occurring abnormal ocular development in C57B1/6J mice. Scanning Electron Microscopy, 3, 1215–1227; panels C and D reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.)

TVL reach their maximal development by day 45 in the dog and then begin to regress. As the peripheral hyaloid vasculature regresses, the reti­ nal vessels develop. Vascular endothelial growth factor (VEGF)‐A is a potent angiogenic peptide in the retina; ­antibody neutralization in vivo results in reduction in the hyaloid and retinal vasculature (Feeney et  al., 2003). Spindle‐shaped mesenchymal cells from the wall of the

hyaloid artery at the optic disc form buds (angiogenesis) that invade the nerve fiber layer. In contrast, vasculogenesis refers to an assembly of dispersed angioblasts into solid cords of mesenchymal cells that later canalize (Fruttiger, 2002; Hughes et al., 2000). Controversy exists as to whether the process of retinal neovascularization occurs primarily through angiogenesis or vasculogenesis (Flower et  al., 1985; Fruttiger, 2002; Hughes et al., 2000). Recent studies

indicate that spindle‐shaped cells dispersed within the ­retina, previously thought to be angioblasts, may be imma­ ture retinal astrocytes, with retinal vascularization occur­ ring primarily through angiogenesis (Hughes et al., 2000). The primitive capillaries have laminated walls consisting of mitotically active cells secreting basement membrane. Those cells in direct contact with the bloodstream differen­ tiate into endothelial cells; the outer cells become pericytes. Zonulae occludens and gap junctions initially join adjacent cells, but later the capillary endothelium is continuous (Ashton, 1966; Mutlu & Leipold, 1964). The primitive cap­ illary endothelial cells are multipotent and can redifferen­ tiate into fibroblastic, endothelial, or muscle cells, possibly illustrating a common origin for these different tissue types (Ashton, 1966). Branches of the hyaloid artery become sporadically occluded by macrophages prior to their gradual atrophy (Jack, 1972). Placental growth factor (PlGF) and VEGF appear to be involved in hyaloid regression (Feeney et  al., 2003; Martin et al., 2004). Proximal arteriolar vasoconstric­ tion at birth precedes regression of the major hyaloid vascu­ lature (Browning et  al., 2001). Atrophy of the pupillary membrane, TVL, and hyaloid artery occurs initially through apoptosis (Ito & Yoshioka, 1999) and later through cellular necrosis (Zhu et al., 2000), and is usually complete by the time of eyelid opening 14 days postnatally. The clinical lens anomaly known as Mittendorf’s dot is a small (1 mm) area of fibrosis on the posterior lens cap­ sule, and it is a manifestation of incomplete regression of the hyaloid artery where it was attached to the posterior lens capsule. Bergmeister’s papilla represents a remnant of the hyaloid vasculature consisting of a small, fibrous glial tuft of tissue emanating from the center of the optic nerve. Both are frequently observed as incidental clinical findings.

Development of the Cornea and Anterior Chamber The anterior margins of the optic cup advance beneath the surface ectoderm and adjacent neural crest mesenchyme after lens vesicle detachment (day 25 in the dog). The sur­ face ectoderm overlying the optic cup (i.e., the presumptive corneal epithelium) secretes a thick matrix, the primary stroma (Hay, 1980; Hay & Revel, 1969). This acellular mate­ rial consists of collagen fibrils and glycosaminoglycans. Mesenchymal neural crest cells migrate between the sur­ face ectoderm and the optic cup, using the basal lamina of the lens vesicle as a substrate. Proteolysis of collagen IX triggers hydration of the hyaluronic acid, creating the space for cellular migration (Fitch et  al., 1998). Initially, this loosely arranged mesenchyme fills the future anterior

chamber, and it gives rise to the corneal endothelium and stroma, anterior iris stroma, ciliary muscle, and most struc­ tures of the iridocorneal angle (Fig. 1.16A). The presence of an adjacent lens vesicle is required for induction of cor­ neal endothelium, identified by their production of the cell adhesion molecule, n‐cadherin (Beebe & Coats, 2000). Type I collagen fibrils and fibronectin secreted by the developing keratocytes form the secondary corneal stroma. Subsequent dehydration results in much of the fibronectin being lost and in a 50% reduction in stromal thickness (Allen et al., 1955; LeDouarin & Teillet, 1974). The endothe­ lium also is important to the dehydration of the stroma. Patches of endothelium become confluent and develop zonulae occludens during days 30–35 in the dog, and dur­ ing this period Descemet’s membrane also forms. The cor­ nea achieves relative transparency at the end of gestation in the dog. Following eyelid opening at approximately 14 days postnatal in the dog, there is an initial decrease in corneal thickness over 4 weeks, presumably as the corneal endothelium become functional. Then, a gradual increase in thickness occurs over the next 6 months (Montiani‐ Ferreira et al., 2003). Neural crest migration anterior to the lens to form the corneal stroma and iris stroma also results in formation of a solid sheet of mesenchymal tissue, which ultimately remod­ els to form the anterior chamber. The portion of this sheet that bridges the future pupil is called the pupillary mem­ brane (Fig.  1.16B, C, and D). Vessels within the pupillary membrane form the TVL, which surrounds and nourishes the lens. These vessels are continuous with those of the ­primary vitreous (i.e., hyaloid). The vascular endothelium is the only intraocular tissue of mesodermal origin; even the vascular smooth muscle cells and pericytes that originate from mesoderm in the rest of the body are of neural crest origin in the eye (Johnston et al., 1979; Smelser & Ozanics, 1971). In humans, the endothelial lining of Schlemm’s canal, like the vascular endothelium elsewhere, is of mesodermal origin. In the dog, atrophy of the pupillary membrane begins by day 45 of gestation and continues during the first two postnatal weeks (Aguirre et al., 1972). Separation of the corneal mesenchyme (neural crest‐cell origin) from the lens (surface ectoderm origin) results in formation of the anterior chamber. In a microphthalmic or nanophthalmic globe, the cor­ nea is correspondingly reduced in diameter. The term microcornea is used to describe a cornea that is propor­ tionally smaller than normal for the size of the globe. As with lens induction, determination of the corneal diam­ eter occurs at the time of contact by the optic vesicle with the surface ectoderm. This induction is also sensi­ tive to timing; if the optic vesicle–ectoderm contact occurs earlier or later than normal, the ectoderm may not be fully capable of responding appropriately, result­ ing in microcornea.

15

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16

B A

C

D

Figure 1.16  A. Scanning electron micrograph of a fetal human eye at approximately 42 days of gestation (equivalent to day 25 in the dog). The lens vesicle (L) has detached, and the neural crest–derived mesenchyme (M) is migrating axially between the optic cup (OC) and the surface ectoderm (SE). B. On day 54 in the human (day 32 in the dog), the pupillary membrane (PM) is seen within the anterior chamber. The corneal stroma (C) is apparent and is covered by the surface ectoderm (SE), which will become the corneal epithelium. OC, anterior margin of the optic cup, which will form the posterior epithelial layers of the iris, including the pupillary muscles. C. Light micrograph obtained at the same stage as in B illustrates the pupillary membrane and tunica vasculosa lentis (arrows) originating from the mesenchyme at the margin of the optic cup (OC). The limbal condensation that will become the scleral spur is indicated by the arrowhead. AC, anterior chamber; C, cornea; L, lens. D. Scanning electron micrograph of a fetal human eye at approximately 63 days of gestation. The AC is deeper and still bridged by the PM. Endothelialization of clefts within the neural crest–derived corneal stroma (C) by mesoderm will form Schlemm’s canal (arrowhead) in the human eye. (Panels A and D reprinted with permission from Cook, C. (1989) Experimental models of anterior segment dysgenesis. Ophthalmic Paediatrics and Genetics, 10, 33–46; panels B and C reprinted with permission from Cook, C., Sulik, K.K., & Wright, K.W. (2003) Embryology. In: Pediatric Ophthalmology and Strabismus (eds. Wright, K.W. & Spiegel, P.H.), pp. 3–38. New York: Springer.)

Development of the Iris, Ciliary Body, and Iridocorneal Angle The two layers of the optic cup (neuroectoderm origin) consist of an inner, nonpigmented layer and an outer, pig­ mented layer. Both the pigmented and nonpigmented epi­ thelium of the iris and the ciliary body develop from the anterior aspect of the optic cup; the retina develops from the posterior optic cup. The optic vesicle is organized with all cell apices directed to the center of the vesicle. During optic cup invagination, the apices of the inner and outer

epithelial layers become adjacent. Thus, the cells of the optic cup are oriented apex to apex. A thin, periodic acid–Schiff‐positive basal lamina lines the inner aspect (i.e., vitreous side) of the nonpigmented epithelium and retina (i.e., inner limiting membrane). By approximately day 40 of gestation in the dog, both the pigmented and nonpigmented epithelial cells show apical cilia that project into the intercellular space. There also is increased prominence of Golgi complexes and associated vesicles within the ciliary epithelial cells. These changes, as well as the presence of “ciliary channels” between the

apical surfaces, probably represent the first production of aqueous humor. The iris stroma develops from the anterior segment mes­ enchymal tissue (neural‐crest cell origin), and the iris pig­ mented and nonpigmented epithelium originate from the neural ectoderm of the optic cup. The smooth muscle of the pupillary sphincter and dilator muscles ultimately differen­ tiate from these epithelial layers, and they represent the only mammalian muscles of neural ectodermal origin. In avian species, however, the skeletal muscle cells in the iris are of neural crest origin, with a possible small contribution of mesoderm to the ventral portion (Nakano & Nakamura, 1985; Yamashita & Sohal, 1986, 1987). Differential growth of the optic cup epithelial layers results in folding of the inner layer, representing early anterior cili­ ary processes (Fig. 1.16B). The ciliary body epithelium devel­ ops from the neuroectoderm of the anterior optic cup, and the underlying mesenchyme differentiates into the ciliary muscles. Extracellular matrix secreted by the ciliary epithe­ lium becomes the tertiary vitreous and, ultimately, is thought to develop into lens zonules. Three phases of iridocorneal angle maturation have been described (Reme et al., 1983a, 1983b). First is separation of anterior mesenchyme into corneoscleral and iridociliary regions (i.e., trabecular primordium formation), followed by differentiation of ciliary muscle and folding of the neural ectoderm into ciliary processes. Second is enlargement of the corneal trabeculae and development of clefts in the area of the trabecular meshwork, which is accompanied by regression of the corneal endothelium covering the angle recess. Third is postnatal remodeling of the drainage angle, associated with cellular necrosis and phagocytosis by mac­ rophages, resulting in opening of clefts in the trabecular meshwork and outflow pathways. This change in the relationship of the trabecular mesh­ work to the ciliary body and iris root during the last trimes­ ter of human gestation occurs through differential growth, with posterior movement of the iris and the ciliary body rela­ tive to the trabecular meshwork exposing the outflow path­ ways. This results in progressive deepening of the chamber angle and normal conformation of the ciliary muscle and ciliary processes (Anderson, 1981). This is in contrast to pre­ vious theories of cleavage of the iris root from the cornea or atrophy of angle tissue (Barishak, 1978; Smelser & Ozanics, 1971; Wulle, 1972). In species born with congenitally fused eyelids (i.e., dog and cat), development of the anterior chamber continues during this postnatal period before eyelid opening. At birth, the peripheral iris and cornea are in contact. Maturation of pectinate ligaments begins by 3 weeks postnatal and rarefac­ tion of the uveal and corneoscleral trabecular meshworks to their adult state occurs during the first 8 weeks after birth. There is no evidence of mesenchymal splitting, cell death, or phagocytic activity (Samuelson & Gelatt, 1984a, 1984b).

Retina and Optic Nerve Development Infolding of the neuroectodermal optic vesicle results in a bilayered optic cup with the apices of these two cell layers in direct contact. Primitive optic vesicle cells are columnar, but by 20 days of gestation in the dog, they form an outer cuboi­ dal layer containing the first melanin granules in the devel­ oping embryo within the future retinal pigment epithelium (RPE). The neurosensory retina develops from the inner, nonpigmented layer of the optic cup, and the RPE originates from the outer, pigmented layer. Bruch’s membrane (the basal lamina of the RPE) is first seen during this time, and becomes well developed over the next week, when the cho­ riocapillaris is developing. By day 45 in the dog, the RPE cells take on a hexagonal cross‐sectional shape and develop microvilli that interdigitate with projections from photore­ ceptors of the nonpigmented (inner) layer of the optic cup. At the time of lens placode induction, the retinal primor­ dium consists of an outer, nuclear zone and an inner, marginal (anuclear) zone. Cell proliferation occurs in the nuclear zone, with migration of cells into the marginal zone. This process forms the inner and outer neuroblastic layers, separated by their cell processes that make up the transient fiber layer of Chievitz (Fig.  1.15C, D). Cellular differentiation progresses from inner to outer layers and, regionally, from central to peripheral locations. Peripheral retinal differentiation may lag behind that occurring in the central retina by 3–8 days in the dog (Aguirre et al., 1972). Retinal histiogenesis beyond formation of the neuroblastic layers requires induction by a differentiated RPE. There are several rodent models of RPE dysplasia resulting in failure of later retinal differentiation and subsequent degeneration (Bumsted & Barnstable, 2000; Cook et  al., 1991b). Retinal ganglion cells develop first within the inner neuroblastic layer, and axons of the ganglion cells collectively form the optic nerve. Cell bodies of the Müller and amacrine cells differentiate in the inner portion of the outer neuroblastic layer. Horizontal cells are found in the middle of this layer; the bipolar cells and photoreceptors mature last, in the out­ ermost zone of the retina (Greiner & Weidman, 1980, 1981, 1982; Spira & Hollenberg, 1973). Significant retinal differentiation continues postnatally, particularly in species born with fused eyelids. Expression of extracellular matrix elements, chondroitin sulfate, and hepa­ rin sulfate occurs in a spatiotemporally regulated manner, with a peak of chondroitin sulfate occurring at the time of eyelid opening, This corresponds to the period of photorecep­ tor differentiation (Erlich et  al., 2003). At birth, the canine retina has reached a stage of development equivalent to the human at 3–4 months of gestation (Shively et al., 1971). In the kitten, all ganglion cells and central retinal cells are pre­ sent at birth, with continued proliferation in the peripheral retina continuing during the first 2–3 postnatal weeks in dogs and cats (Johns et al., 1979; Shively et al., 1971).

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Section I: Basic Vision Sciences

Possible means of retinal regeneration have become reality with the discovery of neural stem cells in the mature eye of warm‐blooded vertebrates (Engelhardt et  al., 2004; Fischer, 2005). These include cells at the retinal margin, pig­ mented cells in the ciliary body and iris, nonpigmented cells in the ciliary body, and Müller glia within the retina. Under the influence of growth factors, these neuroectodermal cells in the avian are capable of undergoing differentiation into retinal cells (Fischer, 2005).

Sclera, Choroid, and Tapetum These neural crest–derived tissues are all induced by the outer layer of the optic cup (future RPE). Normal RPE differentia­ tion is a prerequisite for normal development of the sclera and choroid. The choroid and sclera are relatively differentiated at birth, but the tapetum in dogs and cats continues to develop and mature during the first 4 months postnatally. The initially mottled, blue appearance of the immature tapetum is replaced by the blue/green to yellow/orange color of the adult. These color variations seen in immature dogs can prove a challenge to accurate funduscopic assessment. Posterior segment uveoscleral colobomas most often result from a primary RPE abnormality. Subalbinotic animals have a higher incidence of posterior segment colobomas, with reduced RPE pigmentation being a marker for abnormal RPE development (Bertram et al., 1984; Cook et al., 1991a; Gelatt & McGill, 1973; Gelatt & Veith, 1970; Munyard et al., 2007; Rubin et al., 1991). The most common example is the choroidal hypoplasia of Collie eye anomaly (Barnett, 1979).

Vitreous The primary vitreous forms posteriorly, between the primitive lens and the inner layer of the optic cup (see Fig.  1.10 and Fig. 1.12). In addition to the vessels of the hyaloid system, the primary vitreous also contains mesenchymal cells, collagen­ ous fibrillar material, and macrophages. The secondary vitre­ ous forms as the fetal fissure closes, and contains a matrix of cellular and fibrillar material, including primitive hyalocytes, monocytes, and hyaluronic acid (Akiya et al., 1986; Bremer & Rasquin, 1998). Identification of microscopic vascular rem­ nants throughout the vitreous of adult rabbits has led to specu­ lation for interactive remodeling of the primary vitreous to form secondary vitreous (Los et al., 2000a, 2000b). Plasma pro­ teins enter and leave the vitreous and, in the chick, there is a concentration of 13% of that found in plasma, until a decline to 4% of plasma levels occurs during the last week prior to hatch­ ing (Beebe et al., 1986). Primitive hyalocytes produce collagen fibrils that expand the volume of the secondary vitreous. The tertiary vitreous forms as a thick accumulation of collagen fibers between the lens equator and the optic cup.

These fibers are called the marginal bundle of Drualt or Drualt’s bundle. Drualt’s bundle has a strong attachment to the inner layer of the optic cup, and it is the precursor to the vitreous base and lens zonules. The early lens zonular fibers appear to be continuous with the inner, limiting membrane of the nonpigmented epithelial layer covering the ciliary muscle. Elastin and emulin (elastin microfibril interface located protein) have been identified in developing zonules and Descemet’s membrane (Bressan et  al., 1993; Horrigan et  al., 1992). Experimental exposure of chick embryos to homocysteine results in deficient zonule development and congenital lens luxation (Maestro De Las Casas et al., 2003). Traction of the zonules contributes to expansion of the lens and localized absence of zonules can lead to a corresponding area of the lens that is flattened and inaccurately referred to as a lens coloboma (see later Fig. 1.32). Atrophy of the primary vitreous and hyaloid leaves a clear, narrow central zone, which is called Cloquet’s canal. In the mouse, Doppler ultrasound biomicroscopy has been used to document in vivo the decrease in blood velocity associated with hyaloid regression between birth and postnatal day 13 (Brown et  al., 2005). Most of the posterior vitreous gel at birth is secondary vitreous, with the vitreous base and zonules representing tertiary vitreous.

Optic Nerve Axons from the developing ganglion cells pass through ­vacuolated cells from the inner wall of the optic stalk. A glial sheath forms around the hyaloid artery. As the hyaloid artery regresses, the space between the hyaloid artery and the glial sheath enlarges. Bergmeister’s papilla represents a remnant of these glial cells around the hyaloid artery. Glial cells migrate into the optic nerve and form the primitive optic disc. The glial cells around the optic nerve and the glial part of the lamina cribrosa come from the inner layer of the optic stalk, which is of neural ectoderm origin. Later, a mesenchymal (neural crest origin) portion of the lamina cribrosa develops. Myelinization of the optic nerve begins at the chiasm, progresses toward the eye, and reaches the optic disc after birth.

Eyelids The eyelids develop from surface ectoderm, which gives rise to the epidermis, cilia, and conjunctival epithelium. Neural crest mesenchyme gives rise to deeper structures, including the dermis and tarsus. The eyelid muscles (i.e., orbicularis and levator) are derived from craniofacial condensations of mesoderm called somitomeres. In the craniofacial region, presumptive connective tissue–forming mesenchyme derived from the neural crest imparts spatial patterning information

19

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E Mx

LB A

B

C

D

E

F

Figure 1.17  A. Lateral view of the head of a human embryo at 6 weeks of gestation. The individual hillocks that will form the external ear can be identified both cranial and caudal to the first visceral groove (arrow). The developing eye is adjacent to the maxillary prominence (Mx). LB, forelimb bud. B. Frontal view of the head of a human embryo at 8 weeks of gestation. Formation of the face is largely complete, and the eyelids are beginning to close. C. Eyelid closure begins at the medial and lateral canthi and progresses axially. D. Light micrograph of the eyelid marginal epithelium in a mouse at day 15 of gestation. The actively migrating epithelium forms a cluster of cells adjacent to the corneal epithelium. E and F. Surface view of the fused eyelids from a human embryo at 10 weeks of gestation. (Panels A, B, E, and F reprinted with permission from Sulik, K.K. & Schoenwolf G.C. (1985) Highlights of craniofacial morphogenesis in mammalian embryos, as revealed by scanning electron microscopy. Scanning Electron Microscopy, 4, 1735–1752; panel D reprinted with permission from Cook, C.S. & Sulik, K.K. (1986) Sequential scanning electron microscopic analyses of normal and spontaneously occurring abnormal ocular development in C57B1/6J mice. Scanning Electron Microscopy, 3, 1215–1227.)

upon myogenic cells that invade it (Noden, 1986). The upper eyelid develops from the frontonasal process; the lower eyelid develops from the maxillary process. The lid folds grow together and elongate to cover the developing eye (Fig. 1.17). The upper and lower lids fuse on day 32 of gestation in the dog. Separation occurs 2 weeks postnatally.

Extraocular Muscles The extraocular muscles arise from mesoderm in somi­ tomeres (i.e., preoptic mesodermal condensations; Jacobson, 1988; Meier, 1982; Meier & Tam, 1982; Packard & Meier, 1983; Tam, 1986; Tam et  al., 1982; Tam & Trainor, 1994; Trainor & Tam, 1995). Spatial organization of developing eye muscles is initiated before they interact with the neural crest

mesenchyme. Patterning of the segmental somitomeres follows that of the neural crest; that is, somitomere I (fore­ brain), somitomere III (caudal midbrain), and somitomeres IV and VI (hindbrain; Trainor & Tam, 1995). From studies of chick embryos, it has been shown that the oculomotor‐ innervated muscles originate from the first and second somi­ tomeres, the superior oblique muscle from the third somitomere, and the lateral rectus muscle from the fourth somitomere (Wahl et  al., 1994). The entire length of these muscles appears to develop spontaneously rather than from the orbital apex anteriorly, as had been previously postulated (Sevel, 1981, 1986). Congenital extraocular muscle abnor­ malities are rarely identified and reported in the dog (Martin, 1978). This may be a result of several factors, including the fact that the extraocular muscles are normally less well developed in domestic mammals compared with humans,

SECTION I

20

Section I: Basic Vision Sciences

and the limited ability to assess minor abnormalities which would be manifest as impaired binocular vision.

Developmental Ocular Anomalies Cyclopia and Synophthalmia Formation of a single median globe (i.e., cyclopia) or two incompletely separated or fused globes (i.e., synophthalmia) may occur by two different mechanisms. The “fate maps,” which have been produced for amphibian embryos, have revealed the original location of the neural ectodermal tissue that will form the globes as a single, bilobed area crossing the midline in the anterior third of the trilaminar embryonic disc. An early defect in separation of this single field could result in the formation of a single, or incompletely sepa­ rated, median globe(s) (Fig  1.18A). After separation into

bilateral optic vesicles, later loss of the midline territory in the embryo could result in fusion of the ocular fields. This loss of midline territory, prior to separation into two eye fields, is seen in holoprosencephaly, and the facial features characteristic of human fetal alcohol syndrome represent a mild end of the holoprosencephalic spectrum (Cohen & Sulik, 1992; Sulik & Johnston, 1982). Cases of cyclopia or  synophthalmia are invariably associated with severe craniofacial malformations (Fig.  1.18A and B) and are ­usually nonviable. Cyclopia is rarely identified in dogs (Njoku et  al., 1978). However, in sheep, ingestion of the alkaloids (cyclopamine and jervine) from the weed Veratrum californicum by pregnant ewes on day 14 of gestation (total duration of gestation 150 days) is the best‐documented example of teratogen‐induced cyclopia and synophthalmia in domestic animals (Binns et  al., 1959; Bryden et al., 1971; Cooper et al., 1998; Incardona et al., 1998; Keeler, 1990; Keeler & Binns, 1966; Saperstein, 1975). It has been shown that cyclopamine specifically blocks the Sonic hedgehog (Shh) signaling pathway (Cooper et  al., 1998; Incardona et al., 1998, 2000). The specific timing for veratrum‐ induced cyclopia in sheep corresponds to the period of gastru­ lation and formation of the neural plate before separation of the optic fields. Exposure to the alkaloid earlier in gestation results in fetal death; later exposure causes skeletal malforma­ tion or has no effect, thus demonstrating the importance of narrow, sensitive periods in development.

Microphthalmia and Anophthalmia A

Microphthalmia can occur early in development through a deficiency in the optic vesicle (Fig. 1.19A), or later through failure of normal growth and expansion of the optic cup (Fig. 1.19B). An early deficiency in the size of the globe as a

A B Figure 1.18  A. Cyclopia in a Holstein calf, etiology unknown. Note the single median globe, palpebral fissure, cornea, and pupil. B. Cyclopia in a nonviable kitten. Note the narrow forebrain and midface regions. The limbs and axial skeleton are relatively normal, demonstrating limited effect on the forebrain region of the embryo. (Panel A courtesy of Brian Wilcock.)

B

Figure 1.19  A. Microphthalmia and persistent pupillary membranes in a Chow Chow puppy. Note that the size of the palpebral fissure is proportional to the reduced size of the globe as a whole. This is consistent with microphthalmia induced at the optic vesicle stage. B. Microphthalmia induced at a later stage of gestation, possibly by delayed closure of the optic fissure, although this eye does not exhibit a coloboma. Note the larger size of the palpebral fissure relative to the small globe.

whole is often associated with a correspondingly small, palpebral fissure. The fissure size is determined by the optic vesicle size during its contact with the surface ectoderm, so this supports a malformation sequence beginning at forma­ tion of the optic sulcus, optic vesicle, or earlier. Results from studies of teratogen‐induced ocular malformations have been helpful in identifying sensitive developmental periods. Acute exposure to teratogens before optic sulcus formation results in an overall deficiency of the neural plate, with sub­ sequent reduction in the optic vesicle size. When microph­ thalmia originates during development of the neural plate/ optic sulcus, it is often associated with multiple ocular mal­ formations, including anterior segment dysgenesis, cataract, retinal dysplasia, and persistence of the hyaloid (Table 1.3). Later initiation of microphthalmia can occur through failure to establish early IOP (Berman & Pierro, 1969; Hero et al., 1991). Placement of a capillary tube into the vitreous cavity of the embryonic chick eye reduces the IOP and mark­ edly slows growth of the eye (Coulombre, 1956). Histologic examination of the intubated eyes demonstrates a propor­ tional reduction in the size of all ocular tissues except the neural retina and the lens, which are normal in size for the age of the eye. The retina in these eyes is highly convoluted, filling the small posterior segment. Thus, it has been Table 1.3  Anomalies associated with microphthalmia in dogs. Anomaly

Breed

References

Anterior segment dysgenesis

Saint Bernard, Doberman

Arnbjerg & Jensen (1982); Bergsjo et al. (1984); Boroffka et al. (1998); Lewis et al. (1986); Martin & Leipold (1974); Peiffer & Fischer (1983); Stades (1980, 1983); van der Linde‐Sipman et al. (1983)

Cataract

Old English Sheepdog

Barrie et al. (1979)

Akita

Laratta et al. (1985)

Miniature Schnauzer

Gelatt et al. (1983); Samuelson et al. (1987); Zhang et al. (1991)

Chow Chow

Collins et al. (1992)

Cavalier King Narfstrom & Dubielzig (1984) Charles Spaniel

Retinal dysplasia

English Cocker Spaniel

Strande et al. (1988)

Irish Wolfhound

Kern (1981)

Saint Bernard Martin & Leipold (1974) Doberman

Arnbjerg & Jensen (1982); Bergsjo et al. (1984); Lewis et al. (1986); Peiffer & Fischer (1983)

concluded that growth of the neural retina occurs independ­ ent of the other ocular tissues. Experimental removal of the lens does not alter retinal growth (Coulombre & Coulombre, 1964). Growth of the choroid and sclera appears to depend on IOP, as does folding of the ciliary epithelium (Bard et al., 1975; Cook, 1989, 1995; Cook & Sulik, 1988). Thus, failure of fusion of the optic fissure can result in microphthalmia and associated malformations (i.e., colobomatous microphthal­ mia). A delay in closure of this fissure during a critical growth period may result in inadequate globe expansion as well. If the fissure eventually closes, however, it may be difficult to distinguish between colobomatous and noncolo­ bomatous microphthalmia. If the optic vesicle develops nor­ mally before abnormal (delayed) closure of the optic fissure, the palpebral fissure may not be reduced in size as much as the globe as a whole is reduced (Fig. 1.19B). In most cases, microphthalmia occurs through a combination of cellular deficiency within the optic vesicle/cup compounded by failure of the optic fissure to close on schedule. Anophthalmia represents an extreme on the spectrum of microphthalmia. In most cases, careful examination of the orbital contents will reveal primitive ocular tissue (i.e., actual microphthalmia). True anophthalmia results from a severe developmental deficiency in the primitive forebrain, at a stage before optic sulcus formation. This usually results in a nonviable fetus. Microphthalmia in domestic animals occurs sporadically and is associated with multiple malformations (Table  1.3), including anterior segment dysgenesis, cataract, persistent hyperplastic primary vitreous (Bayon et  al., 2001; Boeve et al., 1992; van der Linde‐Sipman et al., 1983), and retinal dysplasia (Bayon et  al., 2001; Bertram et  al., 1984). In the Doberman Pinscher, microphthalmia, anterior segment dysgenesis, and retinal dysplasia are thought to be inherited as autosomal recessive traits (Bergsjo et al., 1984). Inherited microphthalmia in Texel sheep has as its primary event abnormal development with involution of the lens vesicle followed by proliferation of dysplastic mesenchyme, which develops into cartilage, smooth muscle, fat, and lacrimal gland (van der Linde‐Sipman et al., 2003). A similar spectrum of multiple ocular malformations has been described as a presumably inherited condition associ­ ated with central nervous system malformations in Angus (Rupp & Knight, 1984), Shorthorn (Greene & Leipold, 1974), and Hereford cattle (Blackwell & Cobb, 1959; Kaswan et al., 1987), as well as in nondomestic species, including raptors (Buyukmihci et  al., 1988), camel (Moore et  al., 1999), and white‐tailed deer (Wyand et al., 1972). Colobomatous micro­ phthalmia is initiated later in gestation. In swine, congenital microphthalmia has been historically reported to be associated with maternal vitamin A deficiency (Hale, 1935; Manoly, 1951; Roberts, 1948). Conversely, maternal excess of vitamin A and its analogue, retinoic acid, has been demonstrated (Bayon et al., 2001) to result

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Section I: Basic Vision Sciences

in teratogenic ocular and craniofacial malformations in humans and laboratory animals (Cook, 1989; Cook & Sulik, 1988, 1990; Mulder et al., 2000).

Colobomatous Malformations A coloboma refers broadly to any congenital (present at birth) tissue defect. Ocular colobomas most frequently involve the vascular tunic of the eye, namely the iris and choroid. The spectrum encompasses minor defects (i.e., dys­ coria) as well as major defects (i.e., aniridia). Aniridia occurs rarely in animals (Irby & Aguirre, 1985; Saunders & Fincher, 1951), but is seen as a malformation in humans associated with genetic syndromes including Rieger syndrome (PITX2 gene; Perveen et al., 2000) and PAX6 gene mutations (Sonoda et al., 2000). The iris stroma develops from neural crest mes­ enchyme induced by the bilayered epithelium of the anterior optic cup. Thus, a complete and full‐thickness defect in the iris most likely results from incomplete axial expansion of the anterior optic cup. Iris hypoplasia represents the mild spectrum of this type of coloboma and is seen frequently in dogs (particularly those breeds characterized by subalbinism) and has been recognized as a genetic syndrome in horses (Ewart et al., 2000). The classic explanation for localized colobomatous mal­ formations involves failure of the optic fissure to close. Such failure may result in secondary “colobomatous” microph­ thalmia (Fig. 1.20) and, in experimental models, there may be deviation of the fissure by 90° or more. When defects are located in any inferior location (particularly in a small globe), this is the most likely explanation. This defect in closure of the optic fissure (future RPE and ciliary and iris

epithelium) results in failure of induction of the adjacent choroid and sclera. Any or all of these layers may be affected. The clinically apparent sequella to abnormal fis­ sure closure may be only a subtle degree of dyscoria (Matsuura et al., 2013). Many colobomatous defects, however, occur in other loca­ tions (Briziarelli & Abrutyn, 1975; Gelatt et al., 1969; Gwin et  al., 1981). Differentiation of the neural crest–derived stroma of the choroid and iris is determined by the adjacent structures of the outer layer of the optic cup: anteriorly the iris and ciliary epithelium, and posteriorly the RPE. In sequential analyses of animals exhibiting primary abnor­ malities in differentiation of the outer layer of the optic cup, anterior and posterior segment colobomas are associated with uveal epithelium/RPE defects (Cook et  al., 1991a, 1991b; Zhao & Overbeek, 2001). Prenatal studies of colobomas in the Australian Shepherd dog have demonstrated a primary defect in the RPE, result­ ing in hypoplasia of the adjacent choroid and sclera (Fig. 1.21 and Fig. 1.22; Cook et al., 1991a). This condition is referred to as merle ocular dysgenesis (MOD) because of the correla­ tion with the merle coat coloration (Bertram et al., 1984). A similar spectrum has been identified in cattle (Gelatt et al., 1969), Great Dane dogs, and cats (Gwin et al., 1981) exhibit­ ing incomplete albinism. It is likely that the subalbinism is associated with abnormal RPE that fails to induce the overlying neural crest. Choroidal hypoplasia in the Collie dog (i.e., “Collie eye anomaly” or CEA; Barnett, 1979) may represent a malfor­ mation sequence similar to that of MOD (Fig.  1.23 and Fig.  1.24). Differences between CEA and MOD are illus­ trated in Table 1.4. CEA has been widely described in the Collie, Border Collie, Shetland Sheepdog, and Australian Shepherd (Barnett, 1979; Barnett & Stades, 1979; Bedford, 1982a; Rubin et  al., 1991). Variations of this congenital malformation, including scleral ectasia, sporadically occur in other breeds as well (Bedford, 1998). It has been demon­ strated that choroidal hypoplasia associated with CEA segregates as an autosomal recessive trait with nearly 100% penetrance (Lowe et al., 2003). Optic nerve coloboma as an isolated finding is likely caused by localized failure of closure of the optic fissure that begins to close at the level of the disc with progression ante­ rior and posterior. Optic nerve coloboma is seen unassoci­ ated with genetically identifiable CEA mutation NHEJ1 in the Nova Scotia Duck Tolling Retriever (Brown et al., 2018).

Dermoid Figure 1.20  Microphthalmia and an inferior coloboma of the scleral and uveal tissue allowing vitreous prolapse into the subconjunctival space. In colobomatous microphthalmia, globe expansion is impaired by the inability to establish intraocular pressure because of the optic fissure failing to close. Both mechanisms of microphthalmia may occur in a single eye.

The presence of aberrant tissue (e.g., skin, cartilage, bone) within the orbit may originate early in development through abnormal differentiation of an isolated group of cells. Arrest or inclusions of epidermal and connective tissues (i.e., sur­ face ectoderm and neural crest) may occur during closure of

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B

A

C Figure 1.21  Clinical (A) and gross (B) photographs of the ocular fundus of an adult Australian Shepherd dog affected with merle ocular dysgenesis. Note the large excavation of the equatorial posterior segment. There is also a defect in the ciliary body (arrowhead), which was not apparent clinically. C. At the light microscopic level, defects such as this consist of a thin layer of sclera (S) lined by a glial membrane. Note the abrupt transition from normal retina, retinal pigment epithelium (RPE), and choroid seen on the right to the sudden loss of RPE and choroid at the level indicated by the arrow. (Reprinted with permission from Cook, C., Burling, K., & Nelson E. (1991) Embryogenesis of posterior segment colobomas in the Australian Shepherd dog. Progress in Veterinary & Comparative Ophthalmology, 1, 163–170.)

the fetal clefts. Abnormal invagination of ectodermal tissue later in gestation may result in a pocket of well‐differenti­ ated dermal tissue. Eyelid dermoids may occur though isola­ tion of an island of ectoderm later forming a nodule of tissue that is, strictly speaking, not abnormal in location, but in configuration, a nonneoplastic overgrowth of tissue disor­ dered in structure (Fig. 1.25). These are termed hamartomas (i.e., benign tissue mass resulting from faulty development). Limbal dermoids represent choristomas (i.e., mass formed by tissue not normally found at this site; Fig. 1.26). Both eyelid epidermis and corneal epithelium originate from surface ectoderm, following induction by the optic vesicle, and there appears to be a narrow period during which the surface ecto­ derm can respond to inductive influences to produce a nor­ mal lens. The same may be true for induction of the cornea. Dermoids are seen in all species as an incidental finding, and they are seen as an inherited condition in cattle and some dog breeds (Adams et al., 1983; Barkyoumb & Leipold, 1984).

Anterior Segment Dysgenesis The anterior segment dysgeneses identified in humans encom­ pass a broad range of malformations, including Peters’

anomaly, Axenfeld–Rieger syndrome, iridocorneal endo­ thelium syndrome, posterior polymorphous dystrophy, and Sturge–Weber syndrome. Similar anomalies have been described in domestic animals, generally as sporadic occur­ rences (Irby & Aguirre, 1985; Peiffer, 1982; Rebhun, 1977; Swanson et al., 2001). Anterior segment dysgenesis is often associated with microphthalmia (Arnbjerg & Jensen, 1982; Bergsjo et  al., 1984; Lewis et  al., 1986; Martin & Leipold, 1974; Peiffer & Fischer, 1983). In domestic animals, persistent pupillary membranes rep­ resent the most common manifestation of anterior segment dysgenesis. In the embryo, the pupillary membrane forms a solid sheet of tissue that is continuous with the iris at the level of the collarette (see Fig. 1.19). Regression occurs dur­ ing the first two postnatal weeks, before eyelid opening in the dog. Persistence of some pupillary membrane strands was noted in 0.7% of 575 Beagles aged from 16 to 24 weeks (Bellhorn, 1974). Inherited persistent pupillary membranes occur in the Basenji dog (Bistner et  al., 1971; Roberts & Bistner, 1968), and they may be associated with corneal or lens opacities (or both) at the site of membrane attachments. Complete persistence of a sheet of tissue bridging the pupil is rare and results in visual impairment. Persistent pupillary

SECTION I

A

B

C

D

Figure 1.22  Sequential histology of merle ocular dysgenesis (MOD). A. Normal canine eye on day 30 of gestation. Note the cuboidal appearance of the nonpigmented retinal pigment epithelium (RPE; *), which is closely apposed to the neural retina (R). The nuclei closest to the RPE are those of the outer neuroblastic layer. M, periocular mesenchyme—anlage of the choroid and sclera. B. MOD-affected eye on day 35 of gestation. The RPE (*) is shortened and contains a few intracytoplasmic vacuoles. C and D. MOD-affected eye on day 35 of gestation. The RPE (*) has become progressively thinner and exhibits a large number of vacuoles. Separation of the degenerating RPE from the neural retina also can be seen. (Reprinted with permission from Cook, C., Burling, K., & Nelson, E. (1991) Embryogenesis of posterior segment colobomas in the Australian shepherd dog. Progress in Veterinary & Comparative Ophthalmology, 1, 163–170.)

A

B

Figure 1.23  A. Fundus photograph of choroidal hypoplasia associated with Collie eye anomaly. Note the white sclera with superimposed choroidal and retinal vasculature. B. Optic nerve coloboma in a Collie affected with Collie eye anomaly. The coloboma is located temporally adjacent to an area of mild choroidal hypoplasia (identified by absence of tapetum and visible choroidal vasculature).

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Figure 1.25  Eyelid dermoid in a Boxer dog. The tissue is histologically normal skin in a grossly normal location, but abnormal in configuration, representing a hamartoma. (Courtesy of Robert Peiffer.)

Figure 1.24  Gross photograph of an optic nerve coloboma in a Collie. Note the excavation of thinned sclera lined by glial tissue (neuroectoderm) continuous with retina. (Reprinted with permission from Wilcock, B. (2007) Pathologic Basis of the Veterinary Disease, 4th ed. (eds. McGavin, M.D. & Zachary, J.F.). St. Louis, MO: Elsevier.) Table 1.4  Comparative features of merle ocular dysgenesis and Collie eye anomaly. Merle Ocular Dysgenesis

Collie Eye Anomaly

Coat color

Homozygous merle

No correlation

Microphthalmia

Frequent

Rare/mild

Choroidal hypoplasia

Extensive scleral/ retinal defects

Common, localized

Optic nerve coloboma

Rare

Frequent

Cataract

Frequent

Rare

Iris coloboma

Frequent

Rare

Reprinted with permission from Cook, C., Burling, K., & Nelson, E. (1991) Embryogenesis of posterior segment colobomas in the Australian Shepherd dog. Progress in Veterinary & Comparative Ophthalmology, 1, 163–170.

membranes also occur sporadically in other breeds (Strande et al., 1988). Because most structures of the ocular anterior segment are of neural crest origin, it is tempting in cases of anterior segment anomalies to incriminate this cell population as being abnormal in differentiation, migration, or both. This

Figure 1.26  Limbal dermoid in a Lhasa Apso puppy. This is an example of a choristoma (histologically normal tissue in an abnormal location).

theory has resulted in labeling these conditions, when they occur in humans, as ocular neurocristopathies, ­particularly when other anomalies exist in tissues that are largely derived from the neural crest (e.g., craniofacial connective tissue, teeth; Bahn et al., 1984; Kupfer et al., 1975; Kupfer & Kaiser‐ Kupfer, 1978; Shields et al., 1985; Waring et al., 1975). When considering this theory, it is important to realize two con­ cepts. First, the neural crest is the predominant cell popula­ tion of the developing craniofacial region, particularly the eye. In fact, the list of ocular tissues not derived from neural crest is relatively small (see Table  1.2). Thus, the fact that most malformations of this region involve crest tissues may reflect their ubiquitous distribution rather than their com­ mon origin. The normal development of the choroid and sclera (also of neural crest origin) in most of these “neural crest syndromes” argues against a primary neural crest anomaly. Second, the neural crest is an actively migrating

SECTION I

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Section I: Basic Vision Sciences

population of cells and can be easily influenced by adjacent cell populations. Thus, the perceived anomaly of neural crest tissue may, in many cases, be a secondary effect. Much of the maturation of the iridocorneal angle occurs late during gestation and during early postnatal life in the dog, but earlier events may influence development of the anterior segment. Anterior segment dysgenesis syndromes characterized primarily by axial defects in corneal stroma and endothelium, accompanied by corresponding mal­ formations in the anterior lens capsule and epithelium (i.e., Peters’ anomaly), most likely represent a manifesta­ tion of abnormal keratolenticular separation (Fig. 1.27 and Fig. 1.28). This spectrum of malformations that mimic Peters’ anomaly can be induced by teratogen exposure in mice before optic sulcus invagination (Fig.  1.29 and Fig.  1.30; Cook, 1989; Cook & Sulik, 1988; Cook et al., 1987). Similar syn­ dromes of anterior segment dysgenesis have been identified in humans following ethanol exposure (Miller et  al., 1984; Stromland et al., 1991).

B A D

C

Figure 1.27  Clinical features of Peters’ anomaly (anterior segment dysgenesis) resulting from abnormal separation of the lens vesicle from the surface ectoderm. A. Persistent pupillary membranes. B. Corneal opacity associated with defect in corneal endothelium, Descemet’s membrane, and corneal stroma (neural crest). C. Iris hypoplasia. D. Anterior lenticonus and anterior polar cataract associated with partial defect in anterior lens capsule. (Drawing by Farid Mogannam.)

A

The size of the lens vesicle is determined by the area of con­ tact between the optic vesicle and the surface ectoderm. Thus, factors influencing the size of the optic vesicle or the angle at which the optic vesicle approaches the surface ectoderm may affect the ultimate size of the lens vesicle. Microphakia result­ ing from optic vesicle deficiencies may be initiated very early in gestation (i.e., during formation of the neural plate). Microphakia associated with lens luxation has been described in two unrelated Siamese kittens (Molleda et al., 1995); as the globes were apparently otherwise normal, a primary abnor­ mality in the lens placode ectoderm can be postulated. Aphakia is much more rare, and may occur through failure of contact between the optic vesicle and the surface ectoderm during the period when the surface ectoderm can respond to its inductive influences. As the anterior lens epithelium is required for induction of the corneal endothelium, this early initiation of aphakia would be associated with dysgenesis of the cornea and (likely) anterior uvea. Alternatively, normal induction of a lens vesicle followed by later involution would be expected to result in an eye with more normal anterior segment morphology. The lens aplasia (lap) mouse demonstrates faulty lens basement membrane formation associated with apoptosis and involution of the rudimentary lens vesicle (Aso et al., 1995, 1998). Sporadic cases of aphakia have been described in domestic animals, including a cat with associated retinal detachment but appar­ ently normal iridocorneal structures (histopathology not avail­ able; Peiffer, 1982), and a litter of Saint Bernard puppies with multiple ocular malformations (Martin & Leipold, 1974). In humans, in utero exposure to rubella or parvovirus B can result in aphakia; anterior segment structures are variably affected (Hartwig et  al., 1988). Abnormalities in lens shape (e.g., spherophakia, lens coloboma) may actually represent a pri­ mary abnormality in the ciliary processes, zonular fibers, or both, resulting in a lack of tension on the lens (Fig. 1.31 and Fig. 1.32). Thus, the term coloboma may be inaccurate when used in reference to a flattened equatorial portion of the lens that is not a true lens defect.

B

Figure 1.28  A. Clinical photograph of a puppy with Peters’ anomaly exhibiting microphthalmia, a central corneal opacity, anterior axial cataract, and persistent pupillary membranes. B. A more severe form of anterior segment dysgenesis with visible lens material trapped within the axial cornea, accompanied by persistent pupillary membranes leading to the corneal defect.

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A

B

C

D

Figure 1.29  Keratolenticular dysgenesis induced by teratogen exposure in mice. A. Mouse embryo following acute exposure to ethanol during gastrulation. Delay in separation of the lens vesicle (L) from the surface ectoderm (SE) results in an anterior lenticonus (*) and failure of the mesenchyme (M) to complete its axial migration to form the corneal stroma, endothelium, and iris stroma. R, retinal primordium. Original magnification, 166×. B, C, and D. Mouse embryo following acute exposure to 13-cis-retinoic acid during gastrulation. A large keratolenticular stalk (S) persists and is continuous axially with the SE. The arrow in B indicates the incompletely closed lens pore. D is a transmission electron microscopic view of the stalk seen in C. There is discontinuity between the lens epithelium (LE) and the stalk epithelium (S). Adjacent neural crest mesenchyme (M) is visible, and two layers of basement membrane can be seen in D, bridging the lens–stalk junction as well as dividing the two zones. Mechanical interference with the axial migration of neural crest cells is responsible in this model for malformations, which mimics Peters’ anomaly in the human. OC, optic cup. (Reprinted with permission from Cook, C. (1995) Embryogenesis of congenital eye malformations. Veterinary and Comparative Ophthalmology, 5, 109–123.)

Uveal Cysts Uveal cysts occur through failure of adhesion of the inner and outer layers of the optic cup. In the dog, they are most commonly identified as single or multiple spherical pig­ mented masses within the pupil or free‐floating within the

anterior chamber (Fig.  1.33 and Fig.  1.34). They appear to have a genetic predilection. In the cat, they are more often thick‐walled and remain attached to the posterior iris sur­ face, causing anterior displacement of the iris and shallow­ ing of the anterior chamber, and may result in secondary glaucoma (Gemensky‐Metzler et al., 2004). In cats they also

SECTION I

28

Section I: Basic Vision Sciences EMBRYO forebrain deficiency

abnormal optic vesicle orientation

ADULT

small optic vesicle

small optic vesicle

small optic cup persistent optic fissure small lens vesicle ECM abnormalities ?

“excessive” hyaloid vasculature

small palpebral fissure microphthalmia anterior and posterior segment colobomas microphakia

?

Figure 1.30  The relationship between microphthalmia and associated ocular malformations. An early embryonic insult (during gastrulation) leads to a deficiency in the forebrain and its derivatives, the optic sulci. The subsequently small optic vesicle often exhibits an abnormal relationship to the surface ectoderm, which is programmed (by the underlying neural crest) to form the lens. The result is a spectrum of malformations in the adult, including microphthalmia, microphakia, colobomas, persistent hyperplastic primary vitreous, and anterior segment dysgenesis. ECM, extracellular matrix. (Reprinted with permission from Cook, C. (1995) Embryogenesis of congenital eye malformations. Veterinary and Comparative Ophthalmology, 5, 109–123.)

persistent hyperplastic primary vitreous retinal vascular tortuosity

persistent keratolenticular attachment

anterior segment dysgenesis: (corneal opacity, persistent pupillary membranes, anterior lenticonus, cataract)

Figure 1.31  Microphakia and spherophakia in a cat. Note the elongated ciliary processes. The globe was not microphthalmic, and this most likely represented a primary abnormality in the surface ectoderm destined to become lens placode.

appear to have a genetic predisposition, with Burmese cats overrepresented (Blacklock et  al., 2016). When uveal cysts originate within the ciliary body, they can be nonpigmented (see Fig. 1.32). Uveal cysts are often seen associated with pigmentary uve­ itis or pigmentary and cystic glaucoma in Golden Retriever

Figure 1.32  Nonpigmented ciliary body cysts in a cat. Note the flattened lens equator, which would incorrectly be called a lens coloboma. In this case, a medulloepithelioma of the ciliary body resulted both in the cysts and in the localized absence of zonules. Failure of normal traction by the zonule on the lens equator resulted in this flattened appearance. (Courtesy of Kristina Burling.)

dogs and other breeds. There has been a great deal of specu­ lation about whether the cysts may play a causal role in the inflammatory disease process (Pumphrey et  al., 2013; Townsend & Gornik, 2013). Uveal cysts seen in dogs affected

with uveitis have a unique clinical appearance, being more translucent, irregularly shaped, and often adherent to the lens or cornea. This is in distinct contrast to the cysts commonly seen in other canine breeds with complete lack of inflammation.

Congenital Ocular Anomalies in Horses

A

B Figure 1.33  Iris cysts. A. Single iris cyst in a dog. B. Multiple iris cysts in a cat. In cats, these cysts are often thick-walled and remain attached to the posterior iris surface, causing anterior displacement of the iris and a shallow anterior chamber.

A syndrome of multiple congenital ocular anomalies (MCOA) has been identified as a bilaterally symmetrical, inherited condition in several breeds of horses, most notably the Rocky Mountain breed, silver mutant ponies, and miniature horses (Andersson et al., 2011; Komaromy et al., 2011; Plummer & Ramsey, 2011; Ramsey et  al., 1999a, 1999b; Fig.  1.35). Affected individuals most often have a silver coat color, and correlation with the Silver Dapple locus is suspected. The condition in the heterozygote is characterized by cysts of the posterior iris, ciliary body, and peripheral retina, indicating failure of adhesion of the inner and outer layers of the optic cup. These cysts are consistently located temporally, not associated with the optic fissure. Areas of current or previ­ ous retinal detachment were further manifestations of abnormal cup invagination and adhesion. The spectrum of anterior segment malformations seen in homozygous indi­ viduals included megalocornea, deep anterior chamber, iris hypoplasia, and cataract. Increased thickness of the central and peripheral corneas was noted and increased with age. Intraocular pressures were normal (Ramsey et  al., 1999b). The syndrome in Rocky Mountain horses appears to exhibit codominant inheritance (Ewart et al., 2000). Cataracts have been identified in Exmoor ponies, with a suspected sex‐ linked mode of inheritance (Pinard & Basrur, 2011). Other congenital anomalies appear to occur rarely in horses, with occasional neonatal diagnosis of retinal and conjunctival hemorrhages thought to be due to injury during parturition (Barsotti et al., 2013).

Congenital Cataracts

Figure 1.34  Histologic appearance of a uveal cyst on the posterior iris surface. These cysts form beneath the posterior pigmented epithelium and frequently separate to become free-floating spheres within the anterior chamber. (Courtesy of Robert Peiffer.)

Congenital cataracts resulting from abnormal formation of primary or secondary lens fibers would be expected to be localized to the nuclear region, and be nonprogressive. However, an early effect on the primary lens fibers may extend to involve the secondary fibers, resulting in a congen­ ital cataract that progresses to involve the entire lens. Abnormal lens vesicle invagination, separation, or defects in the lens epithelium or capsule would result in a cataract (with or without anterior or posterior lenticonus; Ori et al., 2000) that would remain associated with the peripheral por­ tion of the lens, with the secondary lens fibers forming underneath (e.g., Old English Sheepdog, Barrie et al., 1979; Cavalier King Charles Spaniel, Narfstrom & Dubielzig, 1984). Congenital cataracts associated with mild microph­ thalmia (Miniature Schnauzer, Gelatt et al., 1983; Monaco

29

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Section I: Basic Vision Sciences

SECTION I

30

A

B

C Figure 1.35  Spectrum of ocular lesions seen in Rocky Mountain horses. A. A large translucent cyst arising from the lateral part of the ciliary body extends into the vitreous cavity and occupies part of the temporal pupillary axis of the right eye. B. Retinal dysplasia is characterized by numerous pigmented folds located in the superior peripapillary neurosensory retina. C. Multiple, well-delineated, darkly pigmented curvilinear streaks of retinal pigment epithelium are present in the peripheral right tapetal fundus. These streaks originate and terminate at the ora ciliaris retinae and extend toward the optic papilla. They represent demarcation lines from previous retinal detachments and are referred to clinically as “high-water markers.” (Reprinted with permission from Ramsey, D.T., Ewart, S.L., Render, J.A., et al. (1999) Congenital ocular abnormalities of Rocky Mountain horses. Veterinary Ophthalmology, 2, 47–59.)

et  al., 1985; Samuelson et  al., 1987) may result from early abnormalities in the lens placode/epithelium, and they may involve the lens nucleus, cortex, or both. In the Miniature Schnauzer, these lesions are recessively inherited, typically bilateral, and initially involve the posterior subcapsular region with rapid progression (Gelatt et  al., 1983; Zhang et al., 1991).

Congenital Glaucoma Malformations of the iridocorneal angle (i.e., goniodysgen­ esis) have been described in several breeds, including the Basset Hound (Martin & Wyman, 1968; Wyman & Ketring, 1976) and the Bouvier des Flandres (van Rensburg et  al., 1992). The iridocorneal angles of affected animals are

malformed at birth, but the IOP often remains normal until middle age. Thus, the relationship between angle conforma­ tion and glaucoma is unclear. In English Springer Spaniels, a correlation was observed between pectinate ligament dys­ plasia and glaucoma (Bjerkas et al., 2002). Although pecti­ nate ligament dysplasia is a congenital malformation, it may appear to clinically progress over time, as assessed by sequential gonioscopic evaluations in Flat‐Coated Retrievers (Pearl et al., 2015). Goniodysgenesis is characterized by abnormal tissue bridg­ ing the ciliary cleft. During normal development, this sheet undergoes rarefaction to form the pectinate ligament during the first three postnatal weeks (Martin, 1974; Samuelson & Gelatt, 1984a). Failure of this membrane to undergo normal atrophy is thought to result in goniodysgenesis. Congenital

glaucoma associated with presumed primary iridoschisis (i.e., degeneration of the anterior iris) has been described in a cat (Brown et al., 1994).

Persistent Hyperplastic Primary Vitreous/ Persistent Hyperplastic Tunica Vasculosa Lentis Variable persistence of the hyaloid occurs in association with many other types of malformations, including micro­ phthalmia, microphakia, cataract, and retinal dysplasia (Fig. 1.36; Bayon et al., 2001; Boeve et al., 1992). Persistent hyperplastic primary vitreous/persistent hyperplastic tunica vasculosa lentis (PHPV/PHTVL) may occur secondary to other malformations or as a primary, spontaneous failure of vascular regression. This condition has been described as an inherited trait in the Doberman (Stades, 1980; van der Linde‐ Sipman et  al., 1983) and the Bouvier des Flandres (van Rensburg et  al., 1992), and has been identified in two cats (Allgoewer & Pfefferkorn, 2001). In the Doberman, the genetics appear to be something more than simple recessive (Stades, 1983). The mechanism involved is failure of normal vascular regression and hyperplasia of the persistent tissue. Normal vitreous may have antiangiogenic properties, and it may be essential for initiating regression of the hyaloid. Expression of the Arf tumor suppressor gene in perivascular cells may repress VEGF expression, thus promoting hyaloid regression in mice (Martin et al. 2004). Thus, the primary abnormality in PHPV/PHTVL may rest with the product of the ciliary epithelium (i.e., secondary vitreous).

Retinal Dysplasia Abnormal retinal differentiation results in rosettes and multifocal disorganization known as retinal dysplasia. Retinal folds without rosette formation may result from inequity in the relative growth rates of the inner (i.e., reti­ nal) and outer (i.e., RPE) layers of the optic cup (Fig. 1.37 and Fig. 1.38). This is a particularly likely pathogenesis in cases in which the folds resolve as the animal matures; this is seen most commonly among Collies. These folds do not represent abnormal differentiation and thus are not

Figure 1.37  Fundus photograph of retinal folds in a young American Cocker Spaniel. These appear as single or multiple white curvilinear streaks. Elevation of a retinal vessel crossing a fold (arrow) can be seen.

Figure 1.36  Persistent hyperplastic primary vitreous in a puppy associated with a posterior subcapsular cataract. This eye is also microphthalmic.

Figure 1.38  Histologic appearance of retinal folds. Note the normal stratification of the retinal layers and the mechanical distortion caused by disparate growth of the neural retina (inner optic cup) and the underlying RPE (outer optic cup). (Courtesy of Robert Peiffer.)

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accurately referred to as dysplasia. Simple folding in the retina has been described in the American Cocker Spaniel (MacMillan & Lipton, 1978) and the Beagle (Heywood & Wells, 1970; Schiavo & Field, 1974). The genetic relation­ ship between simple folds and true retinal dysplasia is undetermined. True retinal dysplasia is characterized by disorganized development, the hallmark of which is the rosette. Abnormal or incomplete contact between the inner and outer layers of the optic cup during embryogenesis can result in dysplasia, with the most severe form associated with complete retinal nonattachment. This usually occurs in eyes that are microphthalmic with multiple ocular anomalies (e.g., Bedlington terrier, Rubin, 1963, 1968; Sealyham terrier, Ashton et  al., 1968; and American Pit Bull terrier, Rodarte‐Almeida et al., 2016). In the Labrador Retriever, retinal dysplasia genetically associated with skeletal anomalies is inherited as an autosomal dominant trait (Barnett et  al., 1970; Carrig et  al., 1988; Nelson & Macmillan, 1983). A similar form of inherited skeletal‐ ocular dysplasia is seen in the Samoyed dog (Aroch et al., 1996; Meyers et al., 1983). Multifocal retinal rosettes in a retina that is partially attached to the underlying RPE represent the most common form of retinal dysplasia (Fig. 1.39 and Fig. 1.40). This condi­ tion has been described extensively in the English Springer Spaniel (Lavach et al., 1978; O’Toole et al., 1983). Retinal dysplasia occurs sporadically in other breeds (Bedford, 1982b) and species (Murphy et  al., 1985). Multifocal, “geographic” retinal dysplasia most likely represents a

Figure 1.40  Histologic appearance of geographic retinal dysplasia. The retina exhibits disorganization and classic rosette formation. Note also the hypoplastic choroid. (Courtesy of Robert Peiffer.)

later initiation of retinal disorganization. The dysplastic changes are first apparent at 45–50 days of gestation. Focal loss of cell junctions of the external limiting membrane is seen, with proliferation of neuroblasts in the retina forming rosettes (Whiteley, 1991). Retinal differentiation and mat­ uration in the dog continue during the first 40 days post­ natal. In  addition, maturation of the tapetum during the first 6 months results in an inconsistent ability to detect mild forms of retinal dysplasia in puppies less than 10 weeks of age (Holle et al., 1999). An unusual form of RPE dysplasia with duplication of neural retina in the outer layer of the optic cup has been described in several mutant mouse strains (Bumsted & Barnstable, 2000; Cook et al., 1991b). Large colobomas of the choroid and sclera in the areas adjacent to the dysplastic RPE illustrate the importance of this layer in coordinating differentiation of the neural crest. Viral‐induced “retinal dysplasia” has been associated with early postnatal exposure to canine herpesvirus and prenatal exposure to bovine viral diarrhea virus (Bistner et al., 1970; Brown et al., 1975; Kahrs et al., 1970), bluetongue virus in lambs (Silverstein & Al, 1971), and feline panleukopenia virus (Percy et  al., 1975). Histopathologically, affected reti­ nas are characterized by early inflammatory cell infiltrate and, later, by necrosis, gliosis, and diffuse disorganization of cell layers. Similar postnatal retinal disorganization can be induced in the dog by radiation exposure (Shively et  al., 1970, 1972). These conditions are more accurately classified as teratogen‐induced necrosis and degeneration rather than as dysplasia.

Optic Nerve Hypoplasia Figure 1.39  Geographic retinal dysplasia in an English Springer Spaniel. The retina is detached and lies just posterior to the lens; there are many folds visible.

Though difficult to document experimentally, optic nerve hypoplasia most likely results from a primary abnormality in the number or ultimate differentiation of the retinal gan­ glion cells (Fig. 1.41). Hypovitaminosis A in cattle can result

33

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Figure 1.41  Optic nerve hypoplasia in an 8-week-old Alsatian puppy. This was a unilateral lesion and the pup presented with anisocoria. (Courtesy of Robert Peiffer.)

Figure 1.42  Eyelid coloboma in a kitten. The eyelid margin is absent from the temporal two-thirds of the upper lid. There is keratitis due to exposure and trichiasis. The eye also exhibits microphthalmia, dyscoria, and persistent pupillary membranes.

in stenosis of the optic foramen with secondary optic nerve degeneration, incorrectly labeled hypoplasia. Colobomas of the optic nerve result from failure of the optic fissure to close, as described for “typical” colobomas. Myelination of the optic nerve progresses from the brain to the eye during the first 3 weeks postnatal (Fox, 1963). Reduction in the amount of myelinization leads to a small optic disc that can mimic hypoplasia but is unassociated with vision deficits (termed micropapilla).

Eyelid Coloboma The eyelids and palpebral fissure are initially induced at the time of contact of the optic vesicle with the surface ecto­ derm. This is also the time of induction of the lens placode. Eyelid agenesis (coloboma) occurs in domestic cats, often with concurrent persistent pupillary membranes, keratolen­ ticular dysgenesis, and subtle to severe microphthalmia (Fig.  1.42; Glaze, 2005; Koch, 1979; Martin et  al., 1997; Narfstrom, 1999). Eyelid colobomas occur less commonly in dogs (Fig. 1.43) and a case of upper eyelid agenesis has also been described in a Peregrine Falcon (Aguirre et  al., 1972; Murphy et  al., 1985) and in two sibling snow leopards (Hamoudi et  al., 2013). The snow leopards also exhibited microphthalmia, typical anterior segment dysgenesis, and persistent hyaloid. The receptivity of the surface ectoderm to the inductive influences of the optic vesicle is highly spatiotemporally

Figure 1.43  A Cavalier King Charles Spaniel with bilateral lower eyelid colobomas and dermoids. Note the notch defects in the central portion of the lower lids and the abnormal hair growth adjacent to the defects.

specific. The fairly consistent location of the defect in the temporal upper eyelid leads to suspicion of an abnormal orientation of the optic vesicle as it approaches the surface ectoderm, possibly eccentrically contacting the surface ectoderm in an area that is only partially receptive.

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Maestro De Las Casas, C., Epeldegui, M., Tudela, C., et al. (2003) High exogenous homocysteine modifies eye development in early chick embryos. Birth Defects Research. Part A, Clinical and Molecular Teratology, 67, 35–40. Manoly, R. (1951) Blindness in newborn pigs. Veterinary Record, 63, 398. Martin, A.C., Thornton, J.D., Liu, J., et al. (2004) Pathogenesis of persistent hyperplastic primary vitreous in mice lacking the Arf tumor suppressor gene. Investigative Ophthalmology & Visual Science, 45, 3387–3396. Martin, C. (1974) Development of the pectinate ligament structure of the dog. American Journal of Veterinary Research, 35, 1433. Martin, C. (1978) Strabismus associated with extraocular muscle agenesis in a dog. Journal of the American Animal Hospital Association, 14, 486–489. Martin, C. & Wyman, M. (1968) Glaucoma in the Basset Hound. Journal of the American Veterinary Medical Association, 153, 1320–1327. Martin, C.L. & Leipold, H.W. (1974) Aphakia and multiple ocular defects in Saint Bernard puppies. Veterinary Medicine, Small Animal Clinician, 69, 448–453. Martin, C.L., Stiles, J., & Willis, M. (1997) Feline colobomatous syndrome. Veterinary & Comparative Ophthalmology, 7, 39–43. Matsuura, T., Tsuji, N., Kodama, Y., et al. (2013) Iridal coloboma induces dyscoria during miosis in FLS mice. Veterinary Ophthalmology, 16, 186–191. Meier, S. (1982) The development of segmentation in the cranial region of vertebrate embryos. Scanning Electron Microscopy, Pt 3, 1269–1282. Meier, S. & Tam, P.P. (1982) Metameric pattern development in the embryonic axis of the mouse: I. Differentiation of the cranial segments. Differentiation, 21, 95–108. Meyers, V.N., Jezyk, P.F., Aguirre, G.D., et al. (1983) Short‐ limbed dwarfism and ocular defects in the Samoyed dog. Journal of the American Veterinary Medical Association, 183, 975–979. Miller, M.T., Epstein, R.J., Sugar, J., et al. (1984) Anterior segment anomalies associated with the fetal alcohol syndrome. Journal of Pediatric Ophthalmology and Strabismus, 21, 8–18. Molleda, J.M., Martin, E., Ginel, P.J., et al. (1995) Microphakia associated with lens luxation in the cat. Journal of the American Animal Hospital Association, 31, 209–212. Monaco, M., Samuelson, D., & Gelatt, K. (1985) Morphology and postnatal development of the normal lens in the dog and congenital cataract in the Miniature Schnauzer. Lens Research, 2, 393–433. Montiani‐Ferreira, F., Petersen‐Jones, S., Cassotis, N., et al. (2003) Early postnatal development of central corneal thickness in dogs. Veterinary Ophthalmology, 6, 19–22. Moore, C.P., Shaner, J.B., Halenda, R.M., et al. (1999) Congenital ocular anomalies and ventricular septal defect in a Dromedary camel (Camelus dromedarius). Journal of Zoo and Wildlife Medicine, 30, 423–430.

Mulder, G.B., Manley, N., Grant, J., et al. (2000) Effects of excess vitamin A on development of cranial neural crest‐ derived structures: A neonatal and embryologic study. Teratology, 62, 214–226. Munyard, K.A., Sherry, C.R., & Sherry, L. (2007) A retrospective evaluation of congenital ocular defects in Australian Shepherd dogs in Australia. Veterinary Ophthalmology, 10, 19–22. Murphy, C.J., Kern, T.J., Loew, E., et al. (1985) Retinal dysplasia in a hybrid falcon. Journal of the American Veterinary Medical Association, 187, 1208–1209. Mutlu, F. & Leipold, I. (1964) The structure of the fetal hyaloid system and tunica vasculosa lentis. Archives of Ophthalmology, 71, 102–110. Nakano, K.E. & Nakamura, H. (1985) Origin of the irideal striated muscle in birds. Journal of Embryology and Experimental Morphology, 88, 1–13. Narfstrom, K. (1999) Hereditary and congenital ocular disease in the cat. Journal of Feline Medicine Surgery, 1, 135–141. Narfstrom, K. & Dubielzig, R. (1984) Posterior lenticonus, cataracts and microphthalmia in the Cavalier King Charles Spaniel. Journal of Small Animal Practice, 25, 669–677. Nelson, D. & Macmillan, A. (1983) Multifocal retinal dysplasia in field trial Labrador Retrievers. Journal of the American Animal Hospital Association, 19, 388–392. Njoku, C.O., Esievo, K.A., Bida, S.A., et al. (1978) Canine cyclopia. Veterinary Record, 102, 60–61. Noden, D. (1993) Periocular mesenchyme: Neural crest and mesodermal interactions. In: Duane’s Foundations of Clinical Ophthalmology (eds Tasman, W. & Jaeger, E.), pp. 1–23. Hagerstown, MD: Lippincott. Noden, D.M. (1986) Patterning of avian craniofacial muscles. Developmental Biology, 116, 347–356. O’Rahilly, R. (1983) The timing and sequence of events in the development of the human eye and ear during the embryonic period proper. Anatomy and Embryology, 168, 87–99. Ori, J.I., Yoshikai, T., Yoshimur, S., et al. (2000) Posterior lenticonus with congenital cataract in a Shih Tzu dog. Journal of Veterinary Medical Science, 62, 1201–1203. O’Toole, D., Young, S., Severin, G.A., et al. (1983) Retinal dysplasia of English Springer Spaniel dogs: Light microscopy of the postnatal lesions. Veterinary Pathology, 20, 298–311. Ozeki, H., Ogura, Y., Hirabayashi, Y., et al. (2000) Apoptosis is associated with formation and persistence of the embryonic fissure. Current Eye Research, 20, 367–372. Ozeki, H., Ogura, Y., Hirabayashi, Y., et al. (2001) Suppression of lens stalk cell apoptosis by hyaluronic acid leads to faulty separation of the lens vesicle. Experimental Eye Research, 72, 63–70. Packard, D.S. & Meier, S. (1983) An experimental study of the somitomeric organization of the avian segmental plate. Developmental Biology, 97, 191–202. Pearl, R., Gould, D., & Spiess, B. (2015) Progression of pectinate ligament dysplasia over time in two populations of Flat‐Coated Retrievers. Veterinary Ophthalmology, 18, 6–12.

Peiffer, R. (1982) Bilateral congenital aphakia and retinal detachment in a cat. Journal of the American Animal Hospital Association, 18, 128–130. Peiffer, R. & Fischer, C. (1983) Microphthalmia, retinal dysplasia and anterior segment dysgenesis in a litter of Doberman Pinschers. Journal of the American Veterinary Medical Association, 183, 875. Percy, D., Scott, F., & Albert, D. (1975) Retinal dysplasia due to feline panleukopenia virus infection. Journal of the American Veterinary Medical Association, 167, 935–937. Perveen, R., Lloyd, I.C., Clayton‐Smith, J., et al. (2000) Phenotypic variability and asymmetry of Rieger syndrome associated with PITX2 mutations. Investigative Ophthalmology & Visual Science, 41, 2456–2460. Pinard, C.L. & Basrur, P.K. (2011) Ocular anomalies in a herd of Exmoor ponies in Canada. Veterinary Ophthalmology, 14, 100–108. Plummer, C.E. & Ramsey, D.T. (2011) A survey of ocular abnormalities in miniature horses. Veterinary Ophthalmology, 14, 239–243. Pumphrey, S.A., Pizzirani, S., Pirie, C.G., & Needle, D.B. (2013) Glaucoma associated with uveal cysts and goniodysgenesis in American Bulldogs: A case series. Veterinary Ophthalmology, 16, 377–385. Ramsey, D.T., Ewart, S.L., Render, J.A., et al. (1999a) Congenital ocular abnormalities of Rocky Mountain horses. Veterinary Ophthalmology, 2, 47–59. Ramsey, D.T., Hauptman, J.G., & Petersen‐Jones, S.M. (1999b) Corneal thickness, intraocular pressure, and optical corneal diameter in Rocky Mountain horses with cornea globosa or clinically normal corneas. American Journal of Veterinary Research, 60, 1317–1321. Rebhun, R. (1977) Congenital anterior staphyloma with rudimentary lens in a calf. Journal of the American Veterinary Medical Association, 171, 440–442. Reme, C., Urner, U., & Aeberhard, B. (1983a) The development of the chamber angle in the rat eye. Graefe’s Archive for Clinical and Experimental Ophthalmology, 220, 139–153. Reme, C., Urner, U., & Aeberhard, B. (1983b) The occurrence of cell death during the remodelling of the chamber angle recess in the developing rat eye. Graefe’s Archive for Clinical and Experimental Ophthalmology, 221, 113–121. Roberts, L. (1948) Microphthalmia in swine. Journal of Heredity, 39, 146. Roberts, S.R. & Bistner, S.I. (1968) Persistent pupillary membrane in Basenji dogs. Journal of the American Veterinary Medical Association, 153, 533–542. Rodarte‐Almeida, A.C.V., Petersen‐Jones, S., Langohr, I.M., et al. (2016) Retinal dysplasia in American Pit Bull terriers – phenotypic characterization and breeding study. Veterinary Ophthalmology, 19, 11–21. Rubin, L. (1963) Hereditary retinal detachment in Bedlington Terriers: A preliminary report. Veterinary Medicine, Small Animal Clinician, 3, 387–389.

Rubin, L. (1968) Heredity of retinal dysplasia in Bedlington Terriers. Journal of the American Veterinary Medical Association, 152, 260–262. Rubin, L., Nelson, E., & Sharp, C. (1991) Collie eye anomaly in Australian Shepherd dogs. Progress in Veterinary & Comparative Ophthalmology, 1, 105–108. Rupp, G. & Knight, A. (1984) Congenital ocular defects in a crossbred beef herd. Journal of the American Veterinary Medical Association, 184, 1149–1150. Samuelson, D. & Gelatt, K. (1984a) Aqueous outflow in the Beagle: Postnatal development of the pectinate ligament and trabecular meshwork. Current Eye Research, 3, 783. Samuelson, D. & Gelatt, K. (1984b) Aqueous outflow in the Beagle: II. Postnatal morphologic development of the iridocorneal angle: Corneoscleral trabecular meshwork and angular aqueous plexus. Current Eye Research, 3, 795–807. Samuelson, D., Das, N., Bauer, J., et al. (1987) Prenatal morphogenesis of the congenital cataracts in the Miniature Schnauzer. Lens Research, 180, 231–250. Saperstein, G. (1975) Congenital defects in sheep. Journal of the American Veterinary Medical Association, 167, 314. Saunders, L. & Fincher, M. (1951) Hereditary multiple eye defects in grade Jersey calves. Cornell Veterinarian, 41, 351–366. Schaepdrijver, L.D., Simoens, P., Lauwers, H., et al. (1989) The hyaloid vascular system of the pig. Anatomy and Embryology, 1989, 549–554. Schiavo, D.M. & Field, W.E. (1974) Unilateral focal retinal dysplasia in Beagle dogs. Veterinary Medicine, Small Animal Clinician, 69, 33–34. Schook, P. (1978) A review of data on cell actions and cell interactions during the morphogenesis of the embryonic eye. Acta Morphologica Neerlando‐Scandinavica, 16, 267–286. Sevel, D. (1981) Reappraisal of the origin of human extraocular muscles. Ophthalmology, 88, 1330. Sevel, D. (1986) The origins and insertions of the extraocular muscles: Development, histologic features, and clinical significance. Transactions of the American Ophthalmological Society, 84, 488–526. Shields, M., Buckley, E., Klintworth, G., et al. (1985) Axenfeld– Rieger syndrome. A spectrum of developmental disorders. Survey of Ophthalmology, 29, 387–409. Shively, J., Phemister, R., Epling, G., et al. (1970) Pathogenesis of radiation‐induced retinal dysplasia. Investigative Ophthalmology & Visual Science, 9, 888–900. Shively, J., Phemister, R., Epling, G., et al. (1972) Dose relationships of pathologic alterations in the developing retina of irradiated dogs. American Journal of Veterinary Research, 33, 2121–2134. Shively, J.N., Epling, G.P., & Jensen, R. (1971) Fine structure of the postnatal development of the canine retina. American Journal of Veterinary Research, 32, 383–392. Silverstein, A. & Al, E. (1971) An experimental virus‐induced retinal dysplasia in the fetal lamb. American Journal of Ophthalmology, 72, 22.

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SECTION I

1: Ocular Embryology and Congenital Malformations

SECTION I

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Section I: Basic Vision Sciences

Smelser, G. & Ozanics, V. (1971) The development of the trabecular meshwork in primate eyes. American Journal of Ophthalmology, 71, 366. Sonoda, S., Isashiki, Y., Tabata, Y., et al. (2000) A novel PAX6 gene mutation (P118R) in a family with congenital nystagmus associated with a variant form of aniridia. Graefe’s Archive for Clinical and Experimental Ophthalmology, 238, 552–558. Spira, A.W. & Hollenberg, M.J. (1973) Human retinal development: Ultrastructure of the inner retinal layers. Development Biology, 31, 1–21. Stades, F. (1980) Persistent hyperplastic tunica vasculosa lentis and persistent hyperplastic primary vitreous (PHTVL/ PHPV) in 90 closely related Doberman Pinschers: Clinical aspects. Journal of the American Animal Hospital Association, 16, 739–751. Stades, F. (1983) Persistent hyperplastic tunica vasculosa lentis and persistent hyperplastic primary vitreous in Doberman Pinschers: Genetic aspects. Journal of the American Animal Hospital Association, 19, 957–964. Strande, A., Nicolaissen, B., & Bjerkas, I. (1988) Persistent pupillary membrane and congenital cataract in a litter of English Cocker Spaniels. Journal of Small Animal Practice, 29, 257–260. Stromland, K., Miller, M., & Cook, C. (1991) Ocular teratology. Survey of Ophthalmology, 35, 429–446. Sulik, K.K. & Johnston, M.C. (1982) Embryonic origin of holoprosencephaly: Interrelationship of the developing brain and face. Scanning Electron Microscopy, Pt 1, 309–322. Swanson, H.L., Dubielzig, R.R., Bentley, E., et al. (2001) A case of Peters’ anomaly in a Springer Spaniel. Journal of Comparative Pathology, 125, 326–330. Tam, P.P. (1986) A study of the pattern of prospective somites in the presomitic mesoderm of mouse embryos. Journal of Embryology and Experimental Morphology, 92, 269–285. Tam, P.P. & Trainor, P.A.A. (1994) Specification and segmentation of the paraxial mesoderm. Anatomy and Embryology (Berlin), 189, 275–305. Tam, P.P., Meier, S., & Jacobson, A.G. (1982) Differentiation of the metameric pattern in the embryonic axis of the mouse: II. Somitomeric organization of the presomitic mesoderm. Differentiation, 21, 109–122. Townsend, W. M. & Gornik, K.R. (2013) Prevalence of uveal cysts and pigmentary uveitis in Golden Retrievers in three Midwestern states. Journal of the American Veterinary Medical Association, 243, 1298–1301. Trainor, P.A. & Tam, P.P. (1995) Cranial paraxial mesoderm and neural crest cells of the mouse embryo: Co‐distribution in the craniofacial mesenchyme but distinct segregation in branchial arches. Development, 121, 2569–2582. van der Linde‐Sipman, J., Stades, F., & De Wolff‐Rouendaal, D. (1983) Persistent hyperplastic tunica vasculosa lentis and persistent hyperplastic primary vitreous in the Doberman

Pinscher: Pathological aspects. Journal of the American Animal Hospital Association, 19, 791–802. van der Linde‐Sipman, J.S., van den Ingh, T.S.G.A.M., & Vellema, P. (2003) Morphology and morphogenesis of hereditary microphthalmia in Texel sheep. Journal of Comparative Pathology, 128, 269–275. van Rensburg, I.B.J., Petrick, S.W., van der Lugt, J., et al. (1992) Multiple inherited eye anomalies including persistent hyperplastic tunica vasculosa lentis in Bouvier des Flandres. Veterinary & Comparative Ophthalmology, 2, 133–139. Wahl, C.M., Noden, D.M., & Baker, R. (1994) Developmental relations between sixth nerve motor neurons and their targets in the chick embryo. Developmental Dynamics, 201, 191–202. Waring, G., Rodriques, M., & Laibson, P. (1975) Anterior chamber cleavage syndrome: A stepladder classification. Survey of Ophthalmology, 20, 3–33. Weiss, P. & Jackson, S.F. (1961) Fine structural changes associated with lens determination in the avian embryo. Developmental Biology, 3, 532–554. Whiteley, H. (1991) Dysplastic canine retinal morphogenesis. Investigative Ophthalmology & Visual Science, 32, 1492–1498. Wrenn, J. & Wessells, N. (1969) An ultrastructural study of lens invagination in the mouse. Journal of Experimental Zoology, 171, 359–368. Wulle, K. (1972) The development of the productive and draining system of the aqueous humor in the eye. Advances in Ophthalmology, 26, 296–355. Wyand, D., Lehav, M., Albert, D., et al. (1972) Intraocular lacrimal gland tissue with other ocular abnormalities occurring in a white‐tailed deer. Journal of Comparative Pathology, 82, 219–221. Wyman, M. & Ketring, K. (1976) Congenital glaucoma in the Basset Hound: A biologic model. Transactions. Section on Ophthalmology. American Academy of Ophthalmology and Otolaryngology, 81, OP645–OP652. Yamashita, T. & Sohal, G. (1986) Development of smooth and skeletal muscle cells in the iris of the domestic duck, chick and quail. Cell and Tissue Research, 244, 121–131. Yamashita, T. & Sohal, G. (1987) Embryonic origin of skeletal muscle cells in the iris of the duck and quail. Cell and Tissue Research, 249, 31–37. Zhang, R.L., Samuelson, D.A., Zhang, Z.G., et al. (1991) Analysis of eye lens‐specific genes in congenital hereditary cataracts and microphthalmia of the Miniature Schnauzer dog. Investigative Ophthalmology & Visual Science, 32, 2662–2665. Zhao, S. & Overbeek, P.A. (2001) Regulation of choroid development by the retinal pigment epithelium. Molecular Vision, 7, 277–282. Zhu, M.D., Madigan, M.C., van Driel, D., et al. (2000) The human hyaloid system: Cell death and vascular regression. Experimental Eye Research, 70, 767–776.

41

2 Ophthalmic Anatomy Jessica M. Meekins1, Amy J. Rankin1, and Don A. Samuelson2 1 2

Department of Clinical Sciences, Veterinary Health Center, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA

Introduction A thorough understanding of normal ophthalmic anatomy is an integral part of the foundational knowledge of a ­veterinary ophthalmologist. It is important to be able to ­differentiate normal anatomic structures from abnormal structures during ophthalmic examinations, histopathologic examinations, or during surgical procedures. The veterinary ophthalmologist examines eyes from a wide variety of animal species. During vertebrate evolution, the eye has largely retained the same basic components, but important and clinically relevant differences do exist. This chapter will primarily present the normal ophthalmic anatomy of dogs, cats, horses, livestock species, and birds. The anatomy of selected exotic species is covered in Section IV, but there is also a tremendous amount of literature elsewhere for reference.

Orbit The orbit is the bony fossa that surrounds and protects the eye while separating it from the cranial cavity. Through numerous foramina, the orbit also provides pathways for various blood vessels and nerves involved in the function of the eye. The size, shape, and position of the orbit are closely associated with time of visual activity and feeding behavior (Table 2.1). In domestic carnivores such as the cat and dog, the orbital axes are set rostrolaterally, approximately 10° and 20° from midline, respectively (Prince et  al., 1960). As a result, these animals possess enhanced binocular vision, which serves to improve predatory feeding behavior. In horses and ruminants, the orbits are positioned more laterally than carnivores, being approximately 40° (i.e., horses) and 50° (i.e., cattle) from midline. Monocular vision in these and other ungulate species is enhanced, providing a strong

panoramic line of vision that allows for scanning the horizon to search for potential predators. In the rabbit, the axis of each eye extends as much as 85° from the midline; this orbit placement also occurs among the majority of lizards, some snakes, and in certain fish. In these latter instances where binocular vision has become greatly reduced, there is a tendency for the eyes to protrude so that the visual axis of the eye can expand what the optic axis of the skull has provided (Prince et al., 1960). In addition to size, shape, and position, all vertebrate orbits are one of two kinds: the enclosed orbit, which is completely encompassed by bone; or the open or incomplete orbit, which is only partially surrounded by bone (Fig. 2.1, Fig.  2.2, and Fig.  2.3). Among domestic animals, horses, sheep, cattle, and goats have enclosed orbits. Pigs and carnivores (i.e., dogs and cats) have open orbits. The enclosed orbit of large herbivorous prey species is theorized to be essential for protection, whereas the open orbit gives animals such as carnivores the ability to open their jaws widely during consumption of prey (Prince, 1956). The bony orbit typically consists of five to seven bones, depending on the species (Table  2.2). The canine orbit is composed of five, and sometimes six, bones, the supraorbital ligament that extends from the frontal to the zygomatic bone, and the periosteum (Fig. 2.1). The orbital rim is formed by the frontal, lacrimal, and zygomatic bones. Laterally, the orbit is formed by the supraorbital ligament which is contiguous with a fibroelastic connective tissue sheath for much of the floor of the orbit. The orbital floor is incomplete, being partially formed by the sphenoid and palatine bones. In the feline orbit, the processes of the frontal and zygomatic bones extend a great deal more toward one another, resulting in a shortened supraorbital ligament (Fig. 2.1). In animals with enclosed orbits, closure of the temporal side of the orbit is accomplished by union of the zygomatic process of the frontal bone with the frontal process of the zygomatic bone

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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(see Fig. 2.2 and Fig. 2.3). In the horse, the zygomatic process of the temporal bone intervenes between these two and completes the orbital rim (see Fig. 2.3). Within the orbit, various foramina and fissures provide osseous pathways for blood vessels and nerves to pass from the cranial cavity and alar canal into the orbital region. Those foramina of rather constant position in domestic animals are the rostral alar, ethmoidal, lacrimal, orbital, ovale, optic, rotundum, and supraorbital. Other foramina closely related to the orbital structures are within the pterygopalatine region, and these are the maxillary, caudal palatine, and sphenopalatine (Table 2.3). The orbital foramen is elongated in most domestic animals except the horse; therefore, it is referred to as the orbital fissure. In cattle, the orbital fissure and foramen rotundum are typically fused to form the foramen orbitorotundum (see Fig. 2.2).

fascia bulbi, and the extraocular muscle (EOM) fascial sheaths (Fig. 2.4). The periorbita is a conically shaped, fibrous membrane that lines the orbit and encloses the globe, EOMs, blood vessels, and nerves. The apex of the periorbita is located where the optic nerve exits the orbit. At this point, it is continuous with the dural sheath of the optic nerve. In the orbit, it is thin, attaches firmly to the orbital bones, and forms their periosteum. In the dog, the periorbita does not always fuse with the periosteum of the frontal and the sphenoid bones (Constantinescu & McClure, 1990). Instead, the periosteum and periorbita often remain distinct and separate in these orbital regions. In animals with an incomplete lateral orbital

Orbital Fascia The orbital fascia consists of a thin, tough connective tissue lining that envelops all the structures within the orbit, including the bony fossa itself. This fascia consists of three anatomic components: the periorbita, Tenon’s capsule or Table 2.1  Orbital dimensions.

Dimension

Feline (mm)

Canine (mm)

Bovine (mm)

Equine (mm)

Width

24

29

  65

  62

Height

26

28

  64

  59

Depth

—

49

120

  98

Distance between orbits

23

36

151

173

Figure 2.2  Bovine orbit. Bones of the orbit: frontal (F), lacrimal (L), sphenoid (S), temporal (T), zygomatic (Z). Orbital foramina: ethmoidal (E), optic (Op), orbitorotundum (Ort), ovale (Ov), supraorbital (So).

A

B

Figure 2.1  A. Canine orbit. B. Feline orbit. Bones of the orbit: frontal (F), lacrimal (L), maxilla (M), sphenoid (S), temporal (T), zygomatic (Z). Orbital foramina: rostral alar (A), ethmoidal (E), optic (Op), orbital fissure (Or).

wall, the periorbita is thicker laterally next to the orbital ligament. Anteriorly, in the dorsolateral part of the orbit, the periorbita separates and surrounds the lacrimal gland. At the orbital rim, it divides again, one part becoming continuous with the periosteum of the facial bones and the other, that is, the septum orbitale, merging with the eyelids and becoming continuous with the tarsal plates (the fibrous sheet in the eyelids). Within the periorbital tissue of carnivores (dogs and cats), smooth muscle has been observed along the lateral wall of the orbit, portions of the roof and floor of the orbit, and next to the periosteal lining of orbital bones (Brunton, 1938). The smooth muscle is oriented circularly so that when observed in the coronal plane, the muscle fibers are seen longitudinally. Contraction of the muscle has been produced by stimulation of the cervical sympathetic nerve trunk and results in forward movement of the globe. Although the function of this fibromuscular tissue remains

unknown, it may facilitate repositioning the eye within the orbit during relaxation of the retractor oculi muscle. Tenon’s capsule (fascia bulbi) is connective tissue on the outer aspect of the sclera. Tenon’s capsule is separated from the sclera by a narrow, cleft‐like space filled with loose connective tissue, Tenon’s space. Tenon’s capsule is attached to the sclera near the corneoscleral junction (i.e., limbus), and it becomes continuous with the fascia surrounding the EOMs. The fascial sheaths of the EOMs are dense, fibrous membranes loosely attached to the muscles with fine trabeculae of connective tissue. These sheaths are continuous with, or reflections of, Tenon’s capsule, but they are not always considered part of it. In the dog, the muscular fasciae consist of three layers. A superficial, thick layer extends caudally from the orbital septum and is penetrated by blood vessels and nerves. A middle layer consists of superficial and deep sheets that anteriorly attach to the outer junction of the sclera and cornea. A deep layer next to the surface of the EOMs separates the recti muscles from the retractor oculi muscles (Constantinescu & McClure, 1990).

Extraocular Muscles and Orbital Fat The three sheets of orbital fascia are separated by orbital fat. Orbital fat fills the dead space in the orbit and acts as a protective cushion for the eye. The amount of orbital fat varies between individuals and to a greater extent between species. The color of orbital fat ranges from white to yellow. The yellow coloration is attributed to higher levels of lutein, beta‐carotene, retinol, and other unidentified carotenoids (Sires et al., 2001). Some animals, including birds and many reptiles, have very little orbital fat (Duke‐Elder, 1958). When the retractor oculi muscle contracts, orbital fat can displace the glandular tissue associated with the nictitating membrane, resulting in its passive movement over the cornea. In the dog, orbital fat surrounds the optic nerve and forms a

Figure 2.3  Equine orbit. Bones of the orbit: frontal (F), lacrimal (L), sphenoid (S), temporal (T), zygomatic (Z). Orbital foramina: rostral alar (A), ethmoidal (E), optic (Op), orbital fissure (Or), supraorbital (So). Table 2.2  Orbital bones. Animal

Lacrimal

Zygomatic

Frontal

Sphenoid

Palatine

Maxillary

Dog

X

X

X

X

X

X

Cat

X

X

X

X

X

X

Horse

X

X

X

X

X

Ox

X

X

X

X

X

X X

Sheep

X

X

X

X

X

Goat

X

X

X

X

X

Pig

X

X

X

X

X

Rabbit

X

X

X

X

X

Human

X

X

X

X

X

Ethmoid

Temporal

X

X X X

X

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Section I: Basic Vision Sciences

SECTION I

Table 2.3  Foramina and associated nerves and vessels. Foramen or fissure

Species

Associated nerves and vessels

Alar, rostral

Canine, equine, feline

Maxillary artery and nerve

Ethmoidal (one or more)

All species

Ethmoidal vessels and nerve

Orbital

Canine, equine, feline

Abducens, oculomotor, ophthalmic, and trochlear nerves

Orbitorotundum

Bovine

Cranial nerves III–IV, retinal, and internal maxillary arteries

Optic

All species

Optic nerve, internal ophthalmic artery

Rotundum

Canine, equine, feline

Maxillary nerve

Supraorbital

Bovine, canine, equine (feline variable)

Supraorbital vessels and nerve

Caudal palatine

All species

Major palatine vessels and nerve

Maxillary

All species

Infraorbital vessels and nerve

Sphenopalatine

All species

Sphenopalatine vessels and pterygopalatine nerve

Periorbita Orbital septum

Tenon’s capsule

Annulus of Zinn

Medial rectus

Dorsal rectus

Trochlea Dorsal oblique

Cornea Lateral rectus Retractor bulbi attachments Muscle fascia

Figure 2.4  Divisions of orbital fascia.

cone that separates the optic nerve from the retractor oculi muscle (Murphy et al., 2012). The EOMs suspend the globe in the orbit and provide ocular motility. There are four rectus muscles: the dorsal, ventral, medial, and lateral recti (Fig.  2.5 and Fig.  2.6). They originate from the orbital apex (i.e., annulus of Zinn) and insert, in the dog, approximately 5 mm posterior to the limbus medially, 6 mm ventrally, 7 mm dorsally, and 9 mm laterally (see Fig. 2.5, Fig. 2.6, and Fig. 2.7). They move the eye in the direction of their names (Table 2.4). The dorsal (superior) oblique originates from the medial orbital apex, continuing forward dorsomedially to pass through a trochlea located near the medial canthus. It then turns acutely, passing dorsolaterally to the globe. It pulls the dorsal aspect of the globe medially and ventrally (intorsion). The ventral (inferior) oblique originates from the anterolateral margin of the palatine bone on the medial orbital wall and passes

Ventral oblique Ventral rectus

Figure 2.5  Arrangement of the orbital muscles of domestic animals.

beneath the eye, crossing the ventral rectus tendon. The muscle divides as it reaches the lateral rectus, with the anterior portion covering the insertion of the lateral rectus and the posterior portion inserting beneath the rectus. The ventral oblique moves the globe medially and dorsally (extorsion) (Prince et al., 1960). The EOM of birds vary among species. For example, the superior oblique in hawks can produce forces greater than those of owls allowing for greater globe torsion which corresponds with globe shape. Hawks have more globular‐ shaped eyes and keep their heads facing forwards when tracking prey in contrast with owls that have tubular eyes and utilize head movement to direct field of view (Plochocki et al., 2018). The retractor oculi (retractor bulbi) muscle originates at the orbital apex and continues forward to form a cone surrounding the optic nerve and inserting posterior and deep to the recti muscles (see Fig. 2.5, Fig. 2.6, and Fig. 2.7). The retractor oculi muscle retracts the globe into the orbit.

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A

B

C

Figure 2.6  Superior lateral view of the canine extraocular musculature. A. Lateral rectus muscle (LR), medial rectus muscle (MR), superior rectus muscle (SR). B. Same view as seen in A but with the superior rectus muscle retracted. RO, retractor oculi muscle. C. Posterior view of the equine extraocular musculature. RO, retractor oculi muscle; ON, optic nerve.

Dorsal rectus muscle

Ophthalmic artery vein Oculomotor nerve Trachlear nerve Abducens nerve

Levator palpebrae muscle Dorsal oblique muscle

Ophthalmic branch of cranial nerve V

Medial rectus muscle Optic nerve

Orbital vein

Optic foramen

Ventral rectus muscle Anastomotic artery Lateral rectus muscle Retractor bulbi muscle

Orbital fissure

Figure 2.7  Orbital apex of the dog, illustrating structures passing through the optic foramen and orbital fissure as well as the extraocular muscle attachments. (Source: Modified from Evans, H. & Christensen, G. (1979) Miller’s Anatomy of the Dog., 2nd ed. Philadelphia, PA: W.B. Saunders. Reproduced with permission of Elsevier.)

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Table 2.4  Muscles of the eye and eyelids. Muscle

Function

Nerve supply

Dorsal (superior) rectus

Rotates globe upward

Oculomotor

Ventral (inferior) rectus

Rotates globe downward

Oculomotor

Medial rectus

Rotates globe medially

Oculomotor

Lateral rectus

Rotates globe laterally

Abducens

Dorsal (superior) oblique

Rotates dorsal part of globe medially and ventrally

Trochlear

Ventral (inferior) oblique

Rotates ventral part of globe medially and dorsally

Oculomotor

Retractor oculi (bulbi)

Retracts globe

Abducens

Levator palpebrae superioris

Raises upper eyelid

Oculomotor

Orbicularis oculi

Closes palpebral fissure

Facial

Retractor anguli oculi

Lengthens lateral palpebral fissure

Facial

The retractor oculi muscle is ubiquitous among mammals, but it is absent in various nonmammalian groups, including birds and snakes. The dorsal, ventral, and medial recti as well as the ventral oblique muscles are innervated by the oculomotor nerve (cranial nerve [CN] III), whereas the lateral rectus and retractor oculi muscles are innervated by the abducens nerve (CN VI), and the dorsal oblique muscle is innervated by the trochlear nerve (CN IV) (see Table 2.4).

Eyelids The eyelids, or palpebrae, are thin folds of skin continuous with the facial skin. The upper (superior) and lower (inferior) eyelids meet to form the lateral and medial canthi (singular canthus). The opening formed by the upper and lower eyelids is the palpebral fissure. This fissure is prevented from assuming a circular shape by the medial (nasal) and lateral (temporal) palpebral ligaments that attach each canthus to the orbital wall. The medial ligament inserts into the periosteum of the nasal bones, whereas the lateral ligament inserts into the temporal fascia and bones associated with the lateral orbit. In the dog, the lateral ligament is essentially replaced by the retractor anguli oculi muscle and its tendon. Closure of the eyelids is achieved by contraction of the orbicularis oculi muscle located deep in the eyelids. Opening the eyelids is accomplished by relaxation of the orbicularis oculi muscle and contraction of the levator palpebrae superioris muscle, which inserts into the upper tarsus. In the dog the upper eyelid has two to four rows of eyelashes (i.e., cilia) that usually begin near the medial quarter or third

Figure 2.8  Canine eye: medial canthus (A), lateral canthus (B), cilia (C), nictitating membrane (D), ciliary zone of iris (E), pupillary zone of iris (F), collarette (G). Insert: Arrows indicate meibomian gland openings.

and either extend across to the lateral canthus or end shortly before the canthus (Fig. 2.8). The lower eyelid has no cilia and has a hairless region approximately 2 mm wide adjacent to the eyelid margin extending the length of the lower eyelid and around the lateral canthus. The medial canthus, unlike the lateral canthus, has variable amounts of facial hair. In the cat neither lid has cilia, but the leading row of hair from the medial third laterally on the upper eyelid is distinct enough in most cats to be considered cilia (accessory cilia or eyelashes). In the horse a protuberance of variable size and pigmentation (i.e., the lacrimal caruncle) is present at the medial canthus (Fig. 2.9). The lateral canthus is more rounded than that of the dog, and small amounts of bulbar conjunctiva and sclera are visible both medially and laterally. The exposed lateral conjunctiva is often pigmented. The cilia are well developed on the upper eyelid but absent on the lower eyelid. The cilia begin near the junction of the medial third and the middle third of the eyelid, and they extend almost to the lateral canthus. The facial hair is sparse adjacent to the lower eyelid margins at both the medial and lateral canthi and often at the medial upper eyelid. Horizontal folds are present in both the upper and lower eyelids. Vibrissae (long, specialized tactile hairs) are present on the base of the lower eyelid and on the medial aspect of the upper eyelid. The eyelids protect the eyes from light, produce part of the tear film, spread the tear film across the cornea, and remove debris from the cornea and conjunctival surfaces. Through closure in a ‘zipper‐like’ fashion from lateral to medial, the eyelids also direct the preocular tear film into the nasolacrimal drainage system. Histologically, the eyelids consist of four parts: the outermost layer contiguous with adjacent skin, the subjacent orbicularis oculi muscle layer, followed internally by a tarsus and stromal layer, and the innermost layer, the palpebral conjunctiva (Fig. 2.10).

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A

B

Figure 2.9  Equine eye. A. Medial canthus (A), lateral canthus (B), cilia (C), nictitating membrane (D), lacrimal caruncle (E), ciliary zone of iris (F), pupillary zone of iris (G), granula iridica (H). B. Arrows indicate vibrissae.

The outer layer of the eyelid is skin covered by a dense coat of hairs with associated sebaceous and tubular glands. In dogs and cats, the hair follicles might be compound. Tactile hairs (pili supraorbitales), similar to the eyebrows of humans, may be present on or near the upper eyelids. Bundles of smooth muscle fibers, arrectores ciliorum, extend from the follicles of the eyelashes toward the tarsus. These muscle bundles are absent in carnivores and humans, but they are common in ruminants (Prince, 1956). The roots of the large cilia are in close association with prominent sebaceous glands (glands of Zeis) and modified apocrine sweat glands (glands of Moll, ciliary glands). The epithelium near the terminus of the gland consists of an outer myoepithelial layer and an inner layer of flattened glandular cells. The structure and location of the glands of Moll are similar in all domestic species (Adam et al., 1970). In primates, including humans, these glands contain a variety of antimicrobial proteins (Stoeckelhuber et al., 2004). These apocrine glands may provide host defense at the margin of the eyelids and possibly in the tears. Deep to the eyelid skin, there is dense collagenous stroma and bundles of striated muscle fibers that comprise the orbicularis oculi muscle. The orbicularis oculi muscle is arranged in parallel rows that extend nearly the full length of each eyelid. In humans, nearly 90% of the orbicularis oculi muscle fibers consist of the fast type (Hwang et al., 2011). In the upper eyelid, the levator palpebrae superioris muscle, which originates from the orbital apex, fans out along the dorsal half of the midstroma. The muscle extends toward the inner connective tissue boundary of the orbicularis oculi muscle ending in individual small tendons. The eyelid muscles are separated from the posterior epithelial lining of the eyelids (i.e., the palpebral conjunctiva) by a narrow layer of dense connective tissue. This tissue is well developed in humans and is referred to as the cartilaginous tarsal plate; in most veterinary species, it is less developed (fibrous tissue) and referred to as the tarsus.

Figure 2.10  Photomicrograph of the eyelid of a dog: hair follicle (HF), cilia follicle (CF), palpebral conjunctiva (PC), tarsal gland (TG), skin (S), orbicularis oculi muscle fibers (O).

The meibomian (tarsal) glands (see Fig. 2.8 and Fig. 2.10) are located in the distal portion of the tarsus near the eyelid margins and contribute to the outer, oily component of the preocular tear film. There are typically 20–40 glands present in each eyelid in the dog (Pollock, 1979), and they are usually more developed in the upper eyelid, especially in cats. These holocrine, modified sebaceous glands form parallel rows of lobules, which have their duct openings on the eyelid margins. The meibomian gland ducts are lined by a keratinized stratified squamous epithelium (Jester et  al., 1981). Each gland is made of a number of holocrine acini, which are arranged in vertical columns and open into a central duct. Individual acini have an associated plexi of nerve fibers, which are believed to stimulate their secretion (Chung et al., 1996; Seifert & Spitznas, 1996). The nerve fibers, which are largely parasympathetic in origin, closely appose the basement membrane of each acinus. The eyelids of the

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Asian elephant, rock hyrax, and birds are devoid of meibomian glands. In addition to the meibomian glands, there are accessory lacrimal glands associated with the eyelids. In humans they are referred to as the glands of Krause and Wolfring. The glands of Wolfring are found along the posterior lining of the eyelids whereas the glands of Krause are located at the conjunctival fornix. In domestic species, these accessory glands are most commonly located in the conjunctiva and have been referred to as conjunctival glands. Their contribution to the volume of tear film in cats is negligible (McLaughlin et al., 1988).

Conjunctiva

Figure 2.11  Palpebral conjunctiva of a porcine eyelid is externally lined by a stratified to pseudostratified columnar epithelium possessing numerous goblet cells (GC) near the fornix.

The conjunctiva is a mucous membrane that lines the inner aspect of the eyelids, the anterior and posterior surfaces of the nictitating membrane (NM), and the exposed sclera. The conjunctiva consists of a thin layer of loose connective tissue beneath a simple to stratified squamous epithelium that becomes consistently stratified toward the eyelid margin. The palpebral conjunctiva lines the inner aspect of the eyelids. As the conjunctiva reflects onto the globe, it is called the bulbar conjunctiva and becomes continuous with the limbal and corneal epithelium. The conjunctiva on the anterior and posterior surfaces of the nictitating membrane is contiguous with the palpebral and bulbar conjunctiva mucosa, respectively. The junction between the palpebral and bulbar conjunctiva is the conjunctival fornix, and the epithelial lining in this region varies according to species, ranging from pseudostratified columnar to stratified cuboidal (Goller & Weyrauch, 1993). Ventrally, an additional fold is formed by reflection of the conjunctiva over the NM. The reflections at the conjunctival fornix and NM form the conjunctival sac. All parts of the conjunctiva are continuous, but for descriptive purposes, it is divided into the palpebral, bulbar, and fornix conjunctiva and further referenced to specific eyelids. The distribution of goblet cells in the conjunctiva is heterogeneous in the dog (Moore et  al., 1987). The highest densities occur along the lower nasal and middle fornix and the lower tarsal portion of the palpebral conjunctiva (Fig. 2.11). In cats the conjunctival goblet cell density varies widely by region but is highest in the anterior surface of the NM and the conjunctival fornices (Sebbag et  al., 2016). Additionally, in most domestic species, the bulbar conjunctiva has been reported to either essentially lack goblet cells or has a much lower population of these mucus‐forming cells (Bourges‐Abella et al., 2007; Doughty, 2002; Grahn et al., 2005). At the fornix, the conjunctiva is arranged into small folds that contain protruding goblet cells and, dorsolaterally, the openings of the lacrimal gland’s ducts (Goller & Weyrauch, 1993).

The substantia propria of the conjunctiva is composed of two layers: a superficial adenoid layer, which in the dog and cat contains a variable presence of lymphatic follicles and glands; and a deep, fibrous layer that contains the conjunctival nerves and vessels. The arteries of the conjunctiva arise from the anterior ciliary arteries, which are branches of the external ophthalmic artery, and from branches of the superior and inferior palpebral and malar arteries (Murphy et al., 2012). The lymphatics of the conjunctiva, called the conjunctiva‐ associated lymphatic tissue (CALT), are arranged in two plexuses: a superficial and a deep system. CALT is generally diffuse with intermittent nodules or follicles. Often the diffuse component of CALT infiltrates and is adjacent to tear‐secreting glands, especially those associated with the NM. Variations in the size and distribution of nodules occur between the upper and lower eyelids and are influenced by exposure to various foreign substances including potentially infectious microorganisms (Fix & Arp, 1991). Cells such as CD8‐positive suppressor/cytotoxic effector cells are generally more prevalent (Knop & Knop, 2005). CALT of domestic and wildlife species can have follicle‐associated conjunctival epithelium where goblet cells are characteristically absent, being replaced by antigen‐absorptive cells called M (i.e., microfold) cells (Samuelson et al., 2011). The ultrastructural appearance of these cells is not identical to those described in mucosa‐associated lymphoid tissues throughout the body (Chodosh et al., 1998). The lymphatic drainage of the conjunctiva is toward both commissures, where the drainage joins the lymphatics of the eyelids. Drainage from the lateral commissure is to the parotid lymph nodes, whereas the medial regions drain to the mandibular lymph nodes. The conjunctiva at the fornix is very thin and translucent, and it lies loosely on the underlying connective tissue. In the domestic carnivore, approximately 3 mm from the limbus, the bulbar conjunctiva, Tenon’s capsule, and sclera become closely united. The connective tissue is much more abundant in this location in the dog than in humans and other species.

In many species, the gland surrounds much of the vertical base of the cartilaginous plate. This gland is serous in horses and cats, mixed (seromucous) in cattle and dogs, and mostly mucous in pigs (Aughey & Frye, 2001; Murphy et al., 2012). The cartilage of the NM is predominately elastic in horses, cats, and pigs and hyaline in ruminants and dogs (Banks, 1993). The three‐dimensional shape of the cartilage varies considerably among domestic species (Schlegel et al., 2001). The horizontal portion of the T cartilage appears as a reverse S‐shape in the cat, a crescent‐shape in the dog, and a hook‐ shape in the horse. The Harderian gland (Harder’s gland) when present, is usually located posterior to the NM, and appears grossly and histologically to be an extension of the NM gland. This glandular tissue in some animals can be considerably larger than the NM gland. The anatomical presence of the Harderian gland among mammals has been found mostly in rodents (mouse, rat, Guinea‐pig, Mongolian gerbil, golden hamster, wood mouse, Plains mouse, various squirrel species, chipmunk, and deer mouse), with only the Mongolian gerbil having the nictitans gland as well. Other mammals that possess the Harderian gland exclusively include members of Insectivora (hedgehog and shrews), species of deer (red deer, fallow deer), nine‐banded armadillo, cottontail rabbit, and

The primary functions of the conjunctiva are to prevent desiccation of the cornea, to allow mobility of the eyelids and the globe, and to provide a physical and physiological barrier against microorganisms and foreign bodies. This latter role is most important considering that conjunctival sacs house considerable microbial flora, including many potential pathogens (Samuelson et al., 1984a).

Nictitating Membrane The NM (membrana nictitans, third eyelid, or plica semilunaris) protrudes from the medial canthus in the ventromedial anterior orbit (see Fig. 2.8). It contains a cartilaginous, T‐shaped plate, the horizontal part of which is parallel with the free or leading edge of the membrane (Fig.  2.12). In many animal species, the free edge is pigmented. The stroma consists of loose to dense connective tissue that supports glandular and lymphoid tissue (Fig. 2.13). The distal portion of the anterior (i.e., palpebral) and posterior (i.e., bulbar) surfaces is usually covered with nonkeratinized stratified squamous epithelium. The NM possesses a prominent accessory lacrimal gland often referred to as the NM gland (nictitans gland) or gland of the NM (Murphy et al., 2012). Figure 2.12  Drawing of a histologic section of the mammalian nictitating membrane. (Source: Modified from Evans, H. & Christensen, G. (1979) Miller’s Anatomy of the Dog, 2nd ed. Philadelphia, PA: W.B. Saunders. Reproduced with permission of Elsevier.)

B

Palpebral surface A

Bulbar surface Lymphoid tissue Cartilage of the nictitating membrane

B A

Gland of the nictitating membrane

G

BS

L G C

C A

B

Figure 2.13  A, B. Nictitating membrane of the horse contains both glandular (G) and lymphoid (L) tissues, with the latter being superficially located within the stroma next to the bulbar surface (BS). C, cartilage. (Original magnification, 10×.)

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Afghan pika. Besides the Mongolian gerbil, mammals with both nictitans and Harderian glands are the pig and rabbit (Sakai, 1992). In mammals, the secretory cells of the Harderian glands are columnar and lined by myoepithelium. The adenomeres are generally tubular or tubuloalveolar and secrete lipid materials in addition to seromucous products. In rodents, the lipids are released uniquely in an exocytotic (merocrine) manner (Payne, 1994). Most importantly, their secretions contain unusual compounds including porphyrins and melatonin (Menendez‐Pelaez & Buzzel, 1992; Spike et al., 1992). Harderian glands contain autonomically controlled nerves and are also under the control of gonadal, thyroid, and pituitary hormones. The functions of this gland remain speculative, but they may include immunologic defense, photoprotection, provision for thermoregulatory lipids, osmoregulation, reproductive influences, and pheromone production. In most domestic animals, the movement of the NM is indirect, resulting from contraction of the retractor oculi muscle, which retracts the globe into the orbital space and causes passive elevation of the NM. However, in the domestic cat, the retractor oculi muscle is less well developed, and small bundles of smooth muscle have been found in the NM that most likely contribute to its more rapid movements. Specifically, there are nine strands of smooth muscle fibers that extend into the feline’s NM and are believed to be involved with its protrusion and retraction (Nuyttens & Simoens, 1995). Each strand is discrete, much like the erector pili muscle associated with hair follicles of skin, but more developed. These smooth muscle bundles or strands contribute to forward movement of the NM, quite possibly in response to an endocrine signal (fight or flight). In birds and other nonmammalian species that lack a retractor oculi muscle, movement of the NM is controlled by the pyramidalis and quadratus muscles, attached to the posterior surface of the sclera (Duke‐Elder, 1958). The pyramidalis and the quadratus muscles are skeletal muscles controlled by the oculomotor nucleus that moves the NM anteriorly (Bravo & Inzunza, 1985; Maier et al., 1972).

The PTF is trilaminar, although all three layers are intricately mingled. The outer, thin, oily layer is produced by the meibomian glands and sebaceous glands of Zeis. This layer reduces evaporation of the underlying aqueous layer and forms a barrier along the lid margins that prevents tear overflow. The middle layer is the aqueous layer and is secreted by the orbital lacrimal gland (61.7%), the accessory glands (3.1%), and the gland of the NM (35.2%) (Gelatt et al., 1975). This layer delivers oxygen and other nutrients to the avascular cornea and provides a volume of fluid to ‘flush’ the ocular surface and remove debris. The innermost layer is the mucin layer and is produced predominately by the conjunctival goblet cells. The glycocalyx, produced by the corneal epithelial cells, also contributes to the mucin layer. The mucin produced by lacrimal and lacrimal‐accessory glands that have mucus‐secreting cells, contributes to the mucin layer as well. The mucin is adsorbed to the corneal epithelial surface and is distributed evenly during normal blinking. This layer provides a hydrophilic surface over which the aqueous tear fluid spreads evenly and lubricates the corneal and conjunctival surfaces. Excess lacrimal fluid collects by gravity in the lower conjunctival sac and is mechanically ‘pumped’ through the upper and lower lacrimal puncta located approximately 1–2 mm inside the margin of the medial eyelid. Each punctum is surrounded by smooth muscle that works in coordination with eyelid blinking to remove excess lacrimal fluid and prevent its backflow. The puncta continue as the upper and lower canaliculi, which pass slightly vertically away from the eyelid margins and turn toward the medial canthus, pass through the periorbita, and meet at a dilation, the lacrimal sac, located in the lacrimal fossa of the lacrimal bone (Fig. 2.14). This sac empties into the nasolacrimal duct, which passes through a short, bony canal and opens into the nasal cavity, where it continues as a duct until it reaches an opening at the floor of the nostril approximately 1 cm from the end of the nares. Approximately 40% of dogs have an

Lacrimal gland

Lacrimal and Nasolacrimal System An adequate precorneal tear film (PTF) is necessary for optical integrity, maintenance of the cornea, and normal ocular function. The PTF serves several functions, including the following 1) maintenance of an optically uniform corneal surface 2) removal of foreign material and debris from the cornea and conjunctival sac 3) delivery of an oxygen source to the avascular cornea, and 4) provision of antimicrobial substances.

Lacrimal puncta

Lacrimal ducts

Canaliculi Lacrimal sac

Nasolacrimal duct

Figure 2.14  The nasolacrimal system.

2: Ophthalmic Anatomy

Globe Components The globe is composed of three basic layers or coats (Fig. 2.15). The outer layer is the fibrous tunic which is further divided into the cornea and sclera. The fibrous tunic provides shape to the eye. In addition, the anterior portion of the fibrous tunic (i.e., the cornea) is transparent, thus enabling light to pass through, and is shaped in a manner that makes it a powerful lens that refracts light rays centrally, toward the visual axis of the eye. The middle layer is the vascular tunic, called the uvea (meaning “grape”). The uvea is further divided into the iris, ciliary body, and choroid and is heavily pigmented and vascularized. It functions to restrict the amount of light entering the eye and to provide nourishment and remove waste products. The innermost layer is the nervous tunic, which consists of

Sclera Choroid

Ciliary body

Retina Cornea

Iris Ciliary body

Figure 2.15  The three tunics that comprise the mammalian globe. Outermost fibrous tunic (light and dark purple), consisting of the cornea and sclera; the middle tunic called the uvea (light orange), consisting of the iris, ciliary body and choroid; and the nervous tunic (dark orange) consisting of the retina and optic nerve.

the retina and optic nerve. The three tunics embrace the large, inner, transparent media of the eye: the aqueous humor, lens, and vitreous humor, which collectively function to transmit and refract light to the retina and provide an internal pressure that keeps the globe firmly distended.

Size, Shape, and Topography The eyes in domestic animals are quite variable in size, but their shapes are comparatively uniform, being spherical in most instances, in which the three axes of the globe (anteroposterior, horizontal or transverse, and vertical) are nearly identical in dimensions (see Table 2.5 and Table 2.6). Some of the larger ungulates, including the cow and horse, possess globes that are relatively flattened in the anteroposterior axis (Fig. 2.16). The geometric axis of the eye is positioned from the center of the cornea (i.e., anterior pole) to the posterior center of the sclera (i.e., posterior pole). Two principal planes, the equatorial and meridional, are traditionally used

Table 2.5  External globe dimensions.

Animal

Meridional A–P axis of the eye, A (mm)

Equatorial axis, V (mm)

Optic nerve

Horizontal, T (mm)

Ratio of A/V/T

Ratio of V/T

Horse

43.68

47.63

48.45

1:1.09:1.10

1:1.10

Cow

35.34

40.82

41.90

1:1.15:1.18

1:1.02

Sheep

26.85

30.02

30.86

1:1.11:1.15

1:1.02

Pig

24.60

26.53

26.23

1:1.08:1.06

1:0.99

Dog

21.73

21.34

21.17

1:0.98:0.97

1:0.99

Cat

21.30

20.60

20.55

1:0.97:0.96

1:0.99

Source: Translated from Bayer, J. (1914) Angenheilkunde. Vienna: Braumueller.

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accessory opening in the canal as it passes by the root of the upper canine tooth (Michel, 1955). For a comprehensive review of the nasolacrimal system anatomy and disorders, the reader is referred to Ali et al. (2019). The lacrimal gland is a diamond‐shaped structure in the dorsolateral aspect of the orbit underneath the orbital ligament (Park et al., 2016). The mean length, width, thickness, and weight of the lacrimal gland in three different breeds of dogs were ~17 ± 0.7 mm, ~13 ± 0.4 mm, ~3 ± 0.1 mm, and ~316 ± 21 mg, respectively (Park et  al., 2016). Fifteen to 20 small ductules drain into the superior conjunctival fornix. Histologically, the gland is a tubuloalveolar type. The lacrimal gland produces the majority of the aqueous portion of the preocular tear film. In rats and rabbits, mucous components are also secreted from the lacrimal gland (Ding et al., 2011; Draper et  al., 1998). The innervation to the lacrimal gland is not fully understood, but the lacrimal branch of CN V, sympathetic, and parasympathetic nerves are all involved in its function. Clinically, certain cholinergic drugs (e.g., pilocarpine) stimulate tear secretion, whereas other drugs (i.e., anticholinergics) decrease tear secretion.

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Table 2.6  Globe dimensions.

Animal

Horse

Axial globe length (mm)

Anterior chamber depth (mm)

Axial lens thickness (mm)

Vitreous chamber depth (mm)

Reference

39.23 ± 1.26 40.4 ± 1.8

5.63 ± 0.86 6.8 ± 0.5

11.75 ± 0.80 11.7 ± 0.6

  21.8 ± 1.3

McMullen & Gilger, 2006 Mouney et al., 2012

7.92 ± 0.86

Konrade et al., 2012 Gilger et al., 1998

Dog

20 ± 1.6

3.8 ± 0.1

6.7 ± 1.0

Cat

19.75 ± 1.59 20.91 ± 0.53

4.66 ± 0.86 5.07 ± 0.36

  7.77 ± 0.23

Figure 2.16  Lateral view of an equine globe. Note the marked flattening in the anteroposterior axis and the marked ventral exit of the optic nerve from the posterior pole. Meridional plane Equatorial plane

Optic nerve

Figure 2.17  The equatorial and meridional planes of the eye.

in references to the three axes (Fig.  2.17). The equatorial plane bisects the anterior and posterior poles and is perpendicular to the meridional plane. Any plane that runs parallel to the equatorial plane is called the frontal, coronal, radial, or transverse plane. The meridional plane moves along the anteroposterior axis of the eye, vertically dividing it into medial and lateral halves, even though meridional planes can be horizontal or oblique. Planes that run parallel to the meridional plane are described as sagittal planes.

Williams, 2004

Figure 2.18  Posterior view of a canine globe. LP, long posterior ciliary artery; ON, optic nerve.

The optic nerve in most domestic animals lies inferior and lateral to the posterior pole. Surrounding the optic nerve are many ciliary nerves and short posterior ciliary arteries. In normal dogs, the mean number of short posterior ciliary arteries is 12 (~7 dorsally and ~5 ventrally) (Frick & Dubielzig, 2016). The posterior ciliary nerves pursue a long intrascleral course (up to 12 mm) before entering the suprachoroidal space to reach the iris, ciliary body, and limbus. In the dog, the long posterior ciliary arteries enter the sclera approximately 3–5 mm from the optic nerve in the horizontal meridian (Fig. 2.18). In the cat, these arteries can enter the sclera immediately adjacent to the optic nerve. These vessels are visible on the nasal and temporal sides of the eye within the sclera at least as far as the equator before entering the choroidal space. At this point, each artery accompanies the long ciliary nerve to the iris and ciliary body. Recurrent vascular branches enter the choroid, but the main vessel trunk continues to be the major supply to the iris. A variable number of vortex veins (usually four) emerge from the sclera posterior to the equator; typically, two vortex veins are present dorsally and two ventrally. Several topographic features help establish the proper anatomic positions of an enucleated globe. For example,

observation of the long posterior arteries and the longer horizontal dimension of the cornea determines the horizontal meridian. Location of the ventral exit of the optic nerve and the dorsal oblique muscle tendon establish the dorsoventral aspect of the globe. Remnants of the NM and the lateral placement of the optic nerve to the posterior pole determine the medial and lateral aspects.

Cornea The cornea is the transparent, anterior portion of the fibrous tunic of the globe. Like the lens, the cornea is normally clear and transmits and refracts light (40–42 diopters in dogs). The avascular cornea relies on both the aqueous humor and tear film for nourishment and on the eyelids and NM for protection from the external environment. The cornea is elliptical in shape, with a horizontal diameter greater than the vertical. In the dog and the cat, the difference between these diameters is small, thus making their corneas appear almost circular (see Fig. 2.8). In most ungulates, this difference is much more pronounced, allowing for a remarkable horizontal field of view (Fig. 2.19) that is further complemented by the lateral positioning of the orbits. The combination of the exaggerated corneal dimensions and orbital positions in these grazing animals appears to be the adaptive result of their feeding behavior, affording them greater protection from predators. Corneal thickness varies between species, breeds, individuals, and location (i.e., central vs. peripheral cornea). In most domestic animals, it is less than 1 mm thick. Table 2.7 lists the central corneal thickness in dogs, cats, and horses using selected noninvasive diagnostic imaging modalities.

One study using ultrasonic pachymetry in cats found there is no significant difference in mean corneal thickness between the central and peripheral cornea (Gilger et  al., 1993). However, another study using the same modality found that the feline cornea is not uniform in thickness; when compared with the axial cornea, the superior nasal area is thinner, and the temporal area is thicker (Schoster et al., 1995). In dogs, the superior peripheral and temporal peripheral cornea are significantly thicker than the central cornea (Gilger et al., 1991). Corneal thickness is also influenced by age and time of day. Corneal thickness increases significantly with age in the dog, cat, and horse (Gilger et al., 1991, 1993; Herbig & Eule, 2015). Additionally, central corneal thickness and intraocular pressure (IOP) in healthy Beagles are significantly lower

Figure 2.19  The globe of the cow viewed anteriorly. Note the horizontally elongated ellipse of the cornea. A, medial canthus; B, lateral canthus; C, cilia; D, nictitating membrane; E, granula iridica.

Table 2.7  Corneal thickness.* Ultrasound pachymetry (μm)

High resolution ultrasound biomicroscopy (μm)

585 ± 79k

560 ± 5.2a 554.95 ± 72.41c 598.54 ± 32.28f 555.49 ± 17.19n 545.6 ± 21.7q

689.77+55.93d

592 ± 80k

578 ± 64b 546 ± 48r

835m

770.0 ± 7.5o 785.6 ± 2.98p (Miniature Horse)

SD-OCT (μm)

Scheimpflug (μm)

Confocal (μm)

Dog

610.56 ± 57.48d 587.72 ± 32.44f 611.2 ± 40.3j 497.54 ± 29.76n 606.83 ± 39.5s

629.73 ± 64.57d 606.83 ± 39.45h

Cat

584.93 ± 39.05e 629.08 ± 47.05g

606.41 ± 44.18e

Horse

812.0 ± 44.1i 800 ± 50l

* Most data is from the central cornea, but not all papers stated measurement location. SD‐OCT, spectral‐domain optical coherence tomography. a  Gilger et al., 1991; b Gilger et al., 1993; c Garzon‐Ariza et al., 2017; d Wolfel et al., 2017; e Cleymaet et al., 2016; f  Alario & Pirie, 2014b; g Alario & Pirie, 2013a; h Alario & Pirie, 2013b; i Pirie et al., 2014; j Alario & Pirie, 2014a; k Kafarnik et al., 2007; l Pinto & Gilger, 2014; m Ledbetter & Scarlett, 2009; n Strom et al., 2016a; o Ramsey et al., 1999; p Plummer et al., 2003; q Martin‐Suarez et al., 2014; r Schoster et al., 1995; s Alario & Pirie, 2013b

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stromal innervations, which exist superficially, consist of main bundles that repetitively branch in a dichotomous manner to create elaborate axonal arborizations. In general, the most superficial layers are primarily innervated with pain receptors, whereas more pressure receptors are found in the stroma. This explains why a superficial corneal injury is often more painful than a deeper wound. The following anatomic factors contribute to the transparency of the cornea

A

B

1) lack of blood vessels 2) nonkeratinized surface epithelium maintained by a PTF 3) lack of pigmentation 4) relative dehydration (deturgescence), and 5) size and organization of stromal collagen fibrils. The cornea comprises four (sometimes five) layers. From superficial to deep, the layers are the epithelium, Bowman’s layer (in some species), stroma, Descemet’s membrane, and endothelium (Fig. 2.21).

C

D

Corneal Epithelium

Figure 2.20  Innervation of the limbus and cornea. The long ciliary nerve (A) supplies the limbal region, then sends branches into the cornea. Nerves also supply the trabecular meshwork (B) and the region of the canal of Schlemm (i.e., angular aqueous plexus in nonprimates). Note the paucity of nerves in the deep cornea (C) and their absence in the region of Descemet’s membrane as compared with a multitude of branched endings of nerves within the anterior stroma (D) and epithelium. (Source: Modified from Hogan, M.J., Alvarado, J.A. & Weddell, J.E. (1971) Histology of the Human Eye. Philadelphia, PA: W.B. Saunders. Reproduced with permission of Elsevier.)

The corneal epithelium is a nonkeratinized, stratified squamous epithelium that covers the anterior corneal surface. The epithelium is approximately 25–40 μm thick in the domestic carnivore and two to four times thicker in the ungulate. In the dog, cat, and bird, the anterior epithelium consists of a single layer of basal cells that lie on a thin basement membrane; two or three layers of polyhedral (i.e., wing) cells and two or three layers of nonkeratinized squamous cells (Fig. 2.21 and Fig. 2.22). In larger animals, the layers of polyhedral and squamous cells are more numerous. The cells are arranged to provide orderly replacement of the surface cells during desquamation. In normal Beagles, the superficial epithelial cell diameter is 43.3 ± 6.6 μm

in the afternoon/evening than in the morning (Garzon‐Ariza et al., 2017; Martin‐Suarez et al., 2014). The cornea is richly supplied with sensory nerves, particularly pain receptors, and this sensitivity provides protection to the cornea and helps maintain transparency (Fig.  2.20). The cornea is innervated by the long ciliary nerves, which are derived from the ophthalmic branch of the trigeminal nerve (Mawas, 1951). The epithelial cell layers are richly innervated, and these nerve endings are unsheathed among the epitheliae. Use of immunohistochemical localization of neuropeptides associated with the ciliary ganglion in the dog has revealed the presence of a well‐developed pattern of epithelial innervation consisting of numerous horizontally oriented leash formations at the level of the epithelial basal cells (Marfurt et al., 2001). These formations comprise anastomotic networks of variously sized nerve fascicles that course circumferentially along the limbus, becoming oblique to eventually radial in orientation centrally. By comparison,

Figure 2.21  Histologic view of the four layers in the equine cornea: anterior epithelium (AE), stroma (S), Descemet’s membrane (DM), and endothelium (E). Insert: Basal cells (B), wing cells (W), squamous cells (S).

and the basal cell diameter is 4.4 ± 0.7 μm as examined via in vivo confocal microscopy (Strom et. al., 2016b). The basal cells are tall, columnar cells with a flattened base and domed apex. They are crowded together, and as a result, the nuclei, which are located in the apical region, are often forced into two or alternating layers. Mitosis is confined to the basal cells or those cells immediately superficial to the basal cells (i.e., stratum germinativum). Adjacent cell surfaces have small infoldings with numerous desmosomal attachments (Hogan et  al., 1971; Shively & Epling, 1970). Occasional lymphocytes are present in the basal epithelium and more superficial layers. Wing cells are polygonal‐shaped cells superficial to the basal cells. Wing cells vary from two or three layers in thickness to several layers, depending on the species and the location in the cornea. These layers form a transition zone between the columnar basal cells and the more superficial squamous cells. There are several layers of flattened superficial squamous cells. The cells appear to be flat and polygonal with straight borders on scanning electron microscopy (SEM) (Fig.  2.23 and Fig. 2.24). Both light and dark cell types can be identified. The light cells contain more microvillae and microplicae. These numerous projections scatter electrons and, as a result, produce a lighter appearance of the cell. The darker cells are older and are occasionally seen to be desquamating

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Figure 2.23  SEM shows the surface of the anterior epithelium of a bovine cornea. The surface cells can be light or dark. Note the round bulges, where the nuclei lie within each cell. Note also that some cells appear to be desquamating. (Original magnification, 400×.)

A

B

Figure 2.22  Basement membrane (arrows) of the anterior epithelium of the canine cornea viewed light microscopically with the aid of PAS stain (A) and ultrastructurally (B). AE, anterior epithelium; HD, hemidesmosomes. (Original magnification, 18,000×.)

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Corneal nerve

Superficial squamous cells Wing cells Basal cells Basal lamina Basement membrane Anterior stroma

Figure 2.25  The corneal epithelium and anterior stroma. Nonkeratinized squamous cells (2–3 layers), wing cells (2–3 layers) basal cells (single layer), basal lamina, and corneal nerves.

Figure 2.24  SEM shows the corneal epithelial surface of a horse. Junction of a light cell with two dark cells (arrows) illustrates the increased numbers of microplicae and microvillae in the light cell. (Original magnification, 3888×.)

(see Fig. 2.23). Cells in the central cornea have more projections (i.e., microplicae and microvillae) than those in the periphery. It has been proposed that the fine microplicae and microvillae that considerably expand the cells’ surface area enable movement of oxygen, potential nutrients, and various metabolic products across the exposed cell membranes of the outermost squamous epithelial cells (Collin & Collin, 2006). However, it is unlikely that the surface expansion would facilitate that process significantly among terrestrial mammals. More than likely, the microprojections of the squamous epithelial cells, which can be sometimes intricate in their patterns, allow mucin of the PTF to adhere firmly to the anterior epithelium which aids in stabilizing the tear film on the corneal surface (Blumcke & Morgenroth, 1976; Harding et al., 1974). The cytoplasm of the superficial cells contains numerous tonofilaments and vesicles but generally lacks the mitochondria, rough endoplasmic reticulum, and ribosomes that are present in the basal and wing cells. Cytokeratins have been demonstrated in the corneal epithelium of several species (Nautscher et  al., 2016). Numerous desmosomal attachments are present, and the surface cells have a zonula occludentes on their lateral membranes. The corneal epithelium is thicker at the periphery of the cornea than in the center. With the junction of the bulbar conjunctiva, however, it abruptly thins, and pigmented cells

are observed. At the limbus, pigment is scattered in all layers except the superficial squamous cells. Nerves enter the epithelium and terminate among the wing cells (Fig.  2.25; Hogan et al., 1971). Beneath the epithelium is a basement membrane, which stains positively with periodic acid–Schiff (PAS) (see Fig. 2.22A). The basal cells are firmly attached to the basal lamina of the basement membrane (i.e., anterior limiting lamina) by hemidesmosomes, anchoring collagen fibrils, and the glycoprotein laminin. Various types of collagen are found within the different layers of the cornea (Table 2.8). Interestingly, evidence of type IV collagen, which is ubiquitous throughout basement membranes of the body, is weak (Nakamura et  al., 1994a, 1994b). Hyaluronan and fibronectin also have been associated with corneal epithelial attachment (Nakamura et al.,1994a). Ultrastructurally, the basement membrane consists of a 30–55 nm thick osmiophilic layer that is separated from the basal cell plasma membrane by a 25 nm wide, electron‐lucent zone (see Fig. 2.22B). Hemidesmosomes attach the basal cells to the basement membrane, which in turn anchors the epithelium to the stroma. The arrangement of hemidesmosomes varies among different animals, being linear among mammals and amphibians, in rosettes among birds and reptiles, and punctate without arrangement, or completely absent, among fish (Buck, 1983). The epithelial cells have strong regenerative abilities (basal cell turnover time is approximately 7 days), but after removal of the basal lamina, weeks to months may be necessary for it to completely reestablish; until the basement membrane is completely reformed, the epithelium can be easily removed from the stroma (Gelatt & Samuelson, 1982; Khodadoust et al., 1968).

Stroma The corneal stroma (i.e., the substantia propria) constitutes 90% of the corneal thickness. It consists of transparent lamellae of collagenous tissue, and these lamellae lie in sheets and separate easily into planes (Fig.  2.26A).

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Location

a

Types of collagen

Glycansa

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Table 2.8  Location of glycans and collagen types in the cornea.

Anterior epithelium/ basement membrane

IV, VI, and VII

Laminin, fibronectin, hyaluronans

Nakamura et al., 1994b; Smolek & Klyce, 1993

Bowman’s layer/ anterior stroma

I, III, V, and VI

Heparan sulfate

Gordon et al., 1994

Stroma

I, III, V, VI, and XII

Chondroitin 6‐ and 4‐sulfates, dermatan sulfate

Cintron & Covington, 1990; Doane et al., 1992; Linsenmayer et al., 1993; Nakamura et al., 1994b; Takahashi et al., 1993

Descemet’s membrane

I, III, IV, V, VI, and VIII

Laminin, fibronectin tenascin, P component, heparan sulfate

Tamura et al., 1991

 Includes glycoproteins and glycosaminoglycans.

A

B

Figure 2.26  A. SEM of corneal stroma in the dog. (Original magnification, 7,400×.) B. TEM of corneal stroma in the horse consists of layers or lamellae (L) of collagen, which are sparsely interspersed with keratocytes (K). (Original magnification, 10,000×.)

Between the lamella are fixed cells and infrequent wandering cells. The fixed cells are fibrocytes, which are called keratocytes, and their extensions contribute to the formation and maintenance of the stromal lamellae. The keratocytes have thin nuclei, ill‐defined borders, and ­delicate cell membranes (Fig. 2.26B). Similar to lens fibers, these cells possess crystallins, which are believed to facilitate tissue transparency (Jester, 2008). Keratocytes can transform into myofibroblasts when deep corneal injury occurs, and they can form scar tissue that is not transparent. In normal Beagles the keratocyte density in the anterior and posterior stroma is ~993 ± 134 cells/mm2 and ~789 ± 87 cells/mm2, respectively. Cell density is significantly greater and nuclei size is significantly smaller in the anterior stroma in comparison with the posterior stroma (Strom et al., 2016b).

The lamellae are parallel bundles of collagen fibrils, with each lamella running the entire diameter of the cornea. All the collagen fibrils within a lamella are parallel, but between lamellae, they vary greatly in direction (Fig. 2.26). The lamellae of the posterior stroma are more regular in arrangement than those of the anterior third of the stroma. The anterior lamellae are more oblique to the surface, and they have more branching and interweaving. The precise organization of the corneal stroma is the most important factor in maintaining corneal clarity, which involves the select integration of collagen and amorphous ground matrix, consisting of select proteoglycans such as lumican, keratocan, osteoglycin, and decorin (Hassell & Birk, 2010). The collagen in the human cornea has a periodicity of 100 nm (Dawson et al., 2011). This special arrangement of the collagen in the stroma is believed to permit 99%

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of the light entering the cornea to pass without scatter (Hogan et al., 1971). The stroma is comprised of at least five types of collagen (see Table 2.8). Of these five, collagen type I is by far the most prevalent, forming the small, evenly sized, striated fibrils. Type VI is associated only with the interfibrillar matrix that forms a network around the fibrils. Evidence from adult mice suggests that type VI is connected with type I through chondroitin/dermatan sulfate glycosaminoglycans (GAGs). Type VI, which is associated with the fibrils and keratocytes, appears to play a role in cell–matrix interactions, which would be especially important during development and repair (Doane et al., 1992). In comparison, type V is combined or coassembled with type I, and it is believed to be responsible for the formation of the small, uniform diameter of the striated fibril, which is approximately 25 nm in most species (Linsenmayer et  al., 1993). Types III and XII are both suspected to be developmental forms, with type III being the more common; their importance during wound repair is unknown. Collagen fibrils, along with the proteoglycans and their associated GAGs and glycoproteins, constitute 15%–25% of the stroma, and they are the principal support structure of the cornea. These collagen fibrils form the matrix for a specialized population of proteoglycans within the corneal stroma (Borcherding et al., 1978; Hassell & Birk, 2010). The cornea is 75%–85% water, and it is relatively dehydrated compared with other tissues. This state of dehydration is termed deturgescence and is, in part, a function of the endothelium and epithelium. These cells move water out of the stroma via energy‐dependent Na+/K+ adenosine triphosphatase (ATPase) pumps, being most active in the endothelium. Other “pumps” for deturgescence might also exist, including carbonic anhydrase. These cells pump Na+ and HCO3‐ ions outward, into the aqueous humor and tears. An osmotic gradient is established, and water flows down the gradient from the corneal stroma into the aqueous humor. Experimentally, removal of the epithelium produces an increase of 200% in corneal thickness after 24 hours because of the influx of water. Removal of the endothelium produces an increase of 500% or more in thickness as the permeability increases sixfold, so the endothelium appears to be more important in maintenance of corneal deturgescence (Watsky et  al., 1995). Figure  2.27 illustrates the primary roles the endothelium plays, both as a pump and as a barrier. The barrier component is provided by the tight junctions occurring apically along the lateral faces of adjoining cells next to the anterior chamber. These tight junctions are sensitive to calcium exposure, and they break down when excess free Ca++ exists in the aqueous humor. The Na+/K+ ATPase pump is located along the lateral membranes of neighboring cells (see Fig. 2.27). A breakdown of the pump, the barrier, or both will result in rapid movement of water into the highly hydrophilic stroma, causing corneal edema to develop.

Pump Na+/K+ ATPase CA Na+ H2O

HCO3+

Barrier Gap junction

Extracellular pathway

Tight junction

Figure 2.27  Location of the corneal endothelial metabolic pump (Na+/K+ ATPase along the lateral membranes and carbonic anhydrase along the apical margins) and barrier (apical tight junctions along the lateral membranes). (Source: Redrawn from Watsky, M.A., Olsen, T.W. & Edelhauser, H.F. (1995) Cornea and sclera. In: Duane’s Foundation of Clinical Ophthalmology (eds Tasman, W. & Jaeger, E.A.), Vol. 2. Philadelphia, PA: J.B. Lippincott.)

The presence of GAGs in the cornea allows the pumps to be effective. Thus, any change in the population of the GAGs, any significant damage to the epithelium or endothelium, or any pressure exerted on the cornea causes a physical rearrangement of the precise collagen organization, which in turn results in opacification of the cornea. GAGs in the cornea consist of heparan sulfates, hyaluronic acid, undersulfated chondroitin sulfates, chondroitin 6‐sulfate, chondroitin 4‐sulfate, keratan sulfates, and dermatan sulfates (see Table 2.8). The most abundant of these is keratan sulfate, followed by dermatan sulfate (Cintron & Covington, 1990). Nearly all keratan sulfates are derived from stromal fibroblasts (i.e., keratocytes), whereas heparan sulfates are largely derived from the corneal epithelium, particularly as individuals mature. Hyaluronic acids, however, are formed to a fair degree by the corneal endothelium. Each corneal cell type contributes its own specific array of distinct GAG classes as well as other glycoconjugates to the extracellular matrix of the cornea. Corneal keratan sulfate, which differs from that in cartilage by length, branching, and cross‐linkage within the polymer, will absorb two to three times more water than chondroitin sulfates, but the latter will retain water eight to nine times more effectively than keratan sulfate. Because of the different water‐binding ability of GAGs, keratan sulfate is concentrated within the posterior bovine cornea, where it facilitates movement of water from the aqueous humor into the cornea (Castoro et  al., 1988). Dermatan sulfate is concentrated within the anterior stroma.

In addition to the differential concentration of GAGs within the corneal stroma, the relative amount of keratan sulfate is lower toward the limbus, whereas the level of dermatan sulfate increases (Borcherding et al., 1978). As the amount of keratan sulfate decreases towards the limbus, a corresponding increase in collagen fiber size and lack of organization, as seen in the sclera, occurs. The anterior‐most stroma has a thin, cell‐free zone corresponding in location with the anterior‐limiting membrane, also known as Bowman’s layer (anterior lamina), in humans and nonhuman primates. Bowman’s layer is also present in birds, giraffes, dolphins, some whales, and large herbivores (Fig.  2.28; Hayashi et  al., 2002; Murphy et  al., 1991; Samuelson et  al., 2005). In avian and human corneas, Bowman’s layer is 10–15 μm thick, relatively acellular, and composed of collagen fibrils of various types (see Fig. 2.28; Table 2.8). Bowman’s layer fibrils are smaller in diameter and less uniform than those of the stroma (Gordon et  al., 1994). The anterior epithelium produces the majority of the collagen associated with this modified, acellular zone of the

cornea. Bowman’s layer is not elastic, and when damaged it is replaced with scar tissue. Bowman’s layers of the land‐ based species share similarities in size, morphology, and histochemistry, differing substantially from that of marine mammals, which may reflect a variation of roles that this structure plays. Among whales, Bowman’s layer is not thought to exist in deep‐diving species, suggesting that its presence may be more closely associated with ocular function near or at the surface of the water.

Descemet’s Membrane Descemet’s membrane is a PAS‐positive, homogenous, acellular membrane that is the basement membrane of the posterior endothelium. Descemet’s membrane is produced throughout life, thus becoming thicker as individuals age. Clinically, the membrane shows elasticity, but it contains only fine collagen fibrils (Jakus, 1956). Descemet’s membrane is normally under some tension and when ruptured it tends to curl like a scroll. Descemet’s membrane ends at the

A

B

C

D

Figure 2.28  Bowman’s layer among mammalian species. A. Rhesus monkey. (Original magnification, 400×; Masson trichrome stain.). B. Bottle-nosed dolphin. (Original magnification, 400×; Masson trichrome stain.). C. Pilot whale. (Original magnification, 400×; PAS stain.). D. Giraffe (Original magnification, 400×; Masson trichrome stain.). (Courtesy of AZ Zivotofsky and D Zivotofsky.)

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apex of the trabecular meshwork in the limbal region. To some degree, its composition is similar to that of the trabeculae of the iridocorneal angle (ICA). Descemet’s membrane is comprised of a number of collagen types, including type VIII, which is found in the ICA but not elsewhere in the cornea (see Table 2.8) (Tamura et al., 1991). Ultrastructurally, Descemet’s membrane is distinctly layered in most animals, usually having a relatively thin anterior, unbanded zone next to the stroma, followed by a broad‐banded zone and then by another broad, posterior unbanded zone located next to the endothelium. Collagen types III and IV comprise the posterior unbanded zone, types IV and VIII the anterior banded zone, and types V and VI the anterior unbanded zone (Smolek & Klyce, 1993).

Transmission electron microscopy (TEM) reveals the extensive, lateral, convoluted interdigitations between adjacent cells in the dog (Fig. 2.30). The cell junctions, including zonulae occludentes and maculae adherentes, are located at the lateral cell margins. The abundance of mitochondria, smooth and rough endoplasmic reticulum, and a variety of vesicles, indicates these cells are metabolically active. There is gradual loss of the hexagonal shape in older animals caused by a gradual decrease in the overall cell density of the

Corneal Endothelium The corneal endothelium is a single layer of flattened cells lining the inner cornea (Fig. 2.21). The regenerative ability of the endothelium varies with species and age. In most species active mitosis of the endothelium occurs primarily in the immature animal (Chi et  al., 1960; Laing et  al., 1976; MacCallum et al., 1983; Oh, 1963; von Sallman et al., 1961). Specular microscopy and SEM of adult eyes reveal that the cells are usually hexagonally shaped (Fig.  2.29). Closer inspection by SEM reveals that the surface is spotted with small microvillae and pores, and that the lateral edges of one cell interdigitate with another (Fig. 2.29B). In young canines (i.e., 1–4 weeks of age), many of the cells do not have the typical hexagonal shape. Pronounced pleomorphism has also been observed in kittens and rabbits (MacCallum et al., 1983).

A

Figure 2.30  The lateral interdigitations observed between endothelial cells along the surface continue throughout the entire thickness of adjacent cells in the canine cornea. Numerous mitochondria (M) are associated with these interdigitations. DM, Descemet’s membrane. (Original magnification, 16,000×.)

B

Figure 2.29  SEM of a 4-year-old canine corneal endothelium reveals occasional variability in cell size (A) and the lateral surface interdigitations (arrows) between cells (B). The most prominent feature of the endothelial cell is the nucleus (N), which bulges slightly into the anterior chamber. (Original magnification: A, 960×; B, 3500×.)

endothelium. In young dogs, endothelial density is greater than 3000 cells/mm2 with approximately 3600 cells/mm2 in dogs younger than 1 year (Kafarnik et al., 2007). As animals age, endothelial density can gradually decrease to 50% or less of that number. With a smaller population of cells, the endothelial cells spread out and produce more pump sites to compensate for increasing leakage. An age‐related decrease in the density of corneal endothelial cells results in little change in overall corneal thickness (Andrew et  al., 2001). If the cell density continues to decrease, however, the cells become too attenuated, resulting in the pumps being unable to withstand the increasing leakage with concomitant corneal thickening and loss of optical clarity. This point is known as corneal decompensation, and it usually occurs when the endothelial cell density decreases to between 500 and 800 cells/mm2.

aqueous plexus (AAP) (Fig. 2.32). In domestic animals the intrascleral plexus is variably connected with the choroidal venous system, the vortex system (Fig.  2.33; Smith et  al., 1988; Van Buskirk, 1979). The intrascleral plexus is variable in size and depth within the sclera (Natiello et  al., 2005; Sharpnack et al., 1984; Troncoso, 1942b; Ujiie & Bill, 1984). For example, in rabbits and primates, the plexus is formed on the outer side of circumferentially coursing canals, and it is composed of small vessels deep in the sclera. In carnivores, the intrascleral plexus is prominent and composed of

Sclera The sclera comprises the remainder of the fibrous tunic of the globe. Anteriorly, it merges with the peripheral cornea and the bulbar conjunctiva to form a transition zone, the limbus (Fig. 2.31). At the limbus, the sclera is variably pigmented, and the overlying epithelium is thicker, with pigmented epithelial cells. The stroma loses the regular arrangement characteristic of the cornea and takes on a less organized appearance of irregular, dense connective tissue. Numerous blood vessels (i.e., the anastomosing branches of the anterior ciliary arteries) terminate in the loops of the marginal plexus, then drain back into the conjunctival venules. Along the outer portion of the scleral stroma is an interconnecting network of veins, the intrascleral plexus, which receives aqueous humor from the veins that drain the angular

A

Figure 2.32  The intrascleral plexus (ISP) of a dog is located within the midsclera (S), and is interconnected to the angular aqueous plexus (AAP) by aqueous veins (AV). ESV, episcleral veins. (Original magnification, 125×.)

B

Figure 2.31  Photomicrographs of canine limbus. A. The irregular connective tissue of the sclera (S) merges with the highly organized connective tissue of the cornea (C). B. Close-up of the outer limbus reveals an anterior epithelium that is markedly thickened, and contains small blood vessels (BV), and melanocytes. (Original magnification, 250×.)

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two to four large, anastomosing vessels in the midsclera. The intrascleral plexus also receives afferent channels superficially via the episcleral network at the limbus. In the horse, the plexus, which is less prominent, collateralizes entirely with the anterior vortex system, because it is oriented radially to facilitate unidirectional flow outward from the angle region toward the vortex veins; in carnivores and primates, the reservoirs receiving aqueous humor are circumferentially oriented. The color of the sclera depends on the thickness of its stroma, appearing blue when thin (less than 0.2 mm) or yellow with increased fat content (carotenoids). The inner

Figure 2.33  Corrosion cast of the canine ocular microvasculature demonstrates collateralization of the intrascleral plexus (ISP) with choroidal veins (CV) of the vortex system. (Original magnification, 410×.)

surface, which is referred to as the lamina fusca, is brown because of the adherent suprachoroidal pigment. The sclera contains elastic fibers that are interlaced among the collagen fibers, as are melanocytes (anteriorly) and fibrocytes. The collagen fibers, fibrocytes, and occasional melanocytes are arranged meridionally, obliquely, and radially in an irregular fashion. Its rigidity provides resistance to intraocular fluid pressure, and several channels, or emissaria, are present for the passage of blood vessels and nerves. The most notable emissaria accommodate the optic nerve, long and short ciliary nerves, long posterior ciliary arteries, vortex veins, and anterior ciliary vessels. Scleral thickness varies considerably among species and in different areas of the globe. The sclera is thinnest near the equator, posterior to the insertions of the EOMs, and in the dog is only 0.12 mm thick (Table 2.9). By comparison, in the pig it thins to 0.43 mm, then nearly doubles its thickness for much of the posterior portion of the eye, being comparable to that of the human eye (Olsen et al., 2002). The region of the intrascleral venous plexus is the thickest area in animals with a well‐developed plexus (e.g., the dog and cat), whereas in ungulates, the region of the optic nerve entrance or posterior pole is the thickest. At the point where the optic nerve passes through the sclera, it becomes sieve‐like in the area known as the lamina cribrosa. In most cetaceans the sclera increases to thicknesses not found elsewhere among vertebrate species. The posteriorly broadened sclera likely maintains the widened and flattened shape of the retina and choroid, which is observed in the large eyes of most cetaceans and of many terrestrial species (Murphy et al., 1991; Walls, 1942). The episclera is a collagenous, vascular, and elastic tissue that is between the sclera and the conjunctiva and attaches to Tenon’s capsule. Tenon’s capsule consists of small, compact bundles of collagen that lie parallel to the surface of the episclera. Besides dense connective tissue, the sclera can be largely composed of cartilage, as in fish, lizards, chelonians, some

Table 2.9  Thickness of the sclera. Animal

Center of fundus (mm)

Optic nerve entry point (mm)

Globe equator (mm)

Limbus (mm)

Horse

1.5–2.2

1.35

0.5–0.3

1.1

1.9

0.4

Cow

1.9

2.20

1.0

1.2–1.5

Sheep

1.0–1.2

No increase in thickness

0.25–0.30

0.4–0.5

Pig

1.0–1.2

Thicker

0.5–0.8

Cat

0.09–0.20

0.13–0.60

0.09–0.20

1.1, in the form of a ring 5–7 mm wide

Dog

Similar to the cat, only thinner

0.3–0.4

0.12–0.20

0.6

Source: Translated from Bayer, J. (1914) Angenheilkunde. Vienna: Braumueller; and from Donovan, R.H., et al. (1974) Histology of the normal collie eye. Annals of Ophthalmology, 6, 257.

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Figure 2.34  Scleral ossicles (SO) in birds vary in size and shape. A. Screech owl with large intraosseous spaces. (Original magnification, 40×.) B. Chicken with smaller scleral ossicles and considerable overlap between adjacent ossicles (Original magnification, 100×). CM, ciliary body musculature (Crampton’s muscle); TM, trabecular meshwork.

amphibians, and birds. When cartilage is found in the sclera, it usually forms a complete cup that extends to the margin of the cornea or, in birds and lizards, to a ring of bony plates or ossicles. Scleral ossicles are located external to the ciliary body (Fig. 2.34). Though birds and reptiles possess this structure, the ossicle is believed to have originated from fish and was eventually passed on to amphibians. Birds with the greatest range of accommodation, such as the kingfisher and other diving birds, have larger ossicles than those species tending to be more confined to land (Curtis & Miller, 1938). Ossicles are believed to have evolved for retaining ocular rigidity. The number of ossicles that comprise a ring can vary within the same species; in individual eyes with fewer ossicles the single ossicle area increases, resulting in a constant scleral ring area (Canavese et al., 1994).

Uvea The iris, ciliary body, and choroid form the uvea. Unlike the fibrous coat, the uveal coat is highly vascular and usually pigmented. The ciliary body and choroid are attached to the internal surface of the sclera (Fig. 2.35). The iris originates from the anterior portion of the ciliary body, and it extends centrally to form a diaphragm anterior to the lens. The iris and ciliary body are the anterior uvea, and the choroid is the posterior uvea.

Iris The iris is a diaphragm that extends centrally from the ciliary body to cover the anterior surface of the lens, except for a central opening, the pupil. It divides the anterior ocular compartment into anterior and posterior chambers, which communicate through the pupil. The shape of the pupil varies among species. Among mammals, it is round in primates,

Figure 2.35  SEM of the canine anterior uvea: cornea (C), ciliary processes (CP), ciliary body musculature (CM), iris (I), sclera (S). (Original magnification, 25×.)

canines, most large felines (cougar, leopard, lion, and tiger) and pigs; it is vertical when constricted in the smaller felines (bobcat, lynx, and domestic cat); and it is oval in a horizontal plane in herbivores (horses, cattle, sheep, and goats) (Fig. 2.8, Fig. 2.9, and Fig. 2.19). In herbivores, along the upper and lower margin of the pupil are several round dark brown ‘masses’ referred to as granula iridica (corpora nigra) (see Fig. 2.9 and Fig. 2.36). Camelids have a pupillary ruff along the dorsal and ventral pupillary margins. These pigmented masses are extensions of the posterior pigmented epithelium that augment the effectiveness of pupillary constriction. Occasional myocytes of the sphincter muscle are present in the basal portion of the granula iridica of goats and horses. The presence of these cells indicates that the granula iridica probably plays more than a passive role during changes of pupillary size and shape. Eyes of animals with pupils that constrict to a slit are believed, in most instances, to be more sensitive to light than those with ­circular pupils (Prince, 1956).

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PE

I

CB

Figure 2.36  Equine iris (I) and anterior ciliary body (CB). The arrow points to the granula iridica, which continues posteriorly as the posterior pigment epithelium (PE).

The iris has a central pupillary zone and a peripheral ciliary zone. The demarcation between these two zones is the collarette, which is best demonstrated with moderate pupillary constriction. The portion of the pupillary zone adjacent to the pupil is sometimes more pigmented than the rest of the iris. The function of the iris is to control the quantity of light entering the posterior segment through a central pupil. Constriction of the pupil reduces the amount of light entering the eye. Narrowing the pupil also eliminates the peripheral portion of the refractive system, which diminishes lenticular spherical and chromatic aberrations. During periods of reduced light, the pupil dilates allowing maximal stimulation of photoreceptor cells. The iris is composed of an anterior border layer, stroma and sphincter muscle, and posterior epithelial layers (see Fig.  2.36). The anterior border layer consists of two cell types: fibroblasts and melanocytes. Results of electron microscopic studies indicate these cells are fibrocytic in nature rather than forming an epithelial sheet (Donovan et  al., 1974a; Rohen, 1961; Tousimis & Fine, 1959). The anterior cells, which lack a basement membrane, form an almost continuous layer with their cellular processes, but

frequent small openings with large intercellular spaces and extension of underlying melanocyte processes break the continuity. This anterior fibrocytic layer can be exquisitely thin and easily overlooked histologically. Particles measuring up to 200 μm in diameter can diffuse into the iris stroma through the anterior portion of the iris (Rodriques et  al., 1988; Smith et al., 1986). One or more layers of melanocytes are deep to the single layer of fibroblasts and compose the remainder of the anterior border layer. For the most part, the melanocytes are oriented parallel to the iris surface, and their processes intermingle with other melanocytes and anterior fibroblasts with no intercellular junctions. The shape of the melanin granules in the stroma varies between species and with the maturity of the granules. The pigment granules in the cat and dog are lanceolate to ovoid in shape, whereas they are round to ovoid in the horse (Sharpnack et al., 1984; Tousimis, 1963). In addition to the scattered melanocytes in the anterior stroma of many dog irides, a dense band of melanocytes can be present in the ciliary zone anterior to the dilator muscle, extending centrally to the sphincter muscle. The granules are generally smaller and more rod‐like than the pigmented granules of the posterior epithelium. Particularly in the horse and the dog, large cells containing pigment are associated with capillaries and venules near the sphincter muscle (Tousimis & Fine, 1959; Woberman & Fine, 1972). These are thought to be macrophages of hematogenous origin. In humans, these cells are known as the clump cells of Koganei (Woberman & Fine, 1972). The iris stroma is composed of fine collagenous fibers, chromatophores, and fibroblasts. The stroma is loosely arranged except around blood vessels and nerves, where it can form dense sheaths. The collagen fibrils are organized to some extent in overlapping, wide arcades running from the pupil to the ciliary body (Shively & Epling, 1969). Despite the dense histologic appearance, considerable extracellular space is evident ultrastructurally. Iridal color varies considerably among individuals, breeds, and species. The variation of iridal color results from the amount and type of pigmentation present. The coloration of irides in most domestic animals is dark brown, golden brown, gold, blue, or blue–green. Several avian species have brightly colored irides. Historically, these bright colors were thought to result from the presence of carotenoids, an idea based on a single study of the yellow iris of chickens performed over 50 years ago. Carotenoid‐bearing cells are referred to as xanthophores, and their presence certainly has been demonstrated to produce brightly colored irides. However, purines and pteridines are also major iridal pigments in a variety of avian species, including doves and great‐horned owls (Oliphant, 1988). Combinations of purines, pteridines, and carotenoids probably occur. Development of these pigments within an individual has been known to take a considerable amount of time, even as long as several years (Oliphant, 1988).

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Figure 2.37  A. In many canine irides, melanocytes are concentrated in a wide band anterior to the dilator muscle (DM), as seen in the lower half of this iris. MAC, major arterial circle. (Original magnification, 100×.) B. The major arterial circle (MAC) in the peripheral iris of a cat.

The major arterial circle is located at the peripheral iris root or the anterior ciliary body (Fig. 2.37). The arteries enter at the nine‐ and three‐o’clock positions as terminations of the medial and lateral branches of the long posterior ciliary arteries. Each artery branches dorsally and ventrally to pass circumferentially toward the opposite artery and forms an incomplete arterial circle in most species. In primates, the major arterial circle forms a completely enclosed ring. The major arterial circle gives rise to numerous radial arteries that end either in a capillary bed near the pupillary margin (i.e., in the dog and cat) or in a minor arterial circle of the iris (i.e., in primates and pigs). There is some debate over the presence of secondary arterial circles in the equine iris (Anderson & Anderson, 1977; Smith et al., 1988). The arteries radial to the pupil are tortuous in most animals. The degree of tortuosity might reflect differences in pupil mobility between species. The radial arteries lose the internal elastic membrane that is present in the major arterial circle artery, and they have only one layer of smooth muscle cells, compared with two to four in the arteries of the major arterial circle. A thick basement membrane is present externally, which also surrounds the smooth muscle cells, but this membrane is interrupted by frequent myoepithelial junctions. A capillary network near the pupillary margin connects the terminal arterioles with the venules, which pass to the base of the iris behind the arterioles in the posterior stroma. The capillary endothelium is not fenestrated, but the type of intercellular junctions varies with species. Mice, monkeys, and humans have tight junctions (zonula occludens), but rats, cats, and pigs have 4 nm gap junctions between desmosomes (maculae occludentes) (Szalay et al., 1975). Venous drainage of the iris occurs through tortuous, radial vessels that empty directly into the anterior choroidal veins and out the vortex veins (Fig. 2.38). These vessels typically

Figure 2.38  SEM corrosion cast of the anterior microvasculature of the equine eye. The iridal arteries (small arrows) and veins (large arrows) have a tortuous appearance as they progress toward the pupil. Note the iridal veins eventually empty posteriorly, into the anterior choroidal venous system (CV). MAC, major arterial circle. (Original magnification, 40×.)

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The iridal dilator muscle is a single layer of smooth muscle fibers in the posterior iridal stroma extending from the iris sphincter to the iris periphery. These muscle fibers apically (i.e., posteriorly) contain pigment around their nuclei and are innervated by sympathetic nerve fibers. The basal regions of each cell, which contain the myofilaments, overlap one another in a shingle‐like fashion. This cell layer could be considered as a highly developed, pigmented myoepithelium. The size of the dilator muscle varies between species, being well developed in the dog and involving the full circumference of the iris. In the horse, it is less developed, and in species with elongated pupils, it is poorly developed adjacent to the long axis of the pupil (Prince et al., 1960). The posterior iridal surface is covered by two layers of epithelium. The anterior layer, which forms the dilator muscle, is continuous with the pigmented epithelium of the ciliary body, whereas the posterior layer, which is densely pigmented, is continuous with the nonpigmented epithelium of the ciliary body. The basal aspect of the posterior epithelium of the iris faces the posterior chamber and has numerous surface projections (Fig. 2.41). The posterior surface of the iris contains folds that extend to the base of the ciliary processes. These folds are radially oriented, but the pigmented epithelial cells are oriented with their long axis running circumferentially in the iris, thus giving rise to two patterns on the posterior surface (Donovan et al., 1974a). A basement membrane separates the cells from the posterior chamber but does not follow all the invaginations of the cell surface. The lateral cell surfaces of the posterior epithelium have numerous slender cell processes with scattered desmosomes. In general, large spaces occur between the lateral cell membranes, which allow free access to the posterior chamber. The nuclei of the iridal posterior epithelium in the dog are oval and moderately indented, whereas the nuclei in the horse are often bizarre‐shaped, being indented by adjacent pigment granules.

number four in humans, pigs, and cats, but may vary in other species (Anderson & Anderson, 1977; Risco & Nopanitaya, 1980; Van Buskirk, 1979). In horses, a unique variation of iridal venous drainage exists where branches of the intrascleral venous plexus empty into the bases of the iridal veins, which in turn empty into the anterior choroidal venous circulation (Smith et al., 1988). The iridal sphincter muscle, which is a flat band of thin, circular bundles of smooth muscle fibers in mammals and striated muscle fibers in nonmammalian species, is located in the iris stroma near the pupil. In the dog and cat, it lies in the posterior stroma, separated from the pigmented epithelium and subjacent dilator muscle by a thin layer of connective tissue (Fig.  2.39A). In the horse, the sphincter occupies the main ­portion of the central stroma and is capped by the granula ­iridica when present (Fig. 2.39B). The shape of the sphincter muscle varies among species according to the pupillary shape (Fig.  2.40; Prince, 1956). The sphincter muscle is innervated primarily by parasympathetic nerve fibers.

Figure 2.39  Sphincter muscle (SM) location in the dog (A) and in the horse (B). The sphincter muscle in the horse is capped by the granula iridica (GI), which is a proliferation of the posterior epithelium (PE). (Original magnification, 200×.)

A

B

C

Figure 2.40  A. Iris sphincter muscles that create a slit pupil when the pupil is constricted found in domestic cats, bobcats, and lynx. B. The circular iris sphincter muscle as found in primates, birds, dogs, and pigs. C. Iris sphincter muscle in an ungulate with a horizontal pupil. (Source: Redrawn from Prince, J.H. (1956) Comparative Anatomy of the Eye. Springfield, IL: Charles C. Thomas.)

Figure 2.41  SEM of the posterior iris surface of a cat. Arrows point to radial folds. Tips of ciliary processes (A). Note circumferential orientation of clumps of posterior epithelium with small bumps from melanin granules. (Original magnification, 81×.)

The apical portion of the cells of the anterior epithelium (iris dilator muscle) contains the nucleus and is located adjacent to the apical portion of the posterior epithelium. Melanin granules are predominately present in the apical portion of the cell. The myoepithelial (basal) portion has scattered melanin granules, forms irregular projections into the stroma, and is covered by a basement membrane. In the horse, basement membrane material fills much of the intercellular space between projections of the myoepithelium. In avian species and other lower vertebrates, the iris muscles are striated. In addition to controlling the amount of light that enters the back of the eye, the iris of birds is thought to contribute to lenticular accommodation. Changes in the pupil diameters of chickens and pigeons result in changes in the positioning of their lenses (Glasser & Howland, 1995). In some birds and other animals, for example, American alligators, the sphincter and dilator muscles are both striated and smooth. Specifically, in great‐horned owls, pupillary constriction occurs mostly by skeletal muscle and pupillary dilation mostly by the radial myoepithelium, which contains smooth muscle myofilaments (Oliphant, 1983). The iris contains numerous myelinated and nonmyelinated nerves for autonomic innervation. The myelinated fibers do not specifically follow the iris vessels, but they have a similar pattern as they follow the collagen fibers of the stroma. Upon entering the iris, each long ciliary nerve forms a dorsal and a ventral branch, to form a circular nerve in the ciliary zone and also to meet their counterparts from the opposite side dorsally and ventrally. Radial nerve bundles

from the circular nerve pass centrally to the pupil with a corkscrew shape, presumably to accommodate pupillary constriction. A circular plexus is formed near the collarette, from which branches continue toward the pupil, then divide, and intersect to form a rhomboid‐shaped mesh (Saari, 1971). The belief that reflex constriction of the mammalian pupil in response to light depends exclusively on neural pathways between the eye and central nervous system may not be true (Lau et al., 1992). In both golden hamsters and hooded rats, effective constriction of the pupil in response to light occurred after a variety of interventions, including bilateral intraorbital optic nerve transection and unilateral intracranial optic nerve transection with enucleation of the contralateral eye, combined in some cases with bilateral removal of the superior cervical ganglia, pinealectomy, or both. The constrictions that occurred after these different interventions were considerably slower than the usual, neuronally driven reflex but present. Interestingly, the slow, nonneural pupillary reflex was not observed in albino animals, which suggests a possible melanin‐mediated component to the slow pupillary light reflex.

Ciliary Body The ciliary body is a heavily pigmented structure that provides nourishment for and removes wastes from the cornea and lens and participates in lens accommodation. The ciliary body is divided into the anterior pars plicata (corona ciliaris) and the posterior pars plana. The pars plicata consists of a ring of 70–100 ciliary processes, depending on the species, with intervening valleys (Fig. 2.42; Prince et al., 1960). The

Figure 2.42  Inner surface of the ciliary body of a dog treated with α-chymotrypsin to remove the lenticular zonules. Note the thin ciliary processes (CP), which posteriorly give rise to smaller secondary folds (small arrows). These folds flatten and disappear in the region called the pars plana (PP), which ends posteriorly at the adjoining retina, forming a line known as the ora ciliaris retinae (arrowheads). (Original magnification, 18×.)

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processes are generally more prominent and numerous in animals with larger anterior chambers (the cow and horse have 100 and 102 processes, respectively) than in animals with smaller anterior chambers (carnivores and primates have 74–76 processes) (Prince et  al., 1960). Ciliary body processes are often absent in lower vertebrates (most fish, lizards, and snakes) (Duke‐Elder, 1958; Prince, 1956; Prince et al., 1960). In anurans, birds, and some reptiles, the ciliary body processes are attached to the lens and participate directly in accommodation. In mammals, the ciliary body processes are attached to the lenticular zonules, which connect to the lens equator. The appearance of individual ciliary body processes varies among species. In carnivores, the processes are thin and bladelike, with rounded tips that are invested with zonular fibers. Between the major ciliary processes, wide valleys with smaller, secondary folds are present. Many of the smaller secondary folds originating near the pars plana merge with the major processes at their base. The surface of each process has numerous convolutions, but most of it is obscured by the attachments of the zonular fibers (Fig. 2.43; Troncoso, 1942a). In some ungulates, the ridge of the ciliary processes is capped by a broad, convoluted surface that overhangs the main body of the processes (Troncoso, 1942a). Numerous zonular fibers extend from a firm attachment on the sides  of the processes to the lens. These fibers also run circumferentially, connecting the broad ridges together (Fig.  2.44). The cap of broad convolutions stops before the anterior tips of the ciliary processes, which are free of fibers. Each ciliary process consists of a central core of stroma and blood vessels covered by a double layer of epithelium: an inner, nonpigmented, cuboidal epithelium, and an outer,

Figure 2.43  SEM (sagittal view) of the inner ciliary body of a dog reveals numerous zonular fibers attached along the epithelial surface. (Original magnification, 130×.)

Figure 2.44  SEM of the ciliary processes and zonular fibers in a horse. Ciliary process (A). White arrows point in the direction of the lens equator as well as to the horizontal fiber network joining adjacent process (B). Zonular fibers in valleys between processes (C). Note also the zonular fiber ensheathment of the ciliary processes (black arrows). (Original magnification, 41×.)

pigmented, cuboidal epithelium (Fig.  2.45). In ungulates, the double‐layered epithelium is more columnar than cuboidal. The nonpigmented ciliary body epithelium is confluent posteriorly with the neurosensory retina at the ora ciliaris retinae and anteriorly with the posterior pigmented epithelium of the iris. The basal surfaces of these cells face the posterior chamber and can be irregular. The basement membrane of this epithelial layer follows the general contour, but it does not pass down into the small irregularities or into the intercellular spaces. The basement membrane helps to anchor the lenticular zonular fibers and vitreous base. The lateral cell surfaces of the nonpigmented epithelium have numerous villous processes along the bottom one‐half to two‐thirds. Cystic intercellular spaces in this region and in the pars plana are filled with material that has the staining characteristics of GAGs. The base of the cells also reacts positively for the same material. The nonpigmented epithelium most likely produces the GAGs of the vitreous humor. These cells secrete the GAGs, which consist mostly of hyaluronans, laterally into the cystic intercellular spaces, which then communicate with the vitreous base (Fine & Yanoff, 1979). The enzyme carbonic anhydrase has been cytochemically localized at or in the nonpigmented epithelium (Streeten, 1988). The types of cellular junctions between the nonpigmented and pigmented epithelium of the ciliary processes consist of many gap junctions interspersed with desmosomes and

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B

Figure 2.45  The bilayered ciliary epithelium that lines the ciliary processes and intervening valleys. The outer layer is pigmented; the inner layer is nonpigmented. A. Feline ciliary processes. Insert: Cross-section of ciliary processes. The bilayered epithelium, which is cuboidal, lines blood vessels (BV), which together form a blood–aqueous barrier. B. Longitudinal section of an equine ciliary epithelium at the base of a process. Both layers are considerably more columnar than those in the dog and cat. (Original magnification, 400×.)

unusual junctions termed puncta adherentes, which resemble desmosomes but lack the larger tonofilaments and associated intercellular central band (Streeten, 1988). The lateral intercellular junctions of the nonpigmented epithelium consist of desmosomes, except at the apical end (Fig.  2.46). The apical ends possess gap junctions, zonula adherens, and zonula occludens, which represent the anatomic site of the blood–aqueous barrier (Fig. 2.46; Shabo et  al., 1976; Smith, 1971; Smith & Raviola, 1983; Smith & Rudt, 1973; Streeten, 1988). There are also dilated portions of the apical intercellular spaces with villous cytoplasmic processes protruding into them. These dilations are termed ciliary channels, and they are usually near the apical termination of two adjacent cells. The ciliary process pigmented epithelium is confluent with the retinal pigment epithelium. Anteriorly, it continues as the anterior pigmented epithelial layer of the iris, which forms the dilator muscle. The pigmented epithelium is generally cuboidal and heavily laden with round‐to‐oval melanin granules. The basal aspect of the pigmented epithelium faces the ciliary body stroma and is covered by a basement membrane. In some instances, the basement membrane of adjacent capillaries in the ciliary processes comes into contact with the basement membrane of the pigmented epithelium to form a thickened, irregular, common basement membrane. The lateral cell surfaces of the pigmented epithelium are joined by desmosomes, and the basal cell surfaces have no specialized junctions. The nuclei of both pigmented and nonpigmented epithelia are located apically. The cytoplasm

Figure 2.46  Apical junctions of nonpigmented (NPE) and pigmented (PE) ciliary epithelium in a cat. The nonpigmented epithelial nuclei are located apically; the wide intercellular spaces and villi can be seen in the basilar aspect of the intercellular spaces of the nonpigmented epithelium. The apical aspect of the nonpigmented intercellular space is the anatomic site of the blood–aqueous barrier and contains a fascia occludens (small arrow) and fascia adherentes (large arrow). The apical cell surfaces contain a fascia adherentes, gap junctions (open arrows), and arch-shaped gap junctions (curved arrows). The basement membrane (B) of the pigmented epithelium. (Original magnification, 9800×.)

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of the pigmented epithelium contains melanin granules, rough endoplasmic reticulum, smooth endoplasmic reticulum, free ribosomes (polysomes), and mitochondria. A thin layer of loose connective tissue with blood vessels and nerves lies under the ciliary epithelium, separating the ciliary body epithelium from the underlying ciliary body musculature. The vascular plexus within the stroma of the ciliary process is leaky, being lined with a fenestrated endothelium. Fibrocytes and melanocytes are sparsely ­populated within the stroma, being more concentrated near the ciliary body muscle (CBM). The pars plana is the flat, posterior portion of the ciliary body that extends from the posterior termination of the processes to the retina (ora ciliaris retinae) (see Fig. 2.42). The width of the pars plana varies because the retina extends more anteriorly in the inferior and medial quadrant in most species, enhancing peripheral vision. Therefore, the pars plana is usually widest superiorly and laterally. In the dog, the ora ciliaris retinae is 8 mm behind the limbus dorsally and laterally but only 4 mm ventrally and medially (Donovan et al., 1974a).

Ciliary Body Musculature The CBM is comprised of smooth muscle fibers in mammals. Contraction of the CBM draws the ciliary processes and body both forward and inward, thus relaxing the lenticular zonules (suspensory ligament of the lens) and altering the shape and refraction of the lens. This muscle is often weakly developed in many nonprimate species and as a result, offers poor accommodative ability. On the basis of ciliary body musculature development, the placental mammalian ICA has been categorized into three main groups: the herbivorous, the carnivorous, and the anthropoid (Henderson, 1926; Tripathi, 1974). The categorization depicted in Fig.  2.47 was originally inspired from observations of the ciliary regions of the dog, pig, and ape (Duke‐Elder, 1958). The herbivorous type has been characterized as the most common and primitive in orders of mammals up to and including ungulates. This type of angle consists of an inner layer of connective tissue that forms a baseplate of the ciliary body and extends from the root of the iris to the ora ciliaris retinae. It also consists of an outer layer of smooth muscle that presses against the sclera externally and runs meridionally from the corneoscleral junction toward the ora ciliaris retinae (Fig. 2.47A and Fig. 2.48A). The two layers are often referred to as “leaves” that separate anteriorly and form the ciliary cleft. The ciliary cleft is then a triangular area that varies both in depth (i.e., length) and height, and functionally may be considered a posterolateral extension of the anterior chamber into the ciliary body. Historically, this region was called the cilioscleral sinus, but because it neither separates the ciliary body from the sclera nor is a part of the ciliary venous sinus,

CC

A

CC

B

CC

C Figure 2.47  Degree of development of the ciliary body musculature among mammalian iridocorneal angles in the ungulate (A), carnivore (B), and ape (C). The ciliary body musculature is most pronounced in primates and least developed in ungulates. The size of the iridocorneal angle and its cilioscleral cleft or sinus (CC) is inversely large or most pronounced in the ungulate. (Source: Redrawn from Duke-Elder, S. (1958) System of Ophthalmology. Vol. I. The Eye in Evolution. London: Henry Kimpton.)

the term cilioscleral sinus has been replaced with ciliary cleft (Duke‐Elder, 1958; Tripathi, 1974; Troncoso, 1938). The ciliary cleft is an area containing wide spaces filled with aqueous humor and interspersed with cell‐lined cords of connective tissue. The spaces between the fibrous cords were initially described in cattle and horses, and they have been often referred to as Fontana’s spaces (Samuelson, 1996). The carnivorous type possesses a bi‐leaflet configuration as well, but the fibrous inner leaf or layer is usually replaced by meridionally oriented smooth muscle and some radially oriented muscle fibers (see Fig. 2.47 and Fig. 2.48B) (Duke‐ Elder, 1958). Similar to the herbivorous type, the two leaves separate anteriorly and hold a wide, deep ciliary cleft. In both the herbivorous and carnivorous types, the ciliary cleft offers little support to properly anchor the iris. Compensation for wide and deep ciliary clefts is provided by a series of pectinate ligaments attaching the anterior iridal root and inner ciliary baseplate to the limbal cornea. The anthropoid type differs sharply in its configuration compared with the other types (see Fig. 2.47C and Fig. 2.48C). The ciliary body musculature of primates is believed to be the most highly developed among mammals. The muscle, which has three components (i.e., radial, meridional, and circular),

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C Figure 2.48  A. The deer has the traditional herbivorous type of iridocorneal angle and associated ciliary body musculature, which forms a single outer “leaf” (arrows) as it lines the outer, posterior portion of the iridocorneal angle. C, cornea; I, iris; S, sclera. (Original magnification, 20×.) B. The cat possesses the traditional carnivorous type of iridocorneal angle, which forms a “bileaflet” anteriorly (arrows). I, iris; S, sclera; AC, anterior chamber. (Original magnification, 25×.) C. The Rhesus monkey has the anthropoid type, which consists of small iridocorneal angle and a well-developed ciliary body musculature (arrows). I, iris; S, sclera; A, iridocorneal angle. (Original magnification, 20×.)

CC

CC

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C Figure 2.49  Three additional configurations of the eutherian nonprimate iridocorneal angle. Ciliary body musculature is indicated by linear shading. Ciliary cleft (CC). A. Small diurnal herbivore. B. Large diurnal herbivore. C. “High” accommodative carnivore. (Samuelson, D.A. (1996) A reevaluation of the comparative anatomy of the Eutherian iridocorneal angle and associated ciliary body musculature. Veterinary & Comparative Ophthalmology, 6, 153–172.)

forms a large, anterior pyramidal structure that provides a strong baseplate for iridal attachment. The anterior portion of the CBM has replaced both the ciliary cleft, which barely exists in the anthropoid angle, and the pectinate ligaments, which vestigially consist of scattered iridal processes.

In addition to the three basic forms of CBM and ICA, three more configurations have been described among nonprimate mammals (Fig. 2.49; Samuelson, 1996). Among herbivores, two other types have been identified: the small diurnal herbivore and the large diurnal herbivore. In the

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small diurnal herbivore, such as the squirrel, a deep ciliary cleft is lined by inner and outer leaves of fibrous tissue and smooth muscle of the ciliary body. In the large diurnal herbivore, such as the pig, there is a well‐developed ciliary cleft and outer leaf of ciliary muscle, which anteriorly includes circularly oriented muscle embedded within a scleral spur. The scleral spur is a small ridge of dense connective tissue that separates the muscle fibers from the posterior ICA. TEM of different ungulates has revealed that many of the muscle fibers, especially those located anteriorly, course more circumferentially than meridionally (Samuelson & Lewis, 1995). This difference in orientation of the musculature is most evident in the pig and water buffalo. In these animals, circular muscle fibers are located near the innermost portion of the posterior end of the ciliary cleft. A third type occurs in “high” accommodative carnivores, such as raccoons and ferrets. In this configuration, the anterior CBM is highly developed but not as an outer leaflet. Instead, the anterior musculature extends as a single leaflet either internally (i.e., raccoons) or intermediately (i.e., ferrets) (Fig. 2.49C and Fig. 2.50). In birds and other nonmammalian species, the CBM consists of skeletal muscle cells that are primarily meridional. At least two distinct muscle bundles are located in this region of the avian eye: an anterior bundle, which is known as the muscle of Crampton, arises near the corneal margin; and a posterior bundle, which is known as Brücke’s muscle. In birds such as the hawk, Brücke’s muscle is well developed and sometimes is referred to as two muscles: Müller’s (anterior) and Brücke’s (Duke‐Elder, 1958). Contraction of Brücke’s muscle causes the ciliary body to push against or compress the lens, thus deforming it, whereas contraction of Crampton’s muscle alters the shape of the cornea by shortening its radius of curvature.

Ciliary Body Vasculature The blood supply of the ciliary body derives from the two long posterior ciliary arteries and the anterior ciliary arteries. As the long posterior arteries pass into the suprachoroidal space equatorially along the lateromedial horizontal plane, they undergo several divisions. These divisions anastomose anteriorly with branches of the anterior ciliary arteries to form the major arterial circle, which is located either in the base of the iris or the anterior ciliary body (see Fig. 2.37 and Fig. 2.38). The anterior ciliary arteries, which arise from branches of the ophthalmic artery, typically enter the globe at the attachment sites for the recti muscles and help to supply the ciliary muscles (Streeten, 1988). The major arterial circle is the primary vasculature supply of the ciliary processes. Numerous anatomic variations of this vasculature have been found among mammals (Funk & Rohen, 1990; Matsuo, 1973; Morrison & Van Buskirk, 1983; Morrison et al., 1987a, 1987b; Natiello & Samuelson, 2005). In primates and rabbits, two types of arterioles supply the major and minor processes, whereas in other species, a single type of arteriole originates from the major arterial circle and supplies the ciliary process vasculature (Morrison & Van Buskirk, 1983; Morrison et al., 1987a, 1987b; Natiello & Samuelson, 2005). Discrete interspecies variations occur in the angioarchitecture of the ciliary processes (Fig.  2.51). Rodents, rats and Guinea pigs have extensive interprocess connections and concentrically parallel capillaries that are irregularly dilated and travel posteriorly, emptying into the anteriormost choroidal veins. Carnivores such as dogs and cats have processes supplied by one arteriole that is directed posteriorly throughout its length, with capillary arcades that extend to each process margin, from which they empty into venous sinuses. The mammalian CBM is supplied by parasympathetic fibers from the oculomotor nerve and by sympathetic nerve fibers. The parasympathetic fibers leave the oculomotor nerve, penetrate the ventral oblique muscle, and synapse in the ciliary ganglion. From the ciliary ganglion, short ciliary nerves penetrate the sclera around the optic nerve to pass into the sclera and suprachoroidal space innervating the ciliary muscle and iris muscles. The sympathetic fibers arrive via the long ciliary nerves from the dorsal or superior cervical ganglia in a similar manner (Gum et al., 2007).

Iridocorneal Angle

Figure 2.50  The mongoose has the “high” accommodative type of iridocorneal angle. CM, ciliary body musculature; UTM, trabecular meshwork. (Original magnification, 100×.)

Aqueous humor is produced by the ciliary body epithelium and enters the posterior chamber before flowing through the pupil into the anterior chamber. In the conventional outflow pathway, aqueous humor exits the eye through the corneoscleral trabecular meshwork. The anatomy of the aqueous humor outflow system has been extensively studied in humans, nonhuman primates,

C C

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B C

C

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D

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Figure 2.51  Comparative angioarchitecture of the ciliary processes. A. Rodents, B. Rabbit, C. Carnivores, D. Ungulates, E. Manatee. C, cornea; CV, choroidal vein; I, iris; MAC, major arterial circle. (Source: Modified from Morrison, J.C., DeFrank, M.P. & Van Buskirk, E.M. (1987) Comparative microvascular anatomy of mammalian ciliary processes. Investigative Ophthalmology Visual Science, 28, 1325–1340; Morrison, J.C., DeFrank, M.P. & Van Buskirk, E.M. (1987) Regional microvascular anatomy of the rabbit ciliary body. Investigative Ophthalmology Visual Science, 28, 1314–1324; Natiello, N. & Samuelson, D. (2005) Three-dimensional reconstruction of the angioarchitecture of the ciliary body of the West Indian Manatee (Trichechus manatus). Veterinary Ophthalmology, 8, 367–373.)

dogs, cats, rabbits, horses, and other ungulate species (Bedford & Grierson, 1986; Bill, 1975b; Inomata et al., 1972; Martin, 1975; McMaster & Macri, 1968; Samuelson & Gelatt, 1984a, 1984b; Samuelson & Lewis, 1995; Samuelson et  al., 1989; Sharpnack et  al., 1984; Smith & Rudt, 1973; Smith et  al., 1986, 1988; Tripathi, 1971a, 1974; Troncoso, 1938, 1942a). This system primarily consists of the ICA, which is

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bounded anteriorly by the peripheral cornea and perilimbal sclera, and posteriorly by the peripheral iris and anterior CBM. From amphibians to higher mammals, the ICA consists of an irregular, reticular network of connective tissue beams called trabeculae that are lined partially or entirely by a single layer of cells (Samuelson, 1996; Tripathi, 1971a, 1974). The size of the ICA varies among species. In dogs of

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different ages and breeds that had undergone cataract surgery, the size of the ICA as determined by the angle opening distance (the distance between the internal limbus and the base of the iris) using ultrasound biomicroscopy was found to vary considerably (Crumley et al., 2009). At the expense of the CBM, a proportionally larger sinus is found in most domestic animals than in humans. The pectinate ligaments consist of long strands anchoring the anterior base of the iris to the inner peripheral cornea (Fig. 2.52 and Fig. 2.53). In the dog and cat, these strands are usually slender and widely separated from each other, thus making it difficult to visualize histologically an intact

pectinate ligament fiber for its entire length. In the rabbit and pig, the strands are somewhat shorter and thicker than those of domestic carnivores (Simones et al., 1996). In contrast, most ungulates possess moderately broad to very stout pectinate ligaments (Fig. 2.54). The pectinate ligaments are entirely lined by cells that are confluent with the anterior surface of the iris. In ICAs with stout pectinate ligaments, the anterior chamber freely communicates with the ICA through pores that lead into a collection of small channels surrounded by cords of densely packed collagen. Posteriorly, the pectinate ligament anastomoses with anterior beams of the trabecular meshwork. In mammals, the network of

Figure 2.52  Gonioscopic view of the anterior ciliary body shows the fibrous strands, known as the pectinate ligaments, that attach the anterior base of the iris to the limbus.

Figure 2.53  Frontal view SEM of the canine iridocorneal angle. Fibrous pillars that attach the iris (I) to the limbus form the pectinate ligaments (PL). Arrows indicate smaller fibrous connections between these pillars and uveal trabeculae located behind the pectinate ligament. (Original magnification, 160×.) Figure 2.54  Frontal view SEM (A) and sagittal view light micrograph (B) of the equine pectinate ligament. Anteriorly pores (arrows) form openings that permit the aqueous humor to move from the anterior chamber into the iridocorneal angle. (Original magnification: A, 200×; B, 100×.)

A

B

trabeculae is usually subdivided into two regions. The uveal trabecular meshwork, which in most animals comprises most of the inner ICA area, thus forming the ciliary cleft, and the corneoscleral trabecular meshwork, which is similar in construction to the uveal meshwork but smaller both in size of the trabecular beams and the channels or spaces between the cell‐lined beams. The uveal meshwork interconnects the inner, anterior CBM with the pectinate ligament. For the most part, the uveal trabeculae are oriented meridionally. In most animals, these beams are completely encased by an endothelium referred to as trabecular cells. The beams branch increasingly toward the CBM in radial and circular directions. As a

result, the posterior uveal trabeculae are smaller, with smaller intertrabecular spaces separating them. The posterior uveal meshwork often merges imperceptibly with the posterior, innermost regions of the corneoscleral trabecular meshwork. The corneoscleral trabecular meshworks of domestic animals are characterized mainly by small trabeculae separated by small intertrabecular spaces. In carnivores, these trabeculae are incompletely lined by trabecular cells (Fig. 2.55). By comparison, in certain ungulates, including horses, bison, and water buffalo, each trabecula is completely lined by trabecular cells. In ruminants and pigs, individual trabeculae can be completely lined, whereas others are incompletely lined.

A

B

C

D

Figure 2.55  A–D. The corneoscleral trabecular meshwork (CM), sclera (S) and adjacent angular aqueous plexus (AAP) in the dog (asterisks indicate intertrabecular spaces). (Original magnification: All, 400×.) B. Bison, C. Horse, D. Pig.

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Composition of the trabeculae varies very little among species (Bedford & Grierson, 1986; Samuelson, 1996; Samuelson & Gelatt, 1984a, 1984b; Samuelson et  al., 1989; Tripathi, 1971a). The core, or center, of each beam is made up of circularly and meridionally oriented collagen fibers interspersed with a modified elastin (Gong et  al., 1989). The core is usually enveloped by a cortical zone consisting of amorphous, granular material surrounded by basement membrane‐like material. In cats, horses, and water buffalo, the larger corneoscleral trabeculae and smaller uveal trabeculae have multiple layers of basement membrane‐like material within the cortical zone (Samuelson et al., 1989; Tripathi, 1974). In horses, a narrow zone of thickened, rounded, corneoscleral trabeculae is present between the outflow veins of the ICA and the pectinate ligament. These trabeculae possess no basement membrane‐like material; instead, they have long‐spacing collagen. Trabecular cells are similar across species, being fibroblast‐like with slender cell processes that attach to adjacent cells and their processes. These processes allow the corneoscleral trabecular meshwork to act as a sieve, thus reducing the size of the particles that can move into the meshwork (Garcia et  al., 1986; Johnson et  al., 1990; Samuelson et al., 1985; Smith et al., 1986). The degree of meshwork porosity varies between species, with the dog having a more porous meshwork when compared with the horse. The trabecular cell also has the ability to ingest a wide variety of particles, which can range greatly in size (Samuelson et  al., 1984b). The phagocytic‐like quality of the trabecular cell provides the ICA with an indigenous clearance mechanism for debris, thus reducing possibilities for an inflammatory response (Grierson & Lee, 1973; Sherwood & Richardson, 1981). An operculum is located within the canine corneoscleral trabecular meshwork (Samuelson et al., 2001). The operculum comprises much of the nonfiltering portion of the trabecular meshwork in the anterior portion of the ICA (Rohen & Lutjen‐Drecoll, 1989). It consists of the peripheral extension of the corneal endothelium (and its subjacent basement membrane, i.e., Descemet’s membrane) and the underlying, anteriormost portion of the corneoscleral trabecular meshwork. The operculum is especially well developed in dogs, rabbits, and nonhuman primates (Fig.  2.56; Samuelson, 1996). The peripheral termination of the corneal endothelium and its basement membrane leads to what is referred to as the cribriform ligament because it branches both posteroexternally, into the corneoscleral trabecular meshwork, and posterointernally, joining with the anterior uveal trabeculae. The function of the operculum is unknown; however, cells intimately associated with the operculum (i.e., Schwalbe’s line cells) are secretory in nature, able to form and release certain enzymes, including enolase and hyaluronans synthase, and phospholipid surfactant‐like material (Fig.  2.57; Allen et  al., 1955; Lutjen‐Decoll & Rohen, 1992; Raviola,

Figure 2.56  In the rabbit, as in most carnivores and monkeys, the peripheral corneal endothelium and its basement membrane extend posteriorly at variable lengths beyond the pectinate ligaments (PL) and form the operculum (O). In turn, the operculum forms a lid-like cover over the anteriormost corneoscleral trabecular meshwork (CTM). I, iris. (Original magnification, 100×.)

Figure 2.57  Cells associated with the operculum in the dog form clusters and can be linearly arranged (SLC, Schwalbe’s line cells) within the anteriormost regions of the corneoscleral trabecular meshwork. O, operculum. (Original magnification, 9800×.)

1982; Samuelson et  al., 2001; Stone et  al., 1984). Although the role these cells play in the mature ICA has yet to be determined, Schwalbe’s line cells represent a distinct subpopulation within most mammalian ICAs. The external boundary of the corneoscleral trabecular meshwork is formed by the sclera and a plexus of aqueous humor collector vessels. In mammals and most lower vertebrates, the aqueous humor chiefly exits the eye through the trabecular meshworks into these vessels (see Fig. 2.55). In most mammals, these vessels consist of a small network of veins collectively termed the AAP (Tripathi, 1971a, 1974). These vessels have radially oriented lumens, differing from the circumferentially coursing canal of Schlemm in primates (Grierson et  al., 1977; Kayes, 1967; Tripathi,

2: Ophthalmic Anatomy

Uveoscleral Outflow

Aqueous humor is not entirely removed by a plexus of collector vessels via the ICA. Some aqueous humor drains either posteriorly into the vitreous humor, anteriorly within the iridal stroma and across the cornea, or exteroposteriorly along a supraciliary–suprachoroidal space into the adjacent sclera (Fig. 2.58; Bill, 1985; Bill & Phillips, 1971; McMaster & Macri, 1968; Smith et al., 1988). The lattermost pathway is called the uveoscleral, or unconventional, outflow pathway. The degree of uveoscleral outflow varies remarkably between species, with cats experiencing the least drainage (3%), followed by humans (4%–14%), rabbits (13%), dogs (15%), and nonhuman primates (30%–65%) (Barrie et  al., 1985; Bill & Phillips, 1971). In the horse, the uveoscleral pathway may be just as important as the conventional route for aqueous humor removal. Large spaces of the outer uveal meshwork become confluent posteriorly, with a uniquely wide and well‐defined meshwork between the CBM and the sclera (i.e., the supraciliary space). This region, which has been found only in the horse, is called the supraciliary meshwork, and most likely represents a major pathway for aqueous humor removal (Fig. 2.59; Samuelson et al., 1989). In pigs, cattle, dogs, cats, and horses, the outer anterior CBM forms longitudinal and circumferential attachments to trabeculae of the ICA (Samuelson & Birkin‐Streit, 2011; Sedacca et  al., 2011). Spaces between the endings of the CBM form avenues for the beginning of the uveoscleral pathway (Fig.  2.60). In pigs, the corneoscleral trabecular meshwork is anchored by a scleral spur, which in turn anchors much of the outer CBM. As a result, the uveoscleral pathway is limited to small intertrabecular spaces of the

C

AC APP

I PC

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Figure 2.58  The majority of aqueous humor flows from the posterior chamber (PC) into the anterior chamber (AC), where it is removed via the iridocorneal angle by the trabecular meshwork and angular aqueous plexus (AAP). Other drainage routes include exchange across the vitreous face (V), iris vessels (I), and corneal endothelium (C), and via the uveoscleral (US) pathway.

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1971b). The plexiform nature of the drainage vessels in most mammals allows removal of a substantial amount of aqueous humor. The single canal in primates most likely represents an evolutionary adaptation for removal of aqueous humor from a relatively small anterior chamber through a small, compact ICA bordered by a large and highly developed CBM essential for accommodation. Adjacent to the meshwork are aqueous collecting channels, which in turn empty into the intrascleral venous plexus and then the vortex veins. The size of the individual collector vessels (i.e., trabecular veins) and the tissue immediately adjacent to the AAP varies considerably among mammals. The trabecular veins in cattle, sheep, and water buffalo are large and extensive. Those associated with dogs, cats, pigs, and horses are less prominent but are still extensive. The manner by which aqueous humor flows into the trabecular veins of the AAP or canal of Schlemm is not completely understood (Allingham et al., 1989; Grierson et al., 1977; Kayes, 1967; Lee & Grierson, 1975; Samuelson, 1996; Tripathi, 1971b). Most of the aqueous humor is thought to move through large, vacuole‐like structures of the inner endothelial cells (see Fig. 2.55). The area adjacent to the trabecular veins typically consists of a zone of cellular elements intermixed with irregularly arranged elastin, collagen, and basement membrane‐like material. These elements are much more compact in the horse than in other mammals, except for humans. They constitute a separate zone, called the juxtacanalicular zone that is readily distinguished from the rest of the outer corneoscleral trabecular meshwork. The function of this zone has yet to be determined, but it may contribute substantially to aqueous humor outflow resistance. In some species, including dogs, rats, rabbits, and humans, smooth muscle‐like cells (myofibroblastic cells) have been observed in the trabecular meshwork, especially adjacent to the aqueous humor outflow channels and along the distal or outer walls of the AAP and Schlemm’s canal (de Kater et al., 1990; Ryland et al., 2003). In the dog, the presence of myofibroblastic cells within the ICA suggests that these cells and the smooth muscle cells of the ciliary body along the same plane of orientation function to facilitate the removal of aqueous humor and are likely to be influenced by vascular mediators. Whether all myofibroblastic cells play a significant role in regulation of aqueous humor outflow is unknown. GAGs form an integral component of trabeculae within the ICA and the area adjacent to the AAP (and canal of Schlemm). Treatment with hyaluronidase results in lowering of the IOP. GAGs appear to regulate IOP via their state of polymerization, which controls hydration capacity and swelling or shrinking (Grierson & Lee, 1975; Gum et  al., 1992; Knepper et  al., 1996; Samuelson & Gelatt, 1998; Samuelson et al., 1987b).

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posterior ICA that interface with the anterior CBM. Within the outer ciliary body, there are blood vessels in close proximity to the sclera. More posteriorly, the supraciliary space contains occasional collagenous trabeculae (Sedacca et al., 2011). In cattle and domestic carnivores, outer anterior muscle bundles attach the CBM to the sclera with an anterior elastic sheath, which is especially well developed in dogs. Initially, the uveoscleral pathway consists of small intercellular spaces lying between the attachments of the anterior smooth muscle bundles of the ciliary body and the posterior uveal trabecular meshwork. Within the supraciliary space, slender

trabeculae are most numerous anteriorly extending from the ciliary body obliquely and radially. In horses, the outer anterior muscle bundles of the ciliary body are connected to branching connective tissue trabeculae within the uveoscleral pathway that are attached radially to the sclera (Samuelson et al., 1989; Sedacca et al., 2011). An elastic sheath lines this portion of the uveoscleral pathway. Trabeculae within the supraciliary space are extensive, consisting of either collagen or muscle. Both types of trabeculae are often branched and lined by melanocytes, becoming less numerous, narrower, and less branched posteriorly.

Aging

Figure 2.59  Located between the ciliary body meshwork and the sclera (i.e., supraciliary space), the supraciliary meshwork likely represents a major pathway for aqueous humor drainage in the horse via uveoscleral outflow. SCT, supraciliary trabecula; TC, trabecular cell. (Original magnification, 3500×.) Insert: Light micrograph of the meshwork. S, sclera. (Original magnification, 200×.)

A number of age‐related changes occur in the ciliary body. As the nonpigmented epithelium grows older, its basement membrane thickens greatly, becoming multilaminar (Streeten, 1988). The pigmented epithelial basement membrane similarly thickens with age, producing a nearly identical multilaminar appearance. The nonpigmented epithelium thins irregularly. The stroma of the ciliary body concomitantly thickens because of increased amounts of collagen and other extracellular materials. The degree of pigmentation in the ciliary body lessens with age, particularly in the pigmented epithelium along the crests of the ciliary processes (Streeten, 1988). Age‐related changes associated with the ICA are well documented in humans and dogs (Bedford & Grierson, 1986; Hogan et al., 1971; Samuelson & Gelatt, 1984a, 1984b, 1998). The cortical zone within the trabecula broadens in older individuals. This thickening is caused by the presence of additional basement membrane‐like material and additional amorphous material. The thickened cortical zone could contribute to increased thickening of the corneoscleral Figure 2.60  Anterior uveoscleral outflow pathway viewed tangentially. A. Bovine anterior uvea. (Original magnification, 20×.) B. Porcine anterior uvea. (Original magnification, 20×.) AC, anterior chamber; CBM, ciliary body musculature; ICA, iridocorneal angle; PC, posterior chamber; S, sclera; SCS, supraciliary space; UTM, uveal trabecular meshwork.

A

B

trabeculae within the canine ICA. Use of PAS stain, which reacts strongly with basement membrane material, on normal laboratory‐quality Beagle ICAs of different ages (from 3 months to 8 years) demonstrates positive reactions within the corneoscleral trabecular meshwork, especially along the posterior extension of Descemet’s membrane. The apparent increase in PAS staining with age occurs mostly within the anteriormost portion of the corneoscleral trabecular meshwork. No age‐related changes have been observed or reported within the uveal trabeculae of the canine ICA (Bedford & Grierson, 1986). Perhaps the most discernable alterations of the canine ICA with regard to age are those associated with the extracellular fibers comprising the bulk of each trabecula. When comparing the average diameter of the collagen fibril as well as the distribution of diameter size within the inner and outer regions of the corneoscleral trabecular meshwork and subjacent sclera next to the aqueous plexus at different ages, several changes are recognized (Gelatt & Samuelson, 1986). The average diameter of collagen fibrils within the outer corneoscleral trabecular meshwork increases by approximately 25% during the second and third years of life compared with the latter half of the first year (Samuelson & Gelatt, 1998). On the other hand, collagen fibrils within the inner corneoscleral trabecular meshwork and adjacent outer uveal trabecular meshwork become progressively thinner during the first 3 years of life. Early age‐related changes in collagen fibrillar size are most remarkable within the sclera forming the outermost lining of the ICA, increasing nearly 100% in average diameter over a 2.5‐year period. The increase of collagen fibrillar size within the inner scleral wall of the limbal region occurs unevenly, with some fibrils remaining small and others attaining considerable widths. The appearance of the trabecular (i.e., endothelial) cells in both the uveal and corneoscleral meshworks changes mostly during the first year of life. As the cells become more separated spatially, they elongate and possess less clustered cytoplasmic processes. In older animals (>4 years of age), fewer cells are observed in both meshworks compared with those in younger animals (60% of the total tear film thickness) and performs the primary functions of the tear film. This layer is composed of ~98% water and ~2% solids, comprising predominantly proteins. The aqueous layer contains inorganic salts, glucose, urea, proteins, glycoproteins, and soluble mucins (Butovich et  al., 2008; Hicks & Carrington, 1997; Hicks et al., 1998). The lacrimal gland, gland of the NM, harderian gland, and accessory lacrimal glands in the conjunctiva all contribute to its formation. Destruction or excision of the lacrimal gland or NM gland results in a variable reduction in aqueous tear production (Gelatt et al., 1975; Helper et al., 1974; McLaughlin et al., 1988; Saito et al., 2001). These studies indicate that approximately two-thirds of the aqueous tear production is produced by the lacrimal gland, approximately one-third by the gland of the third eyelid, and a very minor amount by the accessory lacrimal glands in the conjunctiva; however, there is variability between dogs. The aqueous portion is evaluated clinically primarily through use of the Schirmer tear test (STT), but the phenol red thread test can be used in very small animals.

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The deep, or mucin, layer (∼1 μm) is composed of tear mucins produced by the apocrine conjunctival goblet cells, as well as an underlying glycocalyx which is associated with the corneal and conjunctival microvilli. The distribution of goblet cells varies among species. The fornix is rich in goblet cells in dogs, cats, and horses (Bourges-Abella et al., 2007; Eördögh et al., 2017; Moore et al., 1987; Sebbag et al., 2016), whereas the highest density in chinchillas and guinea pigs is in the palpebral conjunctiva (Gasser et al., 2011; Voigt et al., 2012). All species have lower concentrations of goblet cells in the bulbar conjunctiva. In rats and mice, the goblet cells occur in clusters, while in rabbits, cats, dogs, and humans, they appear as single cells (Huang et al, 1988). Mucin is produced by goblet cells in response to mechanical, immune, histamine, antigenic, or (direct or indirect) neural stimulation (Davidson & Kuonen, 2004). The gel-forming mucin layer contains glycoproteins (20–40 million daltons and classified as MUC1-21), which are carbohydrate–protein complexes characterized by the presence of hexosamines, hexoses, and sialic acid. The glycocalyx comprises polysaccharides that are produced by the stratified squamous epithelial cells of the cornea and conjunctiva and project from the surface microvilli of those cells. They are considered membrane-spanning mucins versus secreted mucins that are described above (Dartt, 2011). In dogs, MUC16 is expressed at a higher level than MUC1 and MUC4, whereas rabbits have relatively equal expression of all three mucins. Additionally, the peripheral corneal epithelium has higher MUC1, MUC4, and MUC16 mRNA expression when compared with the central corneal epithelium (Leonard et  al., 2016). Roles specific to these membrane-associated mucins include promotion of water retention, provision of a dense barrier to pathogens and debris, participation in signal transduction, and direct interaction with the actin cytoskeleton (Gipson & Argueso, 2003). Mucins from the goblet cells and the corneal epithelial cells both play a critical role in lubricating the corneal surface, thus making its hydrophobic surface more hydrophilic (to permit spreading), and in stabilizing the PTF (Van Haeringen, 1981). The mucin layer as well as the integrity of the outermost layer of corneal epithelium are necessary for retention of the tear film on the cornea (Mishima, 1965). Tears are a clear and slightly alkaline solution, with a mean pH of 8.3, 8.1, and 7.8 in cattle, dogs, and horses, respectively (Beckwith-Cohen et  al., 2014). In humans, horses, cattle, and rabbits, tear electrolyte concentration is similar to that of plasma, except for potassium, which is three to six times more abundant in tears, thus indicating an active transport mechanism (Best et  al., 2015; Maidment et al., 1985; Mircheff, 1989). Tear film osmolarity/osmolality is influenced by the rate of tear secretion, evaporation, and composition. It is similar in cats (329 mOsm/L), dogs (356 mOsmol/L), and rabbits (376 mmol/kg; Davis & Townsend, 2011; Korth et al., 2010; Wei et al., 2012), whereas

humans (283 mmol/kg) and horses (284 mmol/kg) have a lower osmolarity (Best et  al., 2015; Wei et  al., 2012). Even though the units are different, osmolarity and osmolality are interchangeable parameters in aqueous solutions such as the tear film. In human patients, increased osmolarity is correlated with a faster tear film break-up time and greater surface tension. Additionally, hyperosmolarity induces expression and production of inflammatory cytokines and activates several signaling pathways that activate inflammatory cells (Davis & Townsend, 2011). Mean total solids concentration in the PTF of horses, cattle, and dogs is ~2 ± 1.3 g/dL, ~1 ± 0.6 g/dL, and ~0.3 ± 0.2 g/dL, respectively (Beckwith-Cohen et  al., 2014). The glucose concentration is lower in human tears than in plasma, but its concentration parallels that in plasma. However, in human patients with diabetes, the elevated glucose concentrations in tears appear to be related to the tissue fluids and are not from the lacrimal gland secretions (Zhang et al., 2011). Normal horses have measurable cortisol in their tears that approximates serum cortisol following adrenocorticotropic hormone (ACTH) stimulation. The results of this study raise the question of whether this cortisol could hinder corneal healing in this species (Monk et al., 2014). The PTF contains both nonspecific and specific antimicrobial substances. Nonspecific substances include lysozyme, lactoferrin, α-lysine, and complement. Specific antimicrobial substances include secretory immunoglobulins A, G, and M. Toll-like receptors that play a role in the defense against many types of microbial infections are expressed by the corneal and conjunctival epithelial cells in humans and horses (Gornik et al., 2011; Kumar & Yu, 2006). Protein concentrations in canine tears average 0.35 g/dL, with 93% globulin, 4% albumin, and 3% lysozyme, which is a ubiquitous antibacterial enzyme that hydrolyzes bacterial cell walls (Roberts & Erickson, 1962). Lysozyme is produced by the conjunctival goblet cells and has antibacterial and antifungal properties; its concentration increases with conjunctivitis (Roberts & Erickson, 1962). Relative to humans and nonhuman primates, domestic animals have very low amounts of lysozyme (e.g., the horse has one-half to onefourth that of human tears) and the cat has none (Bonavida et al., 1968; Erickson et al., 1956; Luchter & Gurisatti, 1974; Marts et al., 1977). Lysozyme activity has not been detected in cattle, but it has been detected in sheep and goats (Daubs, 1976). Lactoferrin has been identified in the PTF of humans, dogs, cats, cattle, and other mammals, and reversibly binds the iron that would be available for bacterial metabolism and growth (Holmberg et  al., 2004). Immunoglobulin A (IgA) contributes to ocular defenses by coating bacterial and viral microorganisms leading to agglutination, neutralization, and lysis. IgA is present in greater concentrations in the PTF than immunoglobulins G and M (Davidson & Kuonen, 2004). Cat tears have a 6.6 mg/mL total protein concentration with 9.7% IgA (Petznick et al., 2012).

The lacrimal nerve, a branch of the trigeminal nerve, is primarily sensory but also provides the lacrimal gland with its parasympathetic (release ACh and VIP neurotransmitters) and sympathetic (release norepinephrine and neuropeptide Y neurotransmitters) fibers (Elsby & Wilson, 1967; Powell & Martin, 1989). Both adrenergic and cholinergic distribution patterns around the acini and blood vessels of the canine lacrimal gland are similar; however, the cholinergic fibers appear to be greater in number than the adrenergic fibers (Powell & Martin, 1989). The acinar cells are primarily responsible for secretion of proteins in lacrimal gland fluid. These proteins are synthesized in the endoplasmic reticulum, modified in the Golgi apparatus, and stored in secretory granules. Stimulation of the cholinergic and adrenergic fibers in the lacrimal gland initiates release of these proteins into the lacrimal fluid. This process requires a series of separate cellular pathways that use secondary messengers and is controlled by signal transduction (Dartt, 1989). Lacrimation is stimulated by painful irritants, eye diseases, mechanical or olfactory stimuli of the nasal mucous membranes, and sinus diseases. Tear production as assessed with the external ocular surfaces anesthetized and the lower conjunctival fornix dried by Dacron swabs (STT II) measures ~50% of that measured without manipulation (STT I) in the cat and dog. Larger dogs also have greater wetting per minute than smaller dogs as measured with the STT I (Berger & King, 1998; Gelatt et al., 1975). Additionally, canine neonates have lower tear production than adults (da Silva et al., 2013; Verboven et al., 2014). In one litter of puppies, both the STT I and STT II increased significantly until 9 and 10 weeks of age, respectively (Verboven et al., 2014). Clinical estimation of the rate of evaporation (and, indirectly, of the mucus component of the PTF) is performed through determining the time (in seconds) for the tear film to break up (Carrington et al., 1987a, 1987b, 1987c). While somewhat subjective, this has been studied in dogs and cats and is covered in Chapter 10. The nasolacrimal drainage system eliminates used tear film and any excessive tears. The PTF accumulates along the palpebral margin of each eyelid and is forced by blinking to move medially into the lacrimal puncta. When the tears are in the lacrimal pool and the facial muscles relax, the tears flow into the canaliculi by capillary action. Normal breathing movements also facilitate this flow into the canaliculi. Reflex blinking of the eyelids closes the lacrimal sac, which acts as a passive pump. Pseudoperistaltic motion of the nasolacrimal duct allows movement of the tears into the nasal cavity (François & Neetens, 1973). Autoregulation of the lacrimal system with receptors in the excretory portion has been suggested in studies of human tear flow (François & Neetens, 1973). Evaluation of canalicular function in humans suggests that destruction of either canaliculus alone does not affect excretion of tears; in domestic animals, the lower canaliculus is considered to be the more important for tear drainage (Jones et al., 1972).

Cornea The clear cornea serves as a window for the eye with two critical optical properties, transparency and refractive power, both of which are essential for vision. The cornea, with the sclera, protects the inner components of the eye from injury through its exquisite structure, biomechanics, and sensitivity.

Transparency The cornea serves as the most powerful refractive structure of the eye. To fulfill this role, it must remain transparent. Corneal clarity is a result of the lattice-like organization of the stromal collagen fibrils as well as the transparency of the cells within the cornea. The state of relative dehydration, hypocellularity, unmyelinated nerve fibers, a nonkeratinized epithelium, and absence of blood vessels and pigment also contribute to corneal transparency. For further details on how the cornea refracts light, see Chapter 4. The corneal stroma comprises the bulk of the cornea and is responsible for 90% of its thickness. It is predominantly composed of water that is stabilized by an organized network of collagens, glycosaminoglycans (GAGs), and glycoproteins. Cellular and nerve components are also present. Type 1 collagen is the most abundant form in the cornea; it aggregates into structural, banded fibrils with a uniform diameter of 25 nm in the central cornea that gradually increase to 50 nm at the limbus (Meek, 2008; White et  al., 1997). Correspondingly, interfibrillar spacing is relatively constant in the central cornea at 20 nm and gradually increases in the paraxial cornea, before rapidly increasing at the limbus (Meek, 2008). The GAGs are important for maintaining this regular spacing between fibrils. The uniformthickness, small collagen fibrils arrange into parallel lamellae running at oblique angles to each other, and are separated by less than a wavelength of light (Fig.  3.2; Maurice, 1960). This formation results in a highly ordered lattice-like arrangement whereby short-range order results in corneal transparency via destructive interference. However, it lacks the precise arrangement of a true crystalline lattice. The parallel arrangement of the corneal collagen fibers extends from the center of the cornea to its periphery, where the fibrils develop a concentric configuration to form a “weave” at the limbus, which in turn provides strength and helps to maintain its curvature. For further details on the constituents and structure of the cornea, see Chapter 2. Quiescent keratocytes lie between collagenous lamellae to form a closed, exquisitely structured syncytium (Nishida et al., 1988). These three-dimensional, stellate-shaped cells comprise a cell body with multiple, extensive dendritic processes that interact with other keratocytes. Abundant corneal crystallins (~25–30% of the intracellular soluble protein), such as aldehyde dehydrogenase and transketolase,

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t ligh ible nm Vis –700 0 39

20 nm

25 nm

A

B

Figure 3.2  In the normal cornea (A), a cross-section of the corneal fibrils demonstrates a nearly perfect lattice arrangement, with equidistant collagen fibrils permitting light transmission and concomitant transparency. By contrast, swelling of the cornea with edema (B) disrupts this highly ordered arrangement, resulting in light diffraction and an opaque, blue cornea.

minimize refractive differences in the keratocyte cytoplasm, thus ensuring transparency of these cells. Furthermore, the dendritic cellular processes of normal keratocytes demonstrate negligible backscatter of light (Jester et al., 1999). The thinness and even spacing of keratocytes in a clockwise circular arrangement throughout the stroma also minimize light scatter. Upon corneal wounding, transformation of keratocytes to activated fibroblasts and myofibroblasts results in a dramatic increase in cell volume and subsequent dilution of corneal crystallins with a concomitant increase in light scatter (Jester et al., 2012). Corneal scarring is now thought to be due to alterations in the light-scattering properties of keratocytes, in addition to changes to the extracellular matrix (Jester, 2008). The epithelium and endothelium are responsible for maintaining the cornea in a relatively dehydrated state. Specifically, loss of the corneal epithelium or endothelium results in a 200% or 500% increase in corneal thickness, respectively, due to stromal edema (Maurice & Giardini,

1951). Anatomic integrity of the epithelium and endothelium provides two-way, physical barriers against the influx of tears and aqueous humor (AH), respectively. However, the multiple-layered epithelium provides a relatively impermeable barrier versus the leaky, single-layered endothelium. The endothelium primarily maintains stromal deturgescence via active transport that is energetically maintained by sodium potassium–activated adenosine triphosphatases (Na+-K+-ATPases; Dikstein & Maurice, 1972). A summary of the molecular mechanisms that contribute to the corneal endothelial pump was provided by Bonanno (2012).

Metabolism Steady-state hydration in the cornea occurs when the endothelial leak and pump rates are equivalent; this process is termed the “pump-leak” mechanism (Maurice, 1960). The leaky barrier function of the endothelium may at first seem counterintuitive, but most nutrients for the cornea, except

oxygen, come from the AH. Thus, leakiness of the endothelium is essential to providing bulk fluid flow through a tissue that lacks blood and lymphatic vessels. Glucose transporters are found on both the apical and basolateral endothelial cell membranes that face the AH and stroma, respectively, to ensure transcellular glucose flux (Kumagai et al., 1994). The corneal epithelium converts glucose to glucose-6-phosphate, where it is subsequently metabolized to pyruvate via glycolysis. Most of this pyruvate is then metabolized into lactate, but some is diverted into the tricarboxylic acid cycle to produce ATP. Glucose is also stored in the epithelium as glycogen, which can be used for energy under stressful conditions such as corneal injury. The corneal epithelium and keratocytes in the anterior stroma obtain oxygen for aerobic glycolysis from the precorneal tear film, while the endothelium and keratocytes in the posterior stroma receive their oxygen from the AH. Upon eyelid closure, oxygenation of the anterior cornea is achieved by exposure to the palpebral conjunctiva and its vasculature. However, the palpebral conjunctiva has approximately one-third the atmospheric oxygen concentration, resulting in reduced corneal oxygenation (Chhabra et  al., 2009). Consequently, the corneal epithelium will rely on anaerobic glycolysis for energetic needs in the absence of oxygen. If excessive lactate is produced by this process, corneal hydration occurs (Forrester et al., 1996; Maurice, 1960). Glucose is also metabolized by the corneal epithelium via the pentose phosphate shunt, which produces nicotinamideadenine dinucleotide phosphate (NADPH), an important free radical scavenger. Other metabolites from this pathway are ribose-5-phosphate (ribose-P) and reduced triphosphatepyridine nucleotide. Ribose-P is used in nucleic acid synthesis of DNA or RNA, whereas triphosphate-pyridine nucleotide is used by the corneal epithelium for lipid synthesis. Keratocytes primarily metabolize glucose via the pentose phosphate shunt as their metabolic needs are limited, and primarily relate to maintenance of the collagen fibrils and GAGs within the stroma. By contrast, the corneal endothelium has immense glucose needs (~5 times that of the epithelium) to sustain its pump mechanism. It uses similar glycolytic pathways as the epithelium: mainly anaerobic glycolysis, with the pentose phosphate and tricarboxylic acid pathways also making substantial contributions.

Biomechanics The cornea is a thick-walled, pressurized, partially intertwined, unidirectionally fibril-reinforced laminate biocomposite, which imparts stiffness, strength, and extensibility to withstand both inner and outer forces that may alter its shape or integrity (Dawson et  al., 2011; US Department of Defense, 1997; Hayes et al., 2007; Thomasy et al., 2014). A soft, fibrous connective tissue, like the cornea, usually is much stronger in the parallel versus perpendicular direction

to the collagen fibrils (Fung, 1981). Consequently, the collagen fibrils are arranged into complex hierarchic structures, which give the cornea its anisotropic mechanical properties (Silver et al., 1992). The collagen lamellar architecture of the cornea varies dramatically between vertebrate species, with nonmammalian vertebrates exhibiting an orthogonal-rotational arrangement with a marked increase in lamellar branching in species such that birds >> reptiles > amphibians > fish; by contrast, the mammalian species exhibit a random pattern (Winkler et al., 2015). In mammals without a Bowman’s membrane, the biomechanical behaviors of the cornea from the macro- to nanoscale are primarily due to the collagen architecture in three composite-like regions: anterior stroma, posterior stroma, and Descemet’s membrane (Fig  3.3; Boyce et  al., 2007; Bron, 2001; Elsheikh et  al., 2008; Jue & Maurice, 1986; Meek & Newton, 1999; Winkler et al., 2015). Tissues are biomechanically characterized by measuring the elastic modulus, a property that defines a material’s ability to resist deformation under an applied stress, which approximates its stiffness. The elastic moduli of the layers of the cornea have been reported and the values can differ markedly depending on methods of measurement and/or sample preparation (McKee et al., 2011). In thin, heterogenous tissues such as the cornea, atomic force microscopy (AFM) is optimal for determining the micron-scale deformations that cells and their adjacent matrix experience. The elastic moduli of the corneal layers as measured by AFM have been reported in the human and the rabbit (Table 3.3); all layers of the human cornea were stiffer than those of the rabbit (Last et  al., 2009, 2012; Thomasy et  al., 2014). The variability in corneal collagen fiber organization and matrix properties observed between species likely contributes to their diverse mechanical properties (Thomasy et  al., 2014; Worthington et al., 2014). For more information on corneal biomechanics, we direct the reader to these excellent summaries: Dawson et al. (2011), Kling and Hafezi (2017), Pinero and Alcon (2015), and Ruberti et al. (2011).

Sensitivity and Innervation The cornea is an exquisitely sensitive tissue, and this sensitivity provides a critical protective function. Upon stimulation of the cornea, involuntary blinking occurs via intermediate relays from the ophthalmic branch of the trigeminal nerve to orbicularis oculi innervation from the facial nerve – a fundamental reaction termed the corneal or blink reflex. Concomitant with the blink reflex is reflex tearing from parasympathetic innervation to the lacrimal gland. During extreme pain, the corneal reflex is exaggerated, and blepharospasm sometimes occurs such that the eyelids cannot be opened voluntarily. Corneal sensitivity varies by species, region of the cornea, and, in the dog and cat, skull conformation (Barrett et al., 1991; Blocker & van der Woerdt,

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Epithelium Cornea

Anterior Basement Membrane Stroma (interwoven)

Anterior Banded Layer

Stroma (parallel)

Posterior Non-Banded Layer

Descemet’s Membrane

Endothelium

Figure 3.3  Schematic of collagen fiber organization in the canine cornea. The epithelium produces an anterior basement membrane with a complex surface topography consisting of a meshwork of fibers and holes. The anterior 10% of the cornea comprises unidirectional, interwoven collagen lamellae, while the posterior 90% consists of unidirectional, nonwoven collagen lamellae with a random orientation. Descemet’s membrane, the specialized basement membrane of the endothelium, can be divided into the anterior banded and posterior non-banded layers. The anterior banded layer is dominated by collagen VIII, which appears as a hexagonal network en face and parallel bands in transverse section. The surface topography posterior non-banded layer has a rich network of intertwined fibers, but with a smaller pore size in comparison to the anterior basement membrane.

2001; Good et al., 2003). For example, corneal sensitivity in dogs, as measured by the Cochet–Bonnet esthesiometer and histology of the corneal nerves, was highest, intermediate, and lowest in the dolichocephalic, mesatocephalic, and brachycephalic skull types, respectively (Barrett et al., 1991). Similarly, the central cornea is less sensitive in brachycephalic cats than Domestic Shorthair (DSH) cats (Blocker &

van der Woerdt, 2001). Corneal sensitivity is greatest in the central cornea and lower in the peripheral cornea (Barrett et al., 1991; Good et al., 2003). For more detailed information on corneal esthesiometry, see Chapter 10. The cornea is one of the most richly innervated tissues in the body. Most corneal nerve fibers are sensory in origin and respond to mechanical, chemical, and thermal stimuli via

Table 3.3  Elastic moduli of layers of the cornea as determined by atomic force microscopy in rabbits and humans. Elastic Modulus (kPa)

Corneal Layer

Rabbit (Thomasy et al., 2014)

Human (Last et al., 2009, 2012)

Epithelium

0.6 ± 0.3

Not assessed

Anterior basement membrane

4.5 ± 1.2

7.5 ± 4.2

Bowman’s layer

Absent

110 ± 13

Stroma

1.1 ± 0.6 (anterior) 0.4 ± 0.2 (posterior)

33 ± 6 (anterior)

Descemet’s membrane 12 ± 7.4

50 ± 18

Endothelium

Not assessed

4.1 ± 1.7

the ophthalmic branch of the trigeminal nerve. However, a small proportion of nerves are sympathetic or parasympathetic in origin and derive from the superior cervical ganglion or ciliary ganglion, respectively. Corneal nerve organization is similar across mammalian species, with only minor interspecies differences. All mammalian corneas contain a dense limbal plexus, multiple radially directed stromal nerve bundles, a dense highly anastomotic subepithelial plexus, and a richly innervated epithelium (Fig. 3.4; Marfurt et al., 2001). In the dog, corneal innervation arises from the corneal limbal plexus, which comprises a 0.8–1 mm wide, ring-like band, surrounding the peripheral cornea. Morphologically, this plexus can be further subdivided into a predominantly perivascular, outer, periscleral zone and a denser and more highly branched inner, pericorneal zone. From the limbal plexus, nerve fibers enter into the stroma as 14–18 prominent, radially directed, superficial stromal bundles that are

Subepithelial Plexus Descemet’s Membrane Stroma

Intraepithelial Nerve Terminals Subbasal Plexus

Anterior Basement Membrane Limbal Plexus

Epithelium

Endothelium

Anterior Basement Membrane

Subbasal Plexus Intraepithelial Nerve Terminals

Epithelium

Descemet’s Membrane Subepithelial Plexus

Stromal Nerve Stroma

Stromal Nerve

Figure 3.4  Schematic of corneal innervation. The limbal plexus is a ring-like band of predominantly myelinated fibers in the sclera adjacent to the cornea. From the limbal plexus, nerve fibers enter into the corneal stroma as nerve bundles and lose their myelin as they traverse to the central cornea. The subepithelial plexus is a dense, anastomosing network of thin axons immediately underlying the anterior basement membrane. The subepithelial plexus gives rise to the subbasal plexus, a whorl-shaped network of axons between the anterior basement membrane and basal epithelium where nerve fibers run horizontally as long parallel nerves, termed leashes. The axons of the subbasal plexus then vertically ascend to terminate in various layers of the epithelium.

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evenly distributed around the limbus (Marfurt et al., 2001). The number of stromal bundles varies among mammals, with 6–8 and ~60 bundles in the rat and human, respectively (Muller et al., 1996; Sasaoka et al., 1984). Any myelinated axons included in stromal nerve bundle will lose their myelin as they traverse toward the central cornea. Each bundle in the canine cornea contains approximately 30 to 40 axons which undergo repetitive dichotomous branching to form complex axonal trees that innervate the anterior cornea (Marfurt et al., 2001). Immediately beneath the anterior basement membrane is a dense, anastomosing network of exceptionally thin, preterminal axons that comprise the subepithelial nerve plexus. The subbasal plexus arises from subepithelial nerve fibers entering the basal epithelium to form unique, preterminal arborizations termed epithelial leashes which exhibit a highly ordered distribution and give rise to a profusion of smaller, ascending branches (Marfurt et al., 2001). The subbasal nerve plexus of dogs, cats, and humans has a centripetal whorl-like pattern, whereas cattle and rabbits exhibit a horizontal pattern that is directed nasally (He et al.,2019; Marfurt et al., 2019). The innervation of the epithelium is denser than any other surface epithelium such that injury to a single epithelial cell may be sufficient to stimulate nociception (Marfurt, 2000). While the anterior cornea is densely innervated, only sparse nerve fibers are present in the posterior cornea and are typically adjacent to the corneal endothelium (Marfurt et al., 2001). Thus, superficial corneal ulcers are typically more painful than deep stromal ulcers. The majority of sensory fibers that innervate the cornea are activated by a variety of exogenous mechanical, chemical, and thermal stimuli, as well as endogenous factors released by tissue injury, and are thus termed polymodal nociceptors (Belmonte & Giraldez, 1981; Belmonte et al., 1991; Gallar et al., 1993). The remainder of the sensory fibers innervating the cornea comprise mechano-nocireceptors and cold thermal receptors, which are only activated in response to mechanical forces or changes in temperature, respectively (Gallar et al., 1993; Tanelian & Beuerman, 1984). Furthermore, electrophysiologic recordings of impulses from corneal nerve fibers of anesthetized cats demonstrated that different types of stimuli evoked variable responses from the three aforementioned sensory receptors (Acosta et al., 2001). In addition to their contributions to corneal protection via the blink reflex and reflex tearing, corneal nerves maintain corneal epithelial health through the secretion of trophic factors and maintenance of basal tear secretions (Lawrenson, 1997; Muller et  al., 2003). Specifically, corneal nerves secrete a variety of neurotransmitters, including acetylcholine, vasoactive intestinal peptide (VIP), and neurotensin, as well as neuropeptides such as substance P and calcitonin gene-related protein (CGRP), which are critical to corneal epithelial proliferation and function (Belmonte et al., 2004; Muller et al., 2003). Thus, impairment

of corneal sensory innervation, termed neurotrophic keratitis, causes decreased corneal healing, increased ­epithelial permeability, and recurrent corneal ulcers (Beuerman & Schimmelpfennig, 1980; Bonini et al., 2003; Muller et al., 2003; Scott & Bistner, 1973). The neuropeptides CGRP and substance P also act as neurogenic mediators of inflammatory responses by inducing vasodilatation, plasma extravasation, and cytokine release following their release from depolarized nociceptor endings (Bynke et al., 1984; Keen et al., 1982). This neurogenic inflammation impacts both the injured cornea and the noninjured conjunctiva, iris, and ciliary body, as nerve impulses from stimulated nociceptors travel not only centripetally through the axon to the central nervous system, but also to nonstimulated peripheral axon branches of the trigeminal nerve. This reflex is likely responsible for the clinical signs of conjunctival hyperemia and anterior uveitis, including miosis, ocular hypotension, and aqueous flare associated with an isolated corneal lesion (Belmonte et al., 2004).

Iris and Pupil Pupillary functions include regulating light entering the posterior segment of the eye, increasing the depth of focus for near vision, and minimizing optical aberrations by the lens. The iris muscles consist of both a constrictor (sphincter) that encircles the pupil and radial dilator muscle. The sphincter muscle is an annular band of smooth muscles near the pupillary margin of the iris and is derived from neural ectoderm. The dilator muscle, also derived from neural ectoderm, consists of a series of myoepithelial cells that extend from near the pupillary margin to the base of the iris and are contiguous posteriorly with the pigmented epithelium of the ciliary body. Pupil size varies on the basis of the balance between these two muscle groups. The constrictor muscle, which is the stronger of the two, is innervated by the oculomotor nerve (CN III) which provides primarily parasympathetic control; by contrast, the dilator muscle is innervated primarily by sympathetic nerves. The constrictor muscle causes miosis, and the dilator muscle is responsible for mydriasis. Bright light decreases pupil size. The sympathetic activity in the iridal dilator muscle and ciliary body musculature (discussed later) is mediated by a combination of β-receptors (β1 and β2) and α-receptors (α1 and α2; Yoshitomi & Ito, 1986). Components of the pupillary light reflex (PLR) are listed in Table 3.4. Species differences of the α- and β-receptors have been demonstrated among humans, rabbits, nonhuman primates, cats, and dogs, and they are summarized in Table 3.5 (Bartlett & Jaanus, 1989; Colasabti & Trotter, 1981; Jones & Studdert, 1975; Lee & Wang, 1975; Loewy et al., 1973; Macri & Cevario, 1974; Murphy & Howland, 1986; Neufeld & Sears, 1974; Ogidigben & Potter, 1993; Piccone et al., 1988; Potter & Rowland,

1978; Shields, 1992; Toyoshima et  al., 1980; van Alphen et al., 1965; Vareilles et al., 1977b; Wallenstein & Wang, 1979; Yoshitomi & Ito, 1986, 1988; Zimmerman, 1993). These receptors alter the effects of drugs on the eye. For example, feline pupils constrict with the use of timolol, a nonselective β-adrenergic antagonist, because the feline iris sphincter muscle has primarily β-adrenergic nerve fibers (van Alphen et al., 1965). Because β-adrenergic nerve fibers are inhibitory to the sphincter muscle, the miosis in response to topically applied timolol is suspected to be the result of its antagonism of inhibitory input to the sphincter muscle (Kiland et  al., 2016). Most synapses in the ciliary ganglion are involved in relaying impulses that result in accommodation; the remainder are concerned with constriction of the pupil. Pure mu opioid agonists such as morphine act on subcortical cells (i.e., oculomotor nuclear complex) to cause constriction of the canine pupil and dilation of the feline pupil because of the release of catecholamines from the adrenal glands (Lee & Wang, 1975; Wallenstein & Wang, 1979). Endogenous prostaglandin F2α appears to be involved in maintaining muscle tone in the sphincter muscle of the iris. Prostaglandins most likely act directly on these muscles, and they appear to act to a lesser extent on the dilator muscles of the canine iris (Yoshitomi & Ito, 1988). Exogenous prostaglandin analogues cause miosis in cats, dogs, and horses, and the receptors Table 3.4  Components of the pupillary light reflex. Stimulus

Illumination of the Retina

Receptors

Photoreceptors (rods and cones)

Afferent pathway

Optic nerve–optic tract to pretectal area (ipsiand contralateral via posterior commissure)

Efferent pathway

Pretectal area to the parasympathetic nucleus of CN III (ipsi- and contralateral), and then parasympathetic fibers to ciliary ganglion (via CN III) Postganglionic fibers to the iris

Effector

Sphincter muscle of the iris

Response

Miosis (constriction of the pupil both direct and consensual reflex)

have been detected in the iris and ciliary body of several mammals (Bhattacherjee & Paterson, 1994; Bhattacherjee et al., 1997; Gum et al., 1991; Willis et al., 2001). Additionally, biologically active peptides have been isolated in the nerve supply of the intraocular muscles. For example, neuropeptide Y has a modulatory role on the iris dilator muscles that enhances adrenergic-induced contractions. By itself, however, neuropeptide Y does not have any potent contractile qualities (Piccone et al., 1988). Iridal color and pupil size vary widely among species, and the irides of the young are often a different color than those of the adult. Iris color, or the amount of melanin, influences the effects of many drugs, as melanin can bind drugs, increasing their time to onset and duration (Ogidigben & Potter, 1993). Pupil shape also varies among species. Vertical pupils are most commonly seen in terrestrial mammals and ­reptiles that are ambush predators and are diurnal. Prey species tend to have horizontally elongated pupils. These respective variations are thought to keep images on the vertical and horizontal contours sharp. In domesticated cats, the constricted pupil is a vertical slit, whereas in the larger, wild felidae, it is circular. On dilation, the vertical sides of the domestic feline pupil expand to produce a circular pupil. The constrictor muscle fibers are vertically oriented, and therefore contraction leads to a vertically oriented slit pupil. Additionally, in prey with horizontal pupils, changing head pitch causes torsional movement of the eye, such that the pupil’s long axis maintains rough alignment with the horizon (Banks et al., 2015). In young horses, the pupil is more circular than in adults. Under illumination, the ends of the oval pupil of mature horses do not constrict, but the dorsal and ventral borders do. In bright daylight, the superior granula iridica occludes the central papillary opening, resulting in two apertures and assisting with focusing through the creation of Scheiner’s disc phenomenon (Murphy & Howland, 1986). With very low illumination or administration of a mydriatic, the dorsal and ventral borders of the pupil dilate, thereby forming a circular pupil. The equine pupil responds relatively slowly to a light stimulus in comparison to that of cats and dogs.

Table 3.5  Adrenergic receptors in the iris and ciliary body. Species

Iris Sphincter

Iris Dilator

Ciliary Muscles

Human

α and β equally

Mainly α, very few or no β

Mainly β, very few α

Rabbit

Mainly β, few α

Mainly α, few β

Mainly α, few β

Monkey

Mainly α, perhaps β

Mainly α, few β

Only β, no α

Cat

Mainly β, some α

Mainly α, some β

Mainly β, some α

Dog

α and β

α And β

?

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The avian pupil is circular and highly motile. The consensual pupillary reflex is usually absent (because of total decussation of nerve fibers at the optic chiasm), but occasionally a strong beam of light may traverse the posterior ocular layers and the thin medial orbital bones to stimulate the opposite retina. As the constrictor and dilator muscles are mainly striated with varying amounts of nonstriated fibers, the pupil is not affected by traditional mydriatic agents, but it can be dilated by various neuromuscular-blocking drugs. When dogs are under combined injectable and inhalation anesthesia, the pupil reaches a steady baseline size. In this state, light stimulation causes a rapid pupil constriction, an initial redilation phase, and a slower secondary recovery to baseline. As light intensity increases, the amplitude of pupil constriction increases, and the latency decreases. Average constriction velocity and initial redilation velocity increase with increasing stimulus intensities, but then gradually decline with intensities greater than 11 log photons/cm2/s. Similar to humans, dogs demonstrate intrinsically photosensitive retinal ganglion cells (ipRGC) that contribute to the PLR. Melanopsin, the ipRGC photopigment, has peak sensitivity at 480 nm. The ipRGCs are slow to activate and have a high threshold. Below the ipRGC threshold, PLRs to blue and red stimuli are similar. However, when the ipRGCs are strongly activated with a blue stimulus at 14.5 log photons/ cm2/s intensity, pupil constriction persists for at least 60 seconds after the stimulus is removed. Additionally in dogs, the stimulus intensity required to elicit a threshold PLR is approximately 10-fold lower than that required to elicit a scotopic threshold ERG response in the dark-adapted state (Whiting et al., 2013).

Nutrition of Intraocular Tissues While allowing light transmission through the eye, nutrients are provided and waste is removed by two systems of blood vessels (i.e., retinal vessels, uveal vessels), the formation and egress of AH, and the vitreous body. Intraocular tissues lack a typical lymphatic system, and the uveal tract (i.e., iris, ciliary body, and choroid) provides this function.

Ocular Circulation The choroid, ciliary body, and iris are supplied by the uveal vessels. The outer retina in some animals (e.g., dogs, cats, ruminants, and pigs) and almost all or the entire retina in others (e.g., horses, guinea pigs) is nourished by diffusion from the uveal vessels in the choroid. The inner retina is supplied by retinal vessels in many species. Blood vessels supplying the cornea and lens in the embryo regress before birth or shortly thereafter, leaving the AH as the primary source of nutrients for the cornea and lens.

Birds have a unique structure, the pecten oculi, which is a heavily pigmented, highly vascularized, and usually fanlike structure projecting from the surface of the optic nerve into the vitreous. A similar structure occurs in reptiles, termed the conus papillaris. The avian pecten likely functions as an important source of nutrients for the inner retina (Bellhorn & Bellhorn, 1975; Wingstrand & Munk, 1965). This assumption is based on the observations that the avian retina is thicker than oxygen could perfuse from the choroid and that the pectinate artery resistive and pulsatility indices are low (Chase, 1982; de Moraes et  al., 2017; Ferreira et  al., 2016). The pecten may also control the intraocular pH, which is affected by acidic retinal waste products (Brach, 1975). Several marine mammals, the bottlenose dolphin (Tursiops truncatus), spotted seal (Phoca largha), and California sea lion (Zalophus californianus), have an ophthalmic rete from which the retinal and choroidal arteries are derived. A higher degree of thermal emission in this area than adjacent areas of the skin suggests that the rete might conserve ocular heat so that photoreceptor and ocular muscle function can be maintained in a cold ambient temperature. Additionally, the rete may have a flow-damping effect by maintaining resistance to blood flow in the orbit (Ninomiya, 2017; Ninomiya et al., 2014).

Ocular Blood Flow The vascular pressure promoting flow, the resistance of blood vessels, and the viscosity of the blood all influence the blood flow through all tissues, including the eye. The pressure head for blood flow (i.e., perfusion pressure) is the difference in pressure between the arteries and the veins. In the eye, the intraocular pressure (IOP) approximates the venous pressure, so the perfusion pressure is the difference in pressure between the small arteries entering the eye and the IOP (Bill, 1963). Of clinical importance is that the perfusion pressure to the eye is reduced by lowering the blood pressure or raising the IOP, as occurs in glaucoma. Studies of hemodynamics in the rabbit ophthalmic artery demonstrate that autoregulation maintains normal blood velocity and resistance when the IOP is below 40 mmHg. However, at higher pressures the autoregulatory capacity is limited (Yang et al., 2011)

Anterior Uveal Blood Flow In most species, the major arterial circle of the iris is formed by the nasal and temporal long posterior ciliary arteries. The iris and ciliary body receive approximately 1% and 10%, respectively, of the ocular blood flow (Bill, 1975). In humans and rabbits, additional iridal blood flow occurs from the anterior ciliary arteries via the extraocular muscles (EOM). Blood flow to the ciliary body in most species that have been studied is provided by the iridal major arterial circle,

branches of the anterior ciliary arteries, and branches of the long posterior ciliary arteries. The cat and monkey iris and ciliary body have autoregulation of their blood flow. Carbon dioxide dilates the anterior uveal vessels, and sympathetic α-adrenergic receptors cause vasoconstriction in the anterior uvea. Parasympathetic muscarinic receptors and prostaglandins, however, cause vasodilation (Alm & Bill, 1972). Prostaglandins E1 and F2α appear to cause a two- to threefold increase in blood flow to the anterior uvea when applied topically (Green et al., 1985).

Choroidal Blood Flow The outer retina (and the entire retina in some species) depends on choroidal blood flow for nutrients and waste removal. In the animal species studied, most of the blood supply to the choroid is supplied by the short posterior ciliary arteries, but some of the peripheral choroid receives blood from the major arterial circle of the iris. The choroidal capillaries are fenestrated and large (diameter 15–50 μm). These vessels are highly permeable and permit glucose, proteins, and other substances in the blood to enter the choroid. Within the choroid, these proteins create a high osmotic pressure gradient that assists in removal of fluids from the retina. The short posterior ciliary arteries appear to supply well-defined territories within the choroid. As a result, these “watershed zones” can develop with marked elevations of IOP, and appear in the dog as pyramidal-shaped areas of choroidal and retinal degeneration extending from the optic nerve head. The rate of uveal blood flow is rapid (1.2 mL/min in the cat), with a mean combined retinal and choroidal circulation time of 3–4 seconds (Bill, 1962; Freidman & Smith, 1965). In monkeys, 95% of the ocular blood flows through the uveal tract, of which 85% is through the choroid. With this high rate of blood flow, oxygen extraction from each millimeter of blood is low (∼5%–10%). The oxygen content of choroidal venous blood is 95% of that in arterial blood. Reduced flow rates result in higher oxygen extraction, so that total extraction is reached. This protects the oxygen supply to the retina, and it also protects the eye from light-generated thermal damage (Bill, 1975). Choroidal vessels have little to no autoregulatory mechanism, but carbon dioxide is a potent vasodilator of choroidal vessels (Kiel & Shepherd, 1992; Mann et  al., 1995; Yu et  al., 1988). Choroidal vessels are under the strong influence of sympathetic stimulation, which can result in a 60% reduction of choroidal blood flow. Parasympathetic fibers have been found in the choroid of monkeys, but no studies concerning the relationship of these fibers to blood flow have been conducted. The α-adrenergic drugs cause vasoconstriction of choroidal vessels, but β-adrenergic drugs have no effect (Bill, 1975). In rabbits, αand β-adrenergic blockade causes choroidal vasodilation and vasoconstriction, respectively (Kiel & Shepherd, 1992).

Retinal Blood Flow The retina receives 4% of the ocular blood flow in the monkey (Bill, 1975). In cats, 20% of the oxygen consumed by the retina is delivered through the retinal circulation and the remaining 80% is via the choroidal circulation (Alm & Bill, 1972). Similar data are not available for other domestic animals. Blood flow in the innermost retina is practically unaffected by moderate changes in perfusion pressure. Autoregulation of retinal blood flow is extensive in the cat, monkey, and pig, and protects the retinal circulation from large variations in perfusion pressure (Alm & Bill, 1972; Attariwala et  al., 1994). Both metabolic and myogenous autoregulation are present in the eye. Metabolic control of retinal blood flow is similar to that of blood flow to the brain. In the brain, increased PO2 and decreased PCO2 cause vasoconstriction, and decreased PO2 and increased PCO2 cause vasodilation. In the cat, maximum retinal vasodilation occurs with an increased PCO2 of 75–80 mmHg, so as to increase flow from 15 to 50 mL/min (Alm & Bill, 1972). Interestingly, retinopathy of prematurity occurs when immature eyes with developing blood vessels are exposed to higher oxygen concentrations than the normal physiologic in utero hypoxia. The increased oxygen causes vasoconstriction and inhibition of vascular development, with obliteration of vessels. With the hypoxic injury is a concomitant, rebound release of angiogenic factors that lead to pathologic angiogenesis. Signs include vasoproliferation, retinal edema, hemorrhages, and possible retinal detachment (Dogra et al., 2017). Neural control of retinal blood flow is limited to those vessels indirectly affecting retinal blood flow. Retinal vessels have α-adrenergic-binding sites that, when stimulated, cause vasoconstriction, thus increasing retinal vascular resistance (Forster et al., 1987; Hoste et al., 1989). Retinal arteries most likely autoregulate through a myogenic mechanism, which is activated based on stretch. During sympathetic stimulation, myogenic autoregulatory responses appear to increase (Hoste et al., 1989). Opening and closing of capillary beds in many tissues occur with varying metabolic needs. Spontaneous contractions and dilations of small retinal arterioles have been observed in kittens, but are rare in adult cats (Bill, 1975). In general, it is believed that choroidal blood flow is constant through all capillary beds; however, regional blood flow in the retina decreases from the optic disc to the periphery (Laatikairen, 1976). The vascular endothelial cells may produce nitric oxide, endothelins, prostaglandins, and renin-angiotensin products in response to chemical stimuli (e.g., acetylcholine, brachykinin), changes in blood pressure and blood vessel wall stress, changes in local oxygen levels, and other stimuli (Brown & Jampol, 1996). As the mechanisms of local autoregulation become better understood, pharmacologic modulation of these processes may become possible.

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The theoretical oxygen diffusion maximum of 143 μm plays a significant role in animal species with avascular retinas; as a result, avascular retinas are usually very thin and have short photoreceptors, no tapeta, high glycogen levels in the Müller cells, and no retinal taper (Chase 1982).

Blood Flow of the Optic Nerve Head Blood flow of the optic nerve head is usually provided primarily by branches from the short posterior ciliary arteries. In humans, cats, and rabbits, optic nerve head blood flow possesses autoregulation over a wide range of IOPs (∼30– 75 mmHg), but in humans, this autoregulation is most efficient when IOP is 6–30 mmHg (Shonat et al., 1992; Weinstein et  al., 1983). Ocular perfusion pressure, the relationship between systemic blood pressure and IOP, determines blood flow in the optic nerve head. The autoregulatory capacity of optic nerve head blood flow is more susceptible to an ocular perfusion pressure decrease induced by lowering the blood pressure, compared with that induced by increasing the intraocular pressure (Wang et al., 2015). Studies of blood flow in the optic nerve head have been limited by the small tissue mass involved. The optic nerve head is subjected to several different pressures as well as to the tissue stress at the level of the scleral lamina cribrosa. Axons from the retinal ganglion cells exit the eye under the effect of IOP, passing through the lamina scleral cribrosa at progressively decreasing tissue pressures to become the optic nerve. The retrolaminar pressure for these axons in the dog is approximately 7 mmHg and relates directly to the cerebrospinal pressure (Morgan et al., 1995). Both short- and long-term elevations in IOP also produce tissue changes within the lamina cribrosa that influence blood flow and axon vitality.

Ocular Barriers The blood–ocular barriers contain endothelial and epithelial tight junctions with varying degrees of “leakiness.” These barriers prevent nearly all protein movement and are effective against low-molecular-weight solutes such as fluorescein and sucrose. The complexities of these structures differ between the various vascular beds, which allow movement of some substances from one compartment to the other. The two primary barriers within the eye are the blood–aqueous barrier (BAB) and the blood–retinal barrier (BRB). Other lesser barriers of the eye exist as well. The zonula occludens of the corneal epithelium prevents the movement of ions and therefore fluid from the tears into the stroma, prevents some evaporation, and protects the cornea from pathogens. The partial obliteration of the intercellular spaces provided by the macula occludens of the corneal endothelial cells ­prevents bulk flow of AH into the corneal stroma but allows moderate diffusion of small nutrients and water.

Blood–Aqueous Barrier The BAB depends primarily on the tight junctions in the nonpigmented ciliary body epithelium, the nonfenestrated iris capillaries, and the posterior iris epithelium. The anterior BAB in the iris allows transcellular transport by means of vesicles. Paracellular transport is controlled by tight junction extensions (Riva et al., 2011). The anterior surface of the iris does not serve as a barrier as it does not have a continuous cellular layer. The epithelial portion of the BAB is the inner, nonpigmented ciliary epithelium, and it controls the flow of fluid into the posterior chamber. The BAB is less effective than the retinal epithelial barrier, because protein can pass into the AH through leakage in other parts of the anterior uvea. Both the ciliary body and choroidal blood vessels are highly fenestrated and thus leak most of their plasma components, including protein, into the stroma. No barrier is present between the AH and the vitreous humor, which allows the diffusion of solutes from the posterior aqueous into the vitreous humor, or between the anterior uvea and the sclera (Elgin, 1964). Breakdown of the BAB is seen clinically as an aqueous flare in anterior uveitis or secondary to loss of AH, as in anterior chamber paracentesis.

Blood–Retinal Barrier The tight junctions between the retinal pigmented epithelial cells comprise the epithelial portion of the BRB. The nonfenestrated retinal capillary endothelium with tight junctions between the cells comprises the endothelial portion of the BRB. The most permeable point of the BRB is the optic nerve head, at which substances from the choroid can pass into the nerve (Rodriquez-Peralta, 1975). The choroidal capillaries are highly permeable to permit passage of all low-molecularweight compounds and proteins. Thus, nutrients from the choroidal blood supply pass readily into the retinal pigment epithelium, where numerous transport systems account for the selectivity of the barrier and elaborate transcellular pathways exist to pass them on into the retina (Mann et al., 2003). This high protein permeability of the choroidal vessels also elevates osmotic pressure, which helps fluid to pass out of the retina. The transport of water from the retina to the choroid is driven by the active transport of chloride to prevent water accumulation in the subretinal space. No significant barrier exists between the vitreous body and the retina.

Aqueous Humor and Intraocular Pressure In the normal eye, IOP is generated by flow of AH against resistance, and is necessary to maintain the appropriate shape and optical properties of the globe. AH is a clear, colorless liquid that fills the anterior and posterior chambers as well as the pupil. It has a refractive index of 1.335, which

is slightly denser than water, and is a critical constituent of the eye’s optical system. As AH is formed by the ciliary body processes, it enters the posterior chamber and flows through the pupil into the anterior chamber, where it leaves the eye through the corneoscleral trabecular and uveoscleral outflow pathways. The rate of AH formation equals the outflow, so the IOP is maintained relatively constant, and the refractive surfaces of the eye are kept in a normal position. This continuous flow of AH supplies the avascular cornea and lens with nutrients and also removes their waste ­products. A convection current exists within the anterior chamber whereby AH circulates downward adjacent to the air-cooled cornea and upward near the lens where the ­temperature is warmer. This thermal circulation is responsible for the deposition of cellular material  –  termed keratic precipitates  –  on the inferior aspect of the corneal endothelium.

Aqueous Humor Formation The ciliary body has several critical functions, including production of AH by active secretion, ultrafiltration, and diffusion; generation of IOP through the aqueous dynamic process; influencing through its musculature the conventional (i.e., corneoscleral trabecular meshwork or pressure-sensitive) AH outflow; provision of blood and nerve supplies for the anterior segment; control of accommodation via its musculature; formation of the BAB; and provision of the entry for nonconventional (i.e., uveoscleral or pressure-insensitive) AH outflow. Furthermore, the ciliary body is also rich in antioxidant systems, with significant concentrations of catalase, superoxide dismutase, and glutathione peroxidase types I and II. In addition, the ciliary body is the major drug detoxification center in the eye, with its microsomes containing the cytochrome P450 proteins, which catalyze many drugs. In avian species, the ciliary body musculature is composed of distinct anterior and posterior components that alter the corneal curvature for corneal accommodation and move the ciliary body anteriorly for lenticular accommodation (Glasser & Howland 1996; Murphy et al., 1995). The bilayered ciliary epithelium, consisting of the outer pigmented epithelium (PE) and inner nonpigmented epithelium (NPE), is the site for AH secretion. At their apical borders, the PE and NPE connect via gap junctions to form an intricate network (Fig. 3.5). Adjacent NPE cells are joined by tight junctions to form a barrier that inhibits paracellular diffusion. AH is formed by three basic mechanisms: diffusion, ultrafiltration, and active secretion by the NPE. The processes of diffusion and ultrafiltration form the “reservoir” of the plasma ultrafiltrate in the stroma of the ciliary body, from which the AH is derived via active secretion by the ciliary epithelium. Diffusion of solutes, such as carbohydrates,

occurs from a region of higher concentration to that of lower concentration. By contrast, ultrafiltration occurs when movement of a compound across a cell membrane is increased by a hydrostatic force; in this case, from differences between ciliary body capillary pressure and IOP. Energy-dependent active transport is required to secrete solutes against a concentration gradient across the basolateral membrane of the NPE; it is the most important factor in AH formation (Cole, 1977; Pederson & Green, 1973). Two enzymes critical in this process, Na+-K+-ATPase and carbonic anhydrase (CA), are abundantly present in the NPE. The Na+-K+-ATPase is membrane-bound and is found in the highest concentrations along the basolateral interdigitation of these cells (Flugel & Lutjen-Drecoll, 1988). Inhibition of the Na+-K+-ATPase with cardiac glycosides (e.g., oubain) or vanadate causes a marked decrease in aqueous formation (Bonting & Becker, 1964; Cole, 1977; Garg & Oppelt, 1970) as differences in osmolarity between plasma and AH are small, thereby making the rate of aqueous production dependent on the rate of solute transfer (Maren, 1995). Due to the primary active secretion of sodium, other molecules and ions cross over the epithelium by secondary active transport. As a consequence, increased concentrations of ascorbate, amino acids, and chloride are observed in AH relative to plasma in most mammalian species (Bito et  al., 1965; Blogg & Coles, 1970; Cole, 1974; Gabelt & Kaufman, 2011; Graymore, 1970; McLaughlin & McLaughlin, 1988; Tulamo et  al., 1990). Electroneutrality is maintained by anions accompanying the actively transported sodium; channels allow passage of chloride on the basolateral NPE membrane and a passive transporter exchanges bicarbonate for chloride. As a result, high osmolarity is produced on the basolateral aspect of the NPE, thus initiating diffusion of water out of the cells by aquaporins (Frigeri et  al., 1995; Verkman, 2003). To continue the process, sodium and chloride constantly enter the PE via Na+/H+ and Cl-/HCO3- antiports and a Na-K-2Cl cotransporter. Chloride is just as critical as sodium in driving AH formation, such that A3 adenosine receptor agonists, which enhance chloride release, increase IOP in mice. CA is abundant in the cytoplasm and on the basal and lateral membranes of the NPE and PE and catalyzes the following reaction: C O2

H 2O

HCO3

H .

Formation of bicarbonate by CA is essential for secretion of AH, such that inhibition of CA results in decreased active transport of sodium by the NPE; it is unclear how this process occurs, although several hypotheses exist (Gabelt & Kaufman, 2011). Topical and systemic CA inhibitors substantially decrease AH production, therefore reducing IOP, and are thus useful in the management of glaucoma (Higginbotham, 1989; Maslanka, 2015).

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140

basolateral membrane

apical membrane gap junctions

HCO3–

Cl–

Na+ CA

Cl–

CA

ATPase

Cl– CO2

2 Cl–

HCO3–

K+ H2O

2K+

3 Na+

Aqueous Humor

Stroma

Na+ nucleus

melanosome

CA

Na+

basolateral membrane

CA

HCO3– H2O CO2 H 2 O H+

HCO3–

CA

CO2

K+

H+ H2O

H2O

Na+ H+

PE

NPE

Plasma

200x

Ascorbate 20x

Urea 1.4x

Lactate 1.5x

Aqueous Humor

Protein

Glucose 1.4x

Figure 3.5  Schematic of aqueous humor (AH) production across the pigmented epithelium (PE) and nonpigmented epithelium (NPE) of the ciliary body. Note the position of the critical enzyme, sodium-potassium-activated adenosine triphosphatase (Na+-K+-ATPase) on the basolateral enzyme of the NPE. Carbonic anhydrase (CA), also critical to AH formation, is abundant in the cytoplasm of both the NPE and PE. Ion transporters and channels facilitate transfer of Na+, K+, chloride (Cl-) and bicarbonate (HCO3-) into, between, and out of the NPE and PE, while aquaporins enable water movement. Relative solute concentrations that most markedly differ between aqueous humor and plasma can be found at the bottom.

Aqueous Humor Composition As an ultrafiltrate of plasma, the compositions of AH and plasma are similar, with a few notable exceptions: a low protein concentration, high ascorbate and lactate concentrations, and reduced amounts of urea, glucose, and nonprotein nitrogen occur within AH versus plasma (Fig. 3.5; Blogg & Coles, 1970; Caprioli, 1987; Cole, 1974; Graymore, 1970). Thus, breakdown of the BAB modifies the composition of the AH, primarily by the addition of proteins and prostaglandins, and increases light scattering. The resultant Tyndall effects makes a slit-lamp beam evident within the anterior chamber, an observation clinically known as aqueous flare. With the addition of proteins, the aqueous composition closely approximates that of plasma and is termed plasmoid aqueous. Plasmoid aqueous in domestic animals forms fibrin clots easily due to high concentrations of the

glycoprotein fibrinogen. Unless treated pharmacologically, these fibrin clots can cause numerous complications, including anterior and/or posterior synechiae or adhesions between the iris and the cornea and/or lens. Ascorbate concentration in the AH exceeds that in plasma due to an active transport mechanism (Chu & Candia, 1988). This high concentration of ascorbate might assist in protecting the anterior segment structures from oxidative damage induced by ultraviolet radiation. For example, AH ascorbate concentrations are ~35 times greater in diurnal versus nocturnal mammals, suggesting the importance of its role as an antioxidant to prevent photic damage (Koskela et al., 1989). Furthermore, ascorbate is a cofactor in electron transfer reactions, is a reducing agent in hydroxylation reactions, helps regulate production of GAGs in the trabecular meshwork, and might play a role in the storage of iridal catecholamines (Chu & Candia, 1988; DiMattio, 1989).

In addition to protein and ascorbate, other organic compounds constitute the AH, and their concentrations vary relative to plasma. In most mammalian species, the concentration of amino acids in the AH is higher than that in the plasma, suggesting active transport of amino acids is occurring across the ciliary epithelium (Dickinson et  al., 1968; Reddy et al., 1977). In the dog, however, amino acid concentrations are less in AH than in plasma (Bito et al., 1965). In this species, the vitreous may act as a “sink” for some of the amino acids, thus causing the deficiency (Dickinson et al., 1968; Reddy et  al., 1977). Carbohydrate concentrations in the AH are ~80% of plasma since they enter by diffusion and are subsequently metabolized by the lens and cornea. Thus, the concentration of diffusible substances in blood can impact its amount in the AH. For example, the concentration of glucose in AH is markedly increased in diabetic patients due to elevated plasma concentrations. Urea concentration in the AH is also ~80% that of plasma. Results of previous studies in the dog have indicated that urea penetrates the BAB very slowly; therefore, a steady concentration as compared to that in plasma is never reached, thus resulting in a lower amount of urea in the AH (Davson & Weld, 1941). By contrast, immunoglobulins, enzymes, and lipids are present in much lower concentrations in AH versus plasma due to the BAB. The major cations in the AH are sodium, potassium, calcium, and magnesium, with sodium comprising 95% of the total cation concentration. Sodium enters the AH via active transport, with a net flow of water into the posterior chamber. The major anions in AH are chloride, bicarbonate, phosphate, ascorbate, and lactate. The chloride and bicarbonate ions enter with sodium, but their concentrations vary among species. For example, in the horse, the aqueous chloride concentration exceeds that of plasma, whereas the amount of bicarbonate in aqueous is less than that of plasma. By contrast, the bicarbonate concentration is higher and the chloride concentration is lower in the AH of the guinea pig (Davson & Weld, 1941; Davson, 1969). Because the total anion and cation concentrations must equal each other, the combined chloride and bicarbonate concentrations equal the sodium concentration. Lactate is found in much higher concentrations in the AH versus plasma likely due to glycolysis by the lens, cornea, ciliary body, and retina, since it does not appear to accumulate in the posterior chamber (Riley, 1972). The viscosity, or resistance of fluid to flow, of normal AH varies markedly between species, with raptors, particularly barred owls, having a much more viscous AH than dogs, cats, and horses (Davis et al., 2015). Similarly, teleosts, specifically rainbow trout, are reported to have an AH viscosity that is 10 times greater than that of dogs; this difference is due to a high concentration of hyaluronic acid in rainbow trout versus canine AH (Hoffert & Fromm, 1969).

Aqueous Humor Regulation The rate of aqueous formation by the ciliary epithelium is influenced by sympathetic and parasympathetic innervation as well as humoral mechanisms to maintain a steadystate IOP. Adrenergic regulation of AH formation is complex and the role of some receptor subtypes remains unclear. The β-adrenergic antagonists, such as timolol, lower IOP by decreasing AH production (Coakes & Brubaker, 1978; Schenker et  al., 1981; Yablonski et  al., 1978); more information on this important drug class for glaucoma management can be found in Chapters 8 and 20. During sleep, AH formation decreases ~50% via modulation of the β-arrestin/ cAMP signaling pathway by β-adrenergic receptors in humans (Brubaker, 1991; Reiss et al., 1984; Sit et al., 2008). Thus, IOP exhibits a circadian rhythm, which varies depending on whether animals are nocturnal or diurnal. For example, diurnal species such as dogs and primates (Gelatt et al., 1981; Komaromy et al., 1998) exhibit the greatest IOP during the day, while in nocturnal species such as cats and rats IOP peaks at night (Del Sole et al., 2007; Moore et al., 1996). Consequently, β-antagonists provide little additional reduction in AH production during sleep and may be less effective at controlling IOP during this time period in glaucomatous patients (Sit et al., 2008). The α-2-adrenergic agonists, including brimonidine, markedly lower IOP in humans by decreasing AH formation, but no change in IOP was observed following topical brimonidine administration to glaucomatous Beagles (Gelatt & MacKay, 2001) or normal horses (Von Zup et al., 2017), suggesting that the effects of this drug class vary by species. Cholinergic regulation of AH formation and composition are similarly ambiguous. For example, parasympathomimetic nerve stimulation or drugs have been demonstrated to increase, decrease, or not change the rate of AH production; these differences are likely due to species and techniquerelated effects (Berggren, 1970; Bill, 1967a; Chiou et  al., 1980; Green & Padgett, 1979; Macri & Cevario, 1974; Stjernschantz, 1976; Uusitalo, 1972). Cholinergic agents may regulate amino acid transport from the blood to the AH as well as modulate inorganic ion concentrations within the AH (Bito et al., 1965; Walinder, 1966; Walinder & Bill, 1969). In aggregate, these studies suggest that the influence of parasympathetic drugs such as pilocarpine is relatively minor in AH formation, and that their efficacy in decreasing IOP is likely due to increased AH outflow. Other pharmacologic agents as well as local, systemic, and surgical factors can influence AH formation, as reviewed by Gabelt and Kaufman (2011). Importantly, an increase in IOP causes a reduction in AH inflow due to an alteration in the hydrostatic pressure gradient. However, IOP depends on systemic blood pressure to a small degree. For example, marked hypotension reduces blood flow to the eye and concomitantly lowers IOP (Green, 1984; Macri & Cevario, 1975).

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In summary, the regulation of AH formation is complex and is influenced by a multitude of factors.

Structural and Biomechanical Attributes The TM is a complex, three-dimensional structure comprising cells supported by an intricate extracellular matrix (ECM). The TM can be divided into three portions: uveal, the innermost portion; corneoscleral, the middle region; and the juxtacanalicular zone, the outermost section nearest the sclera. The pore size of each TM zone decreases from inward to outward, with the juxtacanalicular zone consisting of several endothelial cell layers that produce a matrix comprising GAGs, collagen, fibronectin, and other glycoproteins in which these cells are embedded. Thus, the juxtacanalicular zone, which is immediately adjacent to Schlemm’s canal in primates or the angular aqueous plexus (AAP) in most

Aqueous Humor Outflow AH dynamics involve the balance between production (i.e., active secretion) and outflow via the conventional and nonconventional routes (Fig.  3.6). Conventional outflow consists of AH flow through the corneoscleral trabecular meshwork (TM), while the nonconventional route involves uveoscleral outflow (Cruise & McClure, 1981; Samuelson et  al., 1985). Depending on the species, ~50–95% of AH drains through the TM via conventional outflow (Table 3.6).

a

ne

r Co

Anterior Chamber

Iris AAP SVP

Ciliary Body

Lens

Vitreous

Figure 3.6  Aqueous humor (AH) drainage occurs via the traditional and uveoscleral outflow pathways in the iridocorneal angle of the dog. The ciliary body epithelium produces AH, which flows from the posterior chamber, through the pupil, and into the anterior chamber. Then, AH drains through the pectinate ligament to enter the trabecular meshwork. In the traditional outflow pathway, AH enters the angular aqueous plexus (AAP) to drain anteriorly to the episcleral and conjunctival veins or posteriorly into the scleral venous plexus (SVP) and vortex veins. With uveoscleral outflow, AH flows through the ciliary muscle interstitium to the supraciliary and suprachoroidal spaces to diffuse out the sclera.

Table 3.6  Estimates of aqueous humor dynamics in selected species. Dog

Cat

Rabbit

Cow

Horse

Nonhuman Primate

Estimated normal IOP (mmHg)

15–18

17–19

15–20

20–30

17–28

13–15

“C” outflow (μL/mmHg/min by tonography)

0.24–0.30

0.27–0.32

0.22–0.28

—

0.90

0.24–0.28

Uveoscleral outflow (μL/min)

15%

3%

13%

—

—

30%–65%

Episcleral venous pressure (mmHg)

10–12

8

9

—

—

10–11

Aqueous formation (μL/min)

5.22

6.00–7.00

1.84

—

—

2.75

domestic animals, is thought to be the major site of aqueous outflow resistance. Other studies suggest that the main site of resistance to outflow is the endothelial lining of the AAP and its ECM (Samuelson & Gelatt, 1984a, 1984b; Tripathi & Tripathi, 1972). However, the site of filtration may be different from the site of flow resistance (Johnson et al., 1990). AH transport through the endothelium of the AAP (or Schlemm’s canal in nonhuman primates and domestic chickens) is thought to occur via transcellular pores, large vacuoles, or pinocytotic vesicles. However, paracellular routes between the endothelial cells of Schlemm’s canal have also been proposed and may be pressure sensitive, particularly at higher IOPs (Epstein & Rohen, 1991; Sabanay et al., 2000; Ye et al., 1997). Nevertheless, disputes regarding juxtacanalicular versus inner wall resistance and transcellular versus paracellular transport are unlikely to translate to major differences in therapeutic approaches from a clinical perspective. Excessive deposition of ECM and concomitant stiffening of the TM are critical to the pathogenesis of primary open angle glaucoma (POAG) in humans (Chatterjee et al., 2014; Last et al., 2011) and likely dogs with the ADAMTS10 mutation (Ahonen et al., 2014; Boote et al., 2016; Kuchtey et al., 2011, 2013; Palko et al., 2013, 2016). Thus, phagocytic activity of TM cells and macrophages is important in ECM remodeling and removal of large particulate material (Gasiorowski & Russell, 2009). A malfunction of endothelial phagocytosis and reduced numbers of trabecular endothelial cells may also contribute to the pathogenesis of POAG (Samuelson et  al., 1984). The nonfiltering portion of the canine iridocorneal angle (ICA) has been shown to contain Schwalbe’s line cells, which have both secretory and epithelial characteristics. Recently, a stem cell niche was identified in Schwalbe’s line of cynomolgus macaques, which may serve to repopulate cells in the TM and/or corneal endothelium (Braunger et al., 2014). Changes in the morphology and number of Schwalbe’s line cells correlate with disease progression in Beagles with POAG (Samuelson et al., 2001), suggesting that loss of this cell population is important in the pathogenesis of glaucoma.

ciliary body muscle, supraciliary or suprachoroidal space, and out through the sclera. The traditional pathway is dependent on IOP, while the uveoscleral pathway is not, as long as IOP is greater than 7–10 mmHg (Bill, 1966a, 1967b, 1975). At very low IOP, the net pressure gradient across the nonconventional pathway declines, so that uveoscleral outflow subsequently decreases. It is unknown why uveoscleral outflow is largely independent of IOP, but it may relate to complex relationships between pressure and resistance between the fluid compartments and the soft tissues that comprise this route (Bill, 1975). For example, the pressure gradient between the anterior chamber and suprachoroid is independent of IOP, thus fluid flow between these compartments is also IOP independent. Uveoscleral outflow is primarily impacted by the state of the ciliary body and by the hydrostatic pressure difference between the anterior chamber and the suprachoroidal space (Barrie et  al., 1985; Bill, 1966a; Emi et  al., 1989; Gelatt et  al., 1979). Contraction of the ciliary body musculature decreases unconventional outflow, possibly by reducing the extracellular spaces; in turn, relaxation increases outflow via this route. Thus, pilocarpine, a parasympathomimetic, and atropine, a parasympatholytic, will decrease and increase uveoscleral outflow by contracting and relaxing the ciliary body muscle, respectively (Bill, 1967a; Lutjen-Drecoll & Kaufman, 1993; Rohen et al., 1967). Formulae can be used to describe the formation and drainage of AH (Table 3.7). Table 3.7  Aqueous humor dynamics formulae. I

Fin = Fat + Fuf F = flow (μl/min) Fin = total AH inflow Fat = inflow from active transport Fuf = inflow from ultrafiltration

II

Fout = Ftrab + Fuveo Fout = total AH outflow Ftrab = outflow via the trabecular meshwork Fuveo = outflow via uveoscleral pathway

III

Ctotal = Ctrab + Cuv + Cpseudo C = facility or conductance of flow (μl/min/mmHg) Ctotal = total AH outflow facility Ctrab = facility of outflow via the trabecular meshwork Cuv = facility of outflow via the uveoscleral pathway Cpseudo = pseudofacility

III

At steady state, F = Fin = Fout

IV

F = Ctrab (Pi − Pe) Goldmann equation P = Pressure (mmHg) Pi = IOP Pe = episcleral venous pressure

V

Fin = Ctrab(Pi − Pe) + Fuveo

VI

Pi = Pe + (Fin - Fuveo)/ Ctrab

Fluid Dynamics As the CB produces AH, the tissues comprising the ICA resist AH outflow, thus generating IOP. Steady-state IOP occurs when the rates of AH inflow and outflow are equivalent. The AH exits the eye by passive bulk flow via two routes in the ICA: 1) The traditional or conventional pathway, which involves passage through the TM, AAP, scleral venous plexus, veins of the episclera and conjunctiva (anterior) or vortex veins (posterior), and systemic venous circulation. 2) The uveoscleral or nonconventional pathway, which involves passage through the iris root, anterior face of the

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Episcleral venous pressure or the “backpressure” created by the venous portion of the conventional pathway in the AAP or Schlemm’s canal constitutes approximately 50%–75% of the resistance that determines IOP. While minor anatomic variations in the venous system exist between species, results of pressure studies in humans, nonhuman primates, rabbits, and dogs reveal episcleral venous pressure to be between 8 and 12 mmHg (Bill, 1966b; Gelatt et al., 1982b; Maepea & Bill, 1989; Talusan & Schwartz, 1981; Tripathi & Tripathi, 1973). Arteriovenous anastomoses within the episcleral vasculature have been demonstrated in the rabbit, dog, owl monkey, and cynomolgus monkey. These vascular shunts may function in rabbits and dogs, where the episcleral vasculature appears to lack a capillary system, and in the monkey species as an emergency system to elevate IOP after globe perforation or to retrogradely flush the outflow channels (Funk & Rohen, 1996; Rohen & Funk, 1994). Episcleral venous pressure can be measured by direct cannulation (using very fine glass pipettes) or indirect partial to complete compression schemes (using a string-gauge system or a fluidfilled chamber; Gelatt et al., 1982b). The term pseudofacility refers to pressure-dependent ultrafiltration formation of AH. It was assumed that any measurement procedure for AH dynamics that temporarily elevated IOP (e.g., perfusion of the anterior chamber, tonography, perilimbal ­suction cup) would temporarily decrease the rate of humor formation. This slight decrease in the rate of formation would alter the pressure-sensitive outflow measurements obtained by tonography and was termed false facility, or pseudofacility. Results of studies that involved compressing the episcleral venous pressure of the AH outflow systems in humans and nonhuman primates suggest the pseudofacility to be as high as a 20% error (Brubaker & Kupfer, 1966; Kupfer & Sanderson, 1968). However, fluorophotometric measurements of AH formation rates indicate that these sudden (but limited) increases in IOP do not suppress the rate of AH formation. Indeed, fluorophotometry measurements in both normal and glaucomatous human eyes indicate that rates of AH formation are essentially the same (Beneyto Martin et al., 1995). Thus, the temporary increase in IOP observed in the original experiments by Brubaker and colleagues may be due to immediate dilation of the intraocular blood vessels followed by slow accumulation of AH (Brubaker & Kupfer 1966; Moses et al., 1985). Results of earlier studies indicated that the volume of the anterior chamber directly relates to the rate of aqueous outflow, so that animals with large eyes have faster outflow rates (Tripathi, 1974; Tripathi & Tripathi, 1972, 1973). The resistance to aqueous outflow is inversely proportional to the facility of outflow (Ctotal).

Regulation of Outflow Cholinergic agonists such as pilocarpine decrease outflow resistance by contraction of the ciliary muscle and subsequent spreading of the TM. This effect is rapid, such that intravenous administration of pilocarpine to vervet monkeys results in a near-instantaneous decrease in outflow resistance, suggesting that the effect may be mediated by a structure perfused by arteries (Bárány, 1967). Ciliary muscle disinsertion and removal of the iris obliterate this acute response to pilocarpine, suggesting that it is mediated completely by ciliary muscle contraction rather than a direct effect on the TM (Kaufman & Bárány, 1976). The M3 subtype of the muscarinic receptor is strongly expressed in the ciliary muscle and thought to mediate the changes in outflow facility in response to cholinergic agonists (Gabelt, 1994; Gabelt & Kaufman, 1992; Zhang et  al., 1995). Because the effect of cholinergic agonists on trabecular outflow (increase) is greater than that on uveoscleral outflow (decrease), the net effect is an increase in AH outflow and concomitant decrease in IOP. As expected, cholinergic antagonists such as atropine decrease traditional outflow and increase nontraditional outflow by similar mechanisms. Stimulation of adrenergic receptors by nonspecific agonists such as epinephrine increases outflow, but the precise mechanism remains elusive despite extensive study (Ballintine & Garner, 1961; Bárány, 1968; Bill, 1969, 1970; Krill et al., 1965; Sears, 1966). However, it is likely to involve stimulation of β 2 receptors on TM cells and subsequent increased cyclic adenosine monophosphate (AMP) production (Kaufman, 1987; Neufeld et al., 1972, 1975; Neufeld & Sears, 1975; Sears & Neufeld, 1975). Downstream effects may include disruption of actin filaments within TM cells, changes in cell shape, cell–cell and cell–ECM interactions, altered TM structure, and increased hydraulic conductivity within the TM (Kaufman, 1981; Kaufman & Rentzhog, 1981). Epinephrine also increases uveoscleral outflow, likely by stimulation of β-receptors in the ciliary muscle and subsequent ­relaxation (Bill, 1969; Casey, 1966; Schenker et al., 1981; Tornqvist, 1966; Townsend & Brubaker, 1980; van Alphen et al., 1962, 1965). Many other influences on the rate of AH formation and regulation of IOP have been proposed. For example, a center in the feline diencephalon has been found that, when stimulated, causes alterations in the IOP (Gloster, 1960). Central nervous system (CNS) regulation of IOP is poorly understood, however, and hormonal control of AH production may be involved (Niederer et  al., 1975). The influence of the CNS on AH dynamics was reviewed by Denis and colleagues (1994).

Methods to Measure Aqueous Dynamics Both invasive and noninvasive methods are used to investigate AH dynamics (Table  3.8), and normative values have been described in domestic and laboratory animal species. AH formation has been measured using both invasive and noninvasive techniques. As one may anticipate, early methods were invasive and essentially measured the dilution of intracamerally injected substances over short time periods. With the AH volume within the anterior and posterior chambers measured and the amount of dilution of the tracer estimated, the total amount of AH produced per unit of time could be determined. Knowledge of anterior and posterior chamber volumes is critical to determining the rate of AH Table 3.8  Methods to investigate aqueous humor dynamics. I

Techniques to investigate the formation of aqueous humor Cannulation of anterior chamber: constant rate/constant pressure perfusion Direct view/measurement of newly formed aqueous humor Use of markers in aqueous humor (radioactive, fluorescein, paraminophippuric acid). Measure the decay rate of intracamerally injected isotopes. Fluorophotometry, a noninvasive method, is primarily used today

II

Procedures to investigate the exit of aqueous humor Ocular perfusion to lower IOP Perilimbic suction cup Tonography (conventional outflow/pressure sensitive) Use of markers (fluorescein, nitrotetrazolin, latex spheres, radioactive tracers). Both conventional and uveoscleral outflow routes are measured

III Methods to measure the episcleral venous pressure Partial to complete collapse of the episcleral veins to affect alteration in the blood flow Torsion balance Pressure chamber (filled with air or saline) Air jet Ocular compression Direct cannulation and measurement by transducer

production (Table 3.9; McLaren et al., 1990; Toris et al., 1995). Unfortunately, a major limitation of these studies is variability in the determination of the anterior and posterior chamber volumes. In glaucomatous animals, these chambers may be altered considerably, and their volumes are subsequently difficult to determine. In response to these invasive experiments, fluorophotometry was developed as both an experimental and a clinical procedure to noninvasively determine the rate of AH formation in many species, including humans. Fluorophotometry is a noninvasive method for studying AH flow dynamics, for evaluating ocular pharmaceutical agents used to treat glaucoma, and for determining iris permeability in both normal and disease states (Bartels, 1988; Brubaker, 1991; Kurnik et  al., 1989; McLaren & Brubaker, 1988). Fluorophotometry of the anterior chamber and vitreous can assess the permeability of the BRB in the normal and diseased eye. Fluorophotometry has been used ­extensively in humans (Brubaker, 1991), nonhuman ­primates (Toris et al., 2010), rabbits (Reitsamer et al., 2009; Zhao et al., 2010), cats (Crumley et al., 2012; Lee et al., 1984), dogs (Cawrse et  al., 2001; Skorobohach et  al., 2003; Ward et al., 2001), and, most recently, the red-tailed hawk (Jones & Ward, 2012). This tool can also be used to assess permeability coefficients of the BAB involved in health and disease, and determine the effects of selected drugs on the BAB. To determine AH outflow, perfusion of the anterior chamber (AC) of in vivo and ex vivo eyes has been performed in numerous species. The constant pressure perfusion technique is the most frequently used. It involves maintaining a constant level of IOP with periodic, intermittent, or continuous volumes of perfusate. In the perfusion decay test, either a preselected volume of perfusate is injected or a preselected IOP is achieved. Once the perfusate has been injected, the time for the IOP to regain the baseline or preexisting measurement is obtained. In many ways, the perfusion techniques are similar to the noninvasive tonography methods. The two-step constant perfusion of the anterior chamber, as

Table 3.9  Comparative volumes of the chambers and select structures of the eye.

Species

Anterior Chamber (mL)

Posterior Chamber (mL)

Lens Volume (mL)

Human

0.2

0.06

0.2

Vitreous Volume (mL)

3.9

Rabbit

0.3

0.06

0.2

1.5

Pig

0.3

—

—

3.0

Dog

0.8

0.2

0.5

3.2

Cat

0.8

0.3

0.3

2.8

Cow

1.7

1.5

2.2

20.9

Horse

2.4

1.6

3.1

28.2

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reported by Bárány and Scotchbrook (1954), has become the most frequently reported procedure. Briefly, the technique includes constant perfusion of the anterior chamber at two different IOPs (∼2–3 and 8–10 mmHg above baseline) for several minutes. The total (i.e., perfusion) facility is determined by dividing the difference in perfusion rates between the two IOPs by the pressure difference between them. Pseudofacility may account for approximately 0.02 μL/min/ mmHg with this procedure in humans. Ample literature is available on anterior chamber perfusion in several species. The type of perfusate, duration of perfusion (i.e., the “washout effect”), eye preparation, IOP during perfusion, addition of certain enzymes, and drugs (including anesthesia and other substances) may directly influence the perfusion rate. If perfusion of the anterior chamber is planned, the literature should be consulted and carefully evaluated. In general, the rates of perfusion obtained in the animals investigated have correlated closely with the values obtained by the noninvasive tonographic and fluorophotometric methods. For more information on tonography to noninvasively measure conventional outflow, see Chapter 10. Several methods have been used to demonstrate anatomic routes and quantity of uveoscleral outflow, as well as of conventional (i.e., corneoscleral) outflow. The percentages accounted for by uveoscleral outflow range from 30% to 65% in nonhuman primates, 15% in dogs, 13% in rabbits, 4% to 14% in humans, and 3% in cats (Table  3.6; Barrie et  al., 1985; Bill, 1966a, 1966b; Bill & Phillips, 1971; Zhan et al., 1998). The horse appears to have an extensive uveoscleral outflow system (Smith et al., 1986), but the volume and percentage of the total outflow system have not been reported. For additional information on unconventional outflow in a variety of species under numerous conditions, the reader is referred to the thorough review by Johnson and colleagues (2017). Uveoscleral outflow can be demonstrated using observable tracers measuring from 10.0 nm to 1.0 μm in diameter. As one would anticipate, the smaller-diameter (i.e., pore) tracers penetrate the different tissues to greater extents. After perfusion at different IOPs and for different time intervals, the eyes (especially the root of the iris, entire ciliary body, suprachoroidal space, and choroid, even as far posterior as the optic nerve) are examined by light microscopy, scanning electron microscopy, and transmission electron microscopy for these markers. These same methods have also demonstrated the ability of the trabecular endothelium and wandering macrophages to phagocytize particulate material within the outflow pathways. An alternative method to estimate the amount of uveoscleral outflow (either as μL or %) is by using radioactive isotopes injected into the anterior chamber; the time, amount of the isotope, or both is standardized. At the conclusion of perfusion, the ocular tissues are either dissected into the different sections, analyzed for radioactivity, or the entire globe is sectioned, and the

r­ adioactivity of each area is measured by scintillation counter. Measurements of tracers in the fluids within the intrascleral veins, episcleral veins, and vortex veins are alternate methods of determining the different routes of AH outflow, but these methods require the anatomy of these venous ­systems to be determined. There may be mixing between the ­systems, and the tracer concentrations in the anterior chamber and blood must be established at the same time. Atraumatic entry to the intrascleral or episcleral venous system (or both) must be available.

Ocular Rigidity Another key concept in the measurement of IOP is ocular rigidity (k), or the resistance offered by the fibrous tunics of the eye (i.e., sclera and cornea) to a change in intraocular volume. Ocular rigidity may also be defined as the change in IOP per incremental change in the intraocular volume; this resistance manifests as a change in IOP. Ocular rigidity is determined by Schiotz tonometry, and it estimates the change in volume (open manometer system) when the instrument is placed on the cornea as well as after injections of exact volumes or preselected elevations in IOP. This ­logarithmic relationship between IOP and volume of the globe is: log P2 /P1

k V2

V1 .

Ocular rigidity is a constant characteristic of each eye, but it also depends on IOP. Hence, the distensibility of each globe varies among individuals as well as with the IOP. Dogs and cats have greater scleral elasticity than humans, so less resistance is offered with indentation tonometry, and buphthalmia occurs more readily with prolonged, increased IOP (Peiffer et al., 1978; Wyman, 1973). Manometric studies to develop Schiotz tonometer calibration tables for the dog, rabbit, and cat have not been successful clinically and may, perhaps, be associated with different individual rigidities for the cornea and sclera (Miller & Pickett, 1992). Consequently, Schiotz tonometry is rarely performed in animals.

Intraocular Pressure In many species, IOPs as measured with tonometry in normal animals have been reported (Table 3.10). In humans and animals, fluctuations in IOP occur for a variety of reasons (Table 3.11), and a review of considerations for conducting IOP studies in animals was recently performed (Millar & Pang, 2015). Diurnal IOP variations generally occur in most species; in humans and dogs, the highest pressure occurs in the morning and the lowest in the afternoon (Gelatt et al., 1981). By contrast, the greatest IOPs occur during the day and the lowest IOPs are documented at night in the rabbit, cat, horse, and nonhuman primate (Bertolucci et al., 2009). In glaucomatous canine patients, diurnal IOP fluctuations

Table 3.10  Intraocular pressures in select animal species.

Species

Mean ± SD

Tonometer

Investigator

Alligator

23.7 ± 2.1

TonoPen

Whittaker et al. (1995)

Cat

22.6 ± 4.0 19.7 ± 5.6

Mackay-Marg TonoPen

Miller et al. (1991b)

Cow

28.2 ± 4.6 26.9 ± 6.7

Mackay-Marg TonoPen XL

Gum (1990)

Chinchilla

3.0 ± 1.8 9.7 ± 2.5

TonoVet-D TonoVet-D

Müller et al. (2010) Snyder et al. (2018)

Dog

15.7 ± 4.2 16.7 ± 4.0 17.8 ± 0.9 (pm) 21.5 ± 0.8 (am)

Mackay-Marg TonoPen Mackay-Marg

Miller et al. (1991a)

22.8 ± 5.5 15.4 ± 1.1 14.1 ± 0.4

TonoPen TonoPen Vet TonoVet

Sapienza et al. (1991) Di Girolamo et al. (2013)

16.8 ± 3.9 14.7 ± 1.6

TonoLab-R TonoVet-D

Hausmann et al. (2017)

Goat (pygmy)

11.8 ± 1.5 10.8 ± 1.7

TonoVet-D TonoPen XL

Broadwater et al. (2007)

Guinea pig

18.3 ± 4.6 6.1 ± 2.2

TonoPen Vet TonoVet

Coster et al. (2008)

Horse

25.5 ± 4.0 23.5 ± 6.1 23.3 ± 6.9

Mackay-Marg Mackay-Marg TonoPen

Cohen & Reinke (1970) Miller et al. (1990)

Mouse (no anesthetic)

14.6 ± 0.5

TonoLab

Ding et al. (2011)

14.9 ± 2.1 15.4 ± 2.6

Pneumatonograph TonoPen XL

Bito et al. (1979) Komaromy et al. (1998)

29.3 ± 0.9

TonoVet-P

Liu et al. (2011)

19.5 ± 1.8 17.9 ± 2.1 9.5 ± 2.6 15.4 ± 2.2

Pneumatonograph

Vareilles et al. (1977a, 1977b) Smith & Gregory (1989) Pereira et al. (2011)

Red-tailed hawk

20.6 ± 3.4

TonoPen

Stiles et al. (1994)

Golden eagle

21.5 ± 3.0

Great horned owl

10.8 ± 3.6

White-tailed sea eagle

26.9 ± 5.8

TonoVet

Reuter et al. (2011)

Northern goshawk

18.3 ± 3.8

Red kite

13.0 ± 5.5

Eurasian sparrowhawk

15.5 ± 2.5

Common buzzard

26.9 ± 7.0

Common kestrel

9.8 ± 2.5

Peregrine falcon

12.7 ± 5.8

Tawny owl

9.4 ± 4.1

Long-eared owl

7.8 ± 3.2

Barn owl

10.8 ± 3.8 17.3 ± 5.3

TonoPen

Mermoud et al. (1994)

21.4 ± 1.0

TonoPen

Sappington et al. (2010)

10.6 ± 1.4

Perkins

Gerometta et al. (2009)

Ferret

Frog White’s tree frogs

Nonhuman primate Rhesus (ketamine) Tibetan monkey Rabbit

TonoVet TonoPen Avia

Gelatt et al. (1981)

Raptor

Rat Sheep

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Table 3.11  Factors that cause short- and long-term fluctuations in intraocular pressure. Short-Term

Long-Term

Diurnal changes

Aging

Forced eyelid closure

Race/breed

Contraction of retactor bulbi muscles

Hormones

Coughing/valsalva maneuver

Glucocorticoids

Abrupt changes in blood pressure

Growth hormone

Pulse

Estrogen

Struggling/electroshock

Progesterone

Changes in body/head position

Obesity

Succinylcholine

Myopia

Acidosis

Gender Season

are typically much greater in comparison to normal dogs (Gelatt et  al., 1981). Consequently, antiglaucoma medications administered once daily to dogs should be given in the evening to mitigate IOP spikes in the morning, when pressures are typically the greatest (Gelatt & MacKay, 2001).

Lens The second most powerful refracting structure in the eye is the lens. Like the cornea, the lens is a transparent tissue without a direct blood supply. The lens depends primarily on AH for its metabolic needs. Most of the lens proteins are soluble, with a small amount of glycoproteins, whereas the cornea consists mostly of insoluble collagen and a relatively large amount of glycoproteins. Lens epithelial cells (LECs) are the progenitors of the lens fibers and transition into lens fiber cells of the cortex at the equator. This process is characterized by distinct biochemical and morphologic changes, such as the synthesis of crystallin proteins, cell elongation, loss of cellular organelles, and disintegration of the nucleus (Ochiai et al., 2014). Transparency of the lens depends primarily on the highly ordered lens cell arrangement, as well as on the solubility and physical arrangements of its proteins. The lens behaves as a cell syncytium both biochemically and electrically. The lens consists of approximately 68% water, 38% protein, and small amounts of lipids, inorganic ions, carbohydrates, ascorbic acid, glutathione, and amino acids (Viteri et  al., 2004). Both the anterior and posterior lens capsules are the lens’s extracellular matrix and, like a typical epithelial basement membrane, consist of Type IV collagen and heparan sulfate proteoglycan. The thickness of the anterior lens

c­ apsule increases with age because of the anterior location of the lens epithelial cells (Bernays & Peiffer, 2000). The protein content of the lens is very high in comparison to other organs. Protein synthesis ceases with formation of the lens fiber cells, and all the protein changes that occur after this stage are posttranslational modifications. Lens proteins are divided into water-soluble proteins and water-insoluble proteins. Crystallins comprise 80–90% of the water-soluble lens proteins (Andley, 2007; Piatigorsky, 2003). Most of the insoluble proteins occur in the lens nucleus, whereas the soluble proteins are concentrated in the lens cortex (Harding & Dilley, 1976). The insoluble proteins are associated primarily with membranes of the lens fibers; the soluble proteins comprise the bulk of the refractive fibers of the lens and are considered the structural proteins of the lens. The percentages of soluble and insoluble proteins vary among species and with the pathophysiologic state of the lens. With aging, water-soluble proteins coalesce to make high-molecular-weight aggregates and their hydrophilicity diminishes (Ortwerth & Olesen, 1989). Additionally, when the lens becomes cataractous, the level of water-insoluble proteins increases. The crystallin proteins are classified as classical or taxonspecific. Crystallins evolved from stress proteins and enzymes (Andley, 2007). Classical crystallins comprise α-crystallins and the β/γ-crystallin superfamily. Crystallins form very stable and durable structures. All vertebrate lenses accumulate large amounts of classical crystallins in their fiber cells. Alpha-crystallins are not only refractive, but as members of the family of small heat shock proteins, they also serve as molecular chaperones that function to protect against physiologic stress. Alpha-crystallins account for almost 50% of the protein mass of the human lens and are thought to bind to partially unfolded β/γ-crystallins and

149

diffusion–consumption equation or capillaries used by other tissues (Zampighi et  al., 2002). Homeostasis, especially that associated with solute exchange from the aqueous and vitreous humors to the lens fibers, has been extensively studied. A review by Dahm and colleagues (2011) summarizes current information into four main forms of transport:

SECTION I

interact with cytoskeletal proteins, preventing further aggregation, interaction, and precipitation, which would lead to lens opacification (Andley, 2007). The β/γ-crystallin superfamily is more diverse than the α-crystallins, but its functional role is less evident. Previously the β/γ-crystallins were thought to be two distinct protein families, but protein sequencing has shown that they are closely related. The major difference is that β-crystallins tend to form multimers and γ-crystallins exist as monomers (Driessen et al., 1981). Taxon-specific crystallins vary between species and provide the lens with transparency and enzymatic capacity. This ability to serve in both capacities is referred to as gene sharing. One example is δ-crystallin, which is a soluble protein that also has argininosuccinate lyase activity and accumulates only in the lenses of birds and reptiles. Delta-crystallin is the first and major crystallin (70%) in the lens of the developing chicken (Das & Piatigorsky, 1988; Piatigorsky & Wistow, 1989). Additionally, these crystallins may have been recruited as lens proteins because of their thermodynamic stability, which is required for the long life of fiber cells (Wistow & Piatigorsky, 1987). The long prismatic lens fiber cells are organized in tightly packed units with interdigitations that appear as a threedimensional jigsaw puzzle. The interdigitations stabilize the lateral membranes of the lens fibers, and they are specialized gap junctions that join all the lens cells, thus permitting them to act as a syncytium. Gap junctions mediate cell-tocell transport of molecules, which is critical since most fibers are distant from their nutrient sources, the aqueous and vitreous humors. Lens fiber cells have a higher concentration of gap junctions than any other cells in the body. The lens fiber cytoskeleton contains micro-filaments and intermediate filaments that are composed of vimentin, filensin, and phakinin. These filaments have a knobby structure ­leading to the name, beaded filaments, which are only found in lens fiber cells, suggesting a very specialized role. The functions of the beaded filaments probably relate to crystallin packing and density distribution, as well as their being attachment sites for the crystallin molecules (Ireland & Maisel, 1984). Aquaporins comprise a family of intrinsic membrane proteins involved in water transport in many tissues. Specifically, AQP0 has been localized to the canine lens fibers as well as the lens of other mammals (Karasawa et al., 2011). In rats and most likely other animals, the AQP0 are located on the lens equatorial fiber plasma membranes, both in a diffuse arrangement and in clusters that correspond to specialized junctions between fibers and interact with gap junctions in the apical surface of the fiber. These adaptations are thought to assist the circulating fluxes of ions and water needed to move nutrients into and waste products out of the nucleus. The fluxes are directed from the poles of the lens toward the equator. These adaptations allow the lens to avoid being dependent on the

3: Physiology of the Eye

1) Paracellular transport via the intercellular spaces between the LECs and the underlying lens fibers is driven by Na+ leak conductance. This mechanism accounts for the influx of ions, water, and small molecules such as ­glucose, amino acids, and ascorbic acid. 2) Plasma membrane-based transport of small molecules from the lens’s extracellular space into the lens fiber’s cytoplasm is via ion and water channels and specific transporters for small molecules. 3) Gap-junctional transport accounts for the flux of ions, water, and small molecules from superficial fibers toward the deep fibers, and also accounts for the efflux of waste products at the epithelial cell lens fiber interface in the equatorial regions. 4) Vesicle-mediated active transport by caveoli accounts for the uptake of macromolecules such as growth factors and other regulatory factors necessary for the normal development and maintenance of lens fibers. Coated vesicles are involved in the uptake of lipoproteins and cholesterol by superficial fibers needed for the biogenesis of new membranes, as lens fiber cells increase their length by up to 1,000-fold (Dahm et al., 2011). The lens epithelium is the major site of energy production in the lens. Energy is used for active transport of inorganic ions and amino acids and for protein synthesis. Osmoregulation occurs through active transport and involves the action of Na+-K+- ATPase to maintain high K+ and amino acid concentrations and low Na+, Cl−, and water concentrations within the lens. The movement of water is passive and occurs with the active cation transport. As the Na+ ion is transported from the lens, K+ is transported into the lens (Fig. 3.7) in a manner similar to that in red blood cells. A deficiency of lens Na+-K+-ATPase results in cataracts in mice because of the breakdown of this critical pump mechanism (Kinoshita, 1974). The lens undergoes major oxidative stress due to constant exposure to light and oxidants. Oxidative stress is reduced by radical scavenging antioxidants such as glutathione, carnitine, and ascorbic acid, which are present at high concentrations in the lens. However, some species such as dogs, rabbits, and guinea pigs have lower concentrations of ascorbic acid in the lens than in the AH (Kuck, 1970). The function of lenticular ascorbic acid most likely relates to oxidation–reduction reactions or is coupled to glutathione metabolism (Berger et al., 1988). In humans, the lens epithelium contains transporter molecules for ascorbate, which

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Water 99.9% Na+ 144 Cl– 110 K+ 4.5 Ca++ 1.7 Glucose 6.0 Lactic acid 7.4 Glutathione 0 Ascorbic acid 5 Inositol 0.10 Amino acids 5 Protein 0.04%

S

66% 20 18 125 0.4 1.0 14.0 12.0 S 0.6 5.9 25 AA + AA + RNA 33% S

Active Transport (Pump) Diffusion (Leak) Synthesis

Figure 3.7  Chemical composition of the aqueous humor and lens. Water and protein are expressed as percentages of lens weight. Na+, Cl−, K+, and Ca++ ions are expressed in microequivalent per milliliter of lens water. Other compounds are expressed in micromole per gram of lens weight or micromole per milliliter of aqueous humor. AA, amino acid; RNA, ribonucleic acid.

ensure adequate metabolism and help to protect against damage by free radicals. A deficiency in these protective mechanisms can result in cataractogenic changes (Andley & Clark, 1989). Glutathione is a tripeptide of glutamine, cysteine, and glycine. It is synthesized in the lens epithelial cells and superficial fiber cells and provides most of the protection against oxidative damage in the lens. Glutathione furnishes sulfhydryl groups for the lens proteins, thereby preserving their solubility, and for Na+-K+-ATPases, thereby maintaining these transport “pumps.” Other biologic functions include participation in amino acid transport with γ-glutamyl transpeptidase and as a substrate for glutathione peroxidase, which destroys cytotoxic lipid hydroperoxides. In a normal lens, glutathione is predominantly in the reduced form (GSH), with the concentration of the oxidized form of glutathione at only 2.1%–2.6% that of the reduced form. Concentrations of both the reduced and the oxidized forms of glutathione are decreased in cataract formation, except in advanced cataract patients, where the amount of the oxidized form is 9% that of the reduced form (Gelatt et  al., 1982a). Carnitine is known to have an antioxidative and antiradical role on the ocular surface. The same is suspected to be true in the lens. Recently, the carnitine transporter SLC22A5 was identified in canine lens epithelium and is thought to be responsible for the transport of carnitine to the lens from AH (Ochiai et  al., 2014). A major factor

involved in cataract formation is oxidative damage caused by O2 radicals, peroxide (H2O2), OH−, and ultraviolet radiation. Telomerase is a ribonucleoprotein responsible for maintaining telomere length, preventing chromosomal degradation and recombination, and repairing DNA strand breaks, thereby preventing cell senescence. Telomerase activity has been found in normal canine, feline, and murine lens epithelial cells in the central, germinative, and equatorial regions at equivalent concentrations. Telomerase activity may be in the germinative epithelium to maintain its proliferative potential and prevent cell senescence, whereas it may function in the quiescent, central lens to maintain telomeres damaged by oxidative stress and ultraviolet light exposure, thereby preventing accelerated loss of these elements, which can trigger cell senescence (Colitz et al., 1999). The lens capsule functions as a semipermeable membrane. It prevents direct contact between the lens and the surrounding ocular environment and protects the lens from the invasion of pathogens. However, the capsule allows water, small solutes, many proteins, and waste to pass, thereby enabling the lens to grow and perform metabolic functions (Danysh & Duncan, 2009). Its mechanical functions include maintaining the shape of the lens in association with accommodating and providing for the attachment of the zonules. Additionally, a contractile system appears to exist in the lens epithelial and cortical cells, and though its physiologic function is not completely understood, it seems to stabilize the shape of the lens (Rafferty et al., 1990). The primary source of energy for the lens is glucose, which diffuses from the AH. Energy is derived from anaerobic ­glycolysis and is used for active cation transport and protein synthesis. Oxygen is not necessary for normal lens metabolism, though a small percentage of glucose is metabolized through the Krebs cycle. The hexose monophosphate (i.e., pentose) shunt and the sorbitol pathway are other pathways of glucose metabolism in the lens. The major end product of glucose metabolism in the lens is lactic acid, which diffuses into the AH. The rate of glycolysis is controlled by the amount of hexokinase and the rate of entrance of glucose into the lens. With high concentrations of glucose (>175 mg/dL), the level of glucose-6-phosphate increases, which inhibits hexokinase and limits the rate of glycolysis. This process prevents excessive buildup of lactic acid in the lens, which would lower the pH and activate the lens proteases (Kuck, 1970). With very high blood and AH glucose concentrations, as occur in diabetes mellitus, the enzyme aldose reductase is activated as an alternative route of glucose metabolism in the lens (Sato & Kador, 1989). The result is an accumulation of sorbitol in the lens cells, which causes swelling associated with the increased osmotic pressure. The outcome is a diabetic cataract. Aging changes in the lens include an increase in insoluble proteins and changes in the cytoskeleton. Normal proteolysis

truncates many of the soluble crystallins and contributes to aging changes. The increase in water-insoluble proteins most likely occurs because of crystallin binding and interactions with the cytoskeletal/membrane components. The chaperone role of α-crystallin, whereby the α-crystallin binds to partially unfolded β/γ-crystallins and interacts with cytoskeletal proteins to prevent uncontrolled aggregation, ultimately increases the amount of insoluble proteins. The increase in insoluble proteins is also secondary to covalent interactions between crystallin fragments (Su et  al., 2011). Additionally, with age, the flow of antioxidants from the metabolically active cortex to the lens nucleus decreases, predisposing the lens to cataract development. Iron is also implicated in cataract development, due to its ability to catalyze the formation of free radicals, and aging cataractous lenses have higher concentrations of iron. Normally excess iron is safely stored in ferritin, a ubiquitous protein. One study found that modified fiber cell ferritin L chains are present at the highest amount in the outermost layers of both cataractous and noncataractous canine lenses. They decrease gradually in the inner layers of the fiber mass and are undetectable in the inner two layers of cataractous lenses. By contrast, modified ferritin H chains are ubiquitous throughout noncataractous lens cortex, but are found in decreasing amounts toward the interior of the lens. However, in cataractous lenses, normal-sized ferritin H chains are present in smaller quantities in the outer fiber layers, and increase in quantity and size in the inner layers. These different amounts and types of ferritin may reflect a response of the lens to increased oxidative stress during cataractogenesis (Goralska et al., 2009).

cells, as previously thought. Hyalocytes are important for extracellular matrix synthesis, vitreous cavity immunology regulation, and modulation of inflammation (Sakamoto & Ishibashi, 2011). The embryonic vitreous is very dense and therefore translucent. As an individual matures, however, important structural changes occur in the vitreous. The axial length of the vitreous increases, which is critical for growth of the eye (discussed later). The overall collagen content remains unchanged in the adult, but the HA concentration undergoes a fourfold increase in both cattle and humans (Balazs, 1982; Balazs et al., 1959). This change in the HA-to-collagen ratio contributes to greater dispersal of the collagen fibrils, because the newly synthesized HA molecules push the collagen fibril bundles further apart, thus increasing the optical clarity of the vitreous. These changes in HA–collagen interactions as well as in the GAG contents of the vitreous do not cease upon reaching adulthood. Rather, these alterations continue throughout life, and they are believed to be responsible for the vitreal liquefaction observed as part of the aging process in some species (Sebag, 1989). In humans, rheologic (i.e., the gel-liquid state of the vitreous) changes begin in the central vitreous at 5 years of age and continue throughout life, so that in the geriatric patient, more than 50% of the vitreous is eventually liquefied (Balazs, 1982). As liquefaction progresses, the collagen bundles are packed into the remaining gel fraction, whereas HA molecules are redistributed to the liquid fraction. A common complication of this progressive liquefaction is separation of the posterior vitreous cortex from the retinal inner limiting membrane. This detachment, which predisposes to retinal tears, has been implicated as a risk factor in rhegmatogenous retinal detachment in dogs (Hendrix et al., 1993).

The Vitreous

Vitreous Functions

Vitreal Structure and Aging Physically, the vitreous is a hydrogel that consists of >98% water and fills the posterior cavity of the eye. Collagen comprises the framework of the vitreous and provides its plasticity. Despite the low protein content, a diverse array of >1,200 soluble proteins have been identified in the vitreous (Murthy et  al., 2014). Spaces between the collagen fibers are filled with hyaluronic acid (HA), which provides viscoelasticity to the vitreous (Fig. 3.8). An increase in the collagen content of the vitreous makes it more solid, or gel-like, while a decrease in the collagen content makes its consistency more fluid. Species differ in the collagen content of their vitreous, which accounts for variability in its consistency. Generally, the cortical areas of the vitreous contain more collagen, so they are more rigid than other portions. The vitreous contains few cells, termed hyalocytes. Hyalocytes belong to the monocyte/macrophage lineage and derive from bone marrow. Their origin is not from glial cells or retinal pigment epithelial

The vitreous is the largest structure in the eye, occupying approximately 80% of the globe (Sebag, 1989). It contributes to the development, optics, structure, physiology, and metabolism of the eye. The vitreous plays an important role in the growth of the eye by contributing to the increase in globe size. Inserting a drainage tube into the vitreous cavity of chicken embryos lowers intravitreal pressure and effectively stops the growth of the eye, and vitrectomy of rabbit eyes has a similar inhibitory effect (Arciniegas et al., 1980; Coulombre, 1956). By contrast, vitreal elongation will cause an increase in the axial length of the globe. This lengthens the path of the incoming light, thus providing for greater light refraction. In some aquatic species, such as goldfish, this increased vitreal refractivity is a physiologic mechanism that compensates for the loss of refractive power when the cornea is submerged in water (Seltner et al., 1989). In terrestrial species, the increased refraction by the vitreous leads to myopia. Vitreal elongation resulting in axial myopia has been induced through visual deprivation in a number of species, including

151

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Section I: Basic Vision Sciences Connecting Fibril

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152

Figure 3.8  Schematic of the vitreal ultrastructure. Parallel collagen fibrils are packed into bundles that aggregate and, ultimately, form visible fibers. Hyaluronic acid and water molecules fill the interfibrillar spaces. (Modified with permission from Sebag, J. & Balazs, E.A. (1989) Morphology and ultrastructure of human vitreous fibers. Investigative Ophthalmology & Visual Science, 30, 1867–1873.)

Liquid Channel Collagen Fiber

Na-Hyaluronate Molecular Coils

nonhuman primates, chickens, and cats (Belkin et al., 1967; Hodos et al., 1985; Raviola & Wiesel, 1985). This elongation of the vitreous is affected by the synthesis of collagen. Synthesis, molecular reconfiguration, and hydration of HA molecules likewise change the volume of the vitreous and, hence, of the eye (Sebag, 1989). Diffusion is slow and bulk flow is limited in a gel such as the vitreous. Therefore, topically administered substances are prevented from reaching the retina and optic nerve and systemically administered antimicrobials are unable to reach the center of the vitreous (Lund-Andersen & Sander, 2011). This slow change of substance concentrations has been used in humans to determine time of death and aid in postmortem diagnosis in manatees (Swain et  al., 2015; Varela & Bossart, 2005). The optical transparency of the vitreous is primarily due to a low concentration of structural macromolecules (0.2% w/v) and soluble proteins (Lund-Andersen & Sander, 2011). Additionally, the configuration of highly hydrated glycosaminoglycan chains separating small-diameter collagen fibers aids in the passage of light with minimal scattering (Bettelheim & Balazs, 1968). Another important factor in optical clarity is the blood–vitreous barrier; HA is thought to act as a barrier that prevents diffusion of macromolecules and cells into the vitreous, except in cases of trauma or cortex disruption (Hultsch, 1977). Inflammatory responses, neovascularization, and collagenase activity are likewise suppressed in the vitreous (Hultsch, 1977; Jacobson et al., 1985; Lutty et al., 1983). As a result of these anatomic and physiologic properties, the vitreous trans-

mits 90% of light at wavelengths between 300 and 1400 nm (Boettner & Wolter, 1962). In addition to its refractive role, the vitreous appears to have additional functions in the process of accommodation. In both humans and monkeys, imaging has revealed that the vitreous bows posteriorly as the ciliary body contracts (Croft et al., 2013). This movement is in proportion to the accommodative amplitude. The vitreous also plays an important role in ocular metabolism. It serves as a storage site for retinal metabolites, including glycogen, amino acids, and potassium (Newman, 1984; Reddy, 1979; Weiss, 1972). Retinal and lenticular waste products, including lactic acid and free radicals, are absorbed by the vitreous, which thus serves to protect the lens and retina from toxic compounds (Sebag, 1989; Ueno et al., 1987). In cattle, these molecules (and water) can diffuse across the vitreous through pores that are 400 nm in diameter (Fatt, 1977). HA serves as a barrier to this diffusion process (Foulds et al., 1985); therefore, molecule size and HA concentration are two of the primary factors affecting the diffusion of molecules through the vitreous. A decrease in HA concentration, which results in vitreous liquefaction, will thus lead to an increase in particle diffusion through the vitreous. Therefore, pathologic or aging processes leading to a decreased HA concentration and vitreal liquefaction will affect the nutrient supply, waste removal, and drug delivery in the posterior segment of the eye (Balazs & Denlinger, 1982). The vitreous also provides some mechanical and structural support to the lens and retina (Schmidt & Coulter, 1981). Furthermore, its viscoelastic properties protect the internal eye structures from trauma and stress, especially

during rapid eye movement (REM). Concentrations of ­collagen and HA, as well as the nature of their cross-links, contribute to this viscoelasticity. For example, in humans, the concentration of vitreal HA and collagen is twice as high as in the pig, and this corresponds to a 60% increase in the spring constant of human versus porcine vitreous (Weber et al., 1982). Woodpecker vitreous differs from human vitreous in that it does not have vitreo-retinal attachments. This lack of coupling of the vitreous to the posterior pole, as well as the orientation of the eye with respect to the axis of striking, is thought to reduce relative shearing motions that would be expected to result in ocular trauma from the ­woodpecker’s rapid acceleration–deceleration movements (Wygnanski-Jaffe et al., 2007).

Ocular Mobility As Chapter 5 discusses, higher-resolution vision is subserved by a small section of the retina termed the area centralis. Visual acuity as well as other parameters of vision (e.g., color perception) decrease rapidly in the more peripheral retina outside the area centralis. To keep an object of interest in the center of the visual field, so that its image will stimulate the area centralis (or fovea in birds and primates), vertebrates rely on the actions of six or seven EOM. Domestic species have four rectus EOM  –  dorsal (or superior), ventral (inferior), nasal (medial), and temporal (lateral)  –  all of which move the eye in those respective directions (see Chapter 2). The oculomotor nerve (CN III) innervates the dorsal, ventral, and medial rectus muscles, and the abducens nerve (CN VI) innervates the lateral rectus muscle. Two oblique muscles that work in conjunction with the rectus muscles are also present. The ventral oblique, which is innervated by the oculomotor nerve, rotates the ventral aspect of the eyeball both nasally and dorsally; the dorsal oblique, which is innervated by the trochlear nerve (CN IV), rotates the dorsal aspect of the eyeball both nasally and ventrally. These muscles keep vision horizontally level irrespective of eye position in the orbit. The retractor bulbi, which is present in most species other than primates and birds, is innervated by CN VI and pulls the globe deeper within the orbit. The EOM contain both fast (~85%) and slow (~15%) fibers; however, in contrast to noncranial skeletal muscles, they exhibit both very fast contractility and extreme fatigue resistance. Even among the EOM there is great variation in the composition of each muscle in regard to the myosin heavy chain isoforms that assist with the dynamic physiologic properties and CNS control of eye movements (McLoon, 2011). The EOM are highly aerobic as well as resistant to injury and oxidative stress, with only cardiac muscle having a higher blood flow rate (Wooten & Reis, 1972). Additionally, normal EOM undergo myonuclear addition and subtraction

throughout life while maintaining overall size and function, which is not observed in any noncranial muscles (McLoon et  al., 2004). A motor axon innervates five to ten muscle fibers in the extrinsic eye muscles, whereas thousands may be innervated by a single axon in skeletal muscles, thus allowing for finer control of eye muscles by the CNS (Gum & MacKay, 2013). The EOM of the eyes of birds are generally similar to those of mammals, other than the lack of a retractor bulbi muscle. In addition, the rectus muscles are much less robust than in mammals. Globe shape varies considerably among avian species, but the globes are relatively large, such that the two eyes weigh nearly as much as the brain (Martin, 1982). The globe shape and tight fit within the orbit impede globe movement, thus leading to the less robust rectus muscles. Birds compensate for this restricted globe mobility through ­movement of upper body and neck muscles to obtain a spatial perspective on objects. Simplistically, two fundamental laws govern eye movements. The first, formulated by Sherrington, states that antagonistic muscles (in the same eye) have reciprocal innervation. In other words, stimulation of an agonistic muscle (e.g., medial rectus) occurs concurrently with inhibition of the antagonistic muscle (e.g., lateral rectus) in the same eye (Sherrington, 1947). The second governs innervation of yoked muscle pairs (i.e., the two muscles responsible for moving both eyes in the same direction). In the 19th century, Hering, (1977) discovered that in mammals, yoked muscle pairs are always equally innervated; therefore, a lateral movement of the left eye will be accompanied by an identical, medial movement of the right eye. Additionally, several EOM pulley systems have been hypothesized but not proven (Miller, 2019). The seven EOM are responsible for numerous types of eye movements. Saccadic eye movements are very rapid (up to 1000°/s) and very brief ( 1), it follows that c > ν; that is, the speed of light in the new medium (ν) is less than it was in vacuum (c). For the same reason (n > 1), it follows that λ > λm; that is, the wavelength of light in the new medium (λm) is shorter than it was in vacuum (λ). The third change that occurs when light passes into a dense medium is bending, or refraction. The amount of refraction that occurs as light passes from one medium to another is described by Snell’s law (Fig.  4.4) and is determined by the angle of incidence and by the refractive indices

θi

ni

nr

θr ni ∙ sin θi = nr ∙ sin θr

Figure 4.4  Refraction of light as it passes from one medium to another is governed by Snell’s law, summarized in the formula below the diagram. The angle of refraction (θr) is a function of the angle of incidence (θi) and the refractive indices of the two mediums. In this representation, ni < nr; therefore, θi > θr.

SECTION I

light. Thus, when cumulative transmittances are calculated for the successive components of the eye, a maximal transmittance rate in humans of 84% is obtained for light between 650 and 850 nm (Boettner & Wolter, 1962), while in rabbits the transmittance rate for light between 370 and 500 nm is 90% (McLaren & Brubaker, 1996). Obviously, transmission will be further reduced by ocular opacities. Grade II nuclear cataracts in rats cause a 50% reduction in transmission of light compared with grade I cataracts (Nishimoto & Sasaki, 1995), and in humans the light scatter index for nuclear cataracts is twice that of cortical cataracts (Siik et al., 1999). Age is another factor affecting transmittance. Transmission of light at 480 nm through the human lens decreases by 72% from the age of 10 years to the age of 80 years (Kessel et al., 2010), thus affecting the color perception of the elderly. Surprisingly, however, studies have failed to demonstrate age-related decline in transmittance in the human cornea (van den Berg & Tan, 1994). Ocular surfaces can also reflect back incoming light, depending on the angle of incidence. Light that strikes a surface at an oblique angle is reflected back; it is not transmitted into the new medium. The critical angle for reflection is determined by the difference in the indices of refraction between the two media (discussed in the next section). Most of the reflection that takes place in the eye occurs as incoming light strikes the cornea because of the large difference in refraction indices between the cornea and air. Reflection that occurs at the cornea–air interface affects not only incoming light, but also outgoing light. Thus, internal reflection of outgoing light back into the eye prevents the ophthalmologist from examining the iridocorneal angle. Goniolenses filled with fluid are used to decrease the difference in refractive indices between the cornea and air, thus increasing the critical angle and permitting rays emanating from the iridocorneal angle to pass through the cornea (Wilson, 2006). Light that is not transmitted and not reflected can be either scattered in the eye or absorbed by pigments. Foremost among these pigments are the photopigments of the photoreceptor outer segments, which absorb photons and thus initiate the visual process. Additional absorption processes in the eye may have clinical implications. Cyclophotocoagulation in glaucoma patients is based on the preferential absorbance of 810 and 1064 nm radiation of the diode and Nd : YAG lasers, respectively, by melanincontaining tissue (Bras & Maggio, 2015). In addition, absorption of UV solar radiation has been implicated in diseases such as canine chronic superficial keratitis (Chandler et al., 2008), squamous cell carcinoma in cattle (Pausch et  al., 2012), and pterygium (Zhou et  al., 2016), cataract, and macular degeneration in humans (Delcourt et al., 2014). The interaction of the cornea with UV light may also hold implications for corneal cross-linking treatment (Lombardo et al., 2015).

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of both media. Because various structures of the eye differ in their refraction indices, light is successively refracted (bent) as it passes from air through the precorneal tear film (PTF), cornea, aqueous humor, lens, and vitreous on its way to the retina (see the next section, “Visual Optics”).

The vergence power (i.e., amount of bending) of a lens is measured in units called diopters. One diopter (D) is the vergence power of a lens with a focal length (f) of 1 m when in air. In broader terms,

Vergence

The focal length of a lens is the distance between the center of the lens and the point at which parallel rays of light are brought into focus by that lens. The focal length of a lens is directly proportional to its curvature radius. Therefore, the vergence power (or the diopter power) of the lens increases as its curvature increases (or its radius of curvature decreases). For example, a convex lens with a focal length of 0.1 m will have a power of +10 D (D = 1/f = 1/0.1 m = 10 D), while a flatter convex lens with a focal length of 0.2 m will be “weaker,” with a power of +5 D (D = 1/f = 1/0.2 m = 5 D; compare Fig. 4.5A and Fig. 4.5B). On the other hand, a concave lens with a focal length of 0.2 m will have a power of −5 D (Fig. 4.5C). The vergence powers of lenses in an optical system are additive. Thus, if the lenses in Fig. 4.5A and Fig. 4.5B were placed next to each other, the resulting optical system would have a theoretical power of +15 D. If all three lenses in Fig.  4.5 were combined into one system, it would have a power of +10 D. This principle also holds in the eye, as the refractive contributions of the successive ocular surfaces are added to form a focused or blurred image on the outer segments of the photoreceptors. As noted, the former formula describes the refractive powers of lenses in air. When placed in a medium with a refractive index n, the refractive power of the lens is described by the formula

An object that bends (or refracts) light is called a lens. When a single ray of light strikes a lens, the ray undergoes simple refraction, as depicted in Fig.  4.4. Most objects or images, however, generate a pencil of light rays rather than a single ray. When a pencil of rays strikes a lens, they spread apart (i.e., diverge) or come together (i.e., converge). Convergence, or positive vergence, occurs when light strikes a convex lens (Fig. 4.5A, B). Such a lens has a positive power, indicating that it forms a real image, which means that incoming rays from the object are converged and focused on the other side of the lens (see Fig. 4.5A, B). On the other hand, divergence, or negative vergence, occurs when light strikes a concave lens (Fig. 4.5C). The negative power of the concave lens indicates that it forms a virtual or aerial image, which means that the diverging rays are traced, using imaginary extensions, backward to a “focused” virtual image “located” on the same side of the lens as the object (dashed, “imaginary” lines in Fig. 4.5C).

A

D 1/f .

D

n /f .

Since n > 1 for any medium other than vacuum, it follows that the refractive power of the lens is reduced in other media. This is what happens to lenses in the eye, an effect that is described in detail in the following section. B

Visual Optics Refractive Structures of the Eye Precorneal Tear Film and Cornea

C Figure 4.5  Refraction of light through various lenses. A. A spherical convex lens with a power of 10 D focuses parallel light rays at a distance of 0.1 m. B. A flatter, less spherical convex lens with a power of 5 D focuses parallel rays at a distance of 0.2 m. C. Parallel rays passing through a concave spherical lens diverge. A virtual image is formed by tracing back (dashed lines) the diverging rays.

As mentioned, light is successively refracted by the various ocular structures as it passes through the eye on its way to the retina. Table 4.2 lists the refractive indices and powers of various ocular surfaces in humans. The most anterior optical surface of the eye is the PTF. By strict definition, it could be argued that the tear film is the most refractive layer of the eye. This is due to the large difference in refractive indices as light passes from air, which has a refractive index of almost 1, into the tear film, which has a refractive index of 1.337 (Barbero, 2006). Factoring the refractive indices of air and the tear film into Snell’s law reveals that the human PTF has

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173

Structure

Refractive Index

Refractive Power (D)

Reference

Tear film

1.336

43.0a

Montes-Mico et al. (2004)

Cornea

1.376

42.3a

Duke-Elder (1970); Naeser et al. (2016)

  Anterior surface

1.401

48.2

Patel et al. (1995)

  Posterior surface

1.373

−5.9

Patel et al. (1995)

Lens

1.41

21.9

Chang et al. (2017); Duke-Elder (1970)

  Anterior surface   Posterior surface

8.4

Millodot (1982)

14.0

Millodot (1982)

Vitreous/aqueous

1.336

Duke-Elder (1970)

Retina

1.363

Millodot (1982)

a

 The refractive power of the cornea and tears is not additive. Rather, that of the former arises from the latter, and from its interface with air. The net power of the tears and the anterior and posterior cornea is 43 D.

a refractive power of 43 D (Montes-Mico et  al., 2004). Alterations in the composition (Fish et al., 2004) or breakup time (Montes-Mico et al., 2004) of the PTF may change the refractive power of the eye by as much as 1.3 D and may contribute to the blurry vision complaints commonly encountered in (human) dry eye patients (Koh, 2016). Conversely, successful treatment of dry eye can cause a significant improvement in blurred vision (Toshida et  al., 2017). The effect of PTF deficiencies on the quality of vision in animal patients has yet to be studied. The cornea is the next organ through which incoming light passes. As can be seen in Table 4.2, the human corneal stroma has a refractive index of 1.376. Because this value is slightly higher than the refractive index of the tear film, passage of light from the PTF into the anterior layers of the cornea results in an additional 5 D of refractive power (Courville et al., 2004). However, these 5 D are “lost” when light passes from the posterior cornea into the aqueous humor, which has a refractive index nearly identical to that of the PTF. When combined, the PTF and the cornea of humans contribute a net refractive power of 43 D. Strictly speaking, these 43 D are contributed by the tear film, as they are due to the large difference between the refractive indices of air and the PTF. Still, by convention, this power is usually attributed to the cornea (see Table  4.2). Therefore, in humans, for example, the cornea contributes approximately 70% of the total 60 D power of the eye, thus making it our largest refractive organ (Courville et al., 2004). Another factor affecting the refractive power of the cornea, besides the refractive index, is its curvature. Because the cornea converges light, it acts as a convex lens. As stated earlier, the refractive power of such a lens depends to a large extent on its curvature radius. Therefore, in large eyes, which are characterized by relatively flat corneas, the refractive power of the ­cornea is reduced. Conversely, in small eyes with more spherical corneas, its power is increased. Table 4.3 shows that

the inverse relationship between globe axial length and the refractive power of the cornea is maintained across a large range of species. Furthermore, the central and peripheral corneas have different curvatures and consequently differ in their refractive powers (see “Spherical and Chromatic Aberrations” later in this chapter). It is suggested that evolutionary changes in corneal curvature and shape, especially between mammalian and nonmammalian species, are reflected in collagen lamellar organization in the stroma (Winkler et al., 2015). Lens

As noted, because of the similar refractive indices of the cornea and aqueous humor, the refraction that occurs as light passes from the former into the latter and during its passage through the aqueous has little overall optical significance. Therefore, the next significant refractive structure through which light passes after the cornea is the lens (see Table 4.2 and Table  4.4). As in the case of the cornea, the refractive power of the lens is determined by both its refractive index and its curvature. In humans and in many nonaquatic species, the refractive index of the lens nucleus is about 1.41; it decreases gradually toward the cortex, forming a bell-shaped refractive index curve known as the gradient index (GRIN). In humans, the refractive index in the subcapsular regions is about 1.38 (Piersckionek & Regini, 2012). Since these values are relatively similar to that of the aqueous humor (range, in most species, 1.334–1.338), the lens in these species has a rather low refractive power (Hughes, 1977). In humans, the calculated refractive power of the lens is approximately 22 D (Chang et al., 2017). The implication of this value is that contrary to the popular belief of the general public, the lens is not the main refractive organ of the eye, as its refractive power is less than half of that of the human cornea. The refractive index of the lens increases in aquatic species, where it can be as high as 1.66, resulting in significantly higher refractive power (Sivak, 1978).

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Table 4.2  Refraction constants in the human eye.

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Table 4.3  Eye size (ascending order) and corneal power (descending order) in selected animal species.

a

Species

Axial Length (mm)

Corneal Power (D)

References

Goldfish

4.2

129 (in air)

Hughes (1977)

Rat

6.3

112.7

Hughes (1977)

Chicken

8.9

108

Cohen et al. (2008)

Guinea pig

8.9

83.9

Howlett & McFadden (2007)

Sea otter

14.0

59.2

Murphy et al. (1990)

Rhesus monkey (4 months)

16.3

56

Qiao-Grider et al. (2010)

Rabbit

18.0

44.6

Hughes (1977); Wang et al. (2014)

Cat

21.3

43.0

Habib et al. (1995) a

Dog

19.5–21.9

37.8–43.2

Gaiddon et al. (1991); Nelms et al. (1994); Rosolen et al. (1995)

Ostrich

38.0

25.3

Martin et al. (2001)

Elephant

38.8

21.3

Murphy et al. (1992a)

Horse

39.2

16.5 D

McMullen & Gilger (2006)

Horse

43.7

15.7–19.5

Farrall & Handscombe (1990); Miller & Murphy (2017)

 The range of values in the dog probably reflects a breed difference, because larger breeds have flatter corneas (Gaiddon et al., 1991).

Table 4.4  Lens power and refractive indices (both in descending order) in selected animal species. Species

Lens Power (D)

Refractive Index

References

Rat

243.9

1.683

Hughes (1977)

Guinea pig

160.0

1.649

Howlett & McFadden (2007)

Rabbit

75.0

1.6

Hughes (1977)

58a

a b

Sanchez et al. (2017)

Cat

52.9

1.554

Hughes (1977)

Cynomolgus monkey

52.0

1.42

Borja et al. (2010)

Chicken (90 days)

48.1

1.44

Dog

41.5b

Horse

14.9–15.4

Horse

14b

Iribarren et al. (2014) Davidson et al. (1993)

1.42

Farrall & Handscombe (1990); Mouney et al. (2012) Harrington et al. (2013); Townsend et al. (2012)

Calculated value; Value is based on dioptric strength of intraocular lens needed to regain emmetropia in pseudophakic patients.

The second factor determining lenticular refractivity, the lens curvature, also differs between aquatic and nonaquatic species. Generally, it can be said that the lens is spherical in fish and aquatic mammals, while it is more discoid (i.e., less spherical) in terrestrial species (see Fig. 4.5A and Fig. 4.5B, respectively). Therefore, the lens will have a higher refractive power in the former compared to the latter. The reason for the increased refractive index and lens curvature in aquatic species is the loss of corneal refractive power under water and is discussed later in this chapter. Of course, the curvature (and hence the refractive power) of the lens can also be changed actively through a process termed accommodation (see the next section).

Vitreous

The next refractive organ is the vitreous. Though there is little refraction as light passes from the lens into the vitreous (due to their similar refractive indices), the vitreous plays an important role in the refractive development of the eye. Vitreous elongation increases the axial length of the eye, thereby increasing the refractive path of light and inducing myopia, or nearsightedness (Fig.  4.6). In certain fish, this mechanism serves to increase ocular refraction and compensate for loss of corneal refractive power. In different goldfish strains, for example, the vitreous body can contribute anywhere from 37% to 70% of the total axial length of the eye (Seltner et al., 1989). In visual deprivation studies conducted

A

Focal Plane

B

by pilocarpine (Ostrin et  al., 2014). For a comprehensive review of comparative accommodation in animals, the reader is referred to Ott (2006). Humans and other primates accommodate by changing the curvature of the lens (Fig. 4.7). To view distant objects, sympathetic innervation induces relaxation of the ciliary body muscle, which in turn leads to stretching of the lens zonules. The increased tension of the zonules results in a greater pull on the lens capsule, thus causing the lens to become more discoid and decreasing its overall axial thickness and refractive power in a process of disaccommodation (see Fig. 4.5B and Fig. 4.7B; Glasser, 2011). To accommodate for near objects, the reverse process takes place. Parasym­ pathetic input induces contraction of the ciliary body muscles, leading to relaxation of the zonular fibers and reduced tension on the lens capsule. In turn, this liberates the inherent elasticity of the lens, resulting in a more spherical lens possessing greater axial thickness and refractive power (Fig.  4.4A and Fig. 4.7A; Glasser, 2011; Hughes, 1977). Consequently, anterior chamber depth decreases and

Figure 4.6  The effect of vitreous elongation on ocular refraction. A. A focused, emmetropic eye. B. The refractive power of the eye has not changed, and the light is focused on the same spot as in panel A. However, due to vitreous elongation, the retina has moved posteriorly, and therefore the light is now focused in front of the retina. As a result, the eye is now nearsighted, or myopic.

during critical developmental periods in species as diverse as chickens (Stone et al., 2016), fish (Sivak, 2008), tree shrews (Gawne et al., 2017), and nonhuman primates (Smith et al., 2015), the deprivation-induced myopia was a result of elongation of the vitreous body.

Accommodation

A

Disaccommodation

B

Accommodation

Accommodation is a rapid change in the refractive power of the eye, which is intended to bring the images of objects at different distances into focus on the retina. The stimulus for the accommodative response is a blurred, or defocused, retinal image (Buehren & Collins, 2006). In vertebrates, eyes accommodate by one or more of the following mechanisms (Glasser, 2011): 1) Changing the curvature or position of the lens. 2) Changing the corneal curvature. 3) Changing the distance between the cornea and retina. 4) Having two or more separate optical pathways of ­different refractive powers (discussed under “Static Accommodation” later in this chapter). Accommodation is most commonly measured using infrared photoretinoscopy, which uses reflection of IR light from the fundus to measure dynamic changes in the refractive error. Since mammalian accommodation is mediated by contraction of the smooth ciliary muscle, it can be stimulated

Figure 4.7  Accommodation in the primate lens. A. In an accommodated eye, the ciliary muscle contracts, causing the lens to become more spherical, thereby increasing its refractive power. Light from nearby objects (blue lines) is focused on the retina (emmetropia), whereas light from distant objects (parallel red lines) is focused in front of the retina (myopia, or nearsightedness). B. At rest the lens is discoid (flat) because of relaxation of the ciliary muscle (disaccommodation). In this state, incoming light from distant objects (parallel red lines) is focused on the retina (emmetropia), whereas light from nearby objects (blue lines) is focused behind the retina (hyperopia, or farsightedness). (Reproduced with permission from Maggs, D.J., Miller, P.E., & Ofri, R. (2018) Slatter’s Fundamentals of Veterinary Ophthalmology, 6th ed. St Louis, MO: Elsevier.)

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increases during accommodation and disaccommodation, respectively. The resulting changes in lenticular curvature allow primates such as the young (< 5 years) rhesus monkey to accommodate by as much as 34 D (Bito et al., 1982). As the animal ages, however, it gradually loses its accommodative capability in a process termed presbyopia, and monkeys older than 25 years can accommodate only by an average of 5 D (Bito et  al., 1982). A similar and dramatic age-related reduction has been reported in the chicken, as lenticular accommodation decreases from more than 20 D at hatching to less than 5 D at 1 year of age (Choh et  al., 2002b). In humans, presbyopia causes a reduction of 0.32 D per year in the refractive power (Croft et  al., 2013). Mechanisms proposed for presbyopia include reduction in ciliary muscle contractility, changes in the refractive index of the lens, agerelated changes in the relative position of the lens and ciliary body, and loss of the lens capsule and lens fiber elasticity (Charman, 2008; Glasser, 2011; Reilly, 2014). As with most other aspects of vision research, the mammalian species in which accommodative capabilities have been studied most extensively is the cat. The elasticity of the feline lens capsule is only 5% of the elasticity in humans; thus, the cat is incapable of accommodating by changing its lens curvature (Fisher, 1971). Instead, translation (i.e., the anteroposterior movement of the entire lens) is responsible for accommodative changes in the feline eye (Glasser, 2003; Hughes, 1977; Ott, 2006; Sunderland & O’Neil, 1976). This movement is made possible by the relative abundance of meridional (i.e., longitudinal) fibers in the feline ciliary body muscle and by the relative scarcity of circular fibers, which predominate in primates (Ebersberger et  al., 1993; Prince et al., 1960). Parasympathetic stimulation of the meri­dional muscle fibers in the cat results in anterior displacement of the lens by up to 0.6 mm (O’Neill & Brodkey, 1969), thus inducing anywhere between 2 and 4 D of accommodation (Ott, 2006). The dog’s accommodative power is reportedly lower, only 1–3 D in range (Hughes, 1977; Miller & Murphy, 1995). Factoring these accommodative powers into the D = 1/f formula reveals that though cats and dogs can focus on distant object (by disaccommodating), their depth of field for nearby objects is 50–25 cm (cats) and 100–33 cm (dogs). Closer objects are usually perceived using the sense of smell. In other carnivore species, the same translation mechanism is used to achieve a significantly greater magnitude of accommodation. Anterior lens movement in the raccoon induces accommodation of up to 19 D, 6× more than in the dog (Rohen et al., 1989), while the mongoose accommodates up to 13.5 D (Ott, 2006). A similar wide range of accommodative capability also exists in other closely related species. For example, the gray squirrel does not accommodate (McBrien et  al., 1993), whereas the California ground squirrel can accommodate up to 6 D (McCourt & Jacobs, 1984). It should be noted that in mammals, translation of the accommodating lens results from ciliary muscle contraction, but in teleost

fish, it is affected by a specialized smooth muscle, the retractor lentis, which pulls the lens backward to focus on distant objects (Khorramshahi et  al., 2008). Snakes also accommodate by moving their lens. However, as snakes lack a ciliary muscle, accommodation is accomplished by contraction of the iris, which causes an increase in vitreous pressure that pushes the lens anteriorly (Fontenot, 2008). And in cetaceans, anterior lens displacement is due to increased intraocular pressure mediated by contraction of the retractor bulbi muscle (Mass & Supin, 2007). Rodents (Artal et  al., 1998) and ruminants (Piggins & Phillips, 1996) are generally described as lacking accommodative capabilities. In the former, this lack of accommodation is explained by the absence of a well-defined ciliary muscle (Samuelson, 1996), though the small pupil size and short axial length in species such as the rat and mouse provide these animals with a significant depth of focus (Geng et al., 2011). Lack of accommodation in ruminants, some of which possess a more developed ciliary muscle (Samuelson, 1996; Samuelson & Lewis, 1995), is more difficult to explain, and may be a consequence of the cytoarchitecture of the lens fibers (Kuszak et al., 2006). Other ungulates also have a very limited accommodative capability. Horses, for example, can accommodate only ±1 D (Miller & Murphy, 2017; Sivak & Allen, 1975). Another species in which accommodation has been studied extensively is the chicken, which employs several accommodative mechanisms, enabled by the presence of three ciliary muscles: anterior (Crampton’s muscle), intermediary (Müller’s muscle), and posterior (Brücke’s muscle) (Tedesco et  al., 2005). Lenticular accommodation in the chicken is mediated by the intermediary and posterior ciliary muscles, which (as in mammals) are parasympathetically innervated by postganglionic ciliary nerves. However, several unique anatomic adaptations combine to significantly increase the lenticular accommodative capability of the chicken compared to that of mammals (Fig. 4.8). These include very large ciliary processes, as well as a ring of columnar epithelial cells at the equatorial periphery of the lens (i.e., the annular pad), which increases the diameter of the lens and its contact area with the processes. Lenses are soft and malleable, and the corneoscleral sulcus, which exists as a consequence of the scleral ossicles, permits a greater range of movement (Choh et al., 2002a). Together, these structures make it possible for contraction of the intermediary and posterior ciliary muscles to directly squeeze the lens, as compared to the indirect effect of the mammalian ciliary muscle, which is transmitted to the lens through the zonules. Contraction of the peripheral iris (Ostrin et al., 2011), as well as the posterior and intermediary ciliary muscles (West et al., 1991), induces thickening of the lens by 0.2 mm, steepening of its curvature, and a bulging of the lens into both the anterior and vitreous chambers (Choh et al., 2002a). The cumulative results of all these mechanisms is 15–19 D of lenticular accommodation (Choh et al., 2002a).

inner lamella of the cornea

cornea

circumferential muscle fibers of the iris pectinate ligament Crampton’s muscle scleral ossicle Brücke’s muscle

annular pad

lens

tenacular ligament

Figure 4.8  A generalized scheme of the mechanism of accommodation in birds. Left side: Relaxed state. Note the deep corneoscleral sulcus, the presence of Brucke’s and Crampton’s muscle (Müller’s muscle not shown), the annular pad, and the lack of zonules, which allows direct contact between the ciliary processes and annular pad. All of these features contribute to the great accommodative power of the chicken eye (see text for details). Right side: An accommodated state. The black arrows show the direction of the contracting muscle forces. The open arrowheads show the resulting deformation of both the cornea and the lens. Similar mechanisms have also been found in lizards, snakes, and turtles. (Reproduced with permission from Ott, M. (2006) Visual accommodation in vertebrates: Mechanisms, physiological response and stimuli. Journal of Comparative Physiology A, 192(2), 97–11.)

Unlike mammals, chickens (and possibly lizards) also accommodate by changing the corneal curvature. Corneal accommodation is mediated by the anterior ciliary muscle. Contraction of Crampton’s muscle, which originates in the sclera and inserts in the cornea, flattens the peripheral cornea and increases the curvature of the central cornea (see Fig. 4.8; Chu et al., 2014; Murphy et al., 1995). Corneal accommodation is reported to play an important role in chicken accommodation, contributing 8–9 D (Glasser et al., 1994; Schaeffel & Howland, 1987). Thus, the reported combined (corneal and lenticular) accommodative power of the eye in young chicks is 25 D (Ostrin et al., 2011), compared with a maximal power of 15 D in children (Glasser, 2011). It should be noted that the chicken, as well as other avian (Schaeffel & Wagner, 1992) and reptile (Schmid et al., 1992) species, can accommodate independently in both eyes, potentially resulting in anisometropia (i.e., unequal degree of refraction in the two eyes) of up to 6 D. Similar corneal and lenticular mechanisms of accommodation exist in lizards (Ott, 2006). Finally, in chickens even the choroid plays a role in focusing light on the retina. By changing its choroidal thickness,

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the chicken changes the distance between the retina and the cornea. The result is that in addition to bringing the focal point of incoming light onto the retina (by lenticular and/or corneal accommodation), chickens can also use “choroidal accommodation” to bring the retina into the focal point of the light (a twist on the proverb “If the mountain will not come to Mohammed, Mohammed will go to the mountain”). Once again, the choroidal “accommodation” is mediated by parasympathetic and sympathetic innervation. Transient thickening of the choroid in response to a blurred image is accomplished by changing either the volume of fluid (blood and aqueous humor) flowing through the choroid, or the tone of the choroidal smooth muscle (Nickla & Wallman, 2010). Long-lasting thickening is due to choroidal and scleral remodeling. Additional Refraction in the Pupil and Elsewhere

The pupillary aperture is not considered to be a classic refractive structure as it has no refractive index, but it does make an important contribution to the resolving power of the eye. As the pupil dilates in dim light, the number of photons entering the eye increases, resulting in increased retinal illumination.

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But there is “a price to be paid” for this increased illumination, as mydriasis also decreases the depth of focus of the eye. This means that as the pupil dilates, the range of distances at which objects remain in focus decreases. For example, in an eye that is focused at a distance of 1 m, objects at a distance of between 0.56 and 5.00 m will be in focus when pupil diameter is 1 mm; the range decreases to between 0.78 and 1.40 m when the pupil dilates to 4 mm (Duke-Elder, 1970). This is especially critical in species that have limited accommodative capability, such as the dog. Furthermore, as the pupil dilates, the relative significance of spherical and chromatic aberrations inherent in the eye increases (see the section on “Spherical and Chromatic Aberrations”), thereby reducing its resolving power. Therefore, the pupillary light reflex is, in effect, a constant balancing of two conflicting requirements for vision: maximal retinal illumination and visual resolution. In a scotopic environment, the pupil dilates to improve retinal illumination at the cost of decreased nighttime resolution (which is further attenuated by cone inactivity). In a photopic environment, pupillary constriction improves visual resolution (which is further enhanced by cone activity). As a rule of thumb, constricting the pupil by half increases visual resolution by a factor of two (Duke-Elder, 1970). The “cost” of miosis in a photopic environment is negligible, as there is sufficient retinal illumination under these conditions. This balancing of retinal illumination and visual resolution is especially dramatic in deep-diving animals, which move rapidly from one environment to another. In the Northern elephant seal (Mirounga angustirostris), it has been demonstrated that the pupil constricts from a giant area of 422 mm2 in dark-adapted conditions (approximately 23 mm in diameter) to a pinhole opening of 0.9 mm2 in light-adapted conditions; that is, the range of variation is almost 470 times (Levenson & Schusterman, 1997)! It should be noted that light is also refracted during its passage through ocular structures such as the cornea and lens, not just at their interface with other structures. This refraction results from changes in refractive indices in various layers of these structures. Some of these refractive gradients are probably too small to affect the overall optical performance of the eye, however. For example, refractive indices in the various corneal layers range from 1.401 to 1.373 D in humans (Patel et  al., 1995), whereas the rat retina has a refractive range of 1.369 to 1.385 D (Chen, 1993). But in other cases, regional differences are significant and must be taken into account; for example, in the goldfish eye, the refractive indices of the lens cortex and nucleus are 1.35 and 1.57 D, respectively (Axelrod et al., 1988).

Abnormal Refractive States and Optical Errors Emmetropia and Ametropia

The “purpose” the refractive and the accommodative processes described in the previous sections is to focus an image on the outer segments of the photoreceptors. An emmetropic

eye is one in which parallel light rays (from a distant object) are focused on the outer segments when the eye is disaccommodated. A nonemmetropic, or ametropic, eye is one in which the focused image (from a distant object) falls anterior to the retina (i.e., nearsighted or myopic eye) or posterior to it (i.e., farsighted, hyperopic or hypermetropic eye; Fig. 4.9). Retinoscopy is the most commonly used method to determine the refractive state of the eye. It is based on two assumptions: first, that light emerging from the eye (i.e., emergent rays) follows the same optical path as light entering the eye; and second, that the fundus reflex originates at the level of the outer segments. If those two assumptions hold, then emergent rays exit an emmetropic eye as parallel rays, a hypermetropic eye as diverging rays, and a myopic eye as converging rays (Davidson, 1997). Therefore, the location of the focal point formed by the emergent rays can be used to determine the refractive state of the eye.

A

B

C Figure 4.9  A. In emmetropia, parallel light rays are focused on the retina. B. In a farsighted (hypermetropic or hyperopic) eye, light rays are focused behind the retina. C. In a nearsighted (myopic) eye, the light is focused in front of the retina.

However, it should be noted that the second assumption is not completely accurate. The fundus reflex does not originate at the outer segments but closer to the observer, most likely at the level of the inner limiting membrane (Glickstein & Millodot, 1970). Thus, there is a gap (equal to the thickness of the retina) between the point at which the reflected light is actually measured and the point at which it should be measured. This gap, termed the artifact of retinoscopy, results in shifting refraction values in the direction of hypermetropia and needs to be corrected using an established formula (Glickstein & Millodot, 1970). This error is relatively minor (+0.25 D) in young humans (Millodot & O’Leary, 1978) and monkeys (+1.4 D; Hung et al., 2012), but it becomes significant in small eyes, reaching values as high as +7 D in tree shrews (Norton et  al., 2003). On the other hand, other researchers claim that the fundus reflex originates at the outer limiting membrane, and that the artifact’s significance has been overestimated (Mutti et al., 1997).

Table 4.5 lists refractive errors in selected species. Most of these values have been determined using streak retinoscopy, though autorefractors have also been used in veterinary medicine (Groth et al., 2013; Hernandez et al., 2016; Wang et  al., 2016). As can be seen, few species are truly emmetropic, though once the values are corrected for eye size, most mammals are within ±1 D of emmetropia (Hughes, 1977). A large survey found that on average, dogs are indeed emmetropic, with a mean refractive error of −0.05 D (Kubai et  al., 2008). Nine dog breeds  –  English Springer Spaniel, German Shepherd, Golden Retriever, Siberian Husky, Shetland Sheepdog, Labrador Retriever, Border Collie, Samoyed, and “other” terriers  –  were found to be emmetropic (defined as having a mean refractive error < 0.5 D in either direction). Yet the same study found that 8% of all dogs were hypermetropic, with a refractive error of up to +3.25 D. Three breeds (Australian Shepherd, Alaskan Malamute, and Bouvier des Flandres) were found to have a

Table 4.5  Refractive errors in selected animal speciesa Species

Refractive Value (D)

Cat by habitat

Belkin et al. (1977)

  Street cat

−0.8

  Laboratory cats

1.4

Cat by age

Konrade et al. (2012)

  Kitten ( 4 months)

−2.45

  Adult (> 1 year)

−0.39

Cat by coat length

Konrade et al. (2012)

  DSH

−1.02

  DLH

−0.13

Dog – mean value

−0.05 to (−0.39)

Dog by habitat

a

References

Gaiddon et al. (1996); Groth et al. (2013); Kubai et al. (2008); Murphy et al. (1992b) Gaiddon et al. (1996)

  Indoor dogs

−0.64

  Outdoor dogs

0.17

Dog by breed

–1.87 to (+0.98)

For specific breeds see Black et al. (2008); Kubai et al. (2008, 2013); Mutti et al. (1999); Williams et al. (2011)

Horse

–0.17 to (+0.33)

Bracun et al. (2014); Harman et al. (1999); RullCotrina et al. (2013)

  Horizontal meridian

−0.06 to (+0.41)

Grinninger et al. (2010); McMullen et al. (2014)

  Vertical meridian

0.25 to 0.34

McMullen et al. (2014)

Rabbit (New Zealand White)

1.7

Herse (2005)

Chicken (Cornell-K)

4.1, 3.7 (4 & 17 weeks old, respectively)

Wahl et al. (2015)

Guinea pig (pigmented)

0.7

Howlett & McFadden (2007)

Rat (Norway brown)

4.7, 14.2 (infant & adult, respectively)

Guggenheim et al. (2004)

Mouse (CBL75/6)

–1.5, 4.0 (10 & 102 days old, respectively)

Zhou et al. (2008)

 See reference list for additional refractive studies in wildlife and aquatic species. DSH, Domestic Shorthair; DLH, Domestic Longhair.

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mean refractive error that was hypermetropic. Conversely, 25% of all surveyed dogs were myopic, with a refractive error of up to −6.25 D, and four breeds (Rottweiler, Collie, Miniature Schnauzer, and Toy Poodle) had a mean refractive error that was myopic. Even breeds that were on average emmetropic had population clusters and litters that were myopic. This was especially notable in the Labrador Retriever, in which up to 31% of dogs are reportedly myopic, reinforcing the hypothesis that myopia in this breed may be inherited (Black et  al., 2008). Myopia in the Labrador Retriever is caused by elongation of the vitreous chamber (Mutti et al., 1999; see Fig. 4.6), while in other breeds, including the Toy Poodle, Collie, and English Springer Spaniel, myopia is due to the presence of a steeper, more powerful lens (Kubai et al., 2013; Williams et al., 2011). The pathogenesis of myopia in the Labrador Retriever, and its mode of inheritance, could make this breed a naturally occurring large animal model for the study of myopia in humans, where vitreous elongation (see Fig. 4.6) and inheritance play a significant role (Black et al., 2008; Mutti et al., 1999). A study in cats reported that kittens ( 4 months) are myopic, with a mean error of −2.45 D, while adult cats are close to emmetropia, with a mean error of −0.39 D, thus demonstrating a significant effect of age (Konrade et  al., 2012). It is interesting to note that myopia decreases with age in cats, but in horses and in some dog breeds, notably the English Springer Spaniel and Beagle, it increases with age (Grinninger et al., 2010; Hernandez et al., 2016; Kubai et al., 2008; Maehara et al., 2011). Once again, there was an overall significant positive correlation between feline refractive error and axial globe length, though the correlation was insignificant when only kittens and juvenile cats were examined. Coat length was another significant factor, with domestic shorthair cats more likely to be myopic, and domestic longhair cats more likely to be emmetropic (Konrade et al., 2012). Another study found a significant effect of habitat on the feline refractive error, with hypermetropia (+1.4 D) or myopia (−0.8 D) depending on whether the cats live outdoors or indoors, respectively (Belkin et  al., 1977). This is consistent with findings in humans, demonstrating the correlation between time spent outdoors and prevention of myopia (French et al., 2013). Several large studies have shown horses to be overall emmetropic (Bracun et  al., 2014; Grinninger et  al., 2010; Rull-Cotrina et al., 2013). However, only 48–68% of horses are emmetropic in both eyes, with hyperopia and myopia reported in equal proportions in the ametropic horses, with errors of up to ±3 D (Bracun et  al., 2014; Farrall & Handscombe, 1990; Grinninger et al., 2010). Age and breed may affect the refractive error in horses (Bracun et al., 2014; Rull-Cotrina et  al., 2013). Age, habitat, and working environment have also been shown to be significant factors in other species (Belkin et al., 1977; Murphy et al., 1992b; Ofri et al., 2001, 2004). However, because of low accommodative

capacity in most veterinary patients, cycloplegia has no significant effect on refraction in patients, including dogs and horses (Groth et al., 2013; McMullen et al., 2014). A large range of retinoscopy values is reported in species with small eyes. For example, values range from +20 to −13 D in the rat (Guggenheim et al., 2004; Hughes, 1977) and from -0.7 to +13.7 D in C57BL/6J mice (Pardue et al., 2013). Such a range of results may be due to failure to correct for the artifact of retinoscopy, or because of the significant spherical aberrations (see later section) caused by the very high power of the cornea in small eyes, as shown in Table 4.3. It is recommended that retinoscopy in such small eyes be conducted using an artificial pupil, to occlude the corneal periphery. Ametropia has also been induced in a number of experimental animals, including chickens, fish, and various mammalian species (Schaeffel & Feldkaemper, 2015). Ametropia is usually induced by visual deprivation in young animals, before the eye has completed its development. Initially, eyelid suturing was used to cause visual deprivation, though this has been replaced by exposure to various regimens of ambient light, and the use of pharmacologic agents or refractive contact lenses to degrade the quality of the retinal image. Visual deprivation leads to progressive axial elongation of the vitreous body and the eye, thereby inducing myopia (see Fig. 4.6; Norton, 2016). Additional anatomic changes in the eye induced by visual deprivation include a shallow anterior chamber, thinner lens, and changes in corneal curvature (Choh & Sivak, 2005; Ostrin et al., 2014). On the other hand, removing the lens during the same period retards axial elongation (Lambert, 2016). The aims of these experiments are to develop animal models for the study of the pathogenesis of myopia in humans, to identify molecular and cellular mechanisms controlling emmetropization, and to evaluate new therapeutic approaches (Schaeffel & Feldkaemper, 2015). Identification of genes associated with, or causing, myopia (Guggenheim et al., 2017; Li et al., 2017a) may represent a breakthrough in the prevention and treatment of what is considered to be one of the most prevalent ophthalmic disorders in humans (Morgan et al., 2018). Aphakic Eyes and Intraocular Lenses

Because of the significant refractive role of the lens, cataract surgery (or any surgical lens extraction) resulting in aphakia leaves the eye severely hypermetropic. The aphakic eye lacks the refractive contribution of the lens; therefore, light is not sufficiently refracted, resulting in image formation “behind” the retina (Pollet, 1982). Since the early 1980s, veterinary ophthalmologists have sought to alleviate this problem by implanting IOLs in dogs’ eyes following cataract extraction. The purpose of these implants is to compensate for loss of refraction by the lens, thereby returning the eye to an emmetropic state. Early attempts using 14.5–29.0 D IOLs left the implanted canine eyes hypermetropic (Peiffer & Gaiddon, 1991). Following the results of studies involving large numbers of

dogs of various breeds, it has been determined that the canine IOL should have a power of 40.0–41.5 D (Davidson et al., 1993; Gaiddon et al., 1991, 1996). The 1.5 D range of recommended values probably results from breed differences (Kubai et  al., 2008). Indeed, use of 41 D IOLs in 60 dogs resulted in an average refractive error of 1.2 D (Gift et  al., 2009). However, it is important to note that though 41 D IOLs are used to bring aphakic dogs to emmetropia, this does not mean that aphakic dogs suffer from hypermetropia of 41 D. Indeed, the hypermetropia in aphakic dogs has been shown to range from 14.4 to 15.2 D (Davidson et  al., 1993; Gaiddon et al., 1991). The reason that a 41 D IOL is needed to correct 15 D of hypermetropia is that an IOL is placed in the capsular bag, surrounded by aqueous humor. This environment results in a reduction of its overall refractive power (due to the small difference in refractive indices between the aqueous humor and the IOL), and therefore this power has to be higher than the aphakia it is intended to resolve. If dogs were to be fitted with spectacles to correct aphakia, then indeed these spectacles would require 15 D lenses! While canine IOLs are widely used by veterinary ophthalmologists, their development and use in other species is lagging behind. A study in horses concluded that an IOL of 25–30 D overcorrects the aphakic equine eye (McMullen et al., 2010), even though preliminary calculations showed a theoretical power of up to 30 D is required to restore emmetropia (McMullen & Gilger, 2006; Mouney et  al., 2012). Subsequent studies, supported by a calculated IOL power of 15.4 D (Mouney et  al., 2012), have shown that a 14 D IOL brought five out of six horse eyes to within 0.4 D of emmetropia (Townsend et al., 2012). A 14 D IOL also brought a foal to emmetropia (Harrington et al., 2013), even though calculations showed that adult horses and foals may require different power IOLs (Townsend et  al., 2013). Calculated IOL powers for bald eagles and rabbits are 16.4–17.4 and 58 D, respectively (Kuhn et al., 2015; Sanchez et al., 2017). Studies in the cat indicate that IOLs for this species should have a power of 52–53 D (Gilger et al., 1998). The difference between the canine and feline IOL values stems from differences in the anterior chamber depth of the dog and cat (Fig. 4.10). Though the globe axial length in both species is similar, the cat has a much deeper anterior chamber, which means that the lens (and IOL) is located more posteriorly in the cat. As a result, the distance between the lens and retina in the cat is shorter, and a stronger lens is required to focus the light in the course of such a short optical path. Conversely, humans, who also have a similar size globe, have a much shallower anterior chamber and a more anteriorly located lens. This results in a longer optical path to the retina, and therefore most human IOLs have a power of only 19–22 D. Thus, it is not surprising that a study of pseudophakic dogs found a correlation between the postoperative refractive error and the distance of the IOL from the retina (Gift et al., 2009). Similarly, in Icelandic horses with multiple congenital ocular

anomalies, a deeper anterior chamber is associated with myopia in older horses (Johansson et al., 2017). Besides developing IOLs for additional species, veterinary ophthalmologists could also improve the postoperative refraction of their pseudophakic patients through preoperative calculation of the required IOL power. Such calculations rely on keratometry and intraocular dimension measurements and use established formulas to determine the IOL power (Kuhn et al., 2015; McMullen & Gilger, 2006; Mouney

A

B

C Figure 4.10  The effect of anterior chamber depth on lens curvature in a human (A), dog (B), and cat (C). Though the axial length in the three species is similar, they differ significantly in the depth of their anterior chambers. Humans have the shallowest anterior chamber, and consequently the location of the human lens is relatively anterior. Cats have the deepest anterior chamber, and consequently the location of the feline lens is relatively posterior. As a result, light exiting the lens has a relatively long path before it reaches the retina in a human, and a relatively short path before it reaches the retina in a cat. Therefore, the feline lens needs to have significantly greater power than the human lens, and this is made possible by its greater curvature. The dog has intermediate values in anterior chamber depth, lens location, and lens curvature.

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et al., 2012; Sanchez et al., 2017; Townsend et al., 2013). This approach can be especially beneficial in dogs who suffer from vitreous chamber elongation and who may remain ametropic if implanted with a “one size fits all” 41 D IOL. Ideally, such measurements will become part of the routine preoperative evaluation, and every cataractous animal patient will be fitted with an appropriate IOL that will bring its eye to an emmetropic state. Recently introduced Fo-X IOLs with extended depth of focus of ± 1.5 D represent another approach to establishing postoperative emmetropia, but these have yet to be evaluated in clinical studies. Though veterinary ophthalmologists have made significant progress in restoring emmetropia to pseudophakic patients, little attention has been paid to correcting ametropia in phakic patients. As noted, more than 25% of the canine population has been shown to be significantly myopic (Kubai et al., 2008), and could potentially benefit from such correction through the use of contact lenses or surgery. Indeed, it has been demonstrated that even 1.5–2 D of myopia causes significant deterioration in the visual performance of Labrador Retrievers (Ofri et al., 2012) and in the pattern visual evoked potentials of Beagles (Ito et  al., 2016). Various surgical techniques, mostly involving the use of lasers to ablate the cornea, are employed to correct ametropia and astigmatism in humans, and preliminary work shows that some of these techniques are applicable in the dog (Rosolen et  al., 1995) and cat (Bühren et  al., 2010). Alternatively, lasers have also been used to change the refractive index of the feline cornea (Savage et  al., 2014). Interestingly, Wang et al. (2016) have also shown improvement in canine refractive error following 6 months of nutritional antioxidant supplementation. Astigmatism

Astigmatism is a state of unequal refraction of light along the different meridians of the eye. Normally, a given refractive structure of the eye (e.g., the cornea or lens) has a constant curvature radius in all its meridians (though the cornea may flatten toward the limbus). Astigmatism occurs when the horizontal and vertical meridians of the cornea or lens have different curvature radii. Because of these differing curvatures, light entering the eye through the vertical meridian may be refracted more (i.e., direct, or with-therule, astigmatism) or less (i.e., indirect, or against-the-rule, ­astigmatism) than light entering through the horizontal meridian. There are also cases of irregular astigmatism in which the principal meridians are not perpendicular to each other, as in keratoconus, or because of injury. Therefore, light entering along one meridian will be focused on the retina and result in high-resolution vision, whereas light from the other meridian will be unfocused, leading to blurred vision (Fig.  4.11). Such an aberration is corrected with a cylindrical lens rather than with a spherical lens that is used to correct simple ametropia.

Normal focus

Vertical focus

Horizontal focus

Figure 4.11  A normal eye can see focused horizontal and vertical lines (left). An astigmatic eye will see a focused line in one orientation and a blurred line along the perpendicular axis. Vertical focus: The horizontal lines are blurred (center). Horizontal focus: The vertical lines are blurred (right).

Astigmatism is diagnosed by refracting the eye in both the horizontal and vertical meridians. A difference of 0.5 D or more in the refractive power of the horizontal and vertical meridians in the same eye is defined as astigmatism. Alternatively, astigmatism can be diagnosed using a keratometer to measure the curvature of the steepest and flattest meridians of the cornea, or by use of a corneal topographer, which provides a map based on a large number of photographic sections of the cornea and calibrated into dioptric power (Savini et al., 2017). In humans, most cases of astigmatism result from abnormalities of the anterior surface of the cornea. Only a minority of cases result from lenticular or posterior corneal surface abnormalities (Duke-Elder, 1970). Direct astigmatism accounts for 90% of cases in young eyes, but the proportion of indirect astigmatism increases with age (Nemeth et al., 2013; Xiao et al., 2014). In humans, the prevalence of low-grade astigmatism may be as high as 63% in some populations, but the prevalence of astigmatism > 1.5 D is usually under 5% (Read et al., 2007). The prevalence of significant (> 0.5 D) astigmatism in dogs seems to be equally low, reportedly affecting 1% of all dogs; a higher prevalence of 3.3% was documented in German Shepherds (Kubai et  al., 2008). On the other hand, other species are “naturally astigmatic” because of their corneal topography. In the horse, for example, the mean corneal curvature along the horizontal and vertical meridians is 21.6 D and 22.9 D, respectively. Consequently, the horse has a mean degree of 1.3 D direct astigmatism (Grinninger et al., 2010). For the same anatomic reason, 1.75–2.36 D of astigmatism is reported in pig eyes (Sanchez et  al., 2011) and 0.4–0.6 D in rabbits (Wang et al., 2014). A high prevalence of astigmatism was also demonstrated in gazelles (Ofri et al., 2004) and elephants (Murphy et al. 1992a). In cows, sheep, and pigs, the lens sutures have been identified as the source of astigmatism and other aberrations (Gargallo et al., 2013). Some pathologic processes may induce astigmatism. Corneal disease resulting in edema or scarring will inevitably lead to an uneven corneal surface, resulting in irregular astigmatism. Focal cataracts will cause refractive astigmatism

because of variations in refractivity among different lenticular zones (Duke-Elder, 1970). In addition, cataract surgery (Eslami & Mirmohammadsadeghi, 2015), penetrating keratoplasty (Fadlallah et  al., 2015), and other procedures that involve incising and suturing of the cornea often result in astigmatism because of imperfect alignment of wound edges; however, such surgically induced astigmatism frequently resolves over time. In dogs undergoing cataract extraction, surgically induced astigmatism was significantly different between right and left eyes, with values of 2.01 and 3.05 D for dorsotemporal and dorsonasal incisions, respectively (Pederson et al., 2019). Static Accommodation

Several avian (Hodos & Erichsen, 1990), amphibian (Scheaffel et  al., 1994), and reptilian (Henze et  al., 2004) species possess lower-field myopia. The eyes of these animals are emmetropic along the horizontal and in the upper visual field, but they become progressively myopic below the horizontal (Fig. 4.12). In other words, different parts of the eye have a different refractive power because the shape of the eye is more like a flattened circle, so that the posterior focal length differs for different meridians. This adaptation can be regarded as a static accommodation mechanism (Ott, 2006). Rather than changing the refractive power of its lens to focus on an object (in dynamic accommodation), the animal shifts its gaze to see the object with the appropriate refractive power. Consequently, the animal can match the average 55

viewing distances of different areas of the visual field (Schaeffel et al., 1994). This allows the animal to keep the ground in focus with relaxed accommodation while foraging for food and, at the same time, monitor the sky for predators while focused at infinity (Hodos & Erichsen, 1990). This may be why predators such as raptors do not possess this adaptation (Murphy et al., 1995). The same principle is also found in the eyes of pinnipeds (Hanke et al., 2006; Mass & Supin, 2007; Miller et al., 2010). Regional changes in the refractive powers of different parts of the cornea allow these animals to maintain high-resolution vision in both water and air (see the section on “Emmetropia and Accommodation Under Water”). Therefore, static accommodation may be an evolutionary mechanism helping animals to improve their spatial resolution capabilities in different environments (Shilo, 1977). The horse was also believed to possess a similar, static “accommodating” mechanism, resulting from its nonsymmetric eye shape. According to the ramp retina theory, the superior retina was believed to be farther from the lens than the inferior retina (Farrall & Handscombe, 1999; Harman et al., 1999; Sivak & Allen, 1975). Therefore, it was argued that the horse raises its head to focus distant objects on the ventral retina and lowers it to focus nearby objects on the dorsal retina. An analogy to this would be a person with bifocal glasses trying to peer through one lens or the other to view objects at different distances, though in this case the person is aided by the different refractive powers

Lower visual field

Upper visual field

Refraction [D]

45 35 25 15 5

Optical axis

–5 –15 –30

–20

–10

0

10

20

30

Visual angle [deg]

2 cm

Figure 4.12  Lower-field myopia in the terrestrial turtle Geoemyda as an example of static accommodation. Top panel: The refractive state of the unaccommodated eye changes steadily from hyperopic values in the upper visual field to myopic values in the lower visual field. Black dots represent the focal points at various visual angles apart from the optical axis for this state of focus. Lower panel: Because the refractive power changes with the visual angle, the animal can keep the whole ground in focus, and by changing the angle of its gaze focus on its prey no matter how distant it is. (Reprinted with permission from Ott, M. (2006) Visual accommodation in vertebrates: Mechanisms, physiological response and stimuli. Journal of Comparative Physiology A, 192(2), 97–111.)

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of the lenses rather than by the varying axial lengths of different meridians. Anatomic measurements have now discredited this theory, and the horse is believed to possess an active (though limited) accommodation mechanism of ±1 D (Harman et al., 1999; Miller & Murphy, 2017; Sivak & Allen, 1975). The head movement previously associated with this behavioral “focusing” is now believed to occur when the horse is interchanging monocular and binocular visual fields (Harman et al., 1999). However, a “ramp retina” has been demonstrated in guinea pigs, with the ventral retina further from the lens center than the dorsal retina as a result of differing globe axial lengths and vitreous chamber depths in different quadrants (Zeng et  al., 2013). Consequently, the guinea pig’s inferior visual field is –6 D more myopic than the superior field. As in the case of lower-field myopia of nonmammalian species, it is proposed that this adaptation evolved to allow the ground plane to be well focused while maintaining clear vision on the horizon, presumably important to a small creature that needs to detect both food and predators.

causes blurred vision. In other words, the focusing of rays depicted in Fig. 4.5 and Fig. 4.7 is an “ideal” refraction that in reality does not take place in the eye. The difference between the focal points of the peripheral and central rays, the spherical aberration, is measured in diopters. A comparative study found significant degrees of spherical aberration in the lenses of dogs, cats, and rats, but minimal lenticular aberrations in cows, sheep, and pigs (Sivak & Kreuzer, 1983). Both the cornea and the lens possess anatomic adaptations that are intended to minimize the extent of their inherent spherical aberrations. In the lens, the higher refractive index of the lenticular nucleus increases the refractive power of the central lens. This results in moving its focal point closer to the lens, nearer to the focal point of the peripheral lens (Fig. 4.14). A gradient variation in the refractive index of the lens would result in the formation of a multifocal lens, with a higher refractive index in the nucleus and a lower refractive index toward the equator, leading to further attenuation of the spherical aberration. Corneal spherical aberrations are minimized because the peripheral cornea is flatter than

Spherical and Chromatic Aberrations Spherical Aberrations

The eye is not a perfect optical system. Indeed, Duke-Elder (1970) quotes Hermann von Helmholtz, the 19th-century German physicist who invented the ophthalmoscope, as saying that “if an optician should try to sell me an instrument possessing such faults, I would feel justified in using the most severe language with regard to the carelessness of his work and return the instrument under protest.” Two of the most significant optical problems that affect the eye are spherical and chromatic aberrations. Sperical aberrations occur because in both the cornea and the lens, rays passing through the periphery are refracted more than rays passing through the center. Therefore, rays passing through the periphery are focused closer to the cornea (or lens) than rays passing through its center (Fig.  4.13). Obviously, as the image is not uniformly focused on the retina, the aberration

A

Figure 4.14  Multifocal lenses reduce the amount of spherical aberrations. A higher refractive index of the lens nucleus causes increased refraction of the central light rays (compared to the refraction of the central rays in Fig. 4.13A). Consequently, the focal point of the central rays is shifted closer to the lens and closer to the focal point of the peripheral rays, thus eliminating the spherical aberrations seen in Fig. 4.13A.

B

Figure 4.13  Spherical aberrations occur when light passes through the lens (A) and cornea (B). In both cases, peripheral rays are refracted (bent) more than central rays. Therefore, the focal point of the peripheral rays is closer to the lens/cornea, while the focal point of the central rays is closer to the retina. The result is a blurred image. The distance between the two focal points is called spherical aberration and is measured in diopters (D).

the central (apical) cornea. This decreases the refractive power of the peripheral cornea and moves its focal point toward the retina and closer to that of the central cornea (Millodot & Sivak, 1979). Therefore, refractive surgeons attach great importance to centering the apical cornea so that the aberration-free zone is aligned with the pupil, thereby contributing to a high-quality retinal image (Bühren et  al., 2010; Gobbe et  al., 2015). A similar problem may arise in corneoscleral transposition in veterinary patients, as the flatter peripheral cornea is transposed into the steeper central cornea, potentially increasing spherical aberrations in the patient. For similar reasons, surgeons performing keratoplasty should strive to collect the donor’s cornea from the same region as the intended grafting site. However, the possible effects of corneoscleral transpositions and keratoplasty on visual optics in animal patients have yet to be investigated. Another structure that plays a critical role in reducing spherical aberrations is the pupil. Contraction of the pupil blocks rays of light that enter the eye through the most peripheral (and refractive) cornea. It also prevents light from passing through the peripheral lens. Thus, miosis allows only rays that pass through the central cornea and lens to reach the retina, thereby contributing to the formation of a well-focused image (Fig.  4.15A). A mydriatic pupil, on the other hand, allows more peripheral rays to enter the eye, and their passage through the peripheral cornea and lens increases the amount of spherical aberrations as well as all the other wavefront aberrations (Fig 4.15B). In humans, an 8 mm pupil induces 1 D of spherical aberrations (Millodot, 2018), which is the reason for the significant blurring of vision that is experienced after pupils have been pharmacologically dilated. It is worth noting that nowadays the aberrations of the eye are analyzed by assessing the amount of deviation obtained between an output wavefront emanating from it and a theoretical ideal wavefront (Thibos et al., 2002). This stems from the fact that the eye is not a symmetric globe. These aberrations are reported as Zernike polynomials, of which there are more than 20 types, including astigmatism, spherical aberration, coma, trefoil, and quatrefoil. They are now routinely measured with various types of commercial aberrometers, and a common unit of measurement of all wavefront aberrations is the root mean square (RMS). In a large human survey, Wang and Koch (2003) found that the most significant aberration was spherical aberration, followed by coma. Chromatic Aberrations

Chromatic aberrations result from the fact that the refractive index n (as in the equation D = n/f) is not constant, but rather is wavelength dependent. Once again, therefore, Fig. 4.5 and Fig. 4.7 are somewhat misleading because they portray the ideal situation pertaining to monochromatic light. However, when white light enters a prism (or a lens), each wavelength contained in that light is refracted by a

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A

B Figure 4.15  Pupillary diameter affects the magnitude of spherical aberrations. A miotic pupil (A) blocks the peripheral rays, thereby eliminating the spherical aberrations induced by the peripheral cornea and lens (seen in Fig. 4.13). Only central rays reach the retina, resulting in a focused image. A mydriatic pupil (B) admits peripheral rays into the eye, thereby increasing the amount of spherical aberrations. Panel B is the basis for the blurred vision experienced following pharmacologic dilation of the pupil.

­ ifferent amount. The n of a given wavelength is inversely d proportional to λ. Therefore, waves with a short wavelength (e.g., blue light) have a higher n than waves with a long wavelength (e.g., red light). Consequently, blue light will be more refracted than red light, and its focal point will be closer to the lens (Fig 4.16A). The distance between the focal points of the short and long wavelengths is the chromatic aberration, and once again this distance is measured in diopters. The implication is that when viewing red text on a blue background, for example, the overall image would be blurred, as the text and the background are focused on different planes in the eye. A study comparing chromatic aberrations in different species found that in most animals (including cats, cattle, sheep, pigs, rats, and fish) the amount of chromatic aberration (442–633 nm) of lenses amounts to a relatively constant 4.6% of equivalent focal length; an exception is the dog lens, with 5.7% chromatic aberrations (Kreuzer & Sivak, 1985). As in the case of spherical aberrations, anatomic adaptations may contribute to a reduction in the effect of the chromatic aberrations. For example, fish have been shown to possess multifocal lenses consisting of concentric rings of differing refractive properties (Kröger, 2013). Thus, red light passing through one ring will be more refracted than blue

Section I: Basic Vision Sciences

light passing through another ring, thereby compensating for the blue light’s higher n. Consequently, the image formed on the retina will be chromatically focused (Fig. 4.16B). It is interesting to note that in terrestrial species, multifocal lenses consisting of concentric refractive rings can be found in those species in which the miotic pupil is not round (Land, 2006; Malmström & Kröger, 2006). Such a lens has been demonstrated, for example, in the domestic cat. The vertical slit shape of the cat’s miotic pupil allows light to pass through both the peripheral and central lens during constriction. Therefore, even during miosis, the cat continues to benefit from the advantage of a multifocal lens (Fig. 4.17). On the other hand, in the closely related tiger, a round pupil is associated with a monofocal lens, so that no optical properties of the lens are “lost” when the pupil constricts (Malmström & Kröger, 2006). Therefore, species with a multifocal lens have a steeper GRIN than species with a monofocal lens. In cats, for example, the refractive indices in the lens nucleus and subcapsular areas are 1.48 and 1.39, respectively; in humans, the respective figures are 1.41 and 1.38 (Pierscionek & Regini, 2012). In this context it is noteworthy that the harbor seal, which is a monochromat, has multifocal lenses; since multifocal lenses have evolved to compensate for chromatic aberrations in animals with color vision, the functional significance of such a lens in a monochromat is not understood (Hanke et al., 2008). Additional evolutionary adaptations to decrease the detrimental effect of chromatic aberrations on visual resolution can be found in the anatomy of the retina. The human fovea, for example, contains red and green cones, but does not contain any blue cones (Chen et al., 2015). Therefore, red light, which is focused on the fovea, will be absorbed in this region. Blue light, which is not focused on the fovea, will not be absorbed, and therefore not be perceived, thus contributing to the high-resolution vision of the fovea (at the expense of

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B Figure 4.16  Chromatic aberrations in the lens. A. White light is composed of numerous wavelengths, each of which is characterized by a different refractive index (n). Light with a longer wavelength (e.g., red light) has a lower n than light with a shorter wavelength (e.g., blue light). Consequently, red light will be refracted to a lesser degree than blue light. If the blue light is focused on the retina, the red light converges behind the retina. The distance between the focal points of the short and long wavelengths is the chromatic aberration; this distance is measured in diopters. B. Multifocal lenses reduce the magnitude of chromatic aberrations. A higher refractive index of the lens nucleus causes increased refraction of the red light (compared to its reduced refraction in panel A). Consequently, the focal point of the red light is shifted closer to the lens and closer to the focal point of the blue light, thus eliminating the chromatic aberrations seen in panel A.

A

B

C

Figure 4.17  The functional significance of the slit pupil in combination with a multifocal lens. In the fully dilated state of the pupil (A), all zones of the lens (shown in the colors they are focusing) can be used. A concentrically constricting iris (B) would cover the outer zone of the lens, such that a spectral range (blue in this example) could not be focused on the retina. By contrast, all lens zones can be used if the pupil constricts to a slit (C). (Reprinted with permission from Malmström, T. & Kröger, R.H. (2006) Pupil shapes and lens optics in the eyes of terrestrial vertebrates. Journal of Experimental Biology, 209, 18–25.)

foveal blue color perception). This is why the fovea has been called the blue scotoma region of the retina (Chen et  al., 2015). The chromatic aberrations induced by blue light in the macular region are further reduced by the presence of yellow macular pigment, which is abundant in carotenoids, lutein, and zeaxanthin, with a peak absorption of about 460 nm, which absorbs unfocused short wavelengths (Bernstein et al., 2016). Obviously, chromatic aberrations are less significant in species that have limited color vision, as some of the defocused wavelengths may not be absorbed by the photoreceptors, and hence are not perceived. Thus, in many of our animal patients, who have dichromatic vision, it is possible that this aberration has minor functional implications. Emmetropia and Accommodation Under Water

In aquatic species, the cornea is in contact with water rather than air. Because of the very small (∼0.003) difference between the refractive indices of the cornea and water, the cornea of these species has virtually no refractive power. In fact, because the anterior corneal surface has lower curvature than the posterior surface (Ueno et  al., 2015), under water the cornea acts as a weak divergent lens. Fish are forced to compensate for the absence of corneal refraction by increasing the refractive power of other ocular structures, usually the lens. For this reason, as noted earlier, the lenses of fish eyes are very spherical. Their increased curvature results in significantly larger refractive power. Biochemical changes in lenticular proteins also increase the refractive index of the fish lens to up to 1.66, thereby contributing to significant refraction as light passes from the aqueous humor into the lens (Sivak, 1978). In the sandlance fish, these evolutionary adaptations can increase the refractive power of the lens to as much as 500 D (Pettigrew & Collin, 1995). If it were not for these two lenticular adaptations, the absence of corneal refraction would cause fish to be severely hypermetropic under water. The problem of refraction under water is further complicated in species that move in and out of water because it is physically impossible for an eye to be emmetropic both in air and underwater (Fig. 4.18). Eyes that are emmetropic in the air will be hypermetropic under water because the refractive power of the cornea is lost due to its submersion in water. Conversely, eyes that are emmetropic under water become extremely myopic in the air because now the cornea (due to Snell’s law) contributes refraction that the eye did not possess under water. Therefore, species that live and function in both habitats must “choose” whether they will be emmetropic in the air or under water. It is very interesting to observe that both of these evolutionary strategies exist in the animal kingdom. Birds that hunt under water, such as cormorants (Katzir & Howland, 2003), the Australasian gannet (Machovsky-Capuska et al., 2012), and

penguins (Sivak et al., 1987), as well as sea otters (Murphy et al., 1990), are emmetropic in the air. These species overcome the resulting underwater hypermetropia by increasing the accommodative power of the lens, thus allowing them to actively hunt and chase their prey under water. During accommodation in the cormorant, for example, the lens bulges through the pupil, forming anterior lenticonus that increases the lenticular axial length pathway and consequently its refractive power (Fig. 4.19) (Katzir & Howland, 2003). This combination of forward movement and change in lenticular curvature gives the cormorant lens an accommodative power of 60 D and an incredible accommodation rate of more than 600 D/s, 10 times as fast as nondiving birds (Katzir & Howland, 2003). Sea otters have also been shown to have a similar lenticular accommodative mechanism, combining forward movement and change in the curvature of the lens (Mass & Supin, 2007). As in cormorants, the result is an accommodative power of 55–60 D, which is the highest of any mammal (Murphy et al., 1990). Since the otter loses 59 D of corneal power under water, the equivalent magnitude of lenticular accommodation allows the animal to regain its visual acuity when diving. In penguins, the entire cornea is flat, consequently minimizing the alteration in refractive state when moving from air to water (Sivak et al., 1987).

In air

In water A terrestrial eye

In water

In air An aquatic eye

Figure 4.18  No eye can be emmetropic both in air and under water. An eye of terrestrial animals, which is emmetropic in an aerial environment, loses the refractive contribution of the cornea under water and becomes farsighted (top panel). An eye of a fish that is emmetropic under water becomes severely nearsighted (myopic) in the air because it “gained” corneal refraction that it did not possess under water (bottom panel). Note the difference in shapes of the lenses between the two species. The lens of the fish is more spherical in order to increase its refractive power (to compensate for the absence of corneal refraction under water). (Reproduced with permission from Sivak J.G. & Millodot M. (1977) Optical performance of the penguin eye in air and water. Journal of Comparative Physiology, 119, 241–247.)

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Figure 4.19  A sectioned eye of a cormorant during accommodation. The bulging of the lens through the miotic pupil into the anterior chamber is clearly illustrated. As a result, the axial length of the lens, and its refractive power, increases. This underwater accommodation allows the eye to compensate for the loss of corneal refraction during diving, and the bird can focus on its prey. But if the bird dives into deep, scotopic waters, the inevitable mydriasis will disable this accommodating mechanism. Therefore, the bird is restricted to hunting in shallow, photopic waters. (Courtesy of Gadi Katzir.)

Thus, in cormorants, otters, and penguins, the cornea is the major refractory organ on land, allowing for aerial emmetropia; the lens accommodation provides for underwater ­refraction. However, as usually happens with evolutionary strategies, there is a price to be paid for this well-developed underwater lenticular accommodative capability. The bulging of the lens through the pupil in these species requires miosis. This, in turn, limits the amount of light entering the eye. Therefore, these species can only hunt to a depth of about 9 m (Boyd et al., 2015). In deeper water, the inevitable mydriasis will not allow them to accommodate and focus on their prey. In this context it is worth noting that other piscivorous (fisheating) birds, such as osprey, kingfishers, and sea eagles, do not chase their prey under water. Instead, these birds search for their aquatic prey from the air and capture it while plunging into the water, relying on momentum rather than accommodation to catch the fish (Machovsky-Capuska et  al., 2012). Therefore, it is not surprising that pursuit-diving ducks accommodate, while nondiving ducks do not (Lisney et al., 2013). On the other hand, many aquatic mammals developed an opposing evolutionary strategy (Mass & Supin, 2007). Sea lions, harbor seals, and other pinnipeds are emmetropic under water. Consequently, these animals become severely myopic when they come out of the water to breathe. Various mechanisms have evolved to make up for the increased refractive power of the eye in an aerial environment. Harbor seals have one flattened corneal meridian, with a

slit-shaped pupil oriented along this flattened meridian (Hanke et al., 2006). When the animal exits the water, the bright light causes pupillary constriction along this meridian, which has minimal refractive power as it is not curved (stenopaic vision). Therefore, the resulting aerial myopia along this axis is attenuated significantly. Thus, in the air, the animal suffers from about −20 D myopia along the horizontal meridian, but “only” –7.5 D of myopia in the vertical meridian, the difference in refractive power of the central, flat cornea between water and air (Hanke et  al., 2006). The aerial miosis also serves to minimize aberrations and increase the depth of field, thus allowing for further improvement of aerial acuity, which is comparable to the animal’s underwater acuity (Hanke & Dehnhardt, 2009). Obviously, aerial visual acuity will deteriorate significantly at night, when mydriasis will allow light to enter through the highly curved and refractive quadrants of the cornea. A similar solution has evolved in the California sea lion, which has a specialized, flattened region with very low refractive power in the ventromedial cornea (Miller et  al., 2010), and dolphins, which have a similar region in the medial cornea (Dawson et al., 1987). These regions provide for minimally defocused aerial vision, whereas the rest of the cornea is convex, providing for high underwater acuity. The animal shifts its head as it exits the water to allow light to enter through the flat “window” (Fig. 4.20; Dawson et al., 1987). In both seals and dolphins, underwater mydriasis enables the eye to benefit from the highly curved and refractive quadrants of the cornea, thus allowing for emmetropia and high-resolution aquatic vision. Therefore, unlike diving birds, these animals can accommodate and hunt in deep water, as they use mydriasis, rather than miosis, for improving underwater acuity. The detrimental effect of the flat window, so beneficial in the air, is probably neutralized by underwater accommodation (Hanke et al., 2006). Therefore, what these animals lose in aerial acuity, they gain in hunting depth. More primitive amphibians (e.g., crocodiles) that lack this compensatory accommodative capability simply cannot focus. These animals are emmetropic in air and are severely hypermetropic under water, forcing them to rely on other senses when hunting under water (Nagloo et al., 2016). Another interesting adaptation is observed when semiaquatic garter snakes submerge in water. Contrary to expectations, their pupils constrict under water, rather than dilate. It is suggested that this constriction causes an increase in vitreous pressure in the posterior chamber and pushes the lens forward. The resulting accommodation allows the snake to compensate for the loss of corneal refractive power under water. In other words, aquatic submersion triggers a “pupillary water reflex” that is independent of light intensity; this reflex is intended to prevent hyperopia through lens accommodation, rather than to regulate the amount of light on the retina (Fontenot, 2008).

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A

B

Figure 4.20  A frontal (A) and sectioned (B) view of the anterior segment of a pinniped eye. Note the flattened central cornea, which minimizes the inevitable myopia that occurs when the animal exits the water to an aerial environment. Note in panel A that the pupil constricts around this part of the cornea, so that only light passing through the least refractive part of the cornea will enter the eye. The pinpoint pupil minimizes spherical aberrations and increases depth of focus, further enhancing aerial acuity. (Panel A courtesy of Carmen M. Colitz. Panel B courtesy of Richard R. Dubielzig.)

Visual Processing: From Photoreceptors to Cortex The Retina The optical part of the visual process ends with photons striking the outer segments of the photoreceptors. The neuronal part of the visual process begins with the capture of these photons and absorption of their energy by the photopigments in the outer segments of the cones and rods, where a chain of biochemical reactions starts. In addition to these sensory neurons, the retina also contains secondary and higher-order neurons and an intricate neural circuitry that performs the initial stages of image processing, before trains of electrical impulses are transferred through the axons of the retinal ganglion cells (RGCs) to areas in the brain where secondary processing and eventually visual perception occur. A schematic representation of the retina is shown in Fig. 4.21. The Photoreceptors

The outermost cells in the neural retina are the photoreceptors, which are divided into two classes: rods and cones. Rods and cones differ from each other in their morphology, function, and retinal distribution. Functionally, cone systems are characterized by high resolution of fine details, rapid responses, color perception, and low sensitivity to small fluctuations in light intensity (Lamb, 2016). Rod systems are characterized by poor visual resolution and no color perception, but they are extremely sensitive to minute changes in light levels and detection of motion. Therefore, cones are particularly suitable for daylight photopic vision,

whereas rods contribute mostly to dim-light scotopic vision (Collin et  al., 2009; Lamb, 2013; Lamb et  al., 2007, 2016; Mustafi et al., 2009). Hence, a retinal mosaic containing both cone and rod photoreceptors, which appears to be ubiquitous among mammals (Peichl, 2005), forms a duplex retina, which functions in both low and bright light conditions. These functional differences between rods and cones are partially the result of the morphologic differences discussed in Chapter 2. The rod outer segment is long and thin, about 2 μm in diameter, which permits a high density of rods, thus increasing the probability of absorbing scarce photons at night. Cones are thicker than rods, but both cones and rods in the central part of the retina are thinner than those in the periphery to permit a high photoreceptor density (Mowat et  al., 2008). Rod axons are thin, which is consistent with the cell’s slow response to light and fewer ribbon synapses, whereas cone axons are thick, enabling transfer of information (signals) at higher rates in multiple synapses (Hsu et al., 1998). Cones constitute a minority of the photoreceptors in most mammalian retinas, with ranges of 0.5%–3% in nocturnal species and 5%–10% in crepuscular and arrhythmic species, whereas the proportion of cones in diurnal animals ranges from 8% to 95% (Ahnelt & Kolb, 2000). Hence, the cone-torod ratio roughly reflects the lifestyle of the species. There are also differences in photoreceptor concentrations in different regions of the retina. A specialized, avascular area with higher cone density providing higher spatial resolution (ability to see finer details) in the corresponding part of the visual field is often present in the retina. In diurnal species possessing high acuity, such as haplorrhine primates and many avian species, this region is called the fovea centralis.

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Ch PE OS OLM

R C

ONL H

As

M

OPL

B

Mi

INL A IPL GCL

As Mi

BV

G NFL ILM

Figure 4.21  Schematic drawing of the mammalian retina with part of the choroid (Ch) on top. Below the retinal pigment epithelium (PE) are the layers of the neuroretina: the outer segments of the photoreceptors (OS), the outer limiting membrane (OLM), the outer nuclear layer with nuclei of cones (C) and rods (R), the neuropil of the outer plexiform layer (OPL), the inner nuclear layer (INL) with nuclei of horizontal (H), bipolar (B), and amacrine (A) cells, the inner plexiform layer with synapses in strata, the ganglion cell layer (G), their axons in the nerve fiber layer, and finally the inner limiting membrane (ILM) facing the vitreous. The glial elements of the retina, Müller cells (M), and microglia (Mi), as well as astrocytes (As) embracing retinal blood vessels, are shown. (Reproduced with permission from Vecino, E., Rodriguez, F.D., Ruzafa, N., et al. (2016) Glia–neuron interactions in the mammalian retina. Progress in Retinal and Eye Research, 51, 1–40. doi: 10.1016/j.preteyeres.2015.06.003.)

The primate and avian fovea is actually a depression (or pit) that contains no rods or retinal capillaries, thus permitting more dense packing of cones almost individually connected to retinal interneurons and ganglion cells (Kolb & Marshak, 2003). This area subserves the highest-resolution vision of the eye. Most other species are devoid of such a highly specialized area, but a fovea plana–like area (a fovea without evident foveal pit) temporal to the optic nerve head has recently been identified in the dog (Beltran et  al., 2014). A more diffusely outlined region with increased cone density called the area centralis surrounds the fovea plana in the dog and is usually seen in other mammals that are currently considered to be afoveate (Beltran et al., 2014; Mowat et al., 2008). Though this area has a higher concentration of cones, rods still outnumber the cones in the area centralis (Table 4.6). Because of their higher rod concentration, these eyes have higher sensitivity under low light conditions, albeit sacrificing visual acuity and richer color vision, as they have fewer cones. The primate fovea and area centralis in

lower mammals are surrounded, respectively, by a macula and a visual streak, which are regions of decreasing cone density. In foveate primates, the macular area appears yellowish because of the macular pigments absorbing blue light and scavenging free radicals, thus protecting the retinal area providing the high visual acuity (Provis et  al., 2013). The concentration of cones continues decreasing with retinal eccentricity, and the more peripheral retina is characterized by higher rod-to-cone ratios. Cones are further subdivided into several types depending on their opsin contents (Hunt et al., 2009). Humans (as well as Old World primates) have three cone classes, with peak sensitivities to either long (552–562 nm, usually called red cones, although they are most sensitive to greenish-yellow), medium (525–533 nm, green), or short (410–450 nm, blue) wavelengths of light (Hofmann & Palczewski, 2015a). These cones, known as L-, M-, and S-cones or red, green, and blue cones, respectively, are the basis of human trichromatic vision. Most New World primates and lower mammals have

4: Optics and Physiology of Vision

191

Human (Østerberg, 1935)

Cat (Steinberg et al., 1973)

Dog (Mowat et al., 2008; Beltran et al., 2014*; Yamaue et al., 2015**)

Number of rods (×106)

110–125

Number of cones (×106)

6.5

Maximal cone concentration (×103 per mm2)

199

27

23/127*

Maximal rod concentration (×103 per mm2)

160

460

501

Cone concentration at ora serrata (×103 per mm2)

5

1 was identified in seven of 49 cats with idiopathic uveitis and in four of nine cats experimentally infected with B. henselae, compared with none of 49 healthy controls. The same study also found B. henselae DNA in the aqueous humor of three of 24 cats with uveitis and in four of nine experimentally infected cats, compared with one of 49 healthy cats (Lappin et al., 2000). However, the significance of these findings in relation to feline anterior uveitis is not clear, especially because C values >8 are considered a more rigid criterion for the determination of local antibody production. Furthermore, a later study showed no difference in Bartonella seroprevalence rates between cats with uveitis and healthy cats, and another study of 104 cats with naturally occurring uveitis failed to identify B. henselae DNA within any aqueous humor samples (Fontenelle et al., 2008; Powell et al., 2010). In summary, the significance of B. henselae in the etiology of feline uveitis is debatable and, given the widespread prevalence of the organism in healthy cats, there is little evidence that it is a major uveitis pathogen in cats (Stiles, 2011). Bartonella vinsonii subspecies berkhoffi has been reported to be a possible cause of anterior and posterior uveitis in dogs (Breitschwerdt et al., 2004; Michau et al., 2003). Haemophilus sp.

Haemophilus somnus is a small, gram-negative, coccobacillus that is a commensal of bovine mucosal surfaces, commonly the respiratory tract, reproductive tract, and circulatory

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Section II: Foundations of Clinical Ophthalmology

s­ ystem (Kwiecien & Little, 1991). The organism prefers an intracellular location and commonly invades alveolar macrophages and monocytes, in which it can survive and replicate (Harris & Janzen, 1989). It is an opportunistic pathogen that is the cause of thrombotic meningoencephalomyelitis (TME) (previously called thrombo-embolic meningoencephalomyelitis, TEME). TME occurs in feedlot cattle and in addition to peracute and often fatal meningoencephalitis, it can cause chorioretinitis, retinal detachment, or central blindness. Isolated cases and outbreaks of disease occur (Descarga et al., 2002). The primary pathogenic lesion is in situ thrombus formation. Once the organism has localized to a particular site, it causes endothelial cells of blood vessels to separate, and the exposed underlying basement membrane induces local thrombus formation (Harris & Janzen, 1989). Virulent H. somnus strains are biochemically and antigenically similar to avirulent strains. However, virulent strains possess a number of features that seem to confer pathogenicity, including the production of immunoglobulin Fc binding proteins, lipo-oligosaccharides that mediate apoptosis of host cells, and factors that allow intraphagocytic survival (Siddaramppa & Inzana, 2004). Other Gram-Negative Aerobic Bacteria

Coliform bacteria are a diverse group of gram-negative bacteria found in the normal gastrointestinal tract, as well as in soil and sewage. They include members of the genera Escherichia, Salmonella, Citrobacter, Shigella, Klebsiella, Enterobacteria, Serratia, Proteus, and Yersinia. They are not primary pathogens but can be opportunistic invaders of the eye and have been cultured from cases of conjunctivitis, ulcerative keratitis, dacryocystitis, orbital infections, anterior uveitis, and chorioretinitis (Gerding et al., 1988; Moore et al., 1983; Prado et al., 2005; Salisbury et al., 1995; Whitley, 2000). Neisseria sp. are gram-negative cocci that colonize mucosal surfaces, including the conjunctiva, to cause clinical disease. Pathogenic features include the presence of surface pili, oxidase, protease, and a variety of endotoxins. Branhamella ovis (formerly known as Neisseria ovis) is a gram-negative diplococcus that can be isolated from the conjunctival sac of healthy small ruminants. It causes conjunctivitis and keratoconjunctivitis in sheep and goats, either as a sole agent or as a coinfection with mycoplasmal or chlamydial organisms (Dagnall, 1994a, 1994b; Jansen et al., 2006). B. ovis produces one or more heat-labile toxins that display cytotoxic activity against corneal epithelial cells (Cerny et al., 2006). The organism has also been implicated in cattle as an etiological agent in IBK, although usually it causes only a mild, transient conjunctivitis in calves and only rarely are corneal lesions observed (Nagy et al., 1989). Acinetobacter sp. are gram-negative bacilli that are often normal inhabitants of the conjunctiva of domestic and production animals. They have been isolated from cases of infectious equine keratitis (Moore et al., 1983, 1995).

Pasteurella multocida is a gram-negative coccobacillus that is a major cause of conjunctivitis and dacryocystitis in rabbits, often in conjunction with upper respiratory tract disease (Deeb & DiGiacomo, 2000; DiGiacomo et al., 1983). Leptospira interrogans is a small gram-negative spirochete with a number of antigenically distinct serovars, many of which cause clinical disease in veterinary species. The serovars are maintained in nature by a wide range of subclinically infected wild and domestic animal reservoir hosts that act as a source of infection for incidental animal hosts or humans via contact with contaminated urine (Greene et al., 2012c). L. interrogans is a recognized cause of anterior uveitis in a number of species and is strongly implicated as an etiological factor in equine recurrent uveitis (ERU) (Dwyer et  al., 1995; Faber et  al., 2000). L. interrogans var pomona is the main serovar linked to ERU in the United States, whereas L. interrogans var grippotyphosa is more common in central Europe. Sporadic reports have also associated a number of other serovars with equine uveitis, including australis, autumnalis, icterohaemorrhagiae, and sejroe (Dwyer & Gilger, 2005; Gilger, 2010; Lowe, 2010; Matthews, 1987; Spiess, 2010). Borrelia burgdorferi is a small gram-negative spirochete that is the cause of Lyme disease in humans, dogs, horses, and cats (Greene et al., 2012b). Unlike Leptospira spp., B. burgdorferi is unable to survive as a free-living organism in the environment. Instead it is transmitted between its wild animal reservoir host (rodents, small mammals, and birds) and its incidental animal or human host via a tick vector, primarily Ixodes sp. Infection rates are proportional to contact time between the tick and host, and once inoculated, the organism spreads mainly by tissue migration rather than hematogenously. Infection in dogs is often asymptomatic, but a wide range of signs have been reported, including fever, polyarthropathy, protein-losing nephropathy, and cardiac and neurological disease (Fritz & Kjemtrup, 2003; Krupka & Straubinger, 2010; Little et al., 2010; Littman, 2003). Ocular signs in dogs include anterior and posterior uveitis (Cohen et  al., 1990; Munger, 1990), whereas a single case report identified the organism in the eye of a pony with arthritis and panuveitis (Burgess et al., 1986). Diagnostic testing options for borreliosis include ELISA, IF, Western blotting, and PCR testing (Gerber et al., 2009; Johnson et al., 2008; Littman et al., 2006; Straubinger, 2000). Brucella canis is a small gram-negative coccobacillus that causes abortion, epididymitis, and lymphadenomegaly in dogs (Greene & Carmichael, 2012). It rarely causes anterior and posterior uveitis in dogs in the absence of overt systemic disease (Ledbetter et al., 2009e; Vinayak et al., 2004).

Pathogenic Obligate Intracellular Bacteria Chlamydiaceae and Parachlamydiaceae

The genomic classification of the family Chlamydiaceae (order Chlamydiales) has undergone major revisions since 1999, and now is divided into two genera, Chlamydia and

Chlamydophila (Table 7.2). Prior to 1999, only the Chlamydia genus was recognized, and most of the organisms relevant to veterinary species were classified as C. psittaci variants (Stiles, 2012). However, because of the genomic similarities between the genera and because no easily recognizable phenotype such as host preference or tissue tropism is available, it has been proposed to once again combine the genera (Sachse et al., 2015). Chlamydiaceae are gram-negative, obligate intracellular bacteria that require the metabolic machinery of host cells for survival and replication. They possess a cell wall like that of other gram-negative bacteria except that they lack peptidoglycan. They are relatively labile, although they can survive a few days in the environment at room temperature. Their developmental cycle involves both extracellular (elementary body) and intracellular (reticulate body) forms. Elementary bodies are small, metabolically inactive infectious particles with rigid cell walls that travel extracellularly to infect new cells. Once within the cytoplasm of a host cell, they transform into the larger reticulate bodies, which replicate by a process of binary fission within membrane-bound cytoplasmic vacuoles. Rapid proliferation then ensues as the reticulate bodies transform into a large population of elementary bodies, which are then released after lysis of the host cell and go on to infect new cells (Gruffydd-Jones et al., 2009; Stiles, 2012). The organisms can be found in the ocular, respiratory, gastrointestinal, and urogenital mucous membranes of apparently healthy animals, which can act as carriers. Spread is via direct contact or aerosol. Chlamydophila felis is an important feline pathogen. Seroprevalence studies have shown that the organism is widespread in the worldwide feline population, with more than 10% of unvaccinated household cats and up to 64% of cattery cats having antibodies against Chlamydophila (Di Francesco et  al., 2004a, 2004b; Gunn-Moore et  al., 1995; Holst et al., 2006; Yan et al., 2000). Despite this high exposure rate, C. felis can be isolated from the conjunctiva of only around 6% of clinically healthy cats (Wills et al., 1988).

C. felis is a significant cause of conjunctivitis in cats, with two studies isolating the organism from 30% to 56% of cats with conjunctivitis, respectively (Hartmann et  al., 2010; Wills et al., 1988). Another study, however, isolated it only from around 7% of cats with active conjunctivitis (Low et al., 2007). C. felis can also be present as part of a mixed infection with FHV-1, calicivirus, Mycoplasma spp., or aerobic bacteria (Fernandez et al., 2017; Hartmann et al., 2010; Low et al., 2007). Clinical disease is most commonly seen in cats less than 1 year of age. Clinical signs, primarily conjunctivitis, develop after an incubation period of between 2 and 5 days. Transient fever and inappetance may develop, but most cats remain well and continue to eat. Respiratory and other systemic signs are uncommon. However, the organism can be shed from the gastrointestinal and urogenital tracts, and this can act as a source of infection to other cats (Gruffydd-Jones et al., 2009). Conjunctival shedding of C. felis usually stops from around day 60 postinfection, although untreated cats can shed the organism for up to 215 days and some develop persistent infection (Gruffydd-Jones et al., 2009; O’Dair et al., 1994). Host immunity involves both cellular and humoral responses, and increasing immunity establishes with age (Longbottom & Livingstone, 2006; Stiles, 2012). In sheep, chlamydial species have been isolated from cases of infectious ovine keratoconjunctivitis, as well as polyarthritis, pneumonia, orchitis, epididymitis, and abortion (Dagnall, 1994b; Wilsmore et al., 1990). However, it should be noted that Chlamydophila abortus and C. pecorum can also be isolated from the conjunctiva of healthy sheep, and one study showed no significant difference in isolation rates between flocks affected with conjunctivitis and healthy flocks (Polkinghorne et al., 2009). Chlamydophila sp. also causes conjunctivitis in cattle (Otter et al., 2003), swine (Rogers et al., 1993; Schautteet & Vanrompay, 2011), guinea pigs (Lutz-Wohlgroth et al., 2006; Strik et al., 2005), and koalas (Cockram & Jackson, 1981).

Table 7.2  The Chlamydiaceae family. Genus

Species

Host

Preferential tissues

Chlamydia

trachomatis

Humans

Conjunctiva, urogenital tract, neonatal respiratory tract

muridarum

Rodents

Internal organs

suis

Swine

Conjunctiva, respiratory, and gastrointestinal tracts

psittaci

Birds

Urogenital and respiratory tracts, internal organs

felis

Cats

Conjunctiva

pecorum

Cattle, sheep

Conjunctiva, brain, joints

pneumoniae

Humans, koalas, horses

Respiratory tracts, joints

abortus

Sheep

Placenta, intestines

caviae

Guinea pigs

Conjunctiva, urogenital system, spleen

Chlamydophila

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In general, chlamydial species are considered to have a restricted host range. However, C. psittaci and C. abortus are well-recognized as serious zoonotic pathogens, and there have also been reports documenting transmission of C. felis from cats to humans (Hartley et  al., 2001; Rohde et al., 2010). In addition, C. psittaci has also been isolated from sheep (Lenzko et al., 2011) and C. pneumoniae was identified in cases of feline conjunctivitis (Sibitz et al., 2011). Parachlamydial organisms (order Chlamydiales, family Parachlamydiaceae) are Chlamydial-like bacteria that naturally infect amoeba. Parachlamydia acanthamoebae infects the protozoan Acanthamoeba, the cause of amoebic keratitis in humans, but is also able to infect and multiply in human macrophages (Marciano-Cabral & Cabral, 2003). P. acanthamoebae has been found in the eyes of both healthy cats and those with keratitis or conjunctivitis (Richter et  al., 2010). Another parachlamydial organism, closely related to Neochlamydia hartmannellae, was previously identified in ocular samples from cats with and without conjunctivitis (von Bomhard et al., 2003). The clinical significance of these findings is unknown. Diagnosis of chlamydiosis is most commonly via PCR of conjunctival swabs. Ehrlichia, Anaplasma, and Rickettsia sp.

Prior to 2001, the genera Ehrlichia, Anaplasma, and Rickettsia were all classified as members of the family Rickettsiaceae. However, molecular characterization studies led to the reclassification of Ehrlichia and Anaplasma as members of family Anaplasmataceae (Harrus et al., 2012). Ehrlichia sp. are gram-negative, nonmotile, aerobic, obligate intracellular coccobacilli that are transmitted by ticks. They primarily infect leukocytes (monocytes, macrophages, granulocytes). Ehrlichia canis, which is transmitted by the tick vector Rhipicephalus sanguineus, causes canine monocytic ehrlichiosis (Harrus et al., 2012). During an incubation period of 8–20 days, the organism multiplies in monocytes by a process of binary fission and spreads throughout the body. After the incubation period, three phases of clinical disease are recognized. The acute phase lasts 2–4 weeks and is characterized by fever, anorexia, lethargy, petechiation of mucous membranes, and lymphadenomegaly. Laboratory abnormalities include thrombocytopenia, mild leucopenia, and mild anemia. Ocular signs during the acute phase are related to acute vasculitis and thrombocytopenia and include conjunctival hyperemia, anterior uveitis, chorioretinitis, retinal hemorrhage, and optic neuritis (Komnenou et  al., 2007; Leiva et al., 2005b; Panciera et al., 2001). Untreated dogs will then enter a subclinical disease phase, with apparent recovery and resolution of clinical signs, although platelet counts may remain below reference range. This phase can last months to years and during this period, E. canis is thought to

remain dormant within the spleen. Infected dogs subsequently eliminate the organism, remain symptomless lifelong carriers, or progress to the chronic phase of infection. In the chronic phase, hyperviscosity syndrome can develop as a consequence of a monoclonal gammopathy. This, along with thrombocytopenia, result in ocular signs including hemorrhage and retinal detachment. Eventually bone marrow suppression results in an often fatal pancytopenia. Anaplasma platys (formerly known as Ehrlichia platys) is a gram-negative, nonmotile, aerobic, obligate intracellular bacterium that is presumed to be tick-transmitted, although a vector has not yet been conclusively identified (DantasTorres, 2008; Harrus et al., 2012). It infects canine platelets, and experimental infections often lead to only very mild clinical disease. Some strains, however, can cause more severe signs including fever, lethargy, weight loss, petechiation of mucous membranes, and lymphadenomegaly. Uveitis has been reported after natural infection (Glaze & Gaunt, 1986). Rickettsia rickettsii is the cause of Rocky Mountain spotted fever in dogs. It is an obligate intracellular bacterium that replicates in endothelial cells of smaller arteries and venules (Greene et  al., 2012a). It is transmitted by ticks (predominantly Dermacentor andersoni and Dermacentor variabilis, although Amblyomma americanum and Rhipicephalus sanguineus are also implicated) and causes an acute febrile illness in dogs, characterized by a multifocal vasculitis. Clinical signs include fever, lymphadenomegaly, peripheral edema, joint swelling, hemorrhage of the mucous membranes, icterus, tachypnea, tachycardia, and sometimes neurological signs secondary to meningoencephalomyelitis. Ocular signs include scleral congestion, conjunctival hemorrhage, anterior uveitis, retinal hemorrhage, and optic neuritis (Davidson et al., 1989). Mycoplasma sp.

Mycoplasmas are divided into hemotrophic and nonhemotrophic types, but only the nonhemotrophic types are involved in ocular disease. Mycoplasmas are the smallest free-living microorganisms, with replicating cells as small as 300 nm. They lack a true cell wall and instead are enclosed in a plasma membrane composed of protein, glycoprotein, glycolipid, and phospholipid. The lack of a cell wall makes mycoplasmas relatively fragile outside their host but resistant to lysozyme and cell wall inhibiting antibiotics such as penicillins. Their genome contains as few as 700 genes, which is sufficient to allow for an extracellular existence but restricts their metabolic capability. For this reason they require a rich environment in order to flourish, which they find on mucous membranes of the respiratory and urogenital systems of their hosts, although they are able to survive in the environment for variable time periods depending on the temperature and humidity (typically 7–14 days under dry conditions at 30°C) (Messick & Harvey, 2012).

Mycoplasmas are commonly isolated from mucous membranes of healthy animals, but their increased rate of isolation in disease suggests that they also play a pathogenic role under some circumstances. Pathogenic mechanisms include the production of hemolysin, proteases, and nucleases. They tend to be host specific. In cats, Mycoplasma sp. are rarely isolated from the conjunctival sac of healthy animals, with surveys reporting either an absence of Mycoplasma sp. or isolation rates of less than 3% (Haesebrouck et al., 1991; Low et al., 2007; Shewen et al., 1980). However, in cats with conjunctivitis, isolation rates between 16% and 49% have been reported, frequently in the absence of other pathogens, thus suggesting a pathogenic role (Haesebrouck et al., 1991; Hartmann et al., 2010; Low et al., 2007). Mycoplasma felis is the predominant pathogenic species, but other species isolated from cases of feline conjunctivitis include M. canadense, M. gateae, M. lipophilum, M. hyopharyngis, and M. cynos (Haesebrouck et al., 1991; Hartmann et al., 2010). In sheep and goats, Mycoplasma conjunctivae can be cultured from the conjunctival sac of healthy animals but is more frequently isolated from cases of conjunctivitis and keratoconjunctivitis. Experimental inoculation into the conjunctival sac confirms its role in the etiology of conjunctivitis in this species (Akerstedt & Hofshagen, 2004; Dagnall, 1994b; Degiorgis et al., 2000; Egwu et al., 1989; Giacometti et al., 1998; Jansen et al., 2006; McCauley et al., 1971; Motha et al., 2003; ter Laak, 1988a, 1988b). In cattle, Mycoplasma bovoculi has been implicated as an etiological agent in IBK (Rosenbusch, 1983). In birds, Mycoplasma gallisepticum can cause outbreaks of severe conjunctivitis and upper respiratory tract disease (Dhondt et al., 1998; Nunoya et al., 1995).

Pathogenic Anaerobic Bacteria Obligate anaerobes constitute a large group of gram-positive or gram-negative rods or cocci that exist not only in the environment but also as commensal organisms on the mucous membranes of humans and animals, primarily in the gastrointestinal tract, where they play an important role in the protection of mucosal surfaces from pathogenic bacteria (Jang & Walker, 2012). Anaerobic bacteria can become pathogenic after compromise of a mucosal surface or inoculation of an anaerobic organism into a normally sterile site. They are commonly involved in deep tissue infections, often as part of a mixed infection with facultatively anaerobic organisms such as Staphylococcus, Streptococcus, Escherichia, or Pasteurella sp. A variety of anaerobic bacteria have been isolated from orbital infections in animals, including Bacteroides sp., Clostridium sp., Actinomyces sp., Fusobacterium sp., Peptostreptococcus sp., and Porphyromas sp. (Wang et al., 2009). Tetanus is caused by the action of a neurotoxin produced by the gram-positive soil-dwelling anaerobe Clostridium

tetani. Cranial nerve motor nuclei are commonly affected, resulting in hypertonicity of their respective musculature. Ocular signs are among the most common presenting signs of tetanus, with third eyelid protrusion and enophthalmos developing as a result of globe retraction secondary to retractor bulbi muscle hypertonicity (Burkitt et al., 2007). Botulism is caused by a neurotoxin produced by Clostridium botulinum, a gram-positive anaerobic bacterium that is found in decaying organic matter. The neurotoxin causes inhibition of acetylcholine release at cholinergic synapses, disrupting both autonomic and skeletal muscle function. Ingestion of neurotoxin leads to systemic absorption and progressive clinical signs including ascending flaccid paralysis of the limbs, abnormal cranial nerve motor reflexes, inability to swallow, and excessive salivation. Ocular signs include mydriasis and reduced pupillary light reflexes (Critchley, 1991).

Ocular Fungal and Algal Diseases Introduction Fungi are eukaryotic, nonphotosynthetic organisms that grow as either single-cell yeasts or multicellular molds. Molds grow as branching filaments called hyphae (2–0 μm in diameter) whereas yeasts are unicellular, have oval or spherical appearance (3–5 μm in diameter) and reproduce by budding. Depending on the environment, some species of fungi can grow as either yeast or mold forms, and these species are described as dimorphic. Interestingly, some fungi exhibit multiple forms simultaneously, including budding, pseudohyphae, and hyphae; therefore, these species are described as polymorphic. Environmental temperature, nutrient factors, and genetic factors determine the type of growth observed (Quinn et al., 2011f). Fungi grow aerobically, and many are strict aerobes. The reproductive cycle of fungi is sexual, asexual, or both. The sexual form of a fungal organism is referred to as a telemorph; the asexual form is referred to as an anamorph. The entire fungal replication process, consisting of all known reproductive forms, is referred to as a holomorph. In sexual reproduction, propagules arise through a process of plasmogamy, which is followed by karyogamy of compatible nuclei and subsequent meiosis. The point at which meiosis occurs varies among species. In contrast to meiotic reproduction, asexual reproduction is characterized by propagules formed directly from existing nuclei through mitosis. Via asexual reproduction, molds produce aerial fruiting hyphae that bear spores, the dispersion of which is chiefly through air currents, water, and animals. The optimum temperature for growth of fungi is 20°C–30°C, but pathogenic fungi causing systemic mycoses can tolerate 37°C. Fungal growth is by simple mitosis of

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somatic nuclei and budding or apical extension of the cell wall. Elongation of buds with persistent attachment of cells in some yeasts produces filamentous forms known as pseudohyphae. In filamentous fungi, as hyphae grow by apical extension, they can intertwine to form a mycelial network or colony. Hyphae are often divided at regular intervals by cross partitions called septa, which have one or more small pores that allow for cytoplasmic communication. Chitin is a primary component of the cellular structure of many fungi. Chitin is composed of N-acetylglucosamine residues linked by glycosidic bonds similar to those found in cellulose. Fungal cell wall structures, which contain ergosterol, other lipids, and glycoproteins, serve as unique targets for antifungal drugs. Fungi have been placed in their own kingdom. Fungi are nonmotile and most are strictly aerobic. Because fungi are nonphotosynthetic, they must obtain nutrition by secreting enzymes and absorbing the digested substrate. Medically important fungi have been separated into four traditional classes: Basidiomycetes sp., Ascomycetes sp., Zygomycetes sp., and Deuteromycetes sp. (or Fungi Imperfecti).

General Pathogenic Mechanisms and Host Responses Fungi are commonly recovered from the eyelids and conjunctiva of normal animals, and they are believed to reflect random environmental exposure. Fungi do not appear to be permanent floral residents of the ocular surface but only transient colonizers of the external eye. Filamentous fungi are the predominate fungal isolates reported from the eyes of normal animals. Local defenses to fungi are generally quite effective because ocular infection is not common unless anatomic barriers are compromised. An intact corneal epithelium provides excellent resistance to fungal penetration and infection. Normal ocular surface flora, normal lacrimal flow, and mechanical movements of the eyelids (and third eyelids) create an environment unfavorable to the growth of many opportunistic fungi. In addition, because many fungi will not grow at elevated temperatures, normal body temperature is high enough to prevent some from becoming pathogenic. The lower temperature of the cornea relative to the rest of the body and the eye, however, may partially explain the predilection for keratomycosis as the most common ocular infection with fungi. The role of local antibodies and complement in protection against ocular fungal infection is unclear. A breach of the intact corneal epithelial barrier is usually a prerequisite for keratomycosis, and penetrating injuries can result in direct inoculation of fungi into the cornea. After trauma, colonization of an ocular wound by fungi may occur, particularly when corticosteroids have been administered, whether alone or in combination with antibacterial agents. The clinical observation that topical corticosteroids enhance the risk of fungal ocular infections suggests that

local immune factors may be important in protecting the eye from fungal invasion. Local immunosuppression by corticosteroids possibly results primarily from effects on cellular immune mechanisms because immunity to fungal infections is considered to be more cell-mediated than antibodymediated. Systemic or topical antibacterial agents alter normal flora and can decrease natural microbial barriers as well as encourage colonization and growth of fungi. The second avenue for fungal invasion of the eye is endogenous (i.e., via the bloodstream). Systemic mycoses often occur in otherwise healthy animals living in endemic areas. In animals, intraocular fungal disease most often results from systemic mycoses contracted through respiratory tract exposure. The host inflammatory response to oculomycosis is generally suppurative in acute cases and pyogranulomatous in chronic cases. Host tissues can be damaged directly by inflammatory processes (i.e., by elaborating inflammatory mediators and oxidative products) or by enzymes produced directly by the fungal organisms.

Diagnostic Methods The laboratory methods employed for diagnosis include microscopic examination, fungal culture, PCR (for fungal detection and identification), and serology (Jagger, 2005; Jang & Walker, 2012; Sparagano & Foggett, 2009). Microscopic Examination

Significant fungal elements can be identified by cytological and histological examination of slides containing material from scraped surface lesions, fluids, and/or biopsies. Direct smears can be prepared for cytology as fixed stained smears and/or wet mounts (stained or unstained). Gram and Romanonwsky-type stains (e.g., Leishman’s, Giemsa, Wright’s, Diff-Quik) are routinely used for the cytological detection of fungi, especially yeasts, on direct smears with the fungal cell walls appearing as unstained halos (Fig. 7.11). Regarding cytological examination of wet mounts, there is a useful but less generally available fluorescent method; the collected material is mixed with equal volumes of 10% potassium hydroxide and 0.5% calcofluor white powder on a slide. Calcofluor is a fluorescent material that binds to chitin in fungal cell walls and when excited by light at a wavelength of 500 nm, the bound calcofluor fluoresces blue–green. Some fungal elements can be detected in histological ­sections with hematoxylin and eosin, but employment of specific stains such as periodic acid-Schiff (PAS), Gomori’s methenamine silver, and Meyer’s mucicarmine allows confirmation of fungal infection and differentiation between yeast and hyphal forms. Culture

Sabouraud dextrose agar is the medium most commonly used for culturing ocular fungi from swabs, scrapings,

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Figure 7.11  Smear prepared after centrifugation of vitreous fluid which was aspirated from the right eye of a 12-year-old cat which was presented with blindness and exophthalmia. Microscopic examination revealed the presence of two fungal organisms with their cell wall appearing as an unstained halo. (Original magnification 1000×; modified Giemsa stain.) Serological testing demonstrated a high antibody titer against Cryptococcus as well as the presence of Cryptococcus antigen.

fluid, and tissue samples. Enriched media such as brainheart infusion agar with 5% blood is used for dimorphic fungi. When incubated at 37°C, mycelial fungal growth may convert to the yeast phase of the dimorphic organism. Gentamicin or chloramphenicol are useful additions to culture media to suppress bacterial overgrowth, but media should not include cycloheximide, which inhibits fungal growth. Specimens from external infections of the ocular surface should be collected with a spatula and inoculated directly onto culture media. Scrapings or biopsy specimens from corneal ulcers or aspirates from the anterior chamber or the vitreous cavity should be directly inoculated onto Sabouraud agar, brain-heart infusion broth medium, and blood agar plates. Incubation should be from 24°C to 30°C for at least 30 days. Definitive identification is often made on the basis of the morphologic structure of the organism, including the direct microscopic appearance of the fungus in the clinical specimen, the morphology of the colony and type of pigmentation, the microscopic appearance of the fruiting heads and spores from mold colonies, and the morphology of the yeast and type of budding. Commercially available identification systems utilizing biochemical testing can be used for yeasts and, to a more limited extent, to identify some molds (Pincus et al., 2007). In vitro susceptibility testing of fungi to antifungal drugs has been performed by measuring a suitable concentration end point (i.e., the MIC) for various antifungal drugs (Ledbetter et al., 2007; Pearce et al., 2009; Weinstein et al., 2006). The MIC is the amount of drug (micrograms per milliliter) that inhibits essentially all visible growth in treated test wells compared with duplicate, untreated test wells (see Ocular Bacteriology section previously). Standardized in

The ease with which PCR diagnostics can be performed, the relatively minimal expense of such testing, and the rapidity with which results can be delivered make PCR testing for fungal ocular infections desirable (Garner et al., 2010). However, the high sensitivity of PCR may, in fact, be a limiting factor in the applicability of PCR to diagnosis of keratomycosis in veterinary species. Fungal organisms are often part of the commensal flora depending on geography, season, and environment; standard PCR cannot distinguish transient fungal flora from those that are involved in pathogenesis of disease. Serology

A number of serological techniques are available for the diagnosis of systemic mycoses (Jackson, 1986). Complement-Fixation Test

The complement-fixation (CF) test is used for the diagnosis of histoplasmosis, blastomycosis, and coccidioidomycosis. Cross-reactivity between Histoplasma sp. and Blastomyces sp. occurs. CF titers for mycotic agents are often low (e.g., 1 : 8, 1 : 16), and nonspecific anticomplementary activity can be problematic. Appropriate controls must be used, and acceptable limits of complement activity established. Titers of 1 : 8 or greater offer presumptive evidence of histoplasmosis, blastomycosis, and coccidioidomycosis. Lower titers (e.g., 1 : 2, 1 : 4) might also be important, but a supplementary gel diffusion precipitation test should be performed. CF titers can serve as a prognostic aid. When titers decrease over a period of several weeks, the prognosis is usually good; if titers continue to increase over 8 weeks or longer, the prognosis is more guarded. Gel Diffusion Precipitin

The gel diffusion precipitin (GDP) test is an immunodiffusion test with less cross-reactivity than the CF test. The test is based on the reaction in agar gel of specific antibody to fungal cell extracts or culture filtrates. In addition to its specificity, it is relatively simple to perform. The GDP has been developed for blastomycosis, histoplasmosis, coccidioidomycosis, aspergillosis, candidiasis, and sporotrichosis. In cases of mixed infections, false-negative results can be problematic. In addition, the GDP test is not useful in the diagnosis of advanced histoplasmosis in the cat. Latex Agglutination

The slide latex agglutination (LA) test is rapid, sensitive, and specific for the presence of fungal antigen. This test has been developed for the diagnosis of cryptococcosis, coccidioidomycosis, sporotrichosis, candidiasis, and histoplasmosis,

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vitro susceptibility test criteria are not available, though attempts have been made to estimate MIC susceptibility versus resistance on the basis of correlating clinical responses to antifungal therapy (Brooks et al., 1998).

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and it has been used extensively to detect antigen in body fluids (e.g., cryptococcal antigen in CSF). The course of disease can also be monitored during therapy by quantitating the antigen in fluids. Fluorescence

Fluorescein-labeled antibodies can be used to identify fungi rapidly in tissues and culture, and this test can also be used on fixed specimens. It is particularly useful in the absence of culture and when serum is not available. Fluorescein-labeled lectins with defined specificity for different sugars also have been used to identify fungi in paraffin sections for surgical and postmortem specimens. The indirect FA test can also be used to detect antibody to fungal agents when other procedures are unavailable. Agglutination

The tube agglutination test is a sensitive procedure for the diagnosis of sporotrichosis and cryptococcosis using yeast cells as antigen. It is used in conjunction with the LA ­antigen test to quantitate anticryptococcal antibody for prognostic purposes. Enzyme-Linked Immunosorbent Assay

Detection of antibodies employing an enzyme-linked immunosorbent assay (ELISA) test has been reported for the diagnosis of sporotrichosis in cats (Fernandes et al., 2011). Immunofluorescence

The fluorescent immunoassay is an immunochemical procedure used to detect antibodies to Candida sp., Histoplasma sp., Blastomyces sp., and Coccidioides sp. This test compares favorably with conventional methods in correlating clinical response and predicting relapse of disease.

Pathogenic Fungi Dermatophytes

Dermatophytes are keratinophilic fungi that cause clinical disease in a wide range of animal species. Although many different dermatophyte species have been isolated from animals, a limited number of species are responsible for the majority of cases of clinical disease. They typically cause localized or generalized skin disease that involves the eyelids and periocular skin. Transmission is via direct contact or from contaminated fomites, with an incubation period of 1–3 weeks. The organisms have a relatively wide host range and are significant zoonotic pathogens (Chermette et  al., 2008; Drouot et al., 2009; Moriello et al., 2017; Ramsay, 2011; Warner, 1984). Dermatophytosis is more common in hot, humid environments. The high environmental resistance of arthrospores, the wide range of host species, and the close contact between susceptible animals can all contribute to disease spread and

persistence, such that the disease can become enzootic in certain environments, particularly farms and breeding establishments. Pathogenic mechanisms include the production of keratinase, elastase, and collagenase that are thought to aid initiation and progression of infection (Viani et al., 2007). Microsporum canis, Trichophyton mentagrophytes, and Microsporum gypseum are responsible for the vast majority of canine and feline dermatophyte infections worldwide. Cats are considered to act as reservoirs of M. canis, with surveys of healthy cats showing carrier rates of around 2% (Patel et  al., 2005). The reservoir host of T. mentagrophytes is thought to be rodents, although cats also act as carriers (Patel et al., 2005). M. gypseum is a geophilic organism; exposure is therefore by digging in contaminated soil (Moriello & DeBoer, 2012). In cattle, Trichophyton verrucosum is most commonly isolated, followed by T. mentagrophytes and M. gypseum. In horses, T. equinum is the predominant isolate, with Microsporum equinum and T. mentagrophytes less common. Ringworm is rare in sheep and pigs (Chermette et al., 2008; Soltys & Sumner-Smith, 1969). Diagnosis of dermatophytosis is via direct microscopic examination of skin scrapes or, preferably, fungal culture. Approximately half of all M. canis strains are reported to fluoresce under examination of the haircoat with ultraviolet light, wavelength 320–400 nm (Wood’s lamp examination) (Kefalidou et al., 1997). Ocular Surface Fungal Pathogens: Aspergillus, Penicillium, Alternaria, Cladosporium, Fusarium, and Related Species

These are ubiquitous free-living saprophytic fungi that are commonly found as commensal flora on the skin and mucous membranes, including the conjunctiva, of animals (see Table 7.1). They act as opportunistic pathogens, and a wide range of species have been implicated in ocular surface disease. Presumably caused by environmental housing conditions, fungal ocular surface disease is more commonly seen in horses and production animals than in companion animals (Andrew et  al., 1998, Brooks et  al., 1998; Gaarder et  al., 1998; Gerding et  al., 1988; Marler et  al., 1994; Reed et al., 2013). Fungal keratitis is more commonly seen in hot and humid environments and is a particularly significant problem in horses, in which it can cause devastating corneal disease (Andrew et  al., 1998; Gaarder et  al., 1998). The organisms require an epithelial defect to allow colonization of the corneal stroma, and tear film instability could predispose to infection (Brooks et  al., 2000b). Once inoculated, pathogenic mechanisms include release of proteases and factors that promote adherence and penetration (Hua et al., 2010; Jackson et al., 2007). Although primarily extraocular pathogens, these organisms also cause intraocular disease in association with systemic disseminated spread, or via local extension from the

sinuses via the orbit (Clercx et al., 1996; Willis et al., 1999; Wooff et al., 2018). Systemic Fungal Pathogens: Blastomyces, Histoplasma, Coccidioides, and Cryptococcus sp.

Blastomyces dermatitidis, Histoplasma capsulatum, and Coccidioides immitis are free-living saprophytic fungi that grow filamentously in the environment and produce conidia (asexual spores). Conidia are environmentally robust spores that are thought to be infectious via airborne spread. Their small size (typically 1–4 μm) allows them to enter the alveoli where they establish local infection. Once there, systemic spread ensues via hematogenous or lymphatic routes. Pathogenic fungi possess a large number of virulence factors that allow them to establish themselves in host tissue and to escape host defenses, although to allow systemic spread, some degree of host immunosuppression is usually required (Hogan et al., 1996). Blastomyces dermatitidis

B. dermatitidis prefers sandy, acidic soils with close proximity to water, supported by decaying animal and plant material. Even in endemic regions, the organism is not widely distributed but appears to require an ecological niche of some sort for survival. In contrast to other systemic fungal infections, subclinical infection is rare. Virulence factors for B. dermatitidis include a number of cell wall-associated factors including α-1,3glucan and WI-1 adhesin/antigen (Hogan et al., 1996). Blastomycosis is primarily a disease of North America, with an endemic distribution comprising Mississippi, Missouri, the Ohio River Valley, the mid-Atlantic and southern states, and southeast Canada. It is primarily a disease of dogs; cats are rarely infected. Up to 50% of dogs with blastomycosis have ocular lesions, primarily chorioretinitis, anterior uveitis, and optic neuritis. Hematogenous spread is thought to be the main route by which the organism gains access to the choroid (Arceneaux et  al., 1998; Brömel & Sykes, 2005; Krohne, 2000; Legendre, 2012). Histoplasma capsulatum

H. capsulatum grows preferentially in nitrogen-rich soil such as that contaminated with bird or bat excrement. It prefers warm, moist, and humid environmental conditions and is endemic in many parts of the world. Virulence factors include cell wall α-1,3-glucan, relative thermotolerance, and an ability to modulate local pH and thus inactivate hydrolases released from host phagosomes. Of particular pathogenic relevance is the ability of H. capsulatum to persist and actively replicate within host macrophages once phagocytosed. As well as providing protection against humoral and cell-mediated host defenses, this “Trojan horse” approach allows spread of the organism within the host, as unwittingly infected macrophages

migrate from the lungs to other parts of the body, carrying the fungus with them (Hogan et al., 1996). In the United States, most clinical cases of histoplasmosis can be found in the regions of Ohio, Missouri, and Mississippi (Brömel & Greene, 2012). Up to two-thirds of infected dogs develop ocular lesions. Chorioretinitis is the most common ocular manifestation, although optic neuritis and anterior uveitis also occur (Krohne, 2000; Salfelder et  al., 1965). In cats, histoplasmosis is the second most common systemic mycosis after cryptococcosis. Twenty-four percent of cats with histoplasmosis are reported to have ocular signs, primarily chorioretinitis (Brömel & Sykes, 2005; Davies & Troy, 1996; Gionfriddo, 2000). Coccidioides immitis

C. immitis prefers sandy, alkaline, dry, and warm soils at low elevation and is primarily found in the southwestern United States, Central America, and parts of South America. Virulence factors include the production of extracellular proteinases (Hogan et al., 1996). As with other systemic mycotic infections, ocular involvement primarily manifests as chorioretinitis. The condition is more common in dogs than in cats (Gionfriddo, 2000; Graupmann-Kuzma et al., 2008; Greene & Troy, 1995; Krohne, 2000; Shubitz & Dial, 2005). Cryptococcus sp.

Cryptococcosis in dogs and cats is caused by one of two encapsulated yeast species, Cryptococcus neoformans and Cryptococcus gattii. In contrast to other systemic mycoses, cryptococcosis is less common in dogs than in cats, in which it is the most frequently recognized systemic fungal infection (Gionfriddo, 2000; Sykes & Malik, 2012; Trivedi et al., 2011). C. neoformans has a worldwide distribution, prefers nitrogen-rich soils, and is commonly found in soil contaminated with bird (especially pigeon) excrement. C. gattii is restricted to tropical and subtropical climates. It is found in high concentrations within decaying plant material, and in Australia, koalas are thought to be sentinel hosts for infection (Sykes & Malik, 2012). In animal tissues, the organisms exist as round to oval yeast with a characteristic polysaccharide capsule which provides protection from host phagocytes and is a key virulence factor (Zaragoza et al., 2009). Additional virulence factors include the cell wall-associated oxidative enzyme laccase (Zhu & Williamson, 2004; Zhu et al., 2001) and the production of melanin, mannitol, superoxide dismutase, proteases, and phospholipases (Buchanan & Murphy, 1998). The route of infection is thought to be via inhalation of airborne dehydrated yeast cells or spores. In humans, primary infection is established in the lung. This is usually asymptomatic in healthy individuals, but in immunocompromised patients, hematogenous spread via macrophages allows dissemination to other tissues including the nervous system (Botts & Hull, 2010).

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In contrast to humans, the nasal cavity is the primary site of infection in cats, dogs, koalas, and psittacine birds. Here it causes local disease or disseminates, usually to the central nervous system to cause meningoencephalitis. Intraocular spread is presumed to be via the optic nerves, although infection via the hematogenous route also occurs (Sykes & Malik, 2012). The primary ocular manifestation is chorioretinitis (Gionfriddo, 2000; Sykes & Malik, 2012; Trivedi et al., 2011). Prototheca sp.

Prototheca is a saprophytic alga that is related to the green algae of the genus Chlorella. Unlike Chlorella, however, Prototheca lacks chlorophyll and is a saprophytic organism (Hollingsworth, 2000; Pressler, 2012). Three species are recognized: Prototheca stagnosa, P. wickerhamii, and P. zopfii. Of these, P. wickerhamii and P. zopfii have pathogenic potential. P. zopfii is more often associated with disseminated disease than is P. wickerhamii (Pressler, 2012; Stenner et al., 2007). The organisms are found in sewage, animal waste, and decaying vegetable matter. They are opportunistic pathogens, causing disease if they are ingested or come into contact with damaged skin or mucous membranes. It is thought that some degree of host immunosuppression is required to allow disseminated infection, with cell-mediated immunity playing a major role in host defense mechanisms. In dogs there is an apparent breed predisposition, with an increased reported incidence in Collies and Boxers. Young adult spayed females are also overrepresented (Hollingsworth, 2000; Stenner et al., 2007). In cats, only cutaneous protothecosis has been reported, and disseminated disease does not seem to occur. The most commonly reported clinical sign in dogs is colitis, which is usually intermittent and chronic in nature. Systemic dissemination leads to renal, hepatic, cardiac, CNS, and ocular disease. Ocular disease occurs in three-quarters of reported cases and can be the presenting sign. Chorioretinitis, retinal hemorrhage, retinal detachment, and anterior uveitis are reported (Pressler, 2012; Hollingsworth, 2000). Other Fungal Pathogens

Other fungal species have been sporadically documented to cause opportunistic ocular diseases, including anterior uveitis, chorioretinitis, endophthalmitis, and orbital disease (Clercx et al., 1996; Gionfriddo, 2000; Krohne, 2000; Wooff et al., 2018).

Ocular Protozoal Diseases Introduction The most common protozoa responsible for ocular disease are Toxoplasma, Neospora, Leishmania, Babesia, and Encephalitozoon. For information on the individual organism’s replication and pathological mechanisms, see the respective sections that follow.

Diagnostic Methods Diagnosis is based on a combination of clinical signs, clinicopathological abnormalities, and more specific diagnostic tests (Little & Lindsay, 2012; Murphy & Papasouliotis, 2005). These tests are best either in the detection of the organism itself (microscopic examination, culture, PCR, histology) or immunological tests that detect specific proteins of the organism (antigens) and/or the host’s immune response to the organism (antibodies). Microscopic Examination

Organisms can be detected in dried smears prepared from fresh and anticoagulated blood samples (e.g., Babesia), other body fluids, and fine needle aspirates of affected organs, as well as impression smears from tissue biopsies (e.g., Neospora, Toxoplasma, Leishmania, Encephalitozoon). The most commonly used stains are Giemsa, Wright, and Wright–Giemsa. Diff-Quik can also be used, but both detection and subsequent morphological identification is more difficult. The use of immunocytochemical methods may increase the sensitivity of direct identification, but its commercial availability is very limited. Culture

Culture of whole blood, tissue aspirates, biopsies, or body fluids is not commonly performed because protozoa are generally very difficult to grow in vitro; those that can grow are very slow, and the methodologies are technically demanding and offered by a very limited number of diagnostic laboratories. Polymerase Chain Reaction

The principle of the PCR method, as well as the advantages and disadvantages for diagnosing protozoal infections are similar to those reported above for viral infections (see Ocular Virology section previously). The most common protozoal infections for which PCR is routinely used for their diagnosis are discussed later. At present, PCR assays can be performed on blood, CSF, or aqueous humor samples collected in tubes containing ethylenediaminetetraacetic acid (EDTA) anticoagulant. Histology

Organisms can often be seen during histological examination of biopsies with routine hematoxylin and eosin staining or with electron microscopy. Protozoa can also be identified on frozen sections if an immediate diagnosis is required, but only if the tissue samples have been collected and submitted to laboratory quickly. Biopsies for electron microscopy should be placed in a glutaraldehyde-based fixative. The use of immunohistochemical methods may increase the sensitivity of direct identification, but its commercial availability is not extensive.

Immunological Tests

Immunological tests can be performed in serum samples and less commonly in aqueous humor (Lappin et al., 1992). Measurement of serum antibody titers are commonly available for all ocular protozoal diseases, and the most commonly used techniques are IF, ELISAs, and agglutination/ hemagglutination. For some organisms, point-of-care ELISAs for the detection of serum antibodies are also available, offering reliable results (Couto et al., 2010). For most protozoal diseases, serology detects the presence of IgG. Although for the diagnosis of toxoplasmosis, serological tests detecting IgM are also available. In clinical practice, there are two main approaches in the use of serology for the diagnosis of infection; single measurement of IgM and/ or IgG titers and measurement of IgM and/or IgG titers in paired serum samples. Single Antibody Titer Measurement

High titers of antigen-specific IgM are believed to indicate active or recent infection. IgM is of particular value in the diagnosis of endemic diseases when a high proportion of the animal population may have been exposed to the infection and therefore may have antigen-specific IgG detectable. Limitations of the single measurement of antibodies include the detection of antibodies in vaccinated animals that are not diseased, the absence of antibodies in acutely infected animals that did not have time to produce antibodies, and that detection of IgG antibodies can reflect to the organism and not necessarily active infection. Measurement of Antibody Titers in Paired Samples

A fourfold or greater increase in antibody titer in two samples collected over a 2-week period has been suggested to indicate active infection. However, it should be noted that antibody titers might not increase in immunocompromised animals and maximum antibody levels could have been reached by the time clinical signs develop. In addition, titers from different laboratories vary, and titers can vary between assays performed on different days. For these reasons and in an ideal situation, paired samples should be assayed together (i.e., repeat assay on the first sample) as a fourfold or greater increase is unlikely to be caused by laboratory variability.

Pathogenic Protozoa Toxoplasma gondii

Toxoplasma gondii (phylum Apicomplexa, family Sarcocystidae) is an obligate intracellular protozoal parasite that infects almost all warm-blooded animal species and is one of the most common parasitic infections in humans and animals worldwide. Domestic cats and other Felidae are its definitive hosts and shed infective oocysts via feces. Nonfeline species are intermediate hosts that carry tissue cysts but do not shed oocysts, because they do not support a

gastrointestinal life cycle (Davidson, 2000; Davidson & English, 1998; Dubey & Lappin, 2012; Dubey et al., 2009). There are three major routes of infection: ingestion of infected tissue, ingestion of oocyst-contaminated food or water, and congenital infection. Minor routes of infection include lactational, via organ or tissue transplantation, and via transfusion of infected body fluids. In cats, after ingestion of T. gondii-infected intermediate hosts (usually rodents or birds), bradyzoites are released from tissue cysts into the stomach and small intestine after degradation of the cyst wall by stomach acids. They penetrate the epithelial cells of the small intestine where they undergo asexual or sexual phases of reproduction. The asexual phase involves transformation into tachyzoites, which then spread via the bloodstream to CNS and ocular tissues, skeletal muscle, and visceral organs where they encyst as bradyzoites. The sexual phase is confined to the intestinal epithelial cells. Bradyzoites transform into merozoites and then into either male (micro-) or female (macro-) gamonts. Fertilization of a macrogamont by a microgamont leads to the formation of an oocyst. This is excreted in feces as an unsporulated and noninfectious oocyst. After exposure to air and moisture for 1–5 days, the oocyst sporulates. A sporulated oocyst contains two sporocysts, each with four sporozoites, which are the infectious form of the parasite. They are resistant to extreme environmental conditions and can remain infectious for many months. The enteroepithelial (coccidian) life cycle is completed in 3–10 days after ingestion of tissue cysts and occurs in 97% of infected cats. In contrast, after ingestion of sporulated oocysts, only 20% of cats will progress to patency, and the life cycle takes 18 days or longer to complete. Thus, bradyzoites are more infectious to cats than are oocysts, and it is thought that bradyzoites are the natural precursors for the enteroepithelial life cycle (Dubey & Lappin, 2012). In non-Felidae species, only the asexual extraintestinal life cycle occurs. After ingestion of tissue cysts (containing bradyzoites) or sporulated oocysts (containing sporozoites) the parasite transforms into tachyzoites. These disseminate systemically and encyst as bradyzoites in muscle, CNS, ocular tissue, and visceral organs where they are thought to persist for the lifetime of the host. In pregnant animals and people, tachyzoites are capable of crossing the placenta to infect the fetus, where they can lead to abortion or developmental defects. Toxoplasmosis describes clinical disease associated with T. gondii. Risk factors for seroreactivity and clinical disease include age, a raw meat diet, and an outdoor environment. T. gondii does not produce toxins, and damage to the host is via cell necrosis after intracellular growth of the parasite. Tachyzoites are capable of growing in almost any cell type, and rupture of an infected cell leads to release of more tachyzoites which can then go on to infect and damage other cells either locally or at distant sites. Tissue cysts containing

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bradyzoites can also grow and cause host cell necrosis. The host immune response also contributes to local tissue damage, especially in the eye where autoantibody production can develop in response to infection and damage of host cells, thus perpetuating uveitis even in the absence of active organisms (Davidson & English, 1998). Many T. gondii infections are subclinical, and the reasons why some infected animals develop clinical toxoplasmosis whereas others remain healthy are not fully understood. Age, host species, strain of T. gondii, infectious load, concurrent infections, and the status of the host immune system are all likely contributory factors (Davidson, 2000; Davidson et al., 1993a; Powell & Lappin, 2001). Both cell-mediated and humoral immune responses are important host defenses, and immunosuppression or concomitant illness will predispose to clinical disease in an infected individual. Clinical signs of toxoplasmosis are wide-ranging. In naïve infected cats, transient diarrhea is associated with the initial phases of the enteroepithelial replication. Systemic signs are most commonly seen in transplacentally or lactationally infected kittens, where overwhelming tachyzoite spread and replication can prove fatal. CNS, ocular, hepatic, and respiratory disease can develop. Chorioretinitis is the most common ocular sign in kittens. In adult cats, signs develop caused by tachyzoite spread after acute primary infection or via reactivation of latent tissue cysts after immunosuppression. Most commonly reported signs are pulmonary, CNS, hepatic, pancreatic, cardiac, and ocular disease. Anterior uveitis and chorioretinitis are the principal ocular manifestations (Davidson et al., 1993b). In dogs, clinical signs are also wide-ranging, commonly affecting the neuromuscular, respiratory, or gastrointestinal systems. Ocular signs include chorioretinitis, anterior uveitis, and optic neuritis (Davidson, 2000; Dubey, 1985; Dubey et al., 2009). Diagnosis of toxoplasmosis can be difficult. Clinical signs and hematological and biochemical parameters are nonspecific. Serological diagnosis is seldom definitive, because surveys show that T. gondii is common, with around 30% of healthy dogs and cats in the United States having positive T. gondii IgG antibody titers (Dubey & Lappin, 2012). Because an IgM response develops early in the course of the disease and is generally short-lived, positive IgM titers indicate recent infection. After experimental infection, approximately 80% of cats will develop an IgM antibody response. This usually develops within 1–3 weeks of infection and typically disappears by 12–16 weeks postinfection (Davidson, 2000; Lappin, 1996; Lappin et al., 1989). However, caution should be exercised when interpreting IgM results because not all infected cats will develop an IgM response, whereas in other cases the IgM response may last months to years (Dubey & Lappin, 2012; Powell & Lappin, 2001). Additionally, the IgM titers are not specific for T. gondii. An IgG response develops later than the IgM response, and IgG levels are present for months or years after infection.

Thus, whereas a positive IgG titer is evidence of exposure to T. gondii, it is not proof of recent exposure. Rising IgG titers are used as evidence of recent infection. However, the initial IgG response may not be detectable until 4–6 weeks after infection and, after initial detection of IgG, maximal titers may develop in as little as 2 weeks, leaving a narrow window for demonstration of rising titers (Dubey & Lappin, 2012). For ocular toxoplasmosis, elevated T. gondii-specific aqueous humor antibody levels compared with serum levels indicates ocular production of T. gondii antibodies, and therefore possibly local infection (Chavkin et al., 1994; Lappin, 1996; Lappin et  al., 1992). PCR testing of blood and aqueous humor samples has also been reported (Powell et al., 2010). Neospora sp.

N. caninum (phylum Apicomplexa, family Sarcocystidae) is a protozoan parasite that, until 1998, was misdiagnosed as T. gondii (Dubey et al., 1988). Its definitive host is the domestic dog, which sheds infective oocysts after an enteroepithelial sexual life cycle similar to that of T. gondii in cats. N. caninum is a significant cause of abortion in cattle and of neurological disease in dogs. Ocular signs in dogs are associated with neurological disease and include blindness, anisocoria, optic neuritis, chorioretinitis, anterior uveitis, and extraocular myositis, although there are very few clinical reports in the veterinary literature (Dubey & Lappin, 2012; Dubey et al., 1990, 2007). Leishmania sp.

Leishmaniasis is caused by protozoan parasites of the phylum Euglenozoa, family Trypanosomatidae. Around 30 leishmanial species are recognized worldwide, and around 20 of these cause clinical disease in humans. The majority of these are zoonotic, and dogs are important disease vectors in areas of the world where the disease is endemic. Leishmania infantum and its New World homologue Leishmania chagasi are the main causative agents of canine leishmaniasis (Baneth, 2012). Leishmaniasis is uncommon in cats, but L. infantum causes feline leishmaniasis within endemic areas of Europe (Martín-Sánchez et al., 2007; Pennisi & Persichetti, 2018). In other parts of the world, different species cause disease in cats, including L. chagasi, L. mexicana, L. amazonensis, and L. braziliensis (Petersen, 2009; Trainor et  al., 2010; Vides et al., 2011). In humans, three forms of clinical diseases are recognized: cutaneous leishmaniasis; mucocutaneous leishmaniasis; and visceral leishmaniasis. Dogs and cats typically develop a combination of visceral and cutaneous disease (Baneth, 2012; Leiva et al., 2005a; Trainor et al., 2010; Vides et al., 2011). The parasite is transmitted by sandflies (Phlebotomus sp. in the Old World, Lutzomyia sp. in the New World), which transmit leishmania promastigotes to humans and animals during a blood meal. Once inoculated, the parasites are

phagocytosed by host macrophages, in which they transform into an amastigote form that replicates by binary fission, leading to rupture of the macrophage and release of amastigotes which can then infect new cells. The amastigotes can also be ingested by sandflies, where they transform into an extracellular flagellated promastigote form which undergoes replication within the gastrointestinal tract of the sandfly before being inoculated via saliva into their vertebrate host when the female sandfly feeds. Canine visceral leishmaniasis is a chronic disease, with clinical signs developing from 3 months to 7 years after infection. Clinical signs are vague and wide-ranging, and include lymphadenomegaly, splenomegaly, pale mucous membranes, skin disease, weight loss, lethargy, anorexia, diarrhea, vomiting, epistaxis, melena, and respiratory disease. Cutaneous lesions can be found in up to 90% of dogs and include progressive and symmetric alopecia with exfoliative dermatitis (Baneth, 2012; Ciaramella et  al., 1997). Around 25% of affected dogs develop ocular or periocular signs, most frequently anterior uveitis, periocular dermatitis, and keratoconjunctivitis. Approximately 15% of dogs develop only ocular signs with no evidence of systemic involvement (Peña et al., 2000). Histopathological examination shows granulomatous inflammatory lesions developing in the conjunctiva, cornea, sclera, limbus, ciliary body, iridocorneal drainage angle, iris, choroid, and optic nerve (Peña et al., 2008). Feline ocular leishmaniasis is rare, but has been associated with anterior uveitis, panuveitis, and corneal ulceration (Hervás et al., 2001; Leiva et al., 2005a). Definitive diagnosis of leishmaniasis is by microscopic demonstration of parasites in histopathological samples, serology, culture of the organism in appropriate culture medium, or detection of DNA via PCR testing (Baneth, 2012). Babesia sp.

Babesia sp. (phylum Apicomplexa, family Babesiidae) are tick-borne protozoal parasites of red blood cells that cause fever, hemolytic anemia, jaundice, and hemoglobinuria in a wide range of mammalian host species (Birkenheuer, 2012; Chauvin et al., 2009). Ophthalmic signs develop secondary to systemic disease and include eyelid swelling, subconjunctival and third eyelid hemorrhage, and serous ocular discharge (Sippel et al., 1962; Taylor et al., 1969). Encephalitozoon cuniculi

E. cuniculi (phylum Microsporidia, family Unikaryonidae) is an obligate intracellular protozoal parasite of rabbits and other small mammals. Mature spores are small and oval (1.5 μm × 2.5 μm) and contain a distinctive coiled polar tubule that is used to inoculate the parasite into the host cell. Infection of mammalian hosts is by ingestion or inhalation of spores from contaminated urine or fecal material shed from infected hosts, although vertical transmission is also a

significant route of infection (Wasson & Peper, 2000). Once internalized, the polar tubule inoculates the parasite into the host cell where it develops within a host-derived membrane and replicates by schizogony (a form of binary fission) before rupture of the host cell allows release of infectious spores (Didier et al., 2012). E. cuniculi is a major pathogen in rabbits, where its primary target organs are the kidney, brain, and eye (Ashton et al., 1976; Giordano et al., 2005; Künzel & Joachim, 2010; Smith & Florence, 1925; Wasson & Peper, 2000). In the eye, it causes cataract formation with lens capsule rupture leading to phacoclastic uveitis. It has also been reported to cause cataracts and central nervous system pathology in mink and in blue fox puppies (Bjerkås, 1987, 1990). Experimental inoculation of E. cuniculi into cats leads to infection and damage of the kidneys and brain, although the organism does not appear to be a clinically important cause of renal disease in practice (Hsu et  al., 2011; Pang & Shadduck, 1985). However, the organism was reported to cause anterior uveitis and cataract in a case series of 19 eyes of 11 cats, with infection confirmed by serology, PCR of aqueous humor/lens, and cytological confirmation of spores within lens tissue (Benz et al., 2011).

Ocular Parasitic Diseases Introduction The most common parasitic ocular diseases are caused by infection with mites, nematodes, dipteric larvae, or tapeworms. For information on an individual organism’s replication and pathological mechanisms, see the respective sections that follow.

Diagnostic Methods Diagnosis is based on a combination of clinical signs, clinicopathological abnormalities, and more specific diagnostic tests. The most commonly employed laboratory methods include microscopic examination, fecal examination techniques (Baermann, flotation) (Schnyder et al., 2011a), PCR (Gioia et al., 2010; Wijesundera et al., 1999), and histology or immunological tests that detect antibodies against the organism and/or specific protein antigens of the organism (Schnyder et al., 2011b). The principles of these methods are similar to those reported above (see Ocular Virology and Ocular Bacteriology sections previously). The fecal examination techniques have variable diagnostic yield (Dunkel et  al., 2011; Schnyder et  al., 2011a). Immunological methods for the detection of serum antigen have been designed for in-clinic use, but their diagnostic performance is variable (Lee et al., 2011; Schnyder et al., 2014).

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Parasitic Mites Demodex sp. (phylum Arthropoda, order Trombidiformes, family Demodicidae) are commensal parasitic mites of the skin and hair of mammals. They spend their entire life cycle on the host, being directly transmitted from the dam to her offspring within 2–3 days of birth. There is no evidence of horizontal transmission between adult hosts. Demodex mites undergo four stages of development: a fusiform egg, a sixlegged larva, an eight-legged nymph, and an eight-legged adult. Most species, including Demodex canis, D. cati, D. equi, D. caballi, and D. bovis, live within hair follicles and sebaceous glands, although a few species are found within the epidermis. They feed on dead skin cells, sebum, and cellular debris. In small numbers, the mites are nonpathogenic, but in some hosts, they multiply and cause localized or generalized demodicosis. Immunosuppression, stress, genetic predisposition, poor nutrition, and concurrent infection may all be contributory factors to clinical disease, and T-cell deficiencies have been implicated in the etiopathogenesis of disease in dogs (Gortel, 2006). Localized periocular demodicosis is relatively common and is typically characterized by bilaterally symmetrical nonpruritic alopecia and scaling. Other skin mites include Sarcoptes scabei, Notoedres cati, Otodectes cynotis, Haematopinus asini, Werneckiella equi, Cheyletiella sp., and Psoroptes sp. Unlike Demodex sp., they are unlikely to cause localized periocular dermatitis, but eyelid involvement can be seen as part of generalized skin involvement.

Parasitic Nematodes Angiostrongylus vasorum (Lungworm)

Angiostrongylus vasorum (phylum Nematoda, order Strongylida, family Metastrongylidae) is a parasite of the heart and pulmonary circulation of dogs and foxes that was originally a clinical problem primarily in southwestern France but has since been recorded in many countries across Europe, Africa, Asia, and the Americas. In recent years, an increased incidence has been particularly noted in the United Kingdom and Scandinavia (Bolt et  al., 1994; Helm et al., 2010; Morgan & Shaw, 2010). Male and female adult worms live in the right side of the heart and the pulmonary arterial circulation. Here they reproduce to create eggs which hatch to first-stage larvae (L1) that are then carried to the pulmonary capillaries, where they penetrate the alveoli and are coughed up into the oropharynx before being swallowed and passed in the feces. Intermediate hosts are gastropod mollusks (slugs or snails) in which further larval development to infective stage three larvae (L3) takes place. If the intermediate host is eaten by a dog or fox, the larvae penetrate the intestinal wall and are carried via the bloodstream and/or lymphatic system to the heart and pulmonary arteries, where they mature to adult worms.

The major clinical signs of A. vasorum infestation are coughing, dyspnea, lethargy, and hemorrhagic diatheses (Chapman et  al., 2004). Extensive subconjunctival hemorrhage is a common clinical finding in affected dogs. The mechanism of the coagulopathy is poorly understood, but anemia, thrombocytopenia, antiplatelet antibodies, increased clotting times, hyperglobulinemia, reduced activity of clotting factors VIII and V, and von Willebrand factor deficiency have all been documented, suggesting a consumptive coagulopathy (Cury et al., 2002; Gould & McInnes, 1999; Morgan & Shaw, 2010; Morgan et  al., 2005; Whitley et al., 2005). Aberrant migration of L3 larvae can lead to ocular penetration, and larvae may be found in the anterior chamber or vitreous, where they can stimulate a severe granulomatous uveitis (Manning, 2007). Definitive diagnosis of A. vasorum infestation is by demonstration of L1 larvae in the respiratory tract via bronchoalveolar lavage, or within the feces via Baermann or FLOTAC examination (Barçante et  al., 2008; Humm & Adamantos, 2010; Schnyder et al., 2011a). Dirofilaria immitis (Heartworm)

Dirofilaria immitis (phylum Nematoda, order Spirurida, family Onchocercidae) lives in the pulmonary arteries of dogs, although it may infest other species including cats and humans (Litster & Atwell, 2008; McCall et al., 2008; Ware, 2003). It is widespread in areas of the world where its mosquito intermediate host is endemic, in particular the eastern and gulf coasts and the Mississippi River valley of the United States, Australia, and southern Europe (Dantas-Torres et al., 2009; McCall et al., 2008; Ware, 2003). Adult female worms within the pulmonary arterial system release microfilariae (L1) into the blood stream which are ingested by mosquitoes during a blood meal. The L1 larvae undergo two maturations within the mosquito over a period of 2–2.5 weeks as they develop into the infective L3 stage larvae, which are then inoculated into a host at the next blood meal. L3 larvae migrate within subcutaneous tissues of the host, molting into L4 then L5 larval stages. These then enter the bloodstream approximately 100 days after infection and are transported to the pulmonary arteries where they mature to adult worms. From the time of infection to development of mature heartworms, a period of 6 months or longer is usually required (Bowman & Atkins, 2009; Ware, 2003). Heartworm disease in dogs is a major cause of pulmonary hypertension (cor pulmonale) which develops secondary to progressive damage to the pulmonary arteries. Periarterial edema, vasculitis, and proliferation of smooth muscle cells within the arterial walls lead to arteriolar narrowing and increased local vascular hypertension. Many dogs are asymptomatic at diagnosis, but clinical signs can include lethargy, dyspnea, cough, hemoptysis, weight loss, and progressive right-sided congestive heart failure. Migration of microfilariae may also cause permanent liver damage and cirrhosis,

7: Clinical Microbiology and Parasitology

Onchocerca sp.

Onchocerca cervicalis (phylum Nematoda, order Spirurida, family Onchocercidae) is a nematode parasite of horses transmitted by a Culicoides midge or Simulium fly vector. These inoculate microfilariae into the skin, which then migrate to the nuchal crest where they develop to mature adults. Adult worms release microfilariae that migrate within the dermis and subcutaneous tissues and are ingested by biting midges or flies, in which they develop to the infectious L3 stage in around 25 days (Mellor, 1973a, 1973b; Mellor, 1974a, 1974b; Schmidt et  al., 1982a; Webster & Dukes, 1979). The parasite is common and has a worldwide distribution. However, and presumably because of increased use of antiparasiticide treatments in horses, studies have shown a significant reduction in prevalence rates in recent years. For example, prevalence rates in the eastern, southeastern, and midwestern United States reduced from around 50% to 24% between 1985 and 2000 (Cummings & James, 1985; Lyons et al., 2000). Ocular onchocerciasis occurs when microfilariae migrate to the conjunctival and periocular tissues of infected horses. Ocular involvement has been reported in 18%–49% of horses with onchocerciasis (Lloyd & Soulsby, 1978; Moran & James, 1987). The most commonly reported ocular and periocular lesions associated with the parasite are conjunctivitis, blepharitis, punctate scleral opacities, temporal scleral vitiligo, and uveitis (Cello, 1971; Moran & James, 1987; Schmidt et al., 1982b). Ocular onchocerciasis occurs in many other species, including cattle, camelids, deer, swine, dogs, and humans. Canine ocular onchocerciasis is most commonly reported in southern Europe but has also been identified in the United States (Komnenou et al., 2002; McLean et al., 2017; Otranto et al., 2015; Sréter & Széll, 2008; Zarfoss et al., 2005). Acute canine ocular onchocerciasis is associated with conjunctivitis, chemosis, erythema, and periorbital swelling. In chronic cases, the parasites form granulomatous nodules within the retrobulbar space, eyelid, nictitans, conjunctiva, and sclera.

Thelazia sp.

Thelazia sp. (phylum Nematoda, order Spirurida, family Thelaziidae) are common commensal parasites of the conjunctival fornix and nasolacrimal duct of horses and cattle. Thelazia lacrimalis affects horses, whereas in cattle, T. lacrimalis, T. gulosa, T. rhodesi, and T. skrjabini are reported. Flies, in particular the face fly Musca autumnalis, act as mechanical vectors and transfer larvae to the eyes during feeding. Prevalence rates above 40% have been reported in both horses and cattle at necropsy (Arbuckle & Khalil, 1978; Lyons et al., 2000). In dogs Thelazia callipaeda is a common ocular parasite in Asia and is reported increasingly in other parts of the world, including Europe (Graham-Brown et al., 2017; Miró et al., 2011; Ruytoor et al., 2010). Thelazia spp. are usually asymptomatic, but the parasites may induce conjunctivitis, dacryocystitis, and ulcerative keratitis (Miró et al., 2011). Habronema sp.

Habronema microstoma, H. muscae, and Draschia megastoma (phylum Nematoda, order Spirurida, family Habronematidae) are parasites that inhabit the equine stomach. Larvae are passed in the feces and are ingested by maggots of the intermediate host Stomoxys calcitrans, the stable fly. Here, the larvae develop to the infective L3 microfilaria stage before being deposited around the mouth of the horse where the stable flies congregate. Microfilariae migrate or are mechanically transferred into the mouth before being swallowed to complete the life cycle. The parasite has a worldwide distribution, with postmortem studies in various countries identifying it in 4% to more than 40% of horses (Borgsteede & van Beek, 1998; Bucknell et al., 1995; Lyons et al., 1983). Ocular habronemiasis results from aberrant microfilarial migration. Lesions typically appear as raised yellow gritty plaques in the palpebral and bulbar conjunctivae, or as eyelid granulomas or blepharitis (Rebhun et al., 1981). Setaria sp.

Setaria sp. (phylum Nematoda, order Strongylida, family Filaroideae) parasitize the abdominal cavity of ungulates including horses, cattle, and sheep. Setaria digitata and S. equina are reported in horses, and S. digitata and S. marshalli are reported in cattle. The parasites are common across Asia and parts of Africa, with a prevalence of up to 70% in some areas (Shin et al., 2002). Aberrant migration of microfilariae can lead to ocular involvement, with immature adult worms developing in the anterior chamber (Marzok & Desouky, 2009; Muhammad & Saqib, 2007; Shin et al., 2002). Halicephalobus deletrix

Halicephalobus deletrix (phylum Nematoda, order Rhabditida) is a free-living nematode found in soil and decaying organic matter. Rarely, infection of humans and horses has been reported, involving a wide range of organs and tissues including

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whereas circulating antibody–antigen complexes may induce glomerulonephritis. Aberrant migration of L4 larvae may lead to ocular infiltration, where the parasites develop to L5 and immature adult forms, inducing a severe anterior uveitis (DantasTorres et al., 2009; Eberhard et al., 1977; Lavers et al., 1969; Mallett et al., 1971). Diagnosis of dirofilariasis can be confirmed via heartworm antigen testing kits. It should be noted, however, that in some cases of ocular dirofilariasis, antigen testing has proven negative, presumably because of a low worm burden in such animals. In these cases, diagnosis is made by direct observation of the parasite within the anterior chamber (Dantas-Torres et al., 2009).

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the kidneys, oral and nasal cavities, lymph nodes, spinal cord, and CNS tissue. The route of infection is presumed to be via contamination of open wounds. Migration to the eye has been reported to lead to severe granulomatous chorioretinitis in assocation with fatal encephalitis (Rames et al., 1995). Toxacara canis

Toxacara canis (phylum Nematoda, order Ascarididia, family Toxocaridae) is a common intestinal parasite of the dog with a worldwide distribution. The adult worm lives in the small intestine, where it produces eggs that are excreted in the feces. Larval development to the infective L2 stage occurs within the egg in the environment. When swallowed, L2 larvae are released into the small intestine and penetrate the intestinal wall to enter the portal blood stream to the liver and lungs. In the lungs, development to the L3 stage takes place before the larvae are coughed up and swallowed. Two further molts to adulthood occur in the intestine. This life cycle occurs predominantly in young dogs, whereas in adult dogs, L2 larvae migrate to skeletal muscle, liver, brain, and other tissues where they remain dormant. In pregnant bitches, they mobilize and migrate to the fetal lungs a few weeks prior to parturition. Infection of newborn puppies may also occur via ingestion of infected milk. Aberrant L2 migration in dogs and in nonhost species, including humans, may lead to ocular larval migrans. In dogs, the parasite has been shown to cause focal granulomatous lesions within the fundus and has also been suggested to cause more extensive retinal degeneration (Hughes et al., 1987; Johnson et al., 1989; Rubin & Saunders, 1965). Ancylostoma caninum

Larvae of the canine hookworm Ancylostoma caninum (phylum Nematoda, order Strongylida, family Ancylostomatidae) infect the host via penetration of the skin, hematogenous migration to the lungs, and passage into the gastrointestinal tract. Aberrant migration of the larva has been reported to cause granulomatous endophthalmitis in a dog (Gaunt et al., 1982).

Parasitic Dipteric Larvae Ophthalmomyiasis describes aberrant migration of fly (order Diptera) larvae within the ocular or periocular structures.

Ophthalmomyiasis caused by Cuterebra sp. (the rabbit or rodent botfly) has been reported in humans, dogs, and cats (Baird et al., 1989; Brooks et al., 1984; Crumley et al., 2011; Delgado, 2012; Gwin et al., 1984; Harris et al., 2000; Johnson et  al., 1988; Ollivier et  al., 2006; Stiles & Rankin, 2006; Wyman et al., 2005). The normal life cycle of Cuterebra involves the laying of eggs on vegetation near the nesting areas of rabbits and rodents. The eggs hatch into larvae that invade the skin of the host species. After completion of three developmental stages (instars) within cutaneous and subcutaneous tissues, the larvae exit the host and complete their development in the soil (Baird et al., 1989). Ophthalmomyiasis involves the periocular structures (ophthalmomyiasis externa), the anterior segment (ophthalmomyiasis interna anterior), or the posterior segment (ophthalmomyiasis interna posterior). Migrating larvae cause acute inflammatory disease, especially when involving the periocular structures or anterior segment (Delgado, 2012; Harris et al., 2000; Stiles & Rankin, 2006). Cases involving the posterior segment incite less inflammation and are more commonly identified as an incidental finding on ophthalmoscopic examination. The most commonly reported lesions are curvilinear tracts within the tapetal and non-tapetal fundus (Brooks et al., 1984; Gwin et al., 1984).

Tapeworm Disease Echinococcus granulosus granulosus (phylum Platyhelminthes, order Cyclophyllidea, family Taeniidae) is a tapeworm of wild and domestic dogs, for which equids are the intermediate host. The larval stage of the tapeworm forms hydatid cysts in tissues of the intermediate host. Hydatid cysts have been reported to affect the equine orbit, leading to exophthalmos or blindness (Barnett et  al., 1988; Summerhays & Mantell, 1995). Taenia solium (phylum Platyhelminthes, order Cyclophyllidea, family Taeniidae) is a tapeworm of humans, for which the pig is the natural intermediate host. The larval stage, Cysticercus cellulosae, can invade the orbit or globe to cause orbital or intraocular cysts, the latter giving rise to a severe granulomatous panuveitis in pigs (Cárdenas-Ramírez et al., 1984).

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Simpson, C.F., White, F.H. & Sandhu, T.S. (1976) The structure of pili (fimbriae) of Moraxella bovis. Canadian Journal of Comparative Medicine, 40, 1–4. Sippel, W.L., Cooperrider, D.E., Gainer, J.H., et al. (1962) Equine piroplasmosis in the United States. Journal of the American Veterinary Medical Association, 141, 694–698. Slater, J.D., Gibson, J.S., Barnett, K.C., et al. (1992) Chorioretinopathy associated with neuropathology following infection with equine herpesvirus-1. Veterinary Record, 131, 237–239. Slatter, D.H., Edwards, M.E., Hawkins, C.D., et al. (1982) A national survey of the clinical features, treatment and importance of infectious bovine keratoconjunctivitis. Australian Veterinary Journal, 59, 69–72. Smith, H. (1995) The revival of interest in mechanisms of bacterial pathogenicity. Biological Reviews of the Cambridge Philosophical Society, 70, 277–316. Smith, T. & Florence, L. (1925) Encephalitozoon cuniculi as a kidney parasite in the rabbit. Journal of Experimental Medicine, 41, 25–35. Smith, T.W., Albert, D.M., Robinson, N., et al. (1974) Ocular manifestations of Marek’s disease. Investigative Ophthalmology, 13, 586–592. Soltys, M.A. & Sumner-Smith, G. (1969) Dermatophytes in veterinary practice. Canadian Veterinary Journal, 10, 111–116. Spada, E., Perego, R., Sgamma, E.A., et al. (2018) Survival time and effect of selected predictor variables on survival in owned pet cats seropositive for feline immunodeficiency and leukemia virus attending a referral clinic in northern Italy. Preventive Veterinary Medicine, 150, 38–46. Sparagano, O. & Foggett, S. (2009) Diagnosis of clinically relevant fungi in medicine and veterinary sciences. Advances in Applied Microbiology, 66, 29–52. Spiess, B.M. (2010) Equine recurrent uveitis: the European viewpoint. Equine Veterinary Journal, 42(Suppl. 37), 50–56. Spiesschaert, B., McFadden, G., Hermans, K., et al. (2011) The current status and future directions of myxoma virus, a master in immune evasion. Veterinary Research, 42, 76. Spinelli, T.P., Oliveira-Filho, E.F., Silva, D., et al. (2010) Normal aerobic bacterial conjunctival flora in the Crab-eating raccoon (Procyon cancrivorus) and Coati (Nasua nasua) housed in captivity in pernambuco and paraiba (Northeast, Brazil). Veterinary Ophthalmology, 13(Suppl.), 134–136. Spradbrow, P.B. (1968) The bacterial flora of the ovine conjunctival sac. Australian Veterinary Journal, 44, 117–118. Sréter, T. & Széll, Z. (2008) Onchocercosis: a newly recognized disease in dogs. Veterinary Parasitology, 151, 1–13. Stadtbäumer, K., Leschnik, M.W. & Nell, B. (2004) Tick-borne encephalitis as a possible cause of optic neuritis in a dog. Veterinary Ophthalmology, 7, 271–277. Stavinohova, R., O’Halloran, C., Newton, J.R., et al. (2019) Feline ocular mycobacteriosis: clinical presentation, histopathological features, and outcome. Veterinary Pathology, 56, 749–760. Stavisky, J., Dean, R.S. & Molloy, M.H. (2017) Prevalence of and risk factors for FIV and FeLV infection in two shelters

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analysis of Microsporum canis strains isolated from symptomatic and asymptomatic cats. Revista iberoamericana de micologia: organo de la Asociacion Espanola de Especialistas en Micologia, 24, 19–23. Vides, J.P., Schwardt, T.F., Sobrinho, L.S., et al. (2011) Leishmania chagasi infection in cats with dermatologic lesions from an endemic area of visceral leishmaniosis in Brazil. Veterinary Parasitology, 178, 22–28. Vinayak, A., Greene, C.E., Moore, P.A., et al. (2004) Clinical resolution of Brucella canis-induced ocular inflammation in a dog. Journal of the American Veterinary Medical Association, 224, 1804–1807, 1788–1789. Vincza, S., Stamm, I., Kopp, P.A., et al. (2014) Alarming proportions of methicillin-resistant Staphylococcus aureus (MRSA) in wound samples from companion animals, Germany 2010–2012. PLoS One, 9, e85656. Volopich, S., Benetka, V., Schwendenwein, I., et al. (2005) Cytological findings, and feline herpesvirus DNA and Chlamydophila felis antigen detection rates in normal cats and cats with conjunctival and corneal lesions. Veterinary Ophthalmology, 8, 25–32. von Bomhard, W., Polkinghorne, A., Lu, Z.H., et al. (2003) Detection of novel chlamydiae in cats with ocular disease. American Journal of Veterinary Research, 64, 1421–1428. Wada, S., Hobo, S. & Niwa, H. (2010) Ulcerative keratitis in thoroughbred racehorses in Japan from 1997 to 2008. Veterinary Ophthalmology, 13, 99–105. Wang, A.L., Ledbetter, E.C. & Kern, T.J. (2009) Orbital abscess bacterial isolates and in vitro antimicrobial susceptibility patterns in dogs and cats. Veterinary Ophthalmology, 12, 91–96. Wang, L., Pan, Q., Zhang, L., et al. (2008) Investigation of bacterial microorganisms in the conjunctival sac of clinically normal dogs and dogs with ulcerative keratitis in Beijing, China. Veterinary Ophthalmology, 11, 145–149. Wardley, R.C. & Povey, R.C. (1977a) The clinical disease and patterns of excretion of associated with three different strains of feline calicivirus. Research in Veterinary Science, 23, 7–14. Wardley, R.C. & Povey, R.C. (1977b) The pathology and sites of persistence associated with three different strains of feline calicivirus. Research in Veterinary Science, 23, 15–19. Ware, W.A. (2003) Heartworm disease. In: Small Animal Internal Medicine (eds Nelson, R.W. & Couto, C.G.), 3rd ed., pp. 169–184. St. Louis, MO: Mosby. Warner, R.D. (1984) Occurrence and impact of zoonoses in pet dogs and cats at US Air Force bases. American Journal of Public Health, 74, 1239–1243. Wasson, K. & Peper, R.L. (2000) Mammalian microsporidiosis. Veterinary Pathology, 37, 113–128. Webster, W.A. & Dukes, T.W. (1979) Bovine and equine onchocerciasis in eastern North America with a discussion on cuticular morphology of Onchocerca spp. in cattle. Canadian Journal of Comparative Medicine, 43, 330–332. Weese, J. (2012) Staphylococcal infections. In: Infectious Diseases of the Dog and Cat (ed. Greene, C.E.), 4th ed., pp. 340–348. St. Louis, MO: Saunders Elsevier.

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Weese, J.S., Dick, H., Willey, B.M., et al. (2006) Suspected transmission of methicillin-resistant Staphylococcus aureus between domestic pets and humans in veterinary clinics and in the household. Veterinary Microbiology, 115, 148–155. Weinstein, W.L., Moore, P.A., Sanchez, S., et al. (2006) In vitro efficacy of a buffered chelating solution as an antimicrobial potentiator for antifungal drugs against fungal pathogens obtained from horses with mycotic keratitis. American Journal of Veterinary Research, 67, 562–568. Welchman Dde B., Cox, W.J. & Gough, R.E. (2009) Avian encephalomyelitis virus in reared pheasants: a case study. Avian Pathology, 38, 251–256. Westman, M.E., Malik, R., Hall, E., et al. (2016) The protective rate of the feline immunodeficiency virus vaccine: an Australian field study. Vaccine, 34, 4752–4758. Whitley, N.T., Corzo-Menendez, N., Ng, C., et al. (2005) Cerebral and conjunctival haemorrhages associated with von Willebrand factor deficiency and canine angiostrongylosis. Journal of Small Animal Practice, 46, 75–78. Whitley, R.D. (2000) Canine and feline primary ocular bacterial infections. Veterinary Clinics of North America. Small Animal Practice, 30, 1151–1167. Wijesundera, W.S., Chandrasekharan, N.V. & Karunanayake, E.H. (1999) A sensitive polymerase chain reaction based assay for the detection of Setaria digitata: the causative organism of cerebrospinal nematodiasis in goats, sheep and horses. Veterinary Parasitology, 81, 225–233. Wilcox, G.E. (1970) Bacterial flora of the bovine eye with special reference to the Moraxella and Neisseria. Australian Veterinary Journal, 46, 253–256. Willis, A.M. (2000a) Feline leukemia virus and feline immunodeficiency virus. Veterinary Clinics of North America. Small Animal Practice, 30, 971–986. Willis, A.M. (2000b) Canine viral infections. Veterinary Clinics of North America. Small Animal Practice, 30, 1119–1133. Willis, A.M., Martin, C.L. & Stiles, J. (1999) Sino-orbital aspergillosis in a dog. Journal of the American Veterinary Medical Association, 214, 1644–1647, 1639. Wills, J.M., Howard, P.E. & Gruffydd-Jones, T.J. (1988) Prevalence of Chlamydia psittaci in different cat populations in Britain. Journal of Small Animal Practice, 29, 327–339. Wilsmore, A.J., Dagnall, G.J. & Woodland, R.M. (1990) Experimental conjunctival infection of lambs with a strain of Chlamydia psittaci isolated from the eyes of a sheep naturally affected with keratoconjunctivitis. Veterinary Record, 127, 229–231. Wilson, A.S. & Mellor, P.J. (2009) Bluetongue in Europe: past, present and future. Philosophical Transactions of the Royal

Society of London. Series B, Biological Sciences, 364, 2669–2681. Wolf, E.D., Amass, K. & Olsen, J. (1983) Survey of conjunctival flora in the eye of clinically normal, captive exotic birds. Journal of the American Veterinary Medical Association, 183, 1232–1233. Wooff, P.J., Dees, D.D. & Teixeria, L. (2018) Aspergillus spp. panophthalmitis with intralenticular invasion in dogs: report of two cases. Veterinary Ophthalmology, 21, 182–187. Wu, X., Gupta, S.K. & Hazlett, L.D. (1995) Characterization of P. aeruginosa pili binding human corneal epithelial proteins. Current Eye Research, 14, 969–977. Wyman, M., Starkey, R., Weisbrode, S., et al. (2005) Ophthalmomyiasis (interna posterior) of the posterior segment and central nervous system myiasis: cuterebra spp. in a cat. Veterinary Ophthalmology, 8, 77–80. Yamamoto, J.K., Hansen, H., Ho, E.W., et al. (1989) Epidemiologic and clinical aspects of feline immunodeficiency virus infection in cats from the continental United States and Canada and possible mode of transmission. Journal of the American Veterinary Medical Association, 194, 213–220. Yan, C., Fukushi, H., Matsudate, H., et al. (2000) Seroepidemiological investigation of feline chlamydiosis in cats and humans in Japan. Microbiology and Immunology, 44, 155–160. Yeruham, I., Perl, S. & Elad, D. (2001) Infectious bovine keratoconjunctivitis and lymphofollicular hyperplasia of the third eyelid in heifers. Journal of Veterinary Medicine. B, Infectious Diseases & Veterinary Public Health, 48, 137–141. Zaragoza, O., Rodrigues, M.L., De Jesus, M., et al. (2009) The capsule of the fungal pathogen Cryptococcus neoformans. Advances in Applied Microbiology, 68, 133–216. Zarfoss, M.K., Dubielzig, R.R., Eberhard, M.L., et al. (2005) Canine ocular onchocerciasis in the United States: two new cases and a review of the literature. Veterinary Ophthalmology, 8, 51–57. Zenoble, R.D., Griffith, R.W. & Clubb, S.L. (1983) Survey of bacteriologic flora of conjunctiva and cornea in healthy psittacine birds. American Journal of Veterinary Research, 44, 1966–1967. Zhu, X., Gibbons, J., Garcia-Rivera, J., et al. (2001) Laccase of Cryptococcus neoformans is a cell wall-associated virulence factor. Infection and Immunity, 69, 5589–5596. Zhu, X. & Williamson, P.R. (2004) Role of laccase in the biology and virulence of Cryptococcus neoformans. FEMS Yeast Research, 5, 1–10.

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8.1 Clinical Pharmacology and Therapeutics Part 1: Ocular Drug Delivery Alain Regnier Department of Clinical Sciences, School of Veterinary Medicine, Toulouse, France

In ocular therapy, drug choice is based on knowledge of pharmacodynamic potency and pharmacokinetic properties of therapeutic agents to select the most suitable route of administration and dosage regimen. These parameters should be aimed at ensuring the presence of an effective drug concentration in the target biophase for an appropriate period of time while limiting diffusion of the drug to other ocular structures or parts of the body. In veterinary ophthalmology, the dosage regimen and route of administration may also have to be adapted in order to maximize owner compliance. The dosage forms currently used for the treatment of eye disease in veterinary patients include ophthalmic solutions, suspensions, ointments, and gels, but depending on the clinical context, drugs may also be delivered to the eye via the periocular or systemic route. Unique functional and structural protective mechanisms of the eye act as major obstacles to the access of xenobiotics to the targeted ocular tissues. Therefore, conventional ocular drug delivery systems have several drawbacks, including short duration of action, low ocular bioavailability, and the need for repeated administrations. Research into ocular drug delivery has become an increasingly important field that has led to novel strategies to overcome many of today’s therapeutic dilemmas in human ophthalmology, but has also served to improve the medical treatments of ocular disorders in animals (Kompella et al., 2010; Patel et al., 2013; Weiner & Gilger, 2010; Weng et al., 2017; Yellepeddi & Palakurthi, 2016).

Barriers to Ocular Drug Delivery Compared with drug delivery to other organs of the body, ocular drug delivery is a major challenge because of the presence of permeability barriers depending upon the route of administration. The ocular barriers refer to anatomical and physiological ocular structures that have protective functions for maintaining ocular homeostasis and represent

­ atural defense mechanisms against the entry of xenobiotics n into the eye.

Corneal Membrane Barriers For topically applied drugs, the corneal route has been assumed to be the major route of entry into the eye. The cornea consists of three primary layers: the epithelium, stroma, and endothelium, representing distinct barriers to absorption organized as an aqueous phase (stroma) sandwiched by two lipid layers (epithelium and endothelium). Kinetic studies using in vitro and in vivo techniques have shown that passage of drugs through the corneal epithelium can occur both across the cells (transcellular route) and between the cells (paracellular route) (Grass & Robinson, 1988a, 1998b). However, the paracellular route is blocked by one type of specialized intercellular junction, the tight junction or zonula occludens, characterized by multiple sites of fusion between the plasma membrane of adjoining cells which completely surround and seal the most apical epithelial cells of the cornea to all but the smallest hydrophilic molecules (Sasaki et al.,1999). It is thus anticipated that the transcellular drug penetration will be related to oil/water (o/w) ­partition coefficient of molecules because of the lipophilic nature of the epithelium, whereas paracellular movement will more likely be related to characteristics such as molecular size and aqueous diffusivity (Grass et  al., 1988; Maurice & Mishima 1984). As a consequence, the transcellular route across the lipid cell membrane will contribute to the epithelial transfer of lipophilic drugs, whereas very low molecular‐weight hydrophilic (polar) compounds will diffuse through the intercellular space, which represents the aqueous pore pathways of the corneal epithelium (Grass et al.,1988; Sasaki et al., 1997). The intercellular space has a size ranging from 0.6 nm to less than 3 nm at its most confined point, and because of the negatively charged carboxylic groups of the tight junction components, it has a repulsive interaction with the negatively charged molecules

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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(Grass & Robinson, 1988a; Nettey et al., 2016). Thus, drug penetration through the cornea shows a lipophilicity, molecular weight, and charge dependency on the permeability of the corneal epithelium to transferred compounds (Prausnitz & Noonan, 1998). If the epithelial layer is a rate‐limiting barrier for highly polar drugs, at the opposite, the stroma with its 78% water content allows the free passage of compounds possessing high aqueous solubility and acts as a barrier to lipophilic molecules (Hegeman et  al., 1984). Theoretically, the cube root of the molecular weight is the most important factor of stromal penetration, but because ophthalmic drugs have a relatively narrow molecular weight range, their stromal penetration is nearly the same (Schoenwald, 1997). Although the endothelium is cellular, its permeability displays a strong dependence on both o/w partition coefficient and molecular size. This indicates that the endothelium does not provide significant resistance to lipophilic and hydrophilic ophthalmic drugs (Prausnitz & Noonan, 1998). The significant permeability of the endothelium likely relates to the fact that it is only one cell thick and that these cells are connected by junctional gaps that do not provide any barrier for drug ­penetration (Bartlett & Cullen,1984; Hegeman et al., 1984).

Conjunctiva and Sclera Membrane Barriers There is evidence that penetration across the bulbar conjunctiva, and then sclera, contributes significantly to the intraocular penetration of certain topically applied drugs (Schoenwald, 1997). The conjunctiva is more permeable than the cornea through a significant paracellular route, which makes its permeability to molecules of varying physicochemical characteristics, such as β‐blockers, hydrophilic macromolecules, and [3H]mannitol, 2–30 times higher than that of the cornea (Ashton et  al., 1991; Hämäläinen et  al., 1997; Sasaki et al., 1997; Wang et al., 1991). In addition, there is not a large difference between the permeability coefficients of ionized (polar) and unionized (nonpolar) forms, which can also be explained by the richness of paracellular routes of the conjunctival membrane (Sasaki et  al. 1996). Several reports have concluded that the scleral permeability is approximately 10 times higher than that of the cornea with a direct relationship between the ability of a drug to penetrate the sclera and both the thickness and total surface area of this tunic, and that the molecular radius is a better predictor of scleral permeability than the molecular weight (Ambati et  al., 2000a, 2000b; Hämäläinen et  al., 1997; Prausnitz & Noonan, 1998). However, with molecules of similar radii, the scleral permeability is higher for the more hydrophilic molecules than for the lipophilic ones and greater for negatively charged molecules than for positive ones (Cheruvu & Kompella, 2006). In consideration of the

sclera and the underlying layer, it appears that the choroid‐ Bruch’s layer is a greater barrier than the sclera for the intraocular transport of lipophilic molecules delivered by the periocular route (Cheruvu & Kompella, 2006). The primary route for solute transport through the sclera is by passive diffusion through the interfibrillar aqueous media of the gel‐like proteoglycans (Geroski & Edelhauser, 2001). Transscleral diffusion is unaffected by the intraocular pressure at pressures ranging from 0 to 60 mmHg, and allows the transfer of compounds with a molecular weight as high as 150 kDa (Ahmed & Patton, 1995; Cruysberg et  al., 2005). Other in vitro findings indicate that if a topically applied drug is preferentially absorbed by the scleral route, its transfer will be more rapid through the sclera than it would be through the cornea (Achim & Woodward, 2004). Scleral permeability can be enhanced with exposure to prostaglandins (PGs) or PG analogues, such as latanoprost, suggesting that PG cotreatment might allow sufficient transscleral transport to provide delivery of macromolecules, such as trophic ­factors, to the retina (Aihara et al., 2001; Kim et al, 2001).

Blood–Ocular Barriers Following systemic administration, penetration of drugs into the eye is limited by several barriers localized either in epithelia or vascular endothelia. More precisely, the concept of blood–ocular barriers refers to the permeability restriction associated with morphological characteristics of the endothelial cells of iridial and retinal vessels and epithelial cells of the ciliary body and retinal pigment epithelium (RPE) (Nettey et al., 2016). In these barriers, the paracellular route is blocked because the clefts between the endothelial or epithelial cells are sealed by impermeable tight junctions responsible for inhibiting the entry of solutes into the ocular environment (i.e., aqueous humor and vitreous body) (Raviola, 1977). The blood–aqueous barrier (BAB) is located in the anterior segment of the eye and is formed by iridal blood vessels’ endothelial cells, as well as the nonpigmented cell layer of the ciliary epithelium (Fig. 8.1.1). In the iris, the blood vessels’ endothelial cells represent one anatomic location of the BAB because they lack fenestrae and are joined by tight junctions, therefore preventing movement of macromolecules from the lumen of the iridial vessels into the iris stroma and then into the anterior chamber (Raviola, 1977). In the stroma of the ciliary processes, circulating macromolecules escape through the capillary walls, but their transfer to the posterior chamber is blocked by the tight junctions that interconnect the apices of the nonpigmented cells of the overlying epithelium (Raviola, 1977). They are impermeable to exogenous markers such as peroxidase and represent the other anatomic component of the BAB (Smith & Rudt, 1973). In the posterior segment, the blood–retinal barrier (BRB) provides restricted

IRIS CROSS SECTION

ABL

Stroma

PE

Tight junctions Iridial vessel endothelial cell

CILIARY PROCESS CROSS SECTION

PL

NPL

penetration into the retina and includes the endothelial cells of the retinal vessels and the cells of the RPE, forming the outer and inner BRB, respectively (Fig. 8.1.2). The retinal vessels are nonfenestrated and have tight junctions, creating an obstruction to movement of substances from plasma into the retina and vitreous (Nettey et  al., 2016). Experimentally, it was shown that the tight junctions which connect the endothelial cells of the retinal vessels are not only impermeable to circulating macromolecules, but also block the reverse diffusion of markers injected into the vitreous body (Raviola, 1977). The outer BRB is produced by the tight junctions between the RPE cells, so that substances leaking out from the extremely permeable capillaries of the choriocapillaris encounter this barrier of junctional complexes between RPE cells (Nettey et al., 2016). The morphologic characteristics of the blood–ocular barriers are basically similar in all species investigated to date, and there are no differences between the immature and mature animal (Bellhorn, 1991). Even though it may seem logical to deliver a drug to the intraocular structures via systemic administration because of the presence of the highly vascular uveal tunic, it is still a challenge because of the blood–ocular barriers, which restricts drug permeation from the blood to the inner eye. The blood–ocular barriers have anatomic and functional properties similar to those of the blood–brain barrier (Raviola, 1977; Toda at al., 2011).

NFL

Inner blood–retinal barrier Müller cell

GCL

Pericyte

Tight junctions

INL Retinal capillary endothelial cell

PRL

Outer blood–retinal barrier Tight junctions

Stroma

RPE

Ciliary vessel endothelial cell

Fenestrae

Tight junctions

PL NPL Ciliary epithelium

Figure 8.1.1  Schematic illustration of the blood–aqueous barrier (BAB). In the anterior segment, the endothelial cells of the iris blood vessels and the nonpigmented cell layer of the ciliary epithelium possess tight junctional complexes and form the BAB. ABL, anterior border layer; NPL, non‐pigmented layer of the ciliary epithelium; PE, posterior epithelium; PL, pigmented layer of the ciliary epithelium.

RPE

Choroid Slera

Choroid Choriocapillaris fenestrated vessels

Figure 8.1.2  Schematic illustration of the blood–retinal barrier (BRB). In the posterior segment the BRB operates at two levels, the endothelium of the retinal capillaries and the retinal pigment epithelium. These cell layers display tight junctions responsible for restricting the movements of circulating molecules into the retina. NFL, nerve fiber layer; GCL; ganglion cell layer; INL, inner nuclear layer; PRL, photoreceptor layer; RPE, retinal pigment epithelium. (Source: Adapted from Tomi & Hosoya, 2008.)

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Drug Efflux Transporters Other than cellular tight‐junctional complexes in epithelia and endothelia, the eye possesses homeostatic mechanisms regulating the entry and exit of endogenous substrates. They can contribute to the barrier properties of ocular membranes by restricting absorption of ophthalmic xenobiotics (Gunda et al., 2008). Efflux transporters (also named efflux pumps) are membrane‐bound proteins found in various ocular tissues and are reported to have a major impact on drug tissue penetration and distribution. These transporters lower drug bioavailability by actively expelling the molecules out of the cell membrane and cytoplasm, and therefore constitute significant barriers to the entry of drug molecules (Gaudana et al., 2010). Two multidrug efflux transporters responsible for the development of chemoresistance have been identified in ocular tissues, including the P‐glycoprotein (P‐gp), and multidrug resistance protein (Gaudana et  al., 2010). P‐gp is involved in the active efflux of lipophilic compounds and has been reported in various cell lines and tissues of the conjunctiva, cornea and RPE, whereas multidrug resistance proteins, implicated in the effluxing of conjugated compounds and organic anions, have been identified in human RPE cell line, human corneal epithelium, and rabbit cornea (Gaudana et al., 2009). In studies comparing permeability of various drugs across BAB and BRB in rats, it was found that low‐lipophilic molecules showed the highest permeability across BAB, whereas high‐lipophilic compounds more readily crossed BRB than BAB. In these experiments, it was also shown that P‐gp contributed more to efflux transport of drugs at BAB than at BRB (Toda et al., 2011). Modulation of drug efflux transporters activity has been studied to improve the pharmacological properties of various drugs. Studies in rabbits showed that ocular bioavailability of erythromycin is enhanced in the presence of P‐gp inhibitors such as cyclosporin, quinidine, and verapamil (Gunda et  al., 2008). A prodrug strategy developed to escape efflux pumps efficiently is being explored, and in coming years may play an important role in the design of ophthalmic drugs with better ocular penetration (Gunda et  al., 2008). Genetic polymorphism of efflux transporters has been recognized as a cause of interspecies differences in ocular pharmacology. In the cat, for example, genetic anomalies in the ABCG2 transporter, present in the luminal membrane of endothelial cells of the inner blood–retinal membrane, favor the accumulation of fluoroquinolones in the retina, which may lead to iatrogenic retinal degeneration (Ramirez et al., 2011).

Topical Route of Administration Topical delivery is the most common mode of administration for ophthalmic drugs because of its advantages, including simplicity of application and convenience to reach both

extra‐ and intraocular tissue targets. The pharmacokinetic profile of topically applied ophthalmic drugs is influenced by precorneal factors (i.e., lacrimation, drainage) and the specific characteristics of the formulation itself that will determine the amount of drug penetrating the eye.

Conventional Eye Drops Ophthalmic solutions and suspensions represent the dosage form most widely used in ophthalmology. Ophthalmic solutions are formulations in which the drug is totally dissolved in a given solvent. Typically, they are low‐viscosity aqueous solutions that are mixable with the aqueous tear film. Thus, the drug must be, at least to some degree, water soluble. Some exceptions exist, like compounded preparations of cyclosporine in corn or olive oil (Frangie, 1995). To minimize irritation of the eye, ophthalmic solutions should ideally have an osmolality (tonicity) of about 300 mOsm/kg, a value corresponding to the average tonicity of normal human tears (Craig et al., 1995), and in the range of the tear osmolality values measured in cats, dogs, and horses (Davis & Townsend, 2011; Best et  al., 2015; Sebbag et  al., 2017). Although it is said that eye drops should be isotonic with tears, various studies have shown that the eye can tolerate solutions with an osmolality in the range of 200–600 mOsm/ kg, or 0.2%–2.0% in NaCl equivalents (Bar‐Ilan & Neumann, 1997; Malmberg & Lupo, 2004). Sodium chloride, boric acid, and dextrose are used to adjust tonicity of eye drop formulations. Ophthalmic solutions must fall within a pH between 4.5 and 9, but are usually pH adjusted in the range of 7.0–7.7, corresponding to human tear pH (Fischer & Wiederholt, 1982), to be comfortable for patients and not induce tearing and blinking reflexes (Malmberg & Lupo, 2004). The adjusted pH of most ophthalmic solutions and suspensions is also within the range of physiological tear pH values for small and large animals (Beckwith‐Cohen et al., 2014). To improve stability and sterility, ophthalmic solutions are formulated with appropriate vehicles that may contain buffers, organic or inorganic carriers, emulsifiers, and wetting agents. The advantages of solutions include relative ease in dispensing and use. In addition, most agents are well tolerated, cause little discomfort, and do not affect vision (Bartlett & Cullen, 1984). When frequent applications of ophthalmic solutions are required in horses, a subpalpebral lavage system is necessary to provide frequent instillations with minimum handling (Martin, 2005). Pharmaceutical derivatives of low aqueous solubility, such as acetates and alcohols used as topical corticoids, require formulations as ophthalmic suspensions (Frangie, 1995). Brinzolamide, used to reduce intraocular pressure, and rivoglitazone, a new treatment for dry eye disease in human patients, are also formulated as ophthalmic suspensions. Ophthalmic suspensions are sterile products containing solid particles of active ingredient dispersed in a liquid

0.025% to 0.01%) and thimerosal (at concentrations ranging from 0.0125% to 0.1%) induce severe morphologic changes at all concentrations evaluated (Hendrix et  al., 2002). Experimentally administered to rabbits at concentrations ranging from 0.004% to 0.02%, which are those used in most commercially available eye drops, benzalkonium chloride induced significant inflammatory infiltration of the limbus, conjunctiva, and trabecular meshwork (Burstein, 1980; Liang et al., 2008). Of primary concern with their frequent or prolonged use, is their potential toxicity to the ocular surface epithelium, disruption of tear film stability, and hypersensitivity reactions (Baudoin et  al., 2010). As preservatives are present in most antiglaucoma agents, the surface changes resulting from long‐term topical antiglaucoma treatment in human patients directly influence the outcome of filtering surgery by increasing the risk of postoperative fibrosis. In patients who experience ocular signs compatible with poor tolerance or allergy to preserved eye drops, changing to preservative‐free eye drops rapidly leads to significant decrease in local side effects (Baudoin et al., 2010). Unpreserved eye drops are available in multidose bottles or unit dose containers. Those supplied in multidose bottles should be stored at 2°–8°C after opening to reduce the rate of replication of any microbial contaminants, and they should not be kept in use for more than 7 days (Oldham & Andrews, 1996). An innovation for the prevention of bacterial contamination of the multidose eyedropper has been the development of the Novelia® bottle (Nemara, La Verpillière, France), which has a tip with a one‐way valve and a silicone membrane to avoid any potential retrograde contamination of the bottle (Strauss et al., 2019). Recent data show that it may decrease microbial contamination of plasma eye drops used in canine patients (Strauss et al., 2019).

Drug Disposition After Eye Drop Application As indicated in Fig.  8.1.3, an ophthalmic drug topically applied to the eye is distributed in three ways. It is drained by Corneal absorption Topical drug administration

Lacrimal fluid

v­ ehicle, which includes dispersing and suspending agents, intended for application to the eye. Ophthalmic suspensions generally contain particles relatively insoluble in the aqueous vehicle, but the vehicle can also be considered as a saturated solution of the drug. The drug particles contained in suspension must be less than 10 μm, uniform in size, and micronized for optimum local tolerance and therapeutic efficacy (Bar‐Ilan & Neumann, 1997; Wilson, 1999). The suspensions should be formulated at a tonicity and pH that are safe for the ocular surface, but because they are heterogenous systems, their stability is dependent on the physicochemical features of the suspended solids, and they present problems with regard to methods of sterilization and drug concentration. Unstable dispersed systems can lead to changes in particle size, leading to agglomeration of dispersed particles affecting their uniform dispersion in the vehicle (Ali & Lehmussaari, 2006). Drug concentration can be manipulated by increasing the number of particles, or by the reformulation of ophthalmic suspensions as solutions, either by formulating water‐soluble derivatives of the parent drugs (i.e., sodium phosphate salts for glucocorticoids) or complexing poorly water‐soluble compounds with drug carriers, such as cyclodextrins, to increase their water solubility (Davies et al., 1997). From a practical point of view, potential disadvantages of ophthalmic suspensions include the possibility of irritation caused by suspended crystals or particles, and the need to be adequately shaken before use to disperse drug particles evenly throughout the vehicle and avoid incorrect dosing (Ali & Lehmussaari, 2006; Frangie, 1995; Kwon et al., 1996). All multidose eye preparations must include a bacteriostatic preservative (i.e., benzalkonium chloride, benzethonium chloride, methylparaben, propylparaben, mercurial compounds, thimerosal) to prevent or inhibit microbial growth during clinical use (Malmberg & Lupo, 2004). At appropriate concentrations, these preservatives must be safe, be compatible with the other ingredients of the preparation, and remain effective throughout the period of use of the eye drops. In a human clinical setting, it has been observed that preserved eye drops in multidose containers do not become heavily contaminated for up to 1 month after opening, enabling these eye drops to be used for 4 weeks without increasing the risk of ocular infection (Høvding & Sjursen, 1982). In the same way, it has been reported that multidose eye drops vials of proparacaine hydrochloride, tropicamide, and eye wash bottles did not experience significant aerobic bacterial contamination over a 2‐week period of administration in a veterinary hospital (Betbeze et al., 2007). Although they are useful to prevent bacterial contamination of multiuse ophthalmic solutions and suspensions, preservatives can, however, exert deleterious toxic effects to the ocular surface, as reported in animals and humans. Using canine corneal epithelial cells in tissue culture, it has been shown that both benzalkonium chloride (at concentrations ranging from

Conjunctival absorption

Nasolacrimal drainage

Aqueous humor

Sclera

Iris–Ciliary body

Anterior segment disposition

Posterior segment disposition

General circulation

Drug loss

Figure 8.1.3  Disposition of ophthalmic drugs after topical application to the eye. Only a small portion of a topically applied drug may reach the posterior segment (dashed lines).

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the nasolacrimal apparatus, may penetrate into the eye through the corneal and/or noncorneal routes, and is absorbed into the systemic circulation via the conjunctiva and nasopharynx. Nasolacrimal Drainage and Tear Washout

When eye drops are administered onto the ocular surface, they first mix with the tear film, the volume of which is about 7–10 μL (with 1 μL covering the cornea and about 3–4 μL residing in each conjunctival sac), as estimated in humans and rabbits (Maurice, 1995; Shell, 1982). These values are lower than those recently reported for dogs and cats, with a median basal tear volume of 65 μL (range: 42–87 μL) and 32 μL (range: 29–39 μL), respectively (Sebbag et  al., 2019a). The drop volume delivered by many ophthalmic dropper bottles is about 40 μL on average (Lederer & Harold, 1986), but actually it varies within a range of 25–70 μL depending on the design of the dropper tip, the physicochemical properties of the medication to be dispensed, and the manipulation of the dropper bottle (Van Santvliet & Ludwig, 2004). With an average drop volume of 35 μL, it has been estimated that the drug concentration at the ocular surface is immediately diluted by threefold in dogs and twofold in cats upon mixing with the tear film (Sebbag et al., 2019a). Since the palpebral fissure is capable of holding only 25–30 μL of fluid, the volume of most ophthalmic drops largely exceeds the volume of the cul‐de‐sac, so complete retention of this drop volume is unlikely to occur (Mishima et al., 1966). As a consequence, the sudden increase of volume created by instillation of an eye drop will be diminished rapidly by escape of a large proportion of the instilled fluid (approximately 80%–90%) into the nasolacrimal system and spillage over the lower eyelid (Agrahari et al., 2016; Hegeman et  al., 1984). Scintigraphic studies of ophthalmic solution elimination has shown that, as a result of rapid drainage, most of the instilled solution is lost within the first 15–30 seconds in humans (Shell, 1982; Wilson, 1999). The extra solution volume that enters the nasolacrimal apparatus will then flow to the nasopharynx, where part of the drained fraction may be absorbed and contribute to some systemic side effects (see paragraph on systemic absorption) or may induce salivation caused by a bitter taste (e.g. atropine). Following removal of a substantial proportion of the drug subsequently to administration of such an excess volume, a second mechanism of clearance, represented by continual turnover of the tear film, will prevail until restoration of the normal tear volume occurs (Davies, 2000). In normal, nonirritated human eyes, the secretion and drainage of tears occur at a rate of approximately 1 μL/min corresponding to a 15% turnover of the tear film per minute (Davies, 2000). This washout results in almost complete disappearance of the applied fluid remaining on the ocular surface via lacrimal drainage within approximately 10 minutes (Davies, 2000). This conclusion also applies to dogs and cats, which tear

turn‐over rate is similar at about 11%–12% per minute (Sebbag et al., 2019a). The tear volume and tear flow rate in horses have been reported to be 230 μL, and 33 μL/min, respectively (Chen & Ward, 2010). Assuming an instillation volume of 0.2 mL via a subpalpebral lavage system (Martin, 2005), it has been estimated that the drug concentration in the tear film is diluted by more than half immediately upon instillation, suggesting that increased dosing regimens or continuous infusion techniques for topical administration of ophthalmic drugs would be indicated when treating severe equine corneal disease (Chen & Ward, 2010). Factors Influencing the Nasolacrimal Drainage

The rate at which a topically applied ophthalmic solution is eliminated from the ocular surface because of nasolacrimal drainage is influenced by four main factors: the size of the drop delivered to the eye, the blinking frequency, the viscosity of the ophthalmic solution, and the tear flow dynamics. Within the cul‐de‐sac, the drainage rate of an instilled volume has been shown to be proportional to the volume of the drop that is above the normal lacrimal fluid volume. The larger the volume instilled, the more rapidly it is drained through the nasolacrimal system (Bartlett & Cullen, 1984). Pharmacokinetic models indicate that tear drainage within the first minute after topical application is 13 μL/min and 30 μL/min for a 25‐μL and a 50‐μL eye drop, respectively (Chrai et al., 1973). As a result, 90% of a topically instilled dose in a rabbit eye is cleared within 2 minutes for an instilled volume of 50 μL, 4 minutes for an instilled volume of 25 μL, and 7.5 minutes for an instilled volume of 5 μL (Chrai et al., 1974). Thus, a strategy for minimizing the rate of drug loss through drainage would be to reduce the volume instilled to 5–15 μL (Patton, 1977). Instillations of 10‐μL drops of phenylephrine 10%, or 15‐μL drops of clonidine 0.25% and 0.5% in human eyes, have the same ocular pharmacological effects as 30‐μL to 70‐μL drops of the same concentrations (Petursson et  al., 1984; Whitson et  al., 1993). Similarly, instillation of one drop immediately after another will reduce the availability of the first drug instilled because it will suffer a loss caused by nasolacrimal drainage that is proportional to the time interval between instillations (Schoenwald, 1997). A recent fluorophotometric study on the tear turn‐over rate in dogs showed that ocular instillation of two drops (70 μL) introduces too large a volume of fluid that induces an excess lost by spillage over the eyelid margin and accelerated nasolacrimal drainage (Sebbag et al., 2019b). As an instilled drop is removed in about 10 minutes, dosage guidelines therefore recommend to apply only one drop upon the ocular surface, and that successive instillation of drops of different medications should be spaced by at least a 10‐minute period (Shell, 1982). This recommendation has been extrapolated from data in humans and rabbits, but the recent findings on the canine and feline tear turn‐over rates demonstrate that it also applies in dogs and cats (Sebbag et al., 2019a, 2019b).

Blinking and tear flow dynamics may also alter the drug residence time in the precorneal compartment if the instilled medication is an irritant by virtue of its pH and/or tonicity. As previously discussed, the pH of an ophthalmic preparation should be kept as close to the physiological pH as possible to avoid local irritation or foreign body sensation with enhanced lacrimation and blinking that will promote drug clearance through the lacrimal system (Shell, 1982). In dogs and cats, it has been found that reflex tearing results in a fivefold increase in tear turn‐over rate (50% per minute) compared with the basal value (11%–12% per minute), suggesting that a topically applied ophthalmic solution would be rapidly cleared from the ocular surface if it induces lacrimation for any reason (e.g., caused ocular irritation) (Sebbag et al., 2019). Penetration Across the Cornea

After topical ocular application, drugs may be absorbed into the inner eye through the corneal or conjunctival–scleral route. The rate and extent of absorption through one route or the other is dependent both on transport characteristics of the cornea, conjunctiva, and sclera and on the physicochemical properties of the drug itself. Generally, the cornea has been regarded as the main route of absorption for clinically used ocular drugs because most of them have been developed with adequate properties for corneal absorption (Lee & Robinson, 1986). As shown previously, the cornea is a complex barrier to drug entry into the eye because it has layers with different partitioning properties. Transfer through the epithelium is the rate‐limiting step for absorption of hydrophilic compounds, whereas transfer through the stroma is rate‐limiting for lipophilic compounds. Thus, in order for an ophthalmic drug to penetrate the cornea, it must exhibit intermediate solubility characteristics, being soluble to some degree in both oil and water to penetrate the epithelium and stroma (Bartlett & Cullen, 1984). It is postulated that a good predictor of corneal penetration rate of drugs is the o/w partition coefficient and that maximal corneal penetration is obtained with drugs whose o/w partition coefficient range from 10:1 to 1000:1 (Grass & Robinson, 1984). For moderately lipophilic drugs such as timolol and dexamethasone, the corneal epithelium contributes 50% to the total resistance to transport whereas the stroma and endothelium each contribute 25% (Lee & Robinson, 1986). After topical application, a very lipophilic drug (i.e., cyclosporine) may be sequestrated in the corneal epithelium from which it is then gradually released (Agrahari et al., 2016). For hydrophilic drugs such as epinephrine, pilocarpine, gentamicin, tobramycin, prednisolone sodium phosphate, dexamethasone sodium phosphate, cromolyn, and idoxuridine, the corneal epithelium contributes more to the total resistance to transport, and these molecules will penetrate the epithelium slowly or not at all because of the paracellular pathway predominance

(Lee & Robinson, 1986; Schoenwald, 1997). In humans, ocular bioavailability is predicted to be 5%–7% at maximum for lipophilic drugs (o/w partition coefficient >1) and to be less than 0.5% for hydrophilic ones (o/w partition coefficient 2 mm/min than dogs with STT values of 0–2 mm/min, presumably because of more extensive and irreversible lacrimal acinar destruction in the latter group (Kaswan et al., 1989; Sansom et al., 1995). Tear production in dogs with neurogenic KCS is not likely to improve with CsA treatment (Kaswan et  al., 1989). Beyond improvements in tear production, other clinical benefits of CsA therapy in KCS‐affected animals include reduction of corneal vascularization and pigmentation (Kaswan et al., 1984; Kaswan & Salisbury, 1990). This improvement in keratitis occurs even in dogs whose tear production does not increase (Kaswan et al., 1989; Sansom et al., 1995). In the treatment of KCS, twice daily treatment is generally recommended for control of the disease, although once daily administration appears clinically adequate in some dogs. However, whether or not low‐grade lacrimal adenitis persists during low frequency administration of CsA in KCS‐affected dogs is unknown. Multiple mechanisms of action are likely responsible for the therapeutic efficacy of CsA. T‐cell suppression by CsA undoubtedly plays a major role in restoring tear production in dogs affected with immune‐mediated lacrimal adenitis, where lymphocytic infiltration of lacrimal gland acini and ducts has been documented as a hallmark of the disease (Kaswan et  al., 1984). Improvement in conjunctival mucin stores in KCS affected dogs has also been documented with CsA treatment, which may contribute to its therapeutic effect in this disease (Moore et al., 2001). In dogs with spontaneous chronic idiopathic KCS, topical CsA suppresses lacrimal acinar and conjunctival epithelial cell apoptosis and facilitates lymphocytic apoptosis, leading to reestablishment of the normal apoptotic balance in affected dogs (Gao et  al., 1998). Considering the reversible increase in lacrimation that occurs in normal dogs treated with topical CsA, a direct lacrimal stimulant effect is also likely (Kaswan et al., 1989). Some of its effects may also be related to stimulation of neurotransmitter release (Yoshida et  al., 1999), which appears to be impaired in KCS‐affected animals (Zoukhri & Kublin, 2001). While the route of application of CsA for KCS management has traditionally been topical, surgical placement of

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Salgo, 2010). Although the pathogenic role of the medications, if any, cannot be determined, it was reported in a case series of 26 dogs with corneal squamous cell carcinoma that 16/21 dogs with a known treatment history were receiving topical ophthalmic cyclosporine or tacrolimus prior to tumor diagnosis (Dreyfus et  al., 2011). Finally, in a case series of five dogs with chronic ocular surface disease and being treated with cyclosporine or tacrolimus, ocular surface protozoal infections were reported, raising the potential that long‐term local immunosuppression may have played a role in pathogenesis (Beckwith‐Cohen et al., 2016). Considered in the context of their widespread use and documented efficacy in the management of ocular surface disease in veterinary patients, combined with the rare reports of potential adverse effects, it would appear that the therapeutic benefits of calcineurin inhibitors far outweigh their potential risks.

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episcleral CsA implants has recently been described (Barachetti et al., 2015; Mackenzie et al., 2017). Reports are limited, but this approach would appear to be a viable alternative to topical therapy, potentially useful in cases that either do not tolerate or are medically refractory to topical treatment (Barachetti et al., 2015). A primary limitation to this approach would appear to be the finite pharmacologically effective lifespan of the implant. Topical CsA has the longest history of use in the management of immune‐mediated KCS, but other calcineurin inhibitors have also been investigated and employed clinically for this condition (Berdoulay et al., 2005; Gilger et al., 2013; Nell et al., 2005; Ofri et al., 2009). Topical 0.02% tacrolimus has been shown to increase tear production significantly and improve clinical signs in dogs with naturally occurring KCS (Berdoulay et al., 2005; Hendrix et al., 2011; Radziejewski & Balicki, 2016), including some animals that were nonresponsive to topical CsA treatment (Berdoulay et  al., 2005). While clinical use of pimecrolimus does not appear to be as widespread as that of tacrolimus as a CsA alternative, two studies evaluating it for the treatment of canine KCS have been reported. One demonstrated improvement in STT values and clinical signs in eight KCS affected dogs treated with pimecrolimus (Nell et al., 2005), whereas a subsequent study comparing 1% pimecrolimus with a commercial 0.2% CsA ointment revealed pimecrolimus‐ treated dogs to have significantly improved STT values and clinical scores compared with the CsA‐treated group (Ofri et al., 2009). Topical calcineurin inhibitors are indispensable in the management of canine KCS and other corneal diseases, but the potential for adverse effects of these medications exists. The primary documented side effect of topical CsA is ocular irritation, which occurs in a proportion of dogs, but often improves with continued treatment and resolution of disease (Morgan & Abrams, 1991; Sansom et al., 1995). In this author’s experience, ocular irritation appears to be more common with compounded oil‐based preparations than the commercially available ointment‐based product. However, dogs will, on occasion, also not tolerate the latter. Reduction in blood lymphocyte counts and suppression of lymphocyte proliferation has been demonstrated in dogs receiving topical ophthalmic CsA (Gilger et  al., 1995, 1996; Izci et  al., 2002), although another investigation failed to detect such effects (Williams, 2010). In any case, adverse clinical sequelae related to systemic effects of topical ophthalmic cyclosporine application have not been reported. Concerns regarding the carcinogenic potential of calcineurin inhibitors, stem largely from a 2005 Food and Drug Administration “black box warning” concerning tacrolimus and pimecrolimus (Food and Drug Administration, 2005; Niwa et  al., 2003). However, there remains considerable debate regarding the actual risk of malignancy with topical use (Czarnecka‐ Operacz & Jenerowicz, 2012; Siegfried et al., 2016; Thaci &

8.4: Clinical Pharmacology and Therapeutics

Sirolimus (Rapamycin)

Also known as rapamycin, sirolimus is a macrolide compound with several known biologic effects, including immunosuppression, which shows promise as an alternative treatment option for idiopathic/immune‐mediated KCS. An experimental study employing subconjunctival administration of a liposomal sirolimus formulation in dogs with naturally occurring KCS demonstrated improved tear production in treated animals (Linares‐Alba et al., 2016). In a recently reported clinical trial, topically applied 0.02% sirolimus aqueous suspension was shown to be both well tolerated and similarly efficacious to 0.02% tacrolimus in its lacrimostimulant properties in KCS‐affected dogs (Spatola et al., 2017). Pilocarpine

Topical and oral pilocarpine, a muscarinic cholinergic agonist, have long been recommended for the management of KCS (Rubin & Aguirre, 1967; Severin, 1973), but controlled studies involving KCS‐affected animals are lacking. Applied topically, pilocarpine produces no detectable effect on tear production in normal dogs (Smith et al., 1994). Oral pilocarpine has been described as efficacious in a case series of normal and KCS‐affected animals, but signs of systemic toxicity (e.g. salivation, vomiting, inappropriate defecation, or diarrhea) are common with this route of administration (Rubin & Aguirre, 1967). While largely supplanted in the treatment of KCS by drugs such as CsA, pilocarpine remains a viable treatment in dogs with neurogenic KCS wherein loss of parasympathetic innervation is the presumed cause of impaired lacrimal secretion (Matheis et al., 2012). The efficacy in such cases, however, remains undetermined. Other Potential Lacrimostimulants

In a study of three English Bulldogs with KCS induced by surgical removal of the gland of the nictitans, treatment with topical nerve growth factor resulted in significant improvements in STT, conjunctival goblet cell density, tear mucous,

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corneal haze, corneal sensitivity, and impression cytology (Coassin et  al., 2005). Based upon these findings, further investigation of this treatment would appear warranted. An open label clinical trial evaluating the efficacy of oral alpha‐interferon in dogs with chronic KCS found a favorable response in STT values in 55% of dogs (Gilger et  al.,

1999). The increase in STT values was modest, but posttreatment STT values in responders were significantly greater than their pretreatment STT values (Gilger et al., 1999). The exact role of these treatments as primary or adjunctive therapeutic measures in the management of KCS remains to be determined.

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Nishida, T., Nakamura, M., Mishima, H., et al. (1991) Hyaluronan stimulates corneal epithelial migration. Experimental Eye Research, 53, 753–758. Niwa, Y., Terashima, T. & Sumi, H. (2003) Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin. British Journal of Dermatology, 149, 960–967. Noble, B.A., Loh, R.S., Maclennan, S., et al. (2004) Comparison of autologous serum eye drops with conventional therapy in a randomised controlled crossover trial for ocular surface disease. British Journal of Ophthalmology, 88, 647–652. Nowak, M.R. & Neumann, W. (1987) Refraction of the dog eye. Klinische Monatsblätter für Augenheilkunde, 191, 81–83. Oel, C., Gerhards, H. & Gehlen, H. (2014) Effect of retrobulbar nerve block on heart rate variability during enucleation in horses under general anesthesia. Veterinary Ophthalmology, 17, 170–174. Ofri, R., Lambrou, G.N., Allgoewer, I., et al. (2009) Clinical evaluation of pimecrolimus eye drops for treatment of canine keratoconjunctivitis sicca: a comparison with cyclosporine A. Veterinary Journal, 179, 70–77. Olivero, D.K., Davidson, M.G., English, R.V., et al. (1991) Clinical evaluation of 1% cyclosporine for topical treatment of keratoconjunctivitis sicca in dogs. Journal of the American Veterinary Medical Association, 199, 1039–1042. Palmer, R.M. & Kaufman, H.E. (1995) Tear film, pharmacology of eye drops, and toxicity. Current Opinion in Ophthalmology, 6, 11–16. Pan, Q., Angelina, A., Marrone, M., et al. (2017) Autologous serum eye drops for dry eye. Cochrane Database of Systematic Reviews, 2, CD009327. Papa, V., Aragona, P., Russo, S., et al. (2001) Comparison of hypotonic and isotonic solutions containing sodium hyaluronate on the symptomatic treatment of dry eye patients. Ophthalmologica, 215, 124–127. Park, S.A., Kim, N.R., Park, Y.W., et al. (2009a) Evaluation of the mydriatic effect of intracameral lidocaine hydrochloride injection in eyes of clinically normal dogs. American Journal of Veterinary Research, 70, 1521–1525. Park, S.A., Lee, I., Lee, Y.L., et al. (2009b) Combination auriculopalpebral nerve block and local anesthesia for placement of a nictitating membrane‐to‐superotemporal bulbar conjunctiva flap in dogs. Journal of the American Animal Hospital Association, 45, 164–167. Park, S.A., Park, Y.W., Son, W.G., et al. (2010) Evaluation of the analgesic effect of intracameral lidocaine hydrochloride injection on intraoperative and postoperative pain in healthy dogs undergoing phacoemulsification. American Journal of Veterinary Research, 71, 216–222. Pascoe, P.J., Ilkiw, J.E., Stiles, J., et al. (1994) Arterial hypertension associated with ocular use of phenylephrine in dogs. Journal of the American Veterinary Medical Association, 205, 1562–1564. Peterson, D.R. (1951) Nerve block of the eye and associated structures. Journal of the American Veterinary Medical Association, 118, 145–148.

Petternel, V., Findl, O., Kruger, A., et al. (2000) Effect of tropicamide on aqueous flare before and after cataract surgery. Journal of Cataract and Refractive Surgery, 26, 382–385. Ploog, C.L., Swinger, R.L., Spade, J., et al. (2014) Use of lidocaine‐bupivacaine‐infused absorbable gelatin hemostatic sponges versus lidocaine‐bupivacaine retrobulbar injections for postoperative analgesia following eye enucleation in dogs. Journal American Veterinary Medical Association, 244, 57–62. Pucket, J.D., Allbaugh, R.A., Rankin, A.J., et al. (2013) Comparison of efficacy and duration of effect on corneal sensitivity among anesthetic agents following ocular administration in clinically normal horses. American Journal Veterinary Research, 74, 459–464. Radziejewski, K. & Balicki, I. (2016) Comparative clinical evaluation of tacrolimus and cyclosporine eye drops for the treatment of canine keratoconjunctivitis sicca. Acta Veterinaria Hungary, 64, 313–329. Raffe, M.R., Bistner, S.I., Crimi, A.J., et al. (1986) Retrobulbar block in combination with general anesthesia for equine ophthalmic surgery. Veterinary Surgery, 15, 139–141. Rainin, E.A. & Carlson, B.M. (1985) Postoperative diplopia and ptosis. A clinical hypothesis based on the myotoxicity of local anesthetics. Archives of Ophthalmology, 103, 1337–1339. Ramsay, R.C. & Knobloch, W.H. (1978) Ocular perforation following retrobulbar anesthesia for retinal detachment surgery. American Journal of Ophthalmology, 86, 61–64. Ribeiro, A.P., Crivelaro, R.M., Teixeira, P.P., et al. (2014) Effects of different mydriatics on intraocular pressure, pupil diameter, and ruminal and intestinal motility in healthy sheep. Veterinary Ophthalmology, 17, 397–402. Ripart, J., Lefrant, J.Y., Vivien, B., et al. (2000) Ophthalmic regional anesthesia: medial canthus episcleral (sub‐tenon) anesthesia is more efficient than peribulbar anesthesia: a double‐blind randomized study. Anesthesiology, 92, 1278–1285. Rubin, L.F. (1968) Applications of adrenergic drugs in ophthalmology. Journal of the American Animal Hospital Association, 4, 250–255. Rubin, L.F. & Aguirre, G. (1967) Clinical use of pilocarpine for keratoconjunctivitis sicca in dogs and cats. Journal of the American Veterinary Medical Association, 151, 313–320. Rubin, L.F. & Wolfes, B.S. (1962) Mydriatics for canine ophthalmoscopy. Journal of the American Veterinary Medical Association, 140, 137–141. Salama, H., Farr, A.K. & Guyton, D.L. (2000) Anesthetic myotoxicity as a cause of restrictive strabismus after scleral buckling surgery. Retina, 20, 478–482. Salazar, M. & Patil, P.N. (1976) An explanation for the long duration of mydriatic effect of atropine in eye. Investigative Ophthalmology, 15, 671–673. Salazar, M., Shimada, K. & Patil, P.N. (1976) Iris pigmentation and atropine mydriasis. Journal of Pharmacology and Experimental Therapeutics, 197, 79–88.

Salisbury, M.A., Kaswan, R.L., Ward, D.A., et al. (1990) Topical application of cyclosporine in the management of keratoconjunctivitis sicca in dogs. Journal of the American Animal Hospital Association, 26, 269–274. Sansom, J., Barnett, K.C., Neumann, W., et al. (1995) Treatment of keratoconjunctivitis sicca in dogs with cyclosporine ophthalmic ointment: a European clinical field trial. Veterinary Record, 137, 504–507. Scagliotti, R.H. (1999) Comparative Neuro‐ophthalmology. In: Veterinary Ophthalmology (ed. K. N. Gelatt). Philadelphia: Lippincott Williams and Wilkins. Selk Ghaffari, M., Sabzevari, A. & Radmehr, B. (2009) Effect of topical 1% tropicamide on Schirmer tear test results in clinically normal horses. Veterinary Ophthalmology, 12, 369–371. Severin, G.A. (1973) Keratoconjunctivitis sicca. Veterinary Clinics of North America, 3, 407–422. Shafi, T. & Koay, P. (1998) Randomised prospective masked study comparing patient comfort following the instillation of topical proxymetacaine and amethocaine. British Journal of Ophthalmology, 82, 1285–1287. Sharrow‐Reabe, K.L. & Townsend, W.M. (2012) Effects of action of proparacaine and tetracaine topical ophthalmic formulations on corneal sensitivity in horses. Journal of the American Veterinary Medical Association, 241, 1645–1649. Shilo‐Benjamini, Y., Pascoe, P.J., Maggs, D.J., et al. (2013) Retrobulbar and peribulbar regional techniques in cats: a preliminary study in cadavers. Veterinary Anaesthesia Analgesia, 40, 623–631. Shilo‐Benjamini, Y., Pascoe, P.J., Maggs, D.J., et al. (2014) Comparison of peribulbar and retrobulbar regional anesthesia with bupivacaine in cats. American Journal Veterinary Research, 75, 1029–1039. Siegfried, E.C., Jaworski, J.C., Kaiser, J.D., et al. (2016) Systematic review of published trials: long‐term safety of topical corticosteroids and topical calcineurin inhibitors in pediatric patients with atopic dermatitis. BMC Pediatrics, 16, 75. Slack, J.W., Edelhauser, H.F. & Helenek, M.J. (1990) A bisulfite‐free intraocular epinephrine solution. American Journal of Ophthalmology, 110, 77–82. Smith, E.M., Buyukmihci, N.C. & Farver, T.B. (1994) Effect of topical pilocarpine treatment on tear production in dogs. Journal of the American Veterinary Medical Association, 205, 1286–1289. Smith, L.J., Bentley, E., Shih, A., et al. (2004) Systemic lidocaine infusion as an analgesic for intraocular surgery in dogs: a pilot study. Veterinary Anaesthesia and Analgesia, 31, 53–63. Spatola, R., Nadelstein, B., Berdoulay, A., et al. (2017) The effects of topical aqueous sirolimus on tear production in normal dogs and dogs with refractory dry eye. Veterinary Ophthalmology, 21, 255–263. Stadtbaumer, K., Frommlet, F. & Nell, B. (2006) Effects of mydriatics on intraocular pressure and pupil size in the normal feline eye. Veterinary Ophthalmology, 9, 233–237.

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Stadtbaumer, K., Kostlin, R.G. & Zahn, K.J. (2002) Effects of topical 0.5% tropicamide on intraocular pressure in normal cats. Veterinary Ophthalmology, 5, 107–112. Strichartz, G. (1976) Molecular mechanisms of nerve block by local anesthetics. Anesthesiology, 45, 421–441. Sugiyama, T., Miyauchi, S., Machida, A., et al. (1991) The effect of sodium hyaluronate on the migration of rabbit corneal epithelium. II. The effect of topical administration. Journal of Ocular Pharmacology, 7, 53–64. Summers, W.K. & Reich, T.C. (1979) Delirium after cataract surgery: review and two cases. American Journal of Psychiatry, 136, 386–391. Taylor, N.R., Zele, A.J., Vingrys, A.J., et al. (2007) Variation in intraocular pressure following application of tropicamide in three different dog breeds. Veterinary Ophthalmology, 10(Suppl 1), 8–11. Thaci, D. & Salgo, R. (2010) Malignancy concerns of topical calcineurin inhibitors for atopic dermatitis: facts and controversies. Clinical Dermatology, 28, 52–56. Tsubota, K., Goto, E., Fujita, H., et al. (1999) Treatment of dry eye by autologous serum application in Sjogren’s syndrome. British Journal of Ophthalmology, 83, 390–395. Tsubota, K. & Higuchi, A. (2000) Serum application for the treatment of ocular surface disorders. International Ophthalmology Clinics, 40, 113–122. Tutt, R., Bradley, A., Begley, C., et al. (2000) Optical and visual impact of tear break‐up in human eyes. Investigative Ophthalmology & Visual Science, 41, 4117–4123. Venturi, F., Blocker, T., Dees, D.D., et al. (2016) Corneal anesthetic effect and ocular tolerance of 3.5% lidocaine gel in comparison with 0.5% aqueous proparacaine and 0.5% viscous tetracaine in normal canines. Veterinary Ophthalmology, 20, 405–410 Wallin‐Hakanson, N. & Wallin‐Hakanson, B. (2001) The effects of topical tropicamide and systemic medetomidine, followed by atipamezole reversal, on pupil size and intraocular pressure in normal dogs. Veterinary Ophthalmology, 4, 3–6. Ward, D.A. (1999) Clinical Pharmacology and Therapeutics. Part 3. In: Veterinary Ophthalmology (ed. K. N. Gelatt). 3rd ed. Philadelphia: Lippincott Williams and Wilkins. Wehrman, R.F., Gemensky‐Metzler A.J., Zibura A.E., et al. (2017) Objective evaluation of the systemic effects of topical

application of 1% atropine sulfate ophthalmic solution in healthy horses. Journal of the American Veterinary Medical Association, 251, 1324–1330. Whelan, N.C., Castillo‐Alcala, F. & Lizarraga, I. (2011) Efficacy of tropicamide, homatropine, cyclopentolate, atropine and hyoscine as mydriatics in Angora goats. New Zealand Veterinary Journal, 59, 328–331. Williams, D.L. (2010) Lack of effects on lymphocyte function from chronic topical ocular cyclosporine medication: a prospective study. Veterinary Ophthalmology, 13, 315–320. Williams, D.L. & Mann, B.K. (2014) Efficacy of a crosslinked hyaluronic acid‐based hydrogel as a tear film supplement: a masked controlled study. PLoS One, 9, e99766. Williams, D., Middleton, S., Fattahian, H., et al. (2012) Comparison of hyaluronic acid‐containing topical eye drops with carbomer‐based topical ocular gel as a tear replacement in canine keratoconjunctivitis sicca: a prospective study in twenty five dogs. Veterinary Research Forum, 3, 229–232. Williams, M.M., Spiess, B.M., Pascoe, P.J., et al. (2000) Systemic effects of topical and subconjunctival ophthalmic atropine in the horse. Veterinary Ophthalmology, 3, 193–199. Wittpenn, J.R., Rapoza, P., Sternberg, P., Jr., et al. (1986) Respiratory arrest following retrobulbar anesthesia. Ophthalmology, 93, 867–870. Wong, D.H. (1993) Regional anaesthesia for intraocular surgery. Canadian Journal of Anaesthesia, 40, 635–657. Yoshida, A., Fujihara, T. & Nakata, K. (1999) Cyclosporin A increases tear fluid secretion via release of sensory neurotransmitters and muscarinic pathway in mice. Experimental Eye Research, 68, 541–546. Zekas, L. J. & Lester, G.B. (1998) The effect of ophthalmic atropine on intestinal transit and myoelectric activity in normal adult horses. In: Proceedings of the 29th Annual Conference of the American College of Veterinary Ophthalmologists, 1998. Seattle, WA, USA. p. 28. Zink, J., Sasyniuk, B.I. & Dresel, P.E. (1975) Halothane‐ epinephrine‐induced cardiac arrhythmias and the role of heart rate. Anesthesiology, 43, 548–555. Zoukhri, D. & Kublin, C.L. (2001) Impaired neurotransmitter release from lacrimal and salivary gland nerves of a murine model of Sjogren’s syndrome. Investigative Ophthalmology & Visual Science, 42, 925–932.

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8.5 Clinical Pharmacology and Therapeutics Part 5: Medical Therapy for Glaucoma Caryn E. Plummer Departments of Small and Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA

The primary risk factor and clinical sign of glaucoma that is the most common target of therapy is elevated intraocular pressure (IOP). Control of elevated IOP may be achieved through medical or surgical means. However, a combination of both approaches is often the most successful. Medical treatment of glaucoma is generally directed at lowering the existing IOP to what is considered a “safe” or target level. Topical or systemic pharmacologic agents are grouped into three categories on the basis of their IOP lowering effect: (1) those that reduce the rate of aqueous humor production; (2) those that increase aqueous humor outflow without affecting its formation; and (3) those that affect both aqueous humor outflow and formation. A variety of pharmacologic agents that work through different mechanisms are available, including parasympathomimetic and adrenergic agents, carbonic anhydrase inhibitors (CAIs), prostaglandin analogues, calcium channel blockers (CCBs), and osmotic diuretics. These drugs may be used as monotherapy or in combination to decrease IOP in order to prevent the progressive loss of vision associated with the pathophysiology of glaucoma (Miller et  al., 2000; Willis 2004; Willis et  al., 2002). Most pharmacologic agents employed for the treatment of glaucoma are administered through the topical route in order to target affected tissues and minimize exposure of the rest of the body to a drug that may be associated with adverse effects. Typically, topical solutions or suspensions are used. However, there are increasing numbers of studies that use drug‐laden contact lenses or biodegradable drug‐laden subconjunctival or intraocular implants to deliver antiglaucoma medications more consistently and reliably than pulse drop therapy (Jung et al., 2013; Peng et al., 2012a, 2012b). Contact lenses laden with β‐adrenergic antagonists, CAIs, or prostaglandin analogues have all been shown to be effective at lowering IOP in glaucomatous Beagles (Jung et al., 2013; Peng et al., 2012a, 2012b). Hopefully, soon these will be available for the treatment of glaucoma in humans and companion

animals. While IOP remains the target of mainstay treatment of glaucoma, alternative therapies aimed at preventing disease or pressure‐induced damage to the retinal ganglion cells, optic nerve, and outflow pathways are increasingly being developed and employed (Danesh‐Meyer, 2011).

Cholinergic Agonists (Miotics) Also known as parasympathomimetics or cholinomimetics because they produce biologic responses similar to those of acetylcholine, these agents are classified according to their mechanism of action as either direct or indirect. Direct agents stimulate cholinergic receptors, whereas indirect agents inhibit acetylcholinesterase, permitting acetylcholine to accumulate at the cholinoreceptive sites (Bartlett et al., 2008).

Mechanism of Action Topical application of a parasympathomimetic compound on the eye results in miosis and lowering of IOP. In human and nonhuman primate eyes, contraction of the longitudinal fibers of the ciliary muscle with widening of the scleral spur to decrease resistance of aqueous humor passage through the outflow pathway is the likely mechanism through which these drugs act (Kaufman & Gabelt, 1997). Additionally, an increase in the number of giant vacuoles in the endothelium of Schlemm’s canal may also participate in improved aqueous outflow in these species (Kaufman & Gabeth, 1997). In small animals, the contribution that contraction of ciliary muscle makes on aqueous removal has not been determined and thus the mechanism by which parasympathomimetics lower the IOP is not established. Nevertheless, a cholinergic activity has been identified in the ciliary body musculature of the canine eye, indicating that there is the potential for modulation of outflow facility by the cholinergic nervous system (Gwin et  al., 1979). Further evidence supporting

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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such a hypothesis were observations that either intracameral injection of pilocarpine or N‐demethylated carbachol (Chiou et al., 1980), as well as topical application of pilocarpine in canine eyes (Gum et al., 1993b), induce a substantial increase in the conventional outflow facility. Direct‐Acting Parasympathomimetics

Pilocarpine is a natural alkaloid obtained from the leaves of South African shrubs of the genus Pilocarpus. The drug is used as a nitrate or a hydrochloride and is available in concentrations of 0.5%–8% in methylcellulose or polyvinyl alcohol vehicles. Most commercial pilocarpine eye drops are in solutions with a pH range of 4.5–5.5 to preserve the drug from hydrolysis, which can be highly irritating. Pilocarpine hydrochloride 4% in a high‐viscosity acrylic gel has been introduced to prolong drug‐eye contact time (Kaufman & Gabelt, 1997). Studies in glaucomatous (open‐angle) and normotensive Beagles indicate that a single instillation of 0.5%–8.0% pilocarpine hydrochloride solution reduces IOP by 30%–40% for at least 6 hours (Gwin et al., 1977; Whitley et  al., 1980), whereas the gel formulation reduces IOP by 25%–30% for at least 24 hours in glaucomatous canine eyes (Carrier & Gum, 1989). In these animals, a single drop instillation of pilocarpine (1%, 2%, or 4%) increased the coefficient of tonographic outflow facility from 0.33 μL/min/mmHg prior to treatment up to 0.61 μL/min/mmHg after treatment in normal eyes and from 0.15 μL/min/mmHg prior to treatment up to 0.38 μL/min/mmHg after treatment in glaucomatous eyes (Gum et  al., 1993b). Glaucomatous Beagles responded with a greater reduction of IOP than normotensive dogs and no significant difference in the hypotensive response was found among the different concentrations. Miosis occurred within 10–15 minutes and lasted for 6–8 hours (Gwin et al., 1977). Therapeutic additivity of pilocarpine with adrenergic agents or CAIs has been shown in human eyes (Kaufman & Gabelt, 1997). The combination of 1% epinephrine and pilocarpine hydrochloride (1%, 2%, 3%, 4%, and 6%) produced a significant IOP‐lowering effect in glaucomatous (open‐angle) and normotensive beagles. Following a single instillation of these combinations, the drop in IOP lasted for at least 8 hours and was not dose related (Gelatt et al., 1983). Surprisingly, combined administration of 1% epinephrine with either 1%, 2%, or 4% pilocarpine did not increase tonographic outflow facility in these eyes in comparison to pilocarpine 4% used alone (Gum et al., 1993b). While in research settings pilocarpine has been shown to reliably decrease IOP in both normotensive and glaucomatous animals, its clinical utility is limited because it does not typically lower IOP to a level that either supports vision retention or comfort and its administration is generally very irritating given its low pH. In normotensive mares, once‐daily or twice‐daily topical application of 2% pilocarpine hydrochloride was not associated with significant decrease in both IOP and vertical pupil

size (van der Woerdt et al., 1998). The lack of pharmacologic effect of pilocarpine on IOP was attributed most likely by a decrease in uveoscleral outflow resulting from ciliary muscle contraction. Dilution of the drug in the large equine tear volume leading to a subtherapeutic concentration penetrating the eye might also contribute to low availability of the drug (van der Woerdt et al., 1998). Indirect‐Acting Parasympathomimetics

Carbachol is the carbamyl ester of choline. Because the drug is not lipid‐soluble at any pH and penetrates the intact corneal epithelium poorly, it must be combined with a surfactant, such as benzalkonium chloride, to facilitate its penetration through the corneal epithelium (Kaufman & Gabelt, 1997). Carbachol is stable in solution and is available for topical use in concentrations of 0.75%–3%. A 0.01% solution is used for intracameral administration at completion of intraocular surgery to induce rapid miosis and inhibit postoperative ocular hypertension (Kaufman & Gabelt, 1997). At concentrations of 0.75%, 1.5%, 2.25%, and 3%, carbachol reduced IOP in normotensive and early glaucomatous (open‐angle) Beagles. The reduction in IOP was clearly evident within 1 hour and peaked 2–7 hours after instillation (Gelatt et al., 1984). A minimum concentration of 0.75% carbachol was recommended in the management of open‐angle glaucoma in the Beagle (Gelatt et  al., 1984). In an initial report, 0.01% solution injected into the anterior chamber of dogs at the end of cataract surgery was found to prevent the postoperative increase in IOP associated with phacoemulsification (Stuhr et  al., 1998). This preventive effect on the development of acute postoperative hypertension (POH) was not evident in a different study in which dogs were treated with intracameral administration of 0.3 mL of 0.01% carbachol immediately after phacoemulsification. These dogs had significantly higher IOP than the controls (no treatment) 2 hours after administration and had a number of POH peaks not significantly different from that observed in the controls (Crasta et al., 2010). A more recent study suggests that intracameral carbachol does decrease the incidence of POH in most breeds but may exacerbate POH in the Labrador Retriever (Moeller et al., 2011). The anticholinesterases are divided into the carbamate inhibitors, which bind to the acetylcholinesterase in a reversible manner, and the organophosphorus inhibitors which irreversibly inhibit the enzyme by forming a stable complex. Demecarium bromide is a potent carbamate inhibitor, no longer commercially available, but which can be compounded in 0.125% and 0.25% solutions for veterinary use. The drug remains stable for extended periods and does not require refrigeration (Kaufman & Gabelt, 1997). A single drop of demecarium bromide in a human eye provided a significant reduction of IOP starting a few hours after instillation and lasting for more than 3 days (Shihab, 1987).

The accompanying miosis lasted for up to 10 days (Shihab, 1987). Investigations using single‐drop application of either 0.125% or 0.25% topical demecarium bromide and conducted in normotensive and glaucomatous (open‐angle) Beagles revealed that both formulations induce long‐term miosis (up to 77 hours) and an IOP‐lowering effect that lasts up to 55 hours (Gum et al., 1993a). The mean decrease in IOP is about the same magnitude as that observed with pilocarpine solution and gel as well as with carbachol solution, but is more prolonged (Gum et al., 1993a). This drug is rarely used singly unless it is used as prophylactic therapy for the normotensive fellow eye of a dog previously diagnosed with glaucoma in the contralateral eye, but more often in combination therapy with drugs from other classes when used in a hypertensive globe (Dees et al., 2014). Echothiophate iodide (or phospholine iodide) is another long‐acting organophosphorus compound, which, although no longer commercially available, may be compounded in 0.03%, 0.125%, and 0.25% solutions (Ellis, 1997). The refrigerated solution remains stable for at least 1 month after reconstitution. Instillation of one drop echothiophate iodide 0.125% or 0.25% results in decrease in IOP of about 10 mmHg and about 1 mmHg in normotensive and glaucomatous (open‐angle) Beagle eyes, respectively (Gum et al., 1993a). Reduction in IOP persists for 25–53 hours. Associated miosis becomes maximal within 1–3 hours and persists for 49–55 hours (Gum et al., 1993a).

Clinical Use The major use of parasympathomimetic drugs has been the long‐term treatment of open‐angle glaucoma in the dog. Use of these agents in combination with adrenergic drugs or CAIs would also be of help for initial therapy in most early glaucomas. However, once glaucoma is advanced, parasympathomimetic therapy has little beneficial effect because the filtration angle is usually obliterated by extensive peripheral anterior synechiae (Gaarder, 2000). Parasympathomimetic agents should be avoided in secondary glaucoma associated with iridocyclitis and used with caution in dogs with subluxated or luxated lens, because miosis may predispose to synechia formation and lens dislocation may induce a pupillary block. Pilocarpine solution should be prescribed three to four times daily (Gaarder, 2000), whereas pilocarpine gel is applied once daily. Although demecarium bromide is a long‐acting hypotensive ocular agent, its instillation has been recommended in the dog on a twice‐daily basis to regulate IOP and avoid occasional peaks that may be destructive for the glaucomatous eye (Gum et  al., 1993a). In order to determine the ability of prophylactic antiglaucoma treatment to ­prevent or delay onset of glaucoma in the second eye of dogs with unilateral closed‐angle glaucoma, a combination of 0.25% demecarium bromide (DB) and a topical corticosteroid gentamicin/ betamethasone (GB) (DB/GB) was compared with topical

0.5% betaxolol in a multicenter clinical trial (Miller et  al., 2000). Untreated control eyes developed glaucoma significantly sooner (median 8 months) than eyes treated either with betaxolol (median 30.7 months) or DB/GB (median 31 months). Although both treatment protocols similarly delayed the onset of glaucoma in the fellow eye, DB/GB would be preferable to betaxolol in preventing closed‐angle glaucoma because of less frequent dosing (Miller et al., 2000). A recent study comparing the efficacy and time to medical failure of a variety of antiglaucoma medications with or without concurrent anti‐inflammatory medication suggests that patients receiving demecarium bromide 0.125% had the longest estimated median time to medical failure at 330.0 days, followed by latanoprost 0.005%, dorzolamide hydrochloride 2.0%, and demecarium bromide 0.25% at 284.0 days, 272.5 days, and 143.0 days, respectively (Dees et  al., 2014). The estimated median time to medical failure for patients receiving topical antiglaucoma and anti‐inflammatory medication was 324.0 days versus 195.0 days in patients receiving antiglaucoma medication alone, although the results were not statistically significant (Dees et al., 2014). Pilocarpine is also used topically or orally (well mixed with food) in small animal ophthalmology to stimulate tear production in patients with keratoconjunctivitis sicca, and to improve the ocular and digestive signs of feline dysautonomia.

Adverse Effects Because of the low pH (4.5–5.5) of its ophthalmic solutions, pilocarpine may cause local irritation manifested by blepharospasm, prolapsed nictitans, epiphora, and conjunctival hyperemia which are observed within the first 15 minutes and may last for up to 6 hours (Martin & Wyman 1978; Whitley et al., 1980). These signs are most prominent for the first 72 hours of treatment. Use of a special droptainer with a buffer system in its tip to adjust the pH of the pilocarpine solution to a level close to the physiological pH was evaluated in glaucomatous Beagles (Gelatt et al., 1997). One and two percent pilocarpine solutions instilled by buffer‐tip droptainer (pH 7) showed excellent pharmacological effects determined by miosis and ocular hypotension and were well tolerated (Gelatt et al., 1997). Topical application of pilocarpine transiently increases the permeability of the blood– aqueous barrier (BAB), but does not result in short‐ or long‐term changes (Krohne, 1994). In the dog, systemic side effects are unlikely after topical administration of pilocarpine 0.5%–8% solution or 4% gel (Carrier & Gum 1989; Whitley et al., 1980). Ocular and systemic side effects may occur with topical application of indirect‐acting parasympathomimetics. Since they potentiate the action of acetylcholine on muscles, they produce more severe ciliary and iridal spasms than does pilocarpine. Decreased vision resulting from miosis and induced myopia is the most adverse reaction reported in

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human patients (Kaufman & Gabelt, 1997). A transient increase in BAB permeability, resulting in increase in aqueous humor flare, occurs in the canine eye after topical application of pilocarpine and demecarium bromide, and may represent a potentially adverse effect in dogs with glaucoma (Krohne, 1994). An experimental investigation in dogs showed that miosis and increased flare caused by topical pilocarpine were inhibited by both proparacaine and nonsteroidal anti‐inflammatory drugs (NSAIDs), such as flurbiprofen, suprofen, and diclofenac, whereas IOP was decreased only in proparacaine‐treated eyes and increased in NSAID‐ treated eyes (Krohne et al., 1998). In light of these observations, the investigators concluded that miosis and increased aqueous flare caused by pilocarpine are prostaglandin‐­ mediated events probably secondary to neuropeptide release in aqueous humor (i.e., substance P or calcitonin gene‐ related peptide) from antidromic stimulation (Krohne et al., 1998). In addition, the pilocarpine IOP‐lowering effect observed in the eyes additionally treated with proparacaine was of a comparable amount to that previously reported for eyes treated only with pilocarpine, indicating that this pharmacologic effect is not affected by BAB breakdown (Krohne, 1994; Krohne et  al., 1998). Another relevant conclusion of this investigation was that NSAID should not be used in glaucomatous dogs because it interferes with pilocarpine‐ induced decrease in IOP (Krohne et al., 1998). Systemic toxicity may develop with any cholinesterase inhibitor and may include salivation, vomiting, diarrhea, and abdominal cramps. In order to minimize the risk of toxicity, indirect‐ acting parasympathomimetics should be avoided in subjects treated with flea preparations containing organophosphates (Gum et al., 1993a). When signs are severe, atropine (0.2 mg/ kg IV or IM) and pralidoxime chloride (20 mg/kg IV) are administered to block the action of acetylcholine. In human patients, their long‐term use may result in cataract formation, disruption of the BAB, retinal detachment and, in children, development of iris cysts (Ellis, 1997; Kaufman & Gabelt 1997).

Drugs Acting on Adrenoceptors Drugs that stimulate or block the activity of the ocular sympathetic nervous system may be used to lower IOP. Pharmacologically, their mechanisms of action are still unresolved and continue to be the subject of study and debate.

Epinephrine and Dipivefrin Epinephrine, or adrenaline, is classified as a nonspecific adrenergic agonist which stimulates both α‐ and β‐membrane receptors. Dipivefrin, or dipivalyl epinephrine, is an epinephrine prodrug produced by the addition of two pivalic acid groups to the parent compound. The lipophilic prodrug

penetrates the corneal epithelium barrier, where it is converted by esterases (acetylcholinesterase, cholinesterase, and arylesterase) to its parent drug, epinephrine, which is absorbed in the anterior segment (Nakamura et  al., 1993; Wei et al., 1978). Epinephrine has been used for many years to treat glaucoma in human patients but knowledge of its mechanism of action is still incomplete. Currently, it is believed that its ability to lower IOP is manifested both by reduction in formation of aqueous humor and increase in aqueous outflow. Investigations in human and nonhuman primates indicate that epinephrine and dipivefrin reduce aqueous humor formation most likely by decreasing blood flow in the ciliary body because of their vasoconstrictive action upon the vasculature of the ciliary body (Alm, 1980; Michelson & Groh, 1994). Improvement in conventional aqueous outflow facility by adrenergic drugs has also been clearly identified in nonhuman primate and human eyes (Erickson et  al., 1978; Erickson‐Lamy & Nathanson, 1992; Neufeld, 1984). In the human eye, an increase in aqueous outflow is mediated by β2‐adrenergic receptors and is correlated with increased cyclic adenosine monophosphate (cAMP) production by the trabecular meshwork (Erickson et al., 1978; Erickson‐Lamy & Nathanson, 1992). Concentrations of 1% and 2% topical epinephrine were effective in reducing IOP in glaucomatous (open‐angle) and normotensive Beagles (Gwin et al., 1978). In these animals, the 0.5% solution of dipivefrin manifested hypotensive and mydriatic effects similar to those of the 2% solution of epinephrine (Gwin et al., 1978). Topical epinephrine or dipivefrin, alone or in combination with other antiglaucomatous drugs such as direct‐acting parasympathomimetics, β‐blockers, and CAIs, has its main indication in the management of open‐angle glaucoma. Various local and systemic side effects have been reported in human patients with the ocular instillation of epinephrine and dipivefrin (Fang & Kass, 1997). The most common side effects include local intolerance, formation of adrenochrome deposits in the conjunctiva and cornea, loss of eyelashes, and macular edema in aphakic eyes (Fang & Kass, 1997). Incidence of conjunctival and corneal staining in veterinary patients is unknown. Local irritation consisting of mild conjunctivitis and tearing has been reported in the dog with the 0.5% solution of dipivefrin (Gwin et al., 1978). Since some of the corneal esterases that convert dipivefrin to epinephrine are inhibited by anticholinesterase drugs, combined use of indirect parasympathomimetics (demercarium, echothiophate, or phospholine iodide) and dipivefrin is contraindicated (Abramovsky & Mindel, 1997).

Alpha2‐Adrenergic Agonists The mechanism by which α2‐adrenergic agonists lower IOP is not fully understood. Studies in human eyes have clearly shown that these drugs decrease aqueous formation, but

gave conflicting results as regards their effect on outflow facility (Lee et  al., 1984a). From different investigations, it appears that α2‐adrenergic agonists most likely decrease aqueous humor formation by interfering with presynaptic (nerves) and postsynaptic (nonpigmented epithelial cells) α2‐adrenoceptors at the sympathetic nerve–ciliary body junction (Lee et al., 1984a; Ogidigben et al., 1994; Toris et al., 1995b). Activation of the presynaptic α2‐receptors inhibits norepinephrine release, thereby blocking the tonic adrenergic stimulation of the secretory ciliary epithelium by endogenous norepinephrine. Activation of the postsynaptic ciliary body α2‐receptors, coupled to a Gi protein, suppresses the activity of adenylate cyclase and reduces the intracellular concentration of cAMP in the ciliary body epithelium. The net effect is a decrease in aqueous humor formation (Ogidigben et al., 1994). Apraclonidine (p‐aminoclonidine), a derivative of clonidine with comparable IOP lowering effect and minimal cardiovascular effects, has been developed for use in human patients (Toris et al., 1995b). It is available as a topical 0.5% solution. The IOP lowering ability of apraclonidine has been evaluated in normal dogs and cats. Single topical administration of 0.5% apraclonidine in canine eyes resulted in a 3.0 mmHg (16%) IOP decrease 8 hours after treatment (Miller 1996a). In the cat, apraclonidine‐treated eyes showed mean IOP decrease of 4.8 mmHg (24%) 6 hours after treatment (Miller et al., 1996). The topical application of apraclonidine resulted in ocular and nonocular side effects both in dogs and cats. Mydriasis occurred in 29% of the treated canine eyes and miosis, with a reduction in pupillary diameter of 46%, occurred in treated feline eyes (Miller et  al., 1996b). Reduction in heart rate was more marked in cats than in dogs and undesirable gastrointestinal effects, such as salivation and vomiting, occurred in most cats (Miller et al., 1996a, 1996b). Thus, it appears that apraclonidine is not a first‐line antiglaucoma agent in the dog and is too toxic to be used in the cat. Nonocular side effects most likely result from systemic absorption of the topical drug. This is consistent with the finding that the conjunctival/scleral route is the main pathway for apraclonidine absorption after topical application (Chien et al., 1990). Brimonidine tartrate, a highly selective α2‐agonist, has been introduced for treating acute and chronic elevations of IOP in human patients (Walters, 1996). Its hypotensive effect in human glaucoma patients was found to be similar to that of timolol maleate, a β‐adrenergic antagonist, and was not associated with any systemic side effects (Katz, 1999). Current data indicate that brimonidine reduces IOP in human eyes by a dual mechanism, decreasing aqueous inflow and increasing uveoscleral outflow (Toris et  al., 1995a). Ocular effects of single and multiple doses of topical 0.2% brimonidine has been evaluated in glaucomatous beagles (Gelatt et al., 2002a). After application, a trend to reduction in IOP was observed but not at statistical significance.

As a result, the authors advised to use brimonidine as additive therapy and not as monotherapy in glaucomatous dogs. Side effects observed with brimonidine treatment in dogs included miosis and bradycardia (Gelatt et al., 2002a). A survey conducted in a poison control center documented the clinical signs associated with ingestion of brimonidine ophthalmic solution by dogs (Welch & Richardson, 2002). Severe dose‐dependent cardiovascular effects (hypotension, bradycardia) and central nervous system depression can ensue after the ingestion of brimonidine. Supportive care, as well as systemic administration of an α2‐antagonist, such as yohimbine or atipamezole, is helpful to reverse the signs of toxicosis (Welch & Richardson, 2002).

Beta‐Adrenergic Antagonists (Beta‐Blockers) Topical β‐blockers have become the most widely used medications for the control of ocular hypertension in human patients. In 1967, it was observed that propranolol caused a reduction in IOP after intravenous or topical administration. A number of other β‐blockers used for cardiovascular disease (i.e., practolol, oxprenolol, and atenolol) were then investigated as antiglaucoma agents, but adverse side effects limited their ocular use. In 1977, timolol was found to be a safe and effective agent for lowering IOP in human glaucoma patients. Since the drug was first marketed in 1978, levobunolol, betaxolol, metipranolol, carteolol, and nipradilol have also been released as antiglaucoma medications. Additional agents are currently being investigated and developed for ophthalmic use including nebivolol and carvedilol (Szumny & Szelag, 2014). All but betaxolol are nonspecific β‐blocking agents which block both β1‐ and β2‐receptors. Betaxolol is a β1‐selective ophthalmic β‐blocker. Carteolol is the only compound which possesses intrinsic sympathetic activity when bound to the β‐adrenergic receptors (Frishman et  al., 1994; Juzych & Zimmerman, 1997; Zimmerman, 1993). Many investigations have convincingly shown that topical β‐blockers reduce IOP by decreasing formation of aqueous humor (Coakes & Brubaker, 1978; Helal et al., 1979; Liu et al., 1980; Vogh et al., 1989). A single drop of 0.5% timolol solution suppresses aqueous formation in the range of 13%–48% in normal human eyes (Coakes & Brubaker, 1978). In cat eyes, the rate of aqueous humor formation is reduced 28%, 56%, and 71% by 0.005%, 0.025%, and 0.15% intracamerally injected timolol solution, respectively (Liu et al., 1980). Topical 0.5% timolol given to normal rabbit eyes decreases aqueous flow by 35% as measured by sulfacetamide clearance from aqueous humor (Vogh et  al., 1989). However, their mechanism of action is still uncertain, and three possibilities have been suggested: (1) they may block β‐receptors in the ciliary body processes; (2) they may inhibit active transport and ultrafiltration related to Na+‐K+‐adenosine triphosphatase (ATPase); or (3) they may act through a vasoactive mechanism. According to the classic view, β‐blocking

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agents lower aqueous humor flow by altering the adrenergic neuronal control of aqueous humor formation by blockade of the β‐receptors in the ciliary body processes (Frishman et al., 1994). β2‐adrenergic receptors seem to predominate in the ciliary body processes (Nathanson, 1981; Trope & Clark, 1982), and experimental findings indicate that β‐adrenergic receptors mediating pressure changes in the anterior segment of the cat eye are predominantly β2 (Colasanti & Trotter, 1981). It has been postulated that occupation of the β‐adrenoceptors of the ciliary body epithelium inhibits the tonic influence of norepinephrine released by the sympathetic nerves, thereby inducing a decrease of cAMP levels in the ciliary body epithelium and hence a reduction of the secretory function of the ciliary body epithelium (Juzych & Zimmerman, 1997). However, in vivo and in vitro findings indicated that the correlation between aqueous humor formation and ciliary body epithelial cAMP content was unclear and that β‐blocking drugs might act through mechanisms unrelated to β‐adrenergic blockade in the ciliary body epithelium (Boas et  al., 1981; Shahidullah et  al., 1995). Since plasma membrane ATPases of the ciliary body epithelium are involved in aqueous humor formation, the potential ­relationship between inhibition of ciliary ATPases and the IOP‐lowering effect of the β‐blockers has been investigated. In vitro and in vivo studies support a mechanism for β‐adrenergic antagonist inhibition of ciliary Na+‐K+‐ATPase activity (Rittenhouse & Pollack, 1999; Whikehart et  al., 1992). However, other studies in rabbits showed that neither Na+‐K+‐ATPase nor Mg++‐ATPase was inhibited by timolol, and showed that the IOP‐lowering effect of the drug was related to a significant reduction of blood flow in the iris root‐ciliary body, related to a significant reduction in ­dopamine concentrations in this tissue (Watanabe & Chiou, 1983). β‐blockers have no effect on aqueous outflow (Juzych & Zimmerman, 1997). Topical timolol is available as a 0.25% and 0.50% solution of the maleate salt. In the United States, the drug is also supplied as a 0.25% and 0.50% hemihydrate salt, which has an ocular hypotensive effect similar to that of the maleate salt in human patients (Bartlett et  al., 2008). In 1993, timolol maleate also became available in an anionic heteropolysaccaride gellan gum (Gelrite), which gels in contact with the cations in the tear fluid. This in situ gel‐forming formulation allows increased bioavailability and is administered once daily. Diverging results have been obtained in normotensive dogs after single and repeated instillation of 0.5% timolol maleate. In an early investigation, a mean reduction in IOP of 2.5 mmHg (16%) was observed within 2–4 hours postdosing (Wilkie & Latimer, 1991a), whereas in two other reports the 0.25% and 0.5% timolol formulations were found ineffective at reducing IOP in normotensive dogs (Gum et  al., 1991b; Smith et al., 2010). In clinically healthy cats, a single application of 0.5% solution induced a mean reduction in IOP of 4.1 mmHg (22%), with the maximum IOP reduction

occurring within 6–12 hours after instillation (Wilkie & Latimer, 1991b). A contralateral decrease in IOP also occurred in nontreated eyes, both in dogs and cats (Wilkie & Latimer, 1991a, 1991b). A dose–response study of timolol maleate employing single‐ and multiple‐drop instillations in glaucomatous (open‐angle) Beagles found that 0.25% and 0.5% timolol lowered IOP by approximately 4–5 mmHg (Gum et  al., 1991b). A dose‐related reduction in IOP was observed in normotensive dogs, with concentrations of 2%–8% (Gelatt & MacKay, 1995). In eyes with open‐angle glaucoma, decrease in IOP ranging from 8 to 14 mmHg was observed for up to 6 hours after administration of 4%, 6%, and 8% concentrations (Gelatt & MacKay, 1995). Once‐daily instillation of timolol maleate 0.5% gel‐forming ophthalmic solution in healthy Beagles was found to induce a mean reduction in IOP of 5.4 mmHg (Takiyama et al., 2006). The hypotensive effect persisted for 24 hours after the instillation (Takiyama et al., 2006). A gel formulation of 0.5 % timolol maleate had an inconsistent effect on IOP when dosed once daily in both normal and glaucomatous cats, with maximum IOP‐lowering effect (mean = 5.6 mmHg, 17.4%) observed 6 hours posttreatment in glaucomatous individuals (Kiland et al., 2016). The drug caused significant miosis from 4 to 8 hours posttreatment, but had no effect on heart rate (Kiland et al., 2016). As β2‐receptors predominate in the feline anterior segment, β1‐selective blockers, such as betaxolol, may have lower efficacy in cats (Colasanti & Trotter, 1981). Due to lower sympathetic tone, β‐blockers also are ineffective at lowering IOP during sleep, which may reduce their efficacy in felines that nap frequently during the day and exhibit peak IOP during the nocturnal phase (McLellan & Miller, 2011). The effect of topical application of timolol on IOP has been evaluated in mares with normotensive eyes (van der Woerdt et al., 2000). A significant mean decrease of approximately 4–5 mmHg was observed 8 hours after single‐dose application, and the pressure‐lowering effect was present throughout the 5‐day multiple‐dose study with a maximum reduction in IOP of 27% (van der Woerdt et  al., 2000). No ocular side effects were noted with the exception of 11% reduction in the pupil size. These results indicate that timolol could be of benefit in the management of glaucoma in horses (van der Woerdt et al., 2000). In people, carteolol, metipranolol, and levobunolol have similar potency to that of timolol for decreasing IOP (approximately 20%–30%) (Zimmerman, 1993). In rabbits, most of the topical β‐blockers, including nebivolol and carvedilol, lower IOP to a comparable effect (Szumny & Szelag, 2014). Studies in dogs have looked at timolol, betaxolol, levobunolol, and nipradilol, which seem to lower IOP similarly, but may differ in their local and systemic side effects or in their IOP lowering effects when used in combination with drugs from other classes. The IOP‐lowering effect of β‐blockers, although significant, is generally not large (2–6 mmHg) which limits the utility of these drugs for monotherapy of

overt glaucoma. However, they may be very helpful for lowering IOP when used in combination with drugs from other classes. Typically, such combinations provide an additive effect by using two drugs that work through different mechanisms, usually affecting both aqueous production and outflow. For instance, pilocarpine is often used in combination with β‐blockers. In glaucomatous beagles (open‐angle), the response to either 4% or 6% timolol was enhanced by combination with 2% pilocarpine (Gelatt et al., 1995). Topical 0.5% timolol when used in combination with the topical CAI dorzolamide decreases IOP to a greater extent than does either drug alone in glaucomatous beagles, suggesting a synergistic effect, the underlying mechanism behind which remains unknown (Plummer et al., 2006). Topical instillation of levobunolol 0.5% combined with dorzolamide in normotensive dogs produces a stronger hypotensive effect than the combination of timolol and dorzolamide (Scardillo et  al., 2010). Timolol in combination with the prostaglandin analogue latanoprost lowers IOP to a greater extent than does either drug alone (Smith et al., 2010). When two topical antiglaucoma medications are combined during the same dosing episode, at least 5 minutes should pass between applying the two formulations because coadministration reduces their ocular bioavailability. Pharmacokinetics data in rabbits show that when timolol is coadministered with either pilocarpine or epinephrine, its ocular absorption is reduced by 20%–70% (Lee et al., 1991). Another clinical utility for topical β‐blockers is in the prophylactic treatment of a normotensive fellow eye in an animal in which the contralateral eye has been diagnosed with overt glaucoma. Although the IOP lowering effects of monotherapy of these drugs is modest, it is sufficient in many instances to prolong the onset of overt glaucoma (Miller et al., 2000). As mentioned previously, topical 0.5% betaxolol is an alternative to demecarium bromide to prevent or delay the onset of hypertension in canine eyes predisposed to primary closed‐angle glaucoma (PCAG) (Miller et al., 2000). The most common ocular side effect of topical β‐blocking agents is local intolerance (i.e. stinging, burning) on ocular instillation (Juzych & Zimmerman, 1997). Photophobia, ptosis, blepharoconjunctivitis, and superficial keratitis are other potential ocular side effects of these drugs (Juzych & Zimmerman, 1997). Changes of the ocular surface observed during treatment with timolol have been associated with a significant reduction in tear production and turnover (Shimazaki et  al., 2000). It seems that carteolol has better ocular tolerability than the other compounds (Zimmerman, 1993). In human patients, topical timolol has minimal effect on pupillary diameter. On the contrary, significant reduction in the pupil size is observed in the canine and feline‐treated eyes (Gelatt et  al., 1995; Wilkie & Latimer, 1991a, 1991b). Reduction of pupillary diameter is more marked in cats than in dogs with a maximum duration of persistence 1 week after treatment is discontinued (Wilkie & Latimer, 1991a,

1991b). Timolol has been shown to be more toxic to regenerating corneal epithelium than levobunolol and betaxolol in rabbit eyes (Trope et al., 1988), and therefore may not be the drug of choice in animals with both glaucoma and corneal epithelial defects. Topical β‐blockers are contraindicated in human patients with severe heart failure and bronchial asthma because of their potential cardiopulmonary adverse effects resulting from systemic absorption. It is possible that the partial agonist activity of carteolol may reduce its cardiovascular and bronchopulmonary adverse effects by lessening systemic β‐blockade effect (Frishman et  al., 1994; Zimmerman, 1993). Significant decrease in pulse rate was observed in normotensive and glaucomatous Beagles treated with topical timolol at concentrations ranging from 0.5% to 8% (Gelatt et  al., 1995; Gum et  al., 1991b; Plummer et  al., 2006) and with topical levobunolol (Scardillo et al., 2010). A contralateral effect on IOP and pupillary diameter was also identified in the nontreated eyes when timolol was topically given to dogs and cats (Wilkie & Latimer, 1991a, 1991b). These effects likely result from systemic uptake via transconjunctival route and nasolacrimal duct pathway. Systemic activity of topically applied timolol has been shown in an experimental dog model (Svec & Strosberg, 1986). To prevent occurrence of deleterious cardiovascular effects secondary to systemic absorption, suggestion of using 0.25% timolol in cats as well as dogs weighing less than 10 kg, and 0.5% timolol in dogs with body weight above 10 kg, is given in the literature (Willis, 2004). Use of timolol in cats with asthma is probably contraindicated. The reduction of IOP by 0.25% nipradilol is similar to that of 0.5% timolol maleate, but nipradilol was associated with fewer systemic side effects in dogs, so it may be a useful alternative (Maehar et al., 2004).

Carbonic Anhydrase Inhibitors CAIs that belong to the class of nonbacteriostatic sulfonamide‐related compounds were used in ophthalmology as early as 1954 with the introduction of acetazolamide. Methazolamide and dichlorphenamide were released subsequently. These agents have been widely used ever since, but because their clinical usefulness is limited by various systemic side effects, topical CAIs have virtually replaced them for the treatment of glaucoma.

Mechanism of Action The ciliary body process epithelium contains enzyme systems, such as Na+‐K+‐ATPase and carbonic anhydrase, which are involved in aqueous humor formation. Carbonic anhydrase (CA) is a ubiquitous enzyme for which seven isoenzymes have been identified. CA I, CA II and CA III are located in the cytosol, CA IV is membrane bound, CA V is present in mitochondria, and CA VI and CA VII are only

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found in salivary glands (Jampel et al., 1997). Only CA II, CA III, and CA IV are present in significant amounts in pigmented and nonpigmented ciliary body epithelial cells to catalyze the reversible hydration of carbon dioxide (Jampel et al., 1997). Aqueous humor formation depends on the production of bicarbonate (HCO3−) from CA II, the isoenzyme found in the nonpigmented ciliary body epithelium. Chemically, the enzymatic effect of CA is to catalyze carbon dioxide (CO2) hydration to carbonic acid (H2CO3) which dissociates spontaneously into protons and bicarbonate ions according to the equation: H2O + CO2 ↔ HCO3− + H+. Newly formed bicarbonate ions are neutralized by sodium and other cations and transferred to the intercellular channels and the posterior chamber (Fig.  8.5.1). Water is then osmotically attracted from the vessels of the ciliary stroma to form aqueous humor (Derick, 1994). The common feature of CAIs is a sulfonamide group (‐ So2NH2) attached to an aromatic ring. Competition of the sulfonamide group with carbonic acid for its site on carbonic anhydrase, to make it inactive, is the basis of the pharmacological action of these drugs (Higginbotham, 1989). It is known that 98% inhibition of CA II must be achieved in ciliary body epithelium by systemic or topical inhibitors for full IOP reduction (Brechue & Maren, 1993). In parallel to the decreased appearance of bicarbonate into the posterior chamber, the rate of sodium transport is decreased by an equimolar amount, and entry of water into the posterior chamber is reduced. Accordingly, aqueous humor formation is suppressed by 40%–60% (Friedland & Maren, 1984). In the dog, carbonic anhydrase inhibition by acetazolamide lowers

Pigmented Cell

Unpigmented Cell Carbonic anhydrase

H+

H+ +

Na+ K+

HCO3– ↔ H2O + CO2

Na+ Cl–

aqueous flow from 9 μL/min prior to treatment to 6.4 μL/min after treatment (Friedland & Maren, 1984). In general, sulphonamide CAIs inhibit the enzyme with high specificity, meaning that they have no inhibitory activity against other enzymes, and in a noncompetitive and reversible manner. Although systemic CAIs are diuretics, it is currently believed that their ocular hypotensive effect does not depend on diuresis. There is, however, some indication that the systemic acidosis induced by these agents also inhibits aqueous humor formation and enhances their pressure‐lowering effect (Friedland & Maren, 1984). In addition to their IOP‐ lowering effect, CAIs have also been shown to affect the ocular circulation. Carbon dioxide is a potent vasodilator involved in autoregulation of blood flow in the eye and elsewhere in the body. Blockade of CA in local tissues results in increased levels of CO2 and/or lower tissue pH that can act on blood vessels and produce vascular dilation and increased blood flow (Rassam et al., 1993; Taki et al., 1999). However, the recent observation that the vasodilation induced by these drugs on retinal arterioles is increased by the perivascular retinal tissue, by acidosis, but not by hypercapnia, suggest that mechanisms other than carbonic anhydrase inhibition might also be involved in the vasodilating effect of CAIs, although a contributing action of the enzyme cannot be excluded (Torring et  al., 2009). According to the authors, alternative mechanisms of action could include an effect through voltage‐gated K+ channels or an effect mediated by nitric oxide (NO) (Torring et al., 2009). An increase in ocular blood flow in the retinal circulation has been shown in human eyes after application of topical CAIs, and is expected to be beneficial to patients with glaucoma (Siesky et  al., 2009). In rabbits, topical dorzolamide vasodilates the ciliary body circulation, increasing ciliary blood flow by 18%, but does not alter the choroidal hemodynamics (Reitsamer et al., 2009). This mechanism is in contrast with those of drugs that decrease aqueous formation indirectly by constricting the ciliary body circulation (i.e., epinephrine, β‐blockers) (Reitsamer et al., 2009).

Systemic Carbonic Anhydrase Inhibitors Ultrafiltrate

Cl–

Na+ HCO3–

Osmotic water flux

Figure 8.5.1  Contribution of carbonic anhydrase to aqueous humor formation in the pigmented and non‐pigmented ciliary body epithelium.

Acetazolamide, the first drug in this group to be synthesized, can be administered either orally or intravenously. It is supplied in tablets of 125 and 500 mg as well as in time‐release capsules of 500 mg. A single oral administration of a dose ranging from 10 to 75 mg/kg significantly lowers IOP in normotensive and glaucomatous Beagles for at least 8 hours (Gelatt et  al., 1979). A dosage of 4–8 mg/kg two to three times daily is usually recommended for treatment of canine glaucoma (Gaarder, 2000). In the cat, doses ranging from 10 to 25 mg/kg are effective in lowering the IOP in glaucomatous animals. The hypotensive effect lasts about 5 hours in this species (Othman & Samy, 1987). Acetazolamide is also available for intravenous injection as a lyophilized

­powder (500 mg/vial). Intravenous acetazolamide at a dose of 5–10 mg/kg is useful as adjunctive therapy in the management of acute glaucoma. Topical antiglaucoma drugs should be employed concurrently and diligently continued thereafter for continued effect. Dichlorphenamide is no longer in routine use for the treatment of glaucoma, but it has been recently returned to the market for the treatment of other systemic condition, so although available, it is expensive. The oral dose rate in the dog ranges from 2 to 4 mg/kg, two to three times daily (Gaarder, 2000). In glaucomatous Beagles, the maximal effect occurs at a dose of 10 mg/kg, 3 hours after administration (Gelatt et  al., 1979). Single oral administration of dichlorphenamide in the cat in doses ranging from 0.5 to 2 mg/kg significantly reduced IOP for 4 hours (Othman & Samy, 1987). Methazolamide is supplied in 50 mg tablets. After oral administration of 25 mg or 50 mg methazolamide to healthy Beagle dogs, a significant dose‐dependent decrease in IOP of 18%–21% was observed 3–6 hours after administration. Nevertheless, IOP increased to levels above the control baseline values thereafter (Skorobohach et al., 2003). The lowering effect on IOP occurred because of a mean reduction in aqueous humor formation of 28% (Skorobohach et al., 2003). The rebound effect was ascribed to a possible upregulation of CA after treatment ceased, and it should be kept in mind in a clinical setting when administration of methazolamide is discontinued (Skorobohach et al., 2003). In a study of the systemic CAIs in normal and glaucomatous dogs, results suggested that methazolamide decreases IOP at dosage levels lower than acetazolamide, dichlorphenamide, and ethoxzolamide (Gelatt et al., 1979). In glaucomatous dogs, the IOP decreasing effect of oral metazolamide (5 mg/kg twice daily) was comparable to that achieved with topical dorzolamide instilled twice or three times daily (Gelatt & MacKay 2001b). When coadministered, the drugs did not produce an additional reduction in IOP (Gelatt & MacKay, 2001b).

Topical Carbonic Anhydrase Inhibitors Systemic complications associated with chronic use of oral CAIs in human patients inspired the development of topical formulations of CAIs with the goal of fewer systemic adverse effects. Dorzolamide was the first of these drugs to be marketed in 1995, followed by brinzolamide a few years later. The history of the design and development of the topical CAIs has been extensively reviewed (De Santis, 2000; Higginbotham, 1989). In 1991 MK‐927, another Merck topical CAI, lowered IOP in glaucomatous Beagles; its maximum effect occurred after 5 days of dosing, suggesting a possible drug loading effect (King et al., 1991). Dorzolamide and brinzolamide are most potent against CA II, with less activity against CA IV (De Santis, 2000; Maren, 1997). Experimental data in rabbits indicate that

topical dorzolamide and brinzolamide readily penetrate the eye by both the corneal and scleral routes (Maren, 1997; De Santis, 2000). After topical application onto canine eyes, dorzolamide concentrations achieved in the ciliary body are much higher than those reached in the aqueous humor, suggesting that in the dog, the cornea/scleral route has also a role in the intraocular penetration of the drug (Cawrse et al., 2001). In healthy dogs, administration of a single dose of 2% dorzolamide was associated with a mean reduction in IOP of 3.1 mmHg (18%) from 30 minutes to 6 hours after treatment (Cawrse et al., 2001). Mean aqueous flow rate decreased 43% in treated eyes (Cawrse et al., 2001). In a short‐term study in normotensive dogs, a maximum decrease in IOP of about 6 mmHg was reached after 5 days of treatment at 8‐hour intervals (Kennard & Whelan, 2001). In glaucomatous dogs, 2% dorzolamide decreased IOP to an even greater extent, with a mean reduction of 30% (Plummer et al., 2006). Topical dorzolamide was also found to lower IOP when applied to normotensive feline eyes every 8 or 12 hours (Rainbow & Dziezyc, 2003; Rankin et al., 2012). The amplitude of IOP decrease observed in cats after twice daily applications of dorzolamide was almost the same as that observed previously in dogs with three times daily applications (Cawrse et  al., 2001; Rainbow & Dziezyc, 2003). In cats with primary glaucoma, topical dorzolamide decreases IOP by nearly 46% when administered three times daily (Sigle et al., 2011). Topical dorzolamide seems to influence IOP in horses less than it does in small animals, because its twice daily application to normotensive equine eyes only reduced IOP by an average of 2 mmHg (Willis et al., 2001b). In the light of these findings, the authors’ suggestion was that topical dorzolamide can only be recommended as adjunctive therapy in glaucomatous horses. Anecdotally, many clinicians report a much greater response to topical 2% dorzolamide in glaucomatous equine eyes. The effect of topical administration of 1% brinzolamide on the IOP has been evaluated in small and large animals. In a preliminary study in healthy dogs, 1% brinzolamide instilled twice daily significantly reduced IOP with the peak effect observed between 5 and 6 hours postmedication. The amplitude of the IOP reduction was similar to that induced by topical dorzolamide, but lower than that resulting from oral administration of 5 mg/kg of methazolamide (Whelan et al., 1997). Mean IOP returned to baseline value about 10–11 hours after treatment, indicating that administration every 8 hours would be more appropriate than every 12 hours for optimal pharmacologic effect (Whelan et  al., 1997). Contrary to dorzolamide, brinzolamide topically applied every 12 hours was unable to significantly influence IOP of normotensive feline eyes (Gray et al., 2003), but did significantly reduce IOP when administered every 8 hours, albeit to a lesser extent that dorzolamide (McLellan et al., 2009). In horses, topical application of 1% brinzolamide was well

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t­ olerated, and the mean IOP reduction achieved with once‐ and twice‐daily administration was 3.1 mmHg and 5.0 mmHg, respectively (Germann et al., 2008), which represents a higher IOP‐lowering effect than that previously reported with dorzolamide in equine patients (Willis et al., 2001b). This finding seems to indicate that monotherapy or adjunctive therapy with 1% brinzolamide may represent a valuable option for the treatment of equine glaucoma (Germann et al., 2008).

Clinical Use Because they diminish aqueous humor formation, CAIs can be employed in the treatment of practically all types of glaucoma. Short‐term administration of systemic or topical CAIs may be effective in the management of acute increases in IOP resulting from primary or secondary glaucoma. On the basis of findings in normal and glaucomatous dogs, combined administration of topical and systemic CAI has no additional IOP‐decreasing effects over dorzolamide or brinzolamide alone that would warrant its use in dogs with acute glaucoma (Gelatt et al., 2001a; Whelan et al., 1997). Topical CAIs also represent a valuable substitute for oral methazolamide in the long‐term treatment of chronic glaucoma in dogs because their effects on IOP are comparable and systemic side effects are less likely (Gelatt & MacKay 2001b; Whelan et al., 1997). Theoretically, CAIs can be used in combination with other antiglaucoma agents because their effect is usually additive, reducing IOP more than any single agent. In the dog, the combined use of dorzolamide and latanoprost may be appropriate for the management of chronic glaucoma because dorzolamide given every 8 hours and latanoprost instilled once in the morning were shown to have an additive effect on decreasing IOP (Kennard & Whelan, 2001). The additivity of topical CAIs to topical β‐blockers regarding the decrease in aqueous humor outflow has also been documented in normotensive human eyes. In healthy eyes, 18% and 47% reduction in aqueous flow is observed after topical treatment with dorzolamide alone or in combination with timolol, respectively. Topical administration of an unfixed combination of both drugs leads to an incremental 55% decrease in flow (Wayman et al., 1997). A fixed combination of dorzolamide 2% and timolol 0.5% is currently available. Its administration twice daily in glaucomatous human patients has an IOP‐lowering effect similar to that obtained with dorzolamide alone instilled three times daily (Hutzelmann et  al., 1998). In glaucomatous beagles, the combination product has been compared with monotherapy with either timolol 0.5% or dorzolamide 2% three times daily. After 4 days of treatment, the mean reduction in IOP was 7.50 mmHg, 3.75 mmHg, and 8.40 mmHg for the dorzolamide, timolol, and combination product, respectively (Plummer et al., 2006). Thus, the fixed combination of dorzolamide–timolol seems more effective at decreasing the

IOP in dogs with glaucoma than is either dorzolamide or timolol alone (Plummer et al., 2006). By contrast, data indicate that in horses this combination may not have additional IOP‐lowering effects over dorzolamide alone (Willis et  al., 2001b). However, a recent study showed that the application of a fixed combination of dorzolamide 2% and timolol 0.5% every 12 hours onto normotensive equine eyes led to a mean IOP reduction of 13% (approximately 3.5 mmHg), which is 1.5–1.75 times greater than the reported reduction of IOP in response to dorzolamide alone (Tofflemire et  al., 2015b; Willis et al., 2001b). No significant additive ocular hypotensive effect was observed in normal cats treated with a combination of the CAI, dorzolamide 2%, and timolol 0.5%, relative to the effect of treatment with dorzolamide 2% alone (Dietrich et al., 2007).

Adverse Effects No ocular side effects have been described in relation to the systemic administration of CAIs, but acute overdosage or long‐term therapy may result in a variety of clinical and biochemical disorders. The side effects of the various agents of this class are similar, with dichlorphenamide appearing to cause the fewest and being considered the drug of choice for prolonged treatment in small animals (Gaarder, 2000). Common transient side effects associated with oral or parenteral CAIs include increased diuresis, gastrointestinal disturbances (anorexia, vomiting, diarrhea), and increased respiratory rate secondary to metabolic acidosis. Cats appear to be more susceptible to these drugs and should be observed very closely. The dose should be decreased or therapy discontinued if signs of toxicity are observed. Except for acetazolamide, little is known about either the short‐ or long‐term effects of the other CAIs on blood chemistry in the dog. In this species, the intravenous and oral administrations of acetazolamide were found to cause significant metabolic acidosis that achieved a steady state after 1–5 days of treatment (Haskins et al., 1981; Rose & Carter, 1979). This effect, attributed to increased bicarbonaturia, was associated with an increase in PO2, and a decrease in PCO2, indicative of compensatory hyperventilation. All dogs given acetazolamide had an increase in plasma chloride. A decrease in plasma potassium also develops, reaching its maximum between the second and fifth day of treatment, presumably as a result of increased kaliuresis. Normal food intake usually obviates any serious potassium depletion, but care must be taken in patients with anorexia or preexisting hypokalemia (Haskins et  al., 1981; Rose & Carter, 1979). When acetazolamide administration is discontinued, complete recovery of acid‐base and blood electrolyte disorders occurs within 36 hours, because of the short half‐life of the drug (Haskins et al., 1981). The ophthalmic formulation of 2% dorzolamide has a pH of 5.6, and its instillation may be associated with symptoms

of ocular discomfort (i.e., burning, stinging) on instillation in people (Strahlman et al., 1996). By comparison, 1% brinzolamide is formulated as an ocular suspension with a pH of 7.5 which compares favorably to the pH of the tear fluid and is better tolerated by human patients (Silver & the Brinzolamide Comfort Study Group 2000). In short‐term studies of topical CAIs in the dog, cat, and horse, no local or systemic side effects were reported (Cawrse et  al., 2001; Rainbow & Dziezyc, 2003; Willis et  al., 2001b). However, since those controlled studies were performed several reports of adverse reactions have been made. Topical administration of 2% dorzolamide in dogs in the clinical setting has occasionally been associated with blepharitis which resolves after discontinuation of the drug (Willis et al., 2002). There is a report of keratitis in six dogs that was unresponsive to topical anti‐inflammatory therapy but resolved after discontinuation of topical dorzolamide (Beckwith‐Cohen et  al., 2015). Hypokalemia and suspected renal tubular acidosis associated with topical dorzolamide therapy has been reported in a cat (Thiessen et al., 2016). Despite these sporadic adverse events, the topical CAIs have the advantage over parasympathomimetics and prostaglandin analogs of not causing miosis, and they have the advantage over β‐blockers to be less problematic for animals with cardiac or pulmonary disease.

as tafluprost, continue to be developed and explored (Kwak et al., 2017). Because the naturally occurring PGs are hydrophilic molecules, their carboxylic acid moiety and several hydroxyl groups mean that they penetrate the membranes poorly. Therefore, all commercially available PG analogues used for their IOP‐lowering activity are esterified prodrugs of the PGF2α, more lipophilic, and designed to facilitate penetration through the ocular membranes (Bean & Camras, 2008). Latanoprost is the right‐handed epimer of a phenyl‐ substituted analogue of PGF2α, whereas unoprostone is an isopropyl ester of the 20‐ethyl derivative of PGF2α. Travoprost and bimatoprost are structurally similar to other PGF2α analogues (Fig.  8.5.2) (Eisenberg et  al., 2002). After topical application, the prodrug is enzymatically hydrolyzed during its passage through the corneal epithelium to release the active molecule (the carboxylic acid) which is then delivered to the anterior segment of the eye (Bito 1986; Bito & Baroody, 1987). The major intraocular metabolite that is expected to act on target tissues is 17‐phenyl‐PGF2α for latanoprost, bimatoprost, and travoprost (Bito &Baroody, 1987; Davies et  al., 2003), and a free acid of isopropyl unoprostone for unoprostone (Numaga et al., 2005). It has been established that human and canine ocular tissues have a similar profile of PGF2α prodrug hydrolysis (Woodward et al., 1996).

Mechanism of Action

Prostaglandin Analogues History and Chemistry The prostaglandins (PGs) are a family of biologically active lipids with a wide spectrum of possible pharmacologic activity. Since early studies showed that low doses of PGF2α can decrease IOP, it has been established that most of the naturally occurring PGs, as well as some of their analogues and esters, are potent ocular hypotensive agents in both animals and humans (Alm, 1998; Bito, 1984). The ocular hypotensive effects in healthy dogs and glaucomatous Beagles was first reported in 1991 using topical prostaglandins PGA2, PGA2 isopropyl ester, and PGF2α isopropyl ester. The reduction in both IOP and pupil size were remarkable (Gum et al., 1991a) The PG derivatives currently approved for the reduction of IOP in human and animal glaucoma patients were all developed through chemical modification of PGF2α. Latanoprost and isopropyl unoprostone first emerged as a result of active screening programs. Unosprostone was available in Japan in 1994 and was marketed in 2000 in the United States. It is presently seldom used because it has limited efficacy compared with the other PG analogues (Bean & Camras, 2008; Gelatt et al., 2004). Latanoprost was marketed in 1996, and then two other PG analogues, travoprost and bimatoprost, were approved for use in 2001 (Bean & Camras, 2008; Bito, 1984, 1986). Other agents in this important drug class, such

A common feature of the biologically active forms of latanoprost, bimatoprost, travoprost, and unoprostone is the high affinity and selectivity for the prostaglandin F (FP) receptor, and investigation revealed that the IOP‐lowering action of these PG derivatives is mediated through the binding of their free acid (the active molecule) to FP receptors in humans (Anthony et al., 1996), monkeys (Lee et al., 1984b), and presumably in dogs (Gum et  al., 1991a). Despite their differences in potency at the FP receptor, the free acids of latanoprost, travoprost, and bimatoprost fully activate the receptor relative to the naturally occurring PGF2α (Bean & Camras, 2008). The pivotal role of FP receptors in the ocular hypotensive effects of the PGF2α analogs has also been shown with the use of FP‐receptor deficient (FPKO) mice (Ota et  al., 2005). The IOP‐lowering action of PGs in the feline species reportedly works through EP1 receptors and not FP receptors (Bhattacherjee et al., 1999; Lee et al., 1984b). In the dog, prostaglandin E (EP) receptors mediating PGE2 action also can alter aqueous humor dynamics as shown with a potent and selective EP4‐PGE2 agonist which was able to lower IOP by 5–7 mmHg in healthy Beagles when given topically (Aguirre et  al., 2009). The mechanism by which this EP4‐receptor agonist lowers IOP is currently unknown but may involve trabecular outflow and not uveoscleral outflow (Aguirre et al., 2009). In humans and animal species studied so far, it has been well established that increase in uveoscleral outflow is the

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O O

Unoprostone isopropyl ester

Figure 8.5.2  Chemical structures of the four commercially available prostaglandins in veterinary ophthalmology.

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primary mechanism by which PGs reduce IOP (Hurwitz et al., 1991). Increased uveoscleral outflow has been reported in human and nonhuman primates, rabbits, and dogs treated with PGF2α or its analogues (Gabelt & Kaufman, 1990; Gum et al., 1991a; Payer et al., 1992; Toris et al., 1993), and in cats treated with PGA2 (Toris et al., 1995c). However, data in the current literature indicate that latanoprost, bimatoprost, and unoprostone also affect the pressure‐dependent conventional outflow pathway (Richter et al., 2003; Taniguchi et al., 1998). The mechanisms by which activation of FP receptors lead to an increased uveoscleral outflow are still under investigation, but there is scientific evidence that matrix metalloproteinase (MMP)‐mediated remodeling of the extracellular matrix (ECM) of the ciliary body muscle contribute to this pharmacological effect. This concept is based on in vitro and in vivo observations that after several days of treatment with PGF2α, the MMP‐1, ‐2, and ‐3 are increased within uveoscleral outflow tissues (Gaton et al., 2001; Weinreb et al., 1997), whereas collagen types I, III, and IV are decreased (Sagara et al., 1999). In human ciliary body tissue, the transcription of the genes for MMP‐3 and MMP‐17 is increased after topical treatment with latanoprost (Oh et  al., 2006). MMP‐9 is also present and may contribute to the ECM changes, whereas tissue inhibitor of metalloproteinase 3 (TIMP‐3) is upregulated and may compensate for the increase in MMPs (Oh et  al., 2006). The amount of myocilin, an intra‐ and

extracellular protein of the ciliary body muscle, which may contribute to outflow resistance, also is reduced after topical PGF2α treatment (Lindsey et al., 2001, 2002). Ultrastructurally, remodeling of ECM components within uveoscleral outflow pathway was characterized as lysis of ECM between ciliary body muscle bundles and widening of the intermuscular spaces in monkey eyes treated with PGF2α (Lütjen‐Drecoll & Tam, 1988), latanoprost, or bimatoprost (Richter et al., 2003). In addition to the changes induced within the uveoscleral outflow pathway, various experimental data argue for an effect of PG analogs on alteration of aqueous outflow through the trabecular meshwork. Among these are the identification of FP receptors in human trabecular meshwork and increased expression of different MMPs and TIMPs by trabecular meshwork cell culture treated with latanoprost (Toris et al., 2008). Long‐term treatment with latanoprost or bimatoprost also led to morphologic changes in the trabecular meshwork perhaps in agreement with increased conventional outflow facility (Richter et al., 2003). Increase in both uveoscleral and trabecular outflow has been observed in monkeys given topical tafluprost, a fluoroprostaglandin F2α (Takagi et al., 2004). This drug has also shown to lower IOP in dogs (Kwak et al., 2017). If stimulated induction of MMPs within the ciliary body muscles is the most thoroughly understood effect of PG treatment, it also appears certain that endogenous PGs are released in iris and ciliary body

muscles secondarily to topical administration of PGF2α analogues and may contribute to the observed hypotensive effects (Yousufzai et  al., 1996). Endogenous PGE2, PGD2, and PGF2α are produced via phospholipase A2 stimulation and release of arachidonic acid for PG synthesis (Toris et al., 2008; Yousufzai et al., 1996). Inhibition of the latanoprost‐ induced reduction of IOP in human eyes by ophthalmic NSAID bromfenac (Chibac et al., 2006), and in dogs by topical prednisolone and flurbiprofen (Pirie et al., 2006, 2011), suggest that the IOP‐lowering response to topical latanoprost is mediated in part through formation of endogenous PGs both in humans and dogs. In what manner the endogenous released PGs act to alter aqueous outflow is unclear. Widening of the connective tissue‐filled spaces among the ciliary muscle bundles, caused by relaxation of the ciliary muscle, and with subsequent reduction in outflow resistance via the uveoscleral pathway, has been suggested as responsible for the reduction in IOP induced by PGE2 (Poyer et al., 1995). Investigations showed that scleral permeability is enhanced with exposure to PGs or PG analogues, such as latanoprost (Aihara et al., 2001; Kim et al., 2001), and that these changes are associated with increased intrascleral MMP‐1, MMP‐2, and MMP‐14 expression (Lindsey et  al., 2007). Prostaglandin‐induced changes in the sclera may also be important in the regulation of the uveoscleral outflow (Toris et al., 2008), and suggest that the prospect of increasing transscleral permeability by PG cotreatment might allow sufficient transscleral transport to provide delivery of high molecular weight substances to the posterior segment of the eye (Aihara et al., 2001; Kim et al., 2001). Experiments in human and nonhuman primates and rabbits indicate that in addition to its IOP‐reducing effect, latanoprost increases blood velocity in the optic nerve head (ONH) or dilates the vessels supplying the ONH because of its pharmacologic effect on the vessels (Ishii et  al., 2001). Increased ONH perfusion may be important for preservation of visual function in glaucomatous eyes (Fig. 8.5.3).

Clinical Pharmacology Experimental studies have shown that topical application of 0.005% latanoprost significantly reduces IOP in normotensive and glaucomatous canine eyes (Studer et al., 2000). In normotensive canine eyes, 0.005% latanoprost instilled in the evening, morning, as well as twice daily induced an average decline in IOP of about 25%, whereas in glaucomatous eyes, it produced a mean decline in IOP of about 50% (Gelatt & MacKay, 2001a; Studer et al., 2000). In glaucomatous dogs, a comparable IOP‐lowering action was observed with once or twice daily application of 0.03% bimatoprost (Gelatt & MacKay, 2002b), and 0.004% travoprost (Gelatt & MacKay, 2004; MacKay et  al., 2012). In normal dogs, the amplitude and duration of the IOP‐lowering effect of a ­single application of 0.12% unoprostone isopropyl or

c­ ontinued once or twice daily administration were found to be similar with those observed after similar doses of 0.005% latanoprost (Gelatt & MacKay, 2001a; Gelatt & MacKay, 2004; Ofri et al., 2000). Both drug concentration and dosing schedule can alter PG ocular effects. Using single doses of topical travoprost in glaucomatous Beagles, concentrations of 0.0001% produced only pupillary constrictions but no effect on IOP. Higher concentrations (0.0033% [similar to the 0.004% commercial preparation]; 0.001% and 0.00033%) of travoprost produced both significant IOP reductions and pupillary effects. These studies suggest the canine species is highly sensitive to topical PGs (MacKay et al., 2012). Species differences in prostanoid receptor distribution within different ocular tissues have major implications for the effects and efficacy of topical prostaglandin analog therapy for glaucoma. In contrast to dogs, neither once daily application of 0.005% latanoprost (Studer et  al., 2000) or 0.03% bimatoprost (Bartoe et al., 2005), nor twice daily applications of 0.03% bimatoprost (Regnier et al., 2006) or 0.12% unoprostone (Bartoe et al., 2005), which are all FP receptor agonists, significantly lowered the IOP of normal cats. These observations are in agreement with the fact that FP receptor signaling does not play a crucial role in the IOP response to PGs or PG analogues in cats (Bhattacherjee et al., 1999; Lee et al., 1984b). Topical application of PGs in cats does, however, produce intense miosis (Regnier et  al., 2006; Studer et al., 2000). This is attributable to the presence of exquisitely well‐coupled FP receptors in the iris sphincter muscle of cats, compared with humans (Bhattacherjee & Paterson, 1994, Sharif et al., 2008). Although FP receptors are largely responsible for the effects of prostaglandin analogs on the canine and human ciliary body, these receptors are lacking in the ciliary body of cats and EP receptors are predominantly responsible for relaxation of feline ciliary muscle (Bhattacherjee et al., 1999). Unfortunately, with the refinement of prostaglandin analogs to maximize their specificity for FP receptors on the human ciliary body, in order to minimize adverse effects such as ocular inflammation, commercially available prostaglandin analogs are less likely to have any ocular hypotensive effect in cats. A recent study (McDonald et  al., 2016) indicates that latanoprost 0.005% transiently lowers IOP in glaucomatous cats after a single topical application, but this effect is diminished after 3 weeks of twice daily administration of the drug. The potential of 0.005% latanoprost for lowering IOP has also been evaluated in normotensive equine eyes (Willis et al., 2001a). In clinically normal horses, a once daily application of 0.005% latanoprost resulted in a mean decrease in IOP of 1.03 mmHg or about 5% in males, and 3.01 mmHg or about 17% in females (Willis et al., 2001a). The reason for the gender effect in the response of the equine eye to topical 0.005% latanoprost has not been determined (Willis et  al., 2001a). A more recent study showed a mean IOP reduction

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Figure 8.5.3  Effect on IOP of 0.005% latanoprost in the Beagle with primary open‐angle glaucoma after evening (A) and q 12h dosing (B).

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of 13.7% and 8% in normotensive equine eyes that were treated once daily with latanoprost or latanoprost and diclofenac, respectively. When latanoprost was given alone, the reduction in IOP was greater than when a combined treatment of latanoprost and diclofenac was given, although the difference was not statistically significant. However, latanoprost‐induced discomfort was mitigated by concurrent application of diclofenac (Tofflemire et al., 2017).

Clinical Use In a short time, PG derivatives have reached extensive clinical use in human patients with ocular hypertension and primary open‐angle glaucoma (POAG) (Soltau, 2002). Several

studies documented the IOP‐lowering effect of PG derivatives in humans, but latanoprost has mostly been evaluated as either monotherapy or an adjunctive agent added to another antiglaucoma agent (Alm, 1998). In human patients with either ocular hypertension or POAG, latanoprost, bimatoprost, and travoprost administered once daily in the evening induce a higher reduction in IOP than 0.5% timolol applied twice daily (Alm & Stjernschantz, 1995; Mishima et  al., 1996; Sherwood & Brandt, 2001). Latanoprost twice daily is less effective than once daily in human glaucoma patients (Lindén & Alm, 1998). This reduction of efficacy possibly may result either from desensitization or downregulation of the FP receptor with twice daily administrations (Lindén & Alm, 1998). In glaucomatous patients who are no

longer regulated on one antiglaucoma drug alone, a combination of two drugs is common. In addition to their use as monotherapy, PGF2α‐related drugs became first‐line prescriptions as combination therapies in human patients because about half of the patients require more than one antiglaucoma agent for IOP reduction (Bean & Camras, 2008). Beta‐blockers, topical CAIs, and alpha‐adrenergic agonists are the most common antiglaucoma agents used in combination with PGs analogues in glaucomatous humans (Tabet et al., 2008). Three fixed combinations of timolol 0.5% with either latanoprost 0.005%, travoprost 0.004%, or bimatoprost 0.03% have been evaluated in human patients with primary glaucoma, and almost all published data indicate that each fixed combination has a greater IOP‐lowering effect than monotherapy with either timolol or the PG analogue (Tabet et  al., 2008). Used in unfixed combinations, latanoprost proved efficacious when added either to timolol or pilocarpine (Stewart et  al., 2000; Toris et  al., 2001). When added to β‐blockers, latanoprost compared favorably in IOP‐ lowering efficacy and was similar in safety to brimonidine and dorzolamide (Stewart et  al., 2000). In the dog, the PG derivatives are mostly indicated for the treatment of primary glaucoma and have effectively replaced mannitol and/or acetazolamide as first‐line drugs in the emergency management of acute PCAG (Willis, 2004). Investigations using high resolution imaging of the anterior segment of dogs with primary glaucoma suggested that latanoprost may rapidly lower IOP in PCAG by inducing miosis which breaks the pupillary block, and by opening the collapsed ciliary cleft in POAG (Miller et al., 2003; Tsai et al., 2012). Topically applied to normotensive canine eyes, the latanoprost 0.005%–timolol 0.5% fixed combination caused the IOP to decrease by 1–2 mmHg more than the decrease for latanoprost alone, whereas no ocular hypotensive effect was observed with 0.5% timolol alone (Smith et  al., 2010). Although latanoprost, bimatoprost, and travoprost are instilled once daily in human patients, experimental data in glaucomatous dogs suggest that twice daily instillation of these drugs should be recommended in the dog to result in less daily IOP fluctuations (Gelatt & MacKay, 2001a, 2002b, 2004). Dosing three times a day with latanoprost in the dog may decrease IOP even further. However, this should be done with caution because this drug and the miosis it causes have the potential to narrow the iridocorneal angle and increase episcleral venous pressure significantly, which may impair conventional outflow (Tofflemire et  al., 2015a; Tsai et al., 2013). Latanoprost instilled immediately after phacoemulsification in dogs was found to have no significant effect on the number of POH peaks compared with control untreated dogs (Crasta et al., 2010) in one study. However, in another study, there was a trend towards a decrease in POH with postoperative latanoprost use (Dees et  al., 2017). Primary or secondary intraocular inflammation is often associated with glaucoma in dogs, and therefore ophthalmic

anti‐inflammatory drugs sometimes are administered concurrently to antiglaucoma agents. As mentioned in a previous section, topical prednisolone and flurbiprofen were shown to significantly inhibit the IOP‐lowering effect of latanoprost in normotensive dog eyes (Pirie et  al., 2006, 2011). However, another small study refutes this and showed that prednisolone acetate does not mitigate the IOP‐lowering effect of latanoprost (Kahane et al., 2016a). This potential interaction should be taken into account when prescribing ophthalmic anti‐inflammatory drugs to glaucomatous dogs treated with PGF2α‐related agents.

Adverse Effects Side effects most commonly encountered in glaucomatous human eyes treated with PG2α analogues include conjunctival hyperemia, iris darkening, and eyelash changes (Alm et al., 2008). The secondary effects of elongation and thickening of the human eyelashes after latanoprost therapy has resulted in a new commercial use for this drug in man. Current evidence indicates that these represent only cosmetic concerns with no apparent consequences (Alm et al., 2008). Other potential and relatively rare complications of this therapy include cystoid macular edema, anterior uveitis, iris cysts, herpes simplex reactivation, periocular skin darkening, and headaches (Alm et al., 2008; Schumer et al., 2002). Several PG derivatives used for the treatment of glaucoma cause increased pigmentation of the iris in man, but most of the data have been obtained with latanoprost (Stjernschantz et al., 2002). Increased iris pigmentation was observed in about 5% of the patients during 2 years of treatment with latanoprost, and it appeared that individuals with hazel or heterochromic eye color were at risk of developing this side effect (Stjernschantz et al., 2002). As PGF2α analogues are selective agonists of FP receptors, it is likely that FP receptor activation is involved in this phenomenon. Results of different studies suggested that latanoprost can stimulate tyrosinase gene transcription in the iris (Lindsey et  al., 2001), and that latanoprost‐induced melanogenesis most likely results from stimulation of iridal melanogenesis rather than melanocyte proliferation (Alm & Stjernschantz, 1995; Stjernschantz et  al., 2002). Endogenous PGE2 produced by iridal melanocytes exposed to latanoprost might also contribute to the increased melanogenesis (Bergh et al., 2002). Iris darkening in human subjects has raised concerns about the possibility of development of precancerous lesions or pigmentary glaucoma in some individuals, but presently no evidence of harmful consequences of this phenomenon has been reported (Grierson et  al., 2002; Stjernschantz et  al., 2002). In addition, a recent study showed that there are no histopathological features suggesting premalignant changes in human latanoprost‐treated darkened irides (Albert et al., 2008). Darkening of the latanoprost‐treated irides is associated with a thickening of the

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anterior border layer, and an increased amount of melanin in this layer and within the stromal keratocytes (Albert et  al., 2008). As reported in humans, conjunctival hyperemia has been observed in dogs treated with latanoprost (Studer et al., 2000), which also induced epiphora, blepharospasm, blepharedema, conjunctival hyperemia, and transient corneal edema in some horses, when instilled in equine eyes (Willis et  al. 2001a; Tofflemire et  al., 2017). These clinical signs where alleviated when diclofenac was concurrently applied (Tofflemire et  al., 2017). The mechanism behind the vasodilation of the conjunctival vessels predominantly seems to involve NO release (Alm et  al., 2008). Decreased stromal collagen density has been identified by histopathologic evaluation in latanoprost‐treated conjunctival specimens (Terai et  al., 2008). This reduction in the ECM of the conjunctival stroma might result from marked upregulation of MMP‐2, MMP‐3, and MMP‐9 along with a decrease in TIMP‐1 in this tissue after treatment with latanoprost (Honda et  al., 2010; Terai et  al., 2008). This MMP enhancement observed in the conjunctival matrix and at the ocular surface was said potentially to have a favorable effect on the outcome of glaucoma‐filtering surgery by decreasing the risk of local fibrosis (Terai et  al., 2008), but on the contrary, it also may contribute to lysis of the corneal stroma (Honda et al., 2010). For the latter reason, use of topical latanoprost is not recommended in human patients with keratoconus or after laser‐assisted in situ keratomileusis (Honda et  al., 2010), and by extension should be used with great care in glaucomatous dogs with corneal defects. A moderate to marked miosis is usually present in dogs treated with the PGF2α derivatives (Gelatt & Mackay, 2001a, 2002b, 2004; Studer et al., 2000). The pupillary constriction is more limited when the drug is instilled only in the evening (Gelatt & MacKay, 2001a, 2002b, 2004). The occurrence of miosis reflects the sensitivity of the canine iridal sphincter muscle to the PGF2α which appears to act directly rather than through the release of adrenergic neurotransmitters (Yoshitomi & Ito, 1988). Reports have also described miosis in cats and horses receiving latanoprost (Studer et al., 2000; Tofflemire et al., 2017; Willis et al., 2001a), as well as in cats treated with bimatoprost (Regnier et  al., 2006). The miotic effect of PG derivatives in companion animals may make their use contraindicated in cases of glaucoma secondary to subluxation or anterior luxation of the lens, because of the potential pupillary block that may result from vitreous entrapment (Willis, 2004). The miotic effect may be countered with concurrent administration of either tropicamide or atropine if the pupil must be dilated for diagnostic or surgical purposes (Kahane et  al., 2016b). A study in normal dogs revealed that parasympatholytic agents were able to dilate the pupil in the face of latanoprost. However, further study is needed in the instances of disease and chronic administration of PG (Kahane et al., 2016b).

Prostaglandins at high concentrations were first identified for their ability to induce breakdown of the BAB (Alm et al., 2008). Although PG analogues developed for glaucoma treatment are used at very low concentrations, they retain the potency to induce or enhance BAB breakdown. An experimental study with topical latanoprost showed a significant disruption in the BAB of healthy dogs, compared with topical treatment with a fixed 0.5% timolol‐2% dorzolamide combination (Johnstone‐McLean et al., 2008). For this reason, PG derivatives should be used cautiously in glaucomatous dogs with intraocular inflammation (Seki et  al., 2005), and also in aphake or pseudophake patients because they may increase the existing BAB breakdown in these subjects (Arcieri et al., 2005). Although anterior uveitis is a rare but real potential side effect in human patients treated with topical PG analogues (Alm et al., 2008), recent clinical data observed in human patients with uveitis indicate that there is no significant difference in the frequency of anterior uveitis between the patients treated with PG analogues and those treated with non‐PG agents (Chang et al., 2008). Nevertheless, because most horses with secondary glaucoma develop the condition because of preexisting chronic uveitis and PG analogues have the potential to exacerbate the inflammatory process, they should be used with caution in these animals (Willis et al., 2001a).

Calcium Channel Blockers Calcium channel blockers (CCBs) such as verapamil, diltiazem, nifedipine, and flunarizine, have been long and widely used to treat essential hypertension and certain types of cardiac diseases such as angina pectoris, and they have been shown in experimental models of cerebral ischemia to have neuroprotective effects. Their use in ophthalmology is not yet widespread but given their potential for not only neuroprotection but for IOP lowering effects, they may be a promising adjunctive therapy in the future for ocular disorders including glaucoma (Siegner et al., 2000).

Mechanism of Action CCBs alter the intracellular calcium concentration by modifying calcium flux across cell membranes and affect various intracellular signaling processes. Lipid soluble CCBs act at the central nervous system level, whereas water soluble CCBs act mainly on the cornea and optic nerve. It is also known that calcium influx is the terminal step in axonal death in the glutamate pathway (Brooks et  al., 1997). The ability to block calcium influx can, therefore, produce a neuroprotective benefit. Furthermore, CCBs can improve ocular blood flow through inhibition of endothelin‐1. Despite this, the effect of CCBs on IOP remains controversial (Araie & Mayama, 2011). Calcium influx could have

8.5: Clinical Pharmacology and Therapeutics

Clinical Use CCBs can increase or decrease IOP, depending upon the specific compound and the species. Experiments in rabbits have indicated that topical application of CCBs, especially verapamil, caused significant IOP reductions, whereas ocular hypotensive effects in humans were not substantial (Segarra et al., 1993). Flunarizine, a difluorinated piperazine derivative, is a mixed L‐ and T‐type CCB with additional antagonistic effects on sodium channels and mixed agonist‐antagonist action on opioid receptors (Holmes et al., 1984). In a number of reports, investigators indicated that topical application of the CCB flunarizine lowers the IOP in clinically normal monkeys, rabbits, and dogs (Campana et al., 2002; Greller et al., 2008; Siegner et al., 2000). A significant bilateral decrease in IOP up to 2.6 mmHg in clinically normal dogs was evident after 2 days of twice‐daily unilateral treatment with topically applied 0.5% flunarizine solution in one study (Greller et al., 2008). Throughout the study, there were no significant differences in IOP between treated and untreated eyes, which suggested a systemic effect of flunarizine on the untreated eye in addition to the local effect on the treated eye. A decrease in the IOP of the untreated contralateral eye has also been reported in rabbits, monkeys, and human patients treated topically with CCBs (Segarra et al., 1993; Siegner et al., 2000; Tamaki et  al., 2003). This systemic effect was supported by the detection of flunarizine in serum samples obtained following drug application in normal dogs (Greller et al., 2008). Dogs experienced mild irritation and conjunctival hyperemia while flunarizine was administered (Greller et  al., 2008). Some ophthalmic β‐adrenoceptor antagonists, especially betaxolol, interact with L‐type calcium channels and show CCB activity, which may be partly responsible for the neuroprotective effects of these drugs (Wood et  al., 2001). CCBs may deserve future study to evaluate their use for additive or

synergistic ocular hypotensive effects that would complement their neuroprotective potential.

Osmotic Agents Osmotic agents are a group of antiglaucoma drugs most commonly employed on an emergent basis to lower IOP quickly in cases of acute congestive glaucoma. They are generally only indicated for short‐term use and are almost always used in combination with other drugs that take over and are continued for maintenance therapy.

Mechanism of Action After oral or intravenous administration, osmotic agents (also called hyperosmotic agents) are distributed in the extracellular fluids (primarily plasma), thereby contributing to a substantial increase in their osmolality. This increase creates an osmotic gradient in which the extracellular fluids are hypertonic to intraocular fluids (i.e., aqueous and vitreous humors), from which they are separated by semipermeable membranes (i.e., blood–aqueous and blood–vitreous barriers). This osmotic gradient favors the diffusion of water from the intraocular fluids back into the plasma (Craig 1994; Dugan et al., 1989). This fluid shift has two effects on the eye. First, it inhibits the ultrafiltration process that contributes to aqueous humor formation, and second, it reduces the volume of the vitreous body. Shrinkage of the vitreous displaces the iris‐lens diaphragm posteriorly and subsequently opens the iridocorneal angle, allowing for better drainage through the conventional outflow passage (Gwin, 1980). As a final result, IOP is reduced. For the pharmacologic effects of osmotic agents to occur, they should not cross the blood–aqueous and blood– vitreous barriers. If for any reason the integrity of either barrier is compromised, as in ocular inflammation, the osmotic agent may leak in the intraocular fluids, and the extent of osmosis as well as that of ocular hypotension will be reduced (Brooks, 1990). Because of its large molecular weight, mannitol penetrates in the eye less than other osmotic agents in the presence of ocular inflammation (Singh & Krupin, 1997). Other factors important in the establishment of an adequate osmotic gradient between plasma and intraocular fluids include the dosage of the drug, its molecular weight, and its systemic bioavailability (rate of absorption for oral route and rate of elimination). Water deprivation for up to 4 hours after the use of an osmotic agent will reduce the extracellular fluid volume and will enhance the increase in blood osmolality and the resulting hypotensive ocular effect (Craig, 1994).

Products Available Mannitol, a six‐carbon sugar, is poorly absorbed from the gastrointestinal tract and must, therefore, be administered

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several effects on aqueous humor dynamics, including a hydrostatic component caused by an effect on arterial blood pressure and ciliary body perfusion, and an osmotic component caused by an effect on the active secretion of sodium, calcium, and other ions by ciliary epithelium (Araie & Mayama, 2011). Ocular effects of various CCBs have been studied in selected species, such as rats, rabbits, cats, dogs, and human and nonhuman primates (Segarra et al., 1993; Tamaki et al., 2003). In addition to their direct neuroprotective effects on retinal ganglion cells, CCBs can also increase ocular blood flow and help to prevent retinal ischemia (Saito et  al., 2005; Takahashi et  al., 1992). Several mechanisms have been discussed for the IOP‐decreasing effect of CCBs, including a decrease in production of aqueous humor by inhibition of calcium‐dependent cation transport in the nonpigmented ciliary epithelium and an increase in outflow facilitated by relaxation of trabecular meshwork cells (Mito et al., 1993; Erickson et al., 1995).

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intravenously. It is available in concentrations of 5%–25%, but the 20% solution is most often used in ophthalmology (Craig, 1994). The dose for the lowering of IOP in dogs ranges from 1 to 2 g/kg, infused over a period of 20–30 minutes (Gwin, 1980; Lorimer et al., 1989). To increase the effectiveness of the drug, one fifth of the total dose can be administered rapidly over the first 2–5 minutes (Gwin, 1980). Following intravenous administration of 1.5 g/kg mannitol, IOP of normal canine eyes decreases from baseline values between 0.25 to 5.5 hours postadministration. A mean maximal depression of 9 mmHg occurs 1.5 hours after administration (Lorimer et al., 1989). In patients with acute glaucoma, mannitol is an effective hyperosmotic agent, reducing IOP within 0.5–1 hour, with the effect lasting for some 6–10 hours (Bedford, 1980). Mannitol is not metabolized but is filtered across the glomerulus and excreted in the urine without reabsorption by the renal tubules, causing a marked diuresis. If mannitol is infused during surgery, bladder catheterization is advisable to prevent uncontrolled urination during the recovery period. Saline hypertonic hydroxyethyl starch (HES), used in human patients for the treatment of hemorrhagic shock and intracranial pressure, has been evaluated for its effects on IOP in dogs (Volopich et al., 2006). In healthy normotensive dogs, the IOP‐lowering effect of 4 mL/kg intravenous HES (7.5%/6%) was comparable to that of mannitol 20% but was shorter in duration. Used in a small series of dogs with acute primary glaucoma, intravenous hypertonic HES induced an average maximum decrease in IOP of 24% from baseline values in most subject dogs (Volopich et al., 2006). Major potential side effects of HES include hypernatremia and hypokalemia, particularly in patients with preexisting dehydration. Glycerin, or glycerol, is a trihydric alcohol that is rapidly absorbed from the gastrointestinal tract after oral administration. The drug is marketed as flavored commercial preparations of 50% and 75% glycerin. Glycerin USP, which contains approximately 1.25 g of glycerin per milliliter, may also be used and mixed in milk or syrup to improve palatability (Singh & Krupin, 1997). Administrations of 1.44 g/kg glycerin in healthy dogs led to a significant ocular hypotensive effect, occurring within 1 hour and lasting about 10 hours (Lorimer et  al., 1989). Another study revealed a 17% decrease in IOP from baseline after oral administration of 1.5 g/kg glycerin within 30 minutes which persisted for only 2 hours (Wasserman et al., 2013). Although rarely used for maintenance therapy of glaucoma, glycerin may be administered per os or in food in a daily dose of 1–2 g/kg (Gwin, 1980). It is most often dispensed for emergency treatment of a hypertensive crisis by the pet owner prior to presentation to the veterinarian. Occasionally, animals may experience nausea or vomiting after ingestion of the drug. The incidence of vomiting appears to be dose‐dependent, occurring most frequently with doses higher than 2 g/kg (Gwin, 1980; Lorimer et al., 1989). Glycerin is metabolized

into glucose, so hyperglycemia and glycosuria may ensue (Dugan et al., 1989; Wasserman et al., 2013), and therefore it should be used with caution in diabetic patients. Weight gain may be another consequence of glycerin metabolism if the drug is administered for a prolonged period. As this agent is readily metabolized, it induces less diuresis than mannitol. Isosorbide is a dihydric alcohol that resembles mannitol in chemical structure and can be given orally. It has been shown to decrease IOP with similar efficacy as glycerol in humans, rabbits, and normal dogs. Unlike glycerin, it is not metabolized after systemic absorption and is excreted unchanged in the urine. Therefore, it does not affect glucose homeostasis, which may allow for its use in diabetic patients. Another potential benefit of isosorbide is that its side effects, which include nausea and vomiting, occur less frequently when compared with glycerol. It is available as a 45% flavored solution (Singh & Krupin, 1997). In humans, a dose of 1.5–2.0 g/kg induces an ocular hypotensive effect similar to that of 1–1.5 g/kg glycerin (Craig, 1994). A daily dose of 1.5 g/kg is recommended in the dog (Dugan et al., 1989; Wasserman et  al., 2013). In normal dogs, this dose resulted in a 13.5% decrease in IOP which was sustained for 90 minutes (Wasserman et al., 2013). Although this was not statistically different from control, it is likely that the magnitude of the decrease would be more significant in glaucomatous individuals.

Clinical Use Osmotic agents are used mainly in the emergency treatment of acute glaucoma (Brooks, 1990; Gaarder, 2000; Gwin, 1980). These compounds are employed for short‐term control of IOP because they are not practical for prolonged therapy (Singh & Krupin, 1997). More rapid reduction of IOP is usually achieved with mannitol rather than with glycerin. Both drugs, however, can be used in combination for maintenance of normal IOP. Mannitol is infused first; 6–8 hours later, glycerin can be administered and repeated as necessary to maintain the lowered IOP (Brooks, 1990). More commonly, once an osmotic agent has been administered and IOP has normalized, topical therapy is employed to sustain the IOP within the target range. Osmotic agents are also indicated to reduce IOP in patients with hyphema, but their value in facilitating the resorption of anterior chamber hemorrhage has not been clearly established. Mannitol may be employed preoperatively or intraoperatively to lower IOP and reduce vitreous volume (Singh & Krupin, 1997). This drug may also be used both before and during surgical procedures on the lens (i.e., cataract surgery, removal of a luxated or subluxated lens, manual reduction of an anteriorly luxated lens), because shrinkage of the vitreous body reduces the incidence and severity of vitreous prolapse. Finally, osmotic agents may be indicated after intraocular surgery to relieve ciliary body block glaucoma (Singh & Krupin, 1997).

Adverse Effects and Contraindications The major potential toxicity of intravenous osmotic agents is related to their effect on the volume and distribution of body fluids. Mannitol may quickly expand extracellular fluid volume and subsequently overload the cardiovascular system (Craig, 1994; Dugan et al., 1989; Singh & Krupin, 1997). This acute expansion of extracellular fluid volume may precipitate pulmonary edema in patients with cardiac failure or who are under general anesthesia. Deaths caused by pulmonary edema occurred in a few dogs and cats that underwent ophthalmic surgery and were given mannitol while anesthetized with methoxyflurane in oxygen (Brock & Thurmon, 1979). Subsequent studies have shown that infusion of 2.2 g/kg of 20% mannitol in healthy dogs, under the same anesthetic regimen of methoxyflurane with oxygen maintenance, increases central venous pressure enough to produce pulmonary perivascular and interstitial edema (Brock et al., 1985). Infusion of a lower dose (0.25 g/kg) of 25% mannitol in dogs anesthetized with halothane does not induce significant changes in cardiovascular variables, but has no effect on IOP (Gilroy, 1986). Mannitol does not cross the blood– brain barrier and thus extracts water from cerebral fluid and tissue. Cerebral dehydration induced during the phase of maximal plasma hyperosmolization has been found in association with side effects such as nausea, vomiting, and altered consciousness. Shrinking of the brain could also promote subdural hematoma formation (Craig, 1994). Mannitol should be avoided in patients with renal failure. Glycerin should be avoided in patients with diabetes mellitus because the drug is converted to glucose (Singh & Krupin, 1997).

New Directions Pharmacologic treatment for glaucoma is directed towards lowering IOP to slow disease progression and tissue damage and delay vision loss. The currently available medical treatment options discussed above can be effective, particularly if treatment is initiated early in the disease process. However, they do not stop disease progression and there remains enormous need for improvements and advancements in the medical treatment of glaucoma in both human and veterinary patients. Issues with existing drugs include failure to achieve target IOP with monotherapy, drug‐related side effects, and low patient compliance with multiple daily administration of eye drops. In recent years, the scientific and medical community has seen encouraging development of novel classes of drugs for glaucoma, the majority of which lower IOP by targeting the trabecular meshwork outflow pathway to increase aqueous humor outflow. Among the most promising new pharmacologic candidates are rho kinase inhibitor, adenosine receptor agonists, and modified prostaglandin analogs (Liebmann & Lee 2017; Lu et al., 2017). Hopefully,

these agents and others will be readily available soon and will improve our abilities to control this frustrating disease. Rho‐associated protein kinase (ROCK) inhibits IOP by increasing aqueous outflow through the trabecular meshwork. They disrupt actin stress fibers and focal adhesions in trabecular meshwork cells (Lin et  al., 2018). IOP‐lowering ophthalmic solutions that inhibit ROCK and norepinephrine transporters (Net) are currently under clinical evaluation. Netarsudil, the most well‐investigated topical ROCK inhibitor to date, produces large reductions in IOP in rabbits and monkeys that are sustained for at least 24 h after once daily dosing, with transient, mild hyperemia observed as the only adverse effect (Lin et al., 2108; Sturdivant et al., 2016). Netarsudil, also known as AR‐13324, reduces IOP in normotensive monkey eyes by 53% within 6 hours of administration (Wang et al., 2015). Tonographic studies indicate that a dual mechanism of action, an increase in tonographic outflow facility, and a decrease of aqueous humor flow rates, accounts for this IOP reduction (Wang et al., 2015). Not only do topical ROCK/Net inhibitors lower IOP, they have been observed to promote retinal ganglion cell survival and regeneration after optic nerve crush injuries (Shaw et  al., 2017). Coordinated IOP lowering and neuroprotective or regenerative effects may be advantageous in the treatment of patients with glaucoma. The adenosine receptor agonist, trabodenosine, and similar compounds are showing promise for the treatment of glaucoma in humans. Twice‐daily topical ocular doses of trabodenoson, from 50 μg to 500 μg, were well tolerated and showed a dose‐related decrease in IOP that was statistically significant and clinically relevant in patients with ocular hypertension or primary open angle glaucoma (Myers et al., 2016). No studies on companion animals are currently available. The role of latanoprost in increasing uveoscleral outflow of aqueous humor is well established. This drug and other FP prostaglandin analogues are the leading mode of therapy at present for human and animal glaucoma. Given the success these drugs have had, it follows naturally that modifications of these agents and discoveries of related compounds would occur. A variety of promising E2 prostaglandin analogues are currently in development and study (Prasanna et al., 2009). More exciting, however, is a new strategy that involves modulating physiologic mediators such as NO in concert with the actions of latanoprost. Impacting these mediators is being evaluated as a novel way to impact disease progression by both lowering IOP and improving ONH perfusion. Latanoprostene bunod (LBN) is a topical ophthalmic therapeutic for the reduction of IOP in patients with glaucoma. LBN is composed of latanoprost acid linked to an NO‐donating moiety. It has shown promise in clinical trials and is the first NO‐releasing prostaglandin analogue to be submitted for marketing authorization in the United States. NO released from LBN elicits trabecular meshwork cell

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relaxation by reducing myosin light chain phosphorylation, inducing cytoskeletal rearrangement, and decreasing resistance to current flow (Cavet & DeCory, 2018). As an NO‐ donating prostaglandin F2‐alpha receptor agonist, LBN has been proven to effectively, and with good tolerability, reduce IOP in glaucoma patients. The drug capitalizes on NO’s ability to modulate the conventional aqueous humor outflow system, directly improving outflow through the trabecular meshwork, Schlemm’s canal and distal scleral vessels (Aliancy et al., 2017; Cavet & De Cory, 2018). Importantly, targeting the conventional outflow tissues with NO‐donating drugs represents an opportunity to restore outflow function. This will most likely have the beneficial consequence of additional IOP‐lowering effects by dampening diurnal and other IOP fluctuations, which occurs naturally in the healthy trabecular meshwork (Aliancy et al., 2017). A recent study compared the ocular hypotensive activity of LBN, to that of latanoprost in monkeys with laser‐induced ocular hypertension, dogs with naturally occurring glaucoma, and rabbits with saline‐induced ocular hypertension (Borghi et  al., 2010). In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with LBN at doses of 0.036% and 0.12%, respectively. In comparison, latanoprost

elicited a greater response than vehicle only at 0.1% (much higher than commercially available preparations) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 27% after LBN and latanoprost, respectively (Borghi et al., 2010; Impagnatiello et al., 2011). Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas LBN significantly blunted the hypertensive phase. LBN lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity (Borghi et al., 2010; Krauss et al., 2011). The same effects have been noted in a clinical trial of human glaucoma patients. In these patients, LBN 0.024% dosed once daily shows significantly greater IOP lowering and comparable side effects relative to latanoprost 0.005% (Weinreb et al., 2015). Once daily LBN ophthalmic solution 0.024% was safe and well tolerated in human patients with glaucoma when used for up to 1 year and provides sustained IOP reduction (Kawase et al., 2016). These data indicate that LBN has a dual mechanism of action, increasing aqueous humor outflow through both the uveoscleral (using latanoprost acid) and trabecular meshwork/ Schlemm’s canal (using NO) pathways (Cavet & DeCory, 2018).

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Welch, S.L. & Richardson, J.A. (2002) Clinical effects of brimonidine ophthalmic drops ingestion in 52 dogs. Veterinary and Human Toxicology, 44, 34–35. Whelan, N.C., Welch, P., Pace, A., et al. (1997) A comparison of the efficacy of topical brinzolamide and dorzolamide alone and in combination with oral methazolamide in decreasing normal canine intraocular pressure (abstract). 30th Annual Meeting of the American College of Veterinary Ophthalmologists, 80. Whikehart, D.R., Montgomery, B. & Sorna, D.H. (1992) The inhibition of Na, K‐ATPase, and Mg‐ATPase by timolol maleate in cultured non‐pigmented epithelial cells of the ciliary body. Journal of Ocular Pharmacology, 8, 107–114. Whitley, R.D., Gelatt, K.N. & Gum, G.G. (1980) Dose response of topical pilocarpine in the normotensive and glaucomatous beagle. American Journal of Veterinary Research, 41, 417–424. Wilkie, D.A. & Latimer, C.A. (1991a) Effects of topical administration of timolol maleate on intraocular pressure and pupil size in dogs. American Journal of Veterinary Research, 52, 432–435. Wilkie, D.A. & Latimer, C.A. (1991b) Effects of topical administration of timolol maleate on intraocular pressure and pupil size in cats. American Journal of Veterinary Research, 52, 436–439. Willis, A.M. (2004) Ocular hypotensive drugs. Veterinary Clinics of North America: Small Animal Practice, 34, 755–776. Willis, A.M., Diehl, K.A., Hoshaw‐Woodward, S., et al. (2001a) Effect of topical administration of 0.005% latanoprost solution on eyes of clinically normal horses. American Journal of Veterinary Research, 62, 1945–1951. Willis, A.M., Diehl, K.A. & Robbin, T.E. (2002) Advances in glaucoma therapy. Veterinary Ophthalmology, 5, 9–17. Willis, A.M., Robbin, T.E., Hoshaw‐Woodard, S., et al. (2001b) Effect of topical administration of 2% dorzolamide hydrochloride or 2% dorzolamide hydrochloride‐0.5% timolol maleate on intraocular pressure in clinically normal horses. American Journal of Veterinary Research, 62, 709–713. Wood, J.P., DeSantis, L., Chao, H.M., et al. (2001) Topically applied betaxolol attenuates ischemia‐induced effects to the rat retina and stimulates BDNF mRNA. Experimental Eye Research, 72, 79–86. Woodward, D.F., Chan, M.F., Cheng‐Bennet, A., et al. (1996) In‐vivo activity and enzymatic hydrolysis of novel prostaglandin F2α prodrugs in ocular tissues. Experimental Eye Research, 63, 411–423. Yoshitomi, T. & Ito, Y. (1988) Effects of indomethacin and prostaglandins on the dog iris sphincter and dilator muscles. Investigative Ophthalmology & Visual Science, 29, 127–132. Yousufzai, S.Y., Ye, Z. & Abdel‐Latif, A.A. (1996) Prostaglandin F2 alpha and its analogs induce release of endogenous prostaglandins in iris and ciliary muscles isolated from cat and other mammalians species. Experimental Eye Research, 63, 305–310. Zimmerman, T.J. (1993) Topical ophthalmic beta blockers: a comparative review. Journal of Ocular Pharmacology, 9, 373–384.

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9 Veterinary Ophthalmic Pathology Bruce H. Grahn1 and Robert L. Peiffer2 1 2

Western College of Veterinary Medicine and Prairie Ocular Pathology of Prairie Diagnostic Laboratories, University of Saskatchewan, Saskatoon, SK, Canada School of Medicine, University of North Carolina, Chapel Hill, NC, USA

Introduction and Principles Few would argue that understanding disease processes on a cellular and subcellular level greatly facilitates clinical man­ agement of any disease. With that in mind, one can envision that a thorough understanding of ocular pathology is essen­ tial for the practicing veterinary ophthalmologist. The objec­ tives of this chapter are to facilitate understanding by providing an overview of ocular pathology that compliments with minimal duplication the material that is covered in the other chapters of this book. The gross, subgross, and light microscopic descriptions of the common ocular disorders of animals are emphasized. Current clinical examination techniques provide the vet­ erinary ophthalmologist with enhanced views of most of the intraocular structures allowing observation of gross and sub­ gross pathology in ocular tissues with resolution that approaches that of the light microscope. Clinical findings and results of histopathology unify clinical and pathologic disciplines. This chapter is organized as follows: methods of fixation and processing; general principles of ocular pathology; con­ genital conditions; acquired and inherited disorders, and review of the neoplasms that affect ocular tissues.

Fixation and Processing of Ocular Tissues Ocular tissues are submitted to the pathologist as whole globes with attached orbital tissues, globes without orbital tissues, eviscerated specimens, excisional or incisional biop­ sies, cytology of exfoliative preparations, or aspirates. Each type of sample has unique fixation and preparation require­ ments to optimize the pathologist’s examination. Globes should be fixed promptly after removal to ensure rapid fixa­

tion of the intraocular structures to minimize autolytic changes. The preferred fixative for intact globes is Davidson’s fixa­ tive, which penetrates the globe rapidly to fix the retina and retinal pigment epithelium (RPE) and maintains these tis­ sues in anatomic apposition. However, the most common method of fixation is immersion in 10% buffered formalde­ hyde, which is adequate. Bouin’s fluid, among others (Table 9.1), is occasionally used, notably for research. Tissues are immersed in a one part tissue to 10 parts 10% buffered formalin solution and placed on a rotary mixer for approximately 24 hours (this step is less common in today’s fast‐paced laboratories). In addition, globes should also receive an intravitreous formaldehyde injection (0.5–1 mL) via a 25 gauge needle inserted immediately adjacent to the optic nerve prior to immersion to compensate for limited penetration through the sclera. Globes can be hardened by immersion into graduated concentrations of 60–80% alcohol for 24–48 hours; the resultant dehydration facilitates sectioning. Exenterations are performed as a surgical therapy for orbital neoplasia. It is important that the surgeon clearly identify any margins that they want examined in detail. The volume of tissue removed by an exenteration is large and the orbital tissues should be incised every 2 cm through to the sclera to allow fixation penetration (Fig. 9.1A), or preferably the periocular tissues of interest would be trimmed and iden­ tified with a marker or sutures to facilitate sectioning. Once the globe is trimmed, the pathologist will measure and record the dimensions of cornea, globe, and attached optic nerve. Some prefer to section the optic nerve at this time across its base as it leaves the sclera to provide a cross section for histologic examination that compliments the longitudinal section that will accompany the globe (Fig. 9.1B, C). The globe can be transilluminated to locate intraocular masses or foreign bodies before orienting and sectioning. Enucleated globes from most species are oriented by

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

Table 9.1  Ocular fixatives and their advantages and disadvantages. Triple fixatives paraformaldehyde, glutaraldehyde formaldehyde, and osmium

Zenker’s fluid

Davidson’s fixative

Excellent; however, globes are typically opened

Good

Excellent

Excellent

Excellent

Good

Very good

Good; however, different epitope retrieval is required

Good

Good; however, different epitope retrieval is required

Good; however, different epitope retrieval is required

Good

Better penetration of globe

Excellent fixation of small tissue sections or small globes with thin sclera (mice, rats) destined for electron microscopy

Uncommonly used except in research, osmium is toxic and expensive

Uncommonly used related to toxicity of mercury

Very good immersion fixative

Formaldehyde

Bouin’s fluid

Gluteraldehyde

Maintenance of tissue relationships (neurosensory retina‐RPE)

Marginal

Good

Poor by immersion. Globes must be sectioned and then small pieces immersed

Preservation of membranes for ultrastructure

Poor

Poor

Immuno compatibility

Good

Advantages and disadvantages

Cost, availability

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A

C

E

B

D

F

Figure 9.1  A. An exenterated bovine eye that was immersion fixed in Bouin’s fluid for 72 hours and sectioned. Note the incomplete fixation of the orbital and ocular tissues (*). To ensure adequate fixation of globes that are exenterated or removed by transpalpebral enucleation, the orbital tissues should be trimmed and labels attached prior to immersion in fixatives, or multiple incisions placed circumferentially to the level of the episclera at 0.5–1 cm intervals. B, C. Optic nerves may be sectioned sagittally and in cross section to facilitate thorough examination of the axons and meninges. In the bovine specimen above the thickened pia septae and enlarged subdural space are hallmarks of optic atrophy (Masson’s trichrome stain). D. Gross examination with photographic documentation in this canine globe reveals pseudophakia which would not be obvious on histologic section. E. A Bouin’s fluid fixed globe from a dog that was diagnosed with a chronic lens rupture that was enucleated via a transconjunctival approach. Note the lack of extraocular tissues and adequate fixation. The lens (L) is encased by the plasmoid aqueous (PA) and vitreous (PV), and the lens capsule rupture is evident (*). An exudative retinal detachment (RD) is also present. These gross findings are synonymous with the diagnoses endophthalmitis and phacoclastic uveitis which were confirmed with light microscopy. F. This is a section of the posterior segment from a Sprague Dawley rat with a retinal fold (RF). Note the excellent fixation and minimal artifacts present in this epon-embedded tissue. This globe was triple fixed, plastic embedded, and sectioned. (Original magnification 40×; Toluidine blue stain.)

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identification of the shape of the cornea, extraocular mus­ cle insertions, and location of the vortex veins, ciliary arteries, and optic nerve. This allows the pathologist to bisect the eye in a vertical plane from dorsal to ventral to include both the tapetal and non‐tapetal fundus. Globes from animals with maculae are sectioned horizontally to allow histologic examination of the macula and fovea. Unused brain, razor, or histosectioning blades are utilized for sectioning the globe. Examination with a dissecting microscope and documentation of findings is performed with the globe under fluid (Fig. 9.1D). Once the pathologist has determined a preferred hemi­ sphere, a cap is removed to permit wax to penetrate the entire globe. Then the collotte is placed in an embedding chamber of appropriate size and labelled. An alternative to hemisection (which can dislocate the lens) is the removal of the cap, cutting from just inside the limbus to adjacent to the optic disc on the same side, followed by subgross intraocular examination and making a parallel cut to the first to end up with a central section and two calottes. Rodent and other small globes are fixed by immersion, then oriented appropriately with embedding, and processed whole. Multiple sections are taken until the appropriate area in the eye is examined. Fetal rodents have very small globes that are difficult to remove intact. Fixation of the whole body in Bouin’s fluid and then serial sections of the skull horizon­ tally to view both globes is the method of choice for light microscopy. Photographs of the gross sections may facilitate histologic examination (Fig. 9.1D, E). The commonly preferred stains for light microscopic examination of ocular tissues are hematoxylin and eosin (H&E), periodic acid Schiff (PAS), and Luxol fast blue (for myelin) and Bodian stain (for axons). These stains allow for a thorough examination of the cellular morphology, base­ ment membranes, and optic nerve. Additional histochemi­ cal stains for evaluating ocular tissues and infectious organisms are provided in Table 9.2 and Table 9.3. Biopsies of eyelid skin, conjunctiva, and adnexa are also common submissions. The clinician should identify the sur­ faces with India ink, sutures, or other labels and provide drawings on the acquisition forms to facilitate orientation and margin evaluation. Paraffin embedding is performed routinely for all globes and biopsies. Some histotechnologists prefer sectioning lux­ ated lenses in a separate block to improve the quality of the subgross section, whereas others replace these within the posterior segment for sectioning with the globe. Fine needle aspirates or exfoliative cytology of intraocular, orbital, and eyelid tumors, and exudates are occasionally submitted. Usually these aspirates are submitted as smears on glass slides and are stained routinely with Wright’s Giemsa, or they are submitted as a small liquid aspirate in an ethylenediaminetetraacetic acid (EDTA) tube and submitted for cytospin analysis.

Transmission and occasionally scanning electron micros­ copy are useful to identify cells of origin of poorly differenti­ ated neoplasms, specific infectious agents, and as research tools. Specimens destined for electron microscopy have spe­ cific fixation, embedding, sectioning, and staining require­ ments to obtain optimal electron microscopic evaluation. Small biopsies of eyelid skin, conjunctiva, sclera, or cornea are adequately fixed by immersion in glutaraldehyde. Although biopsies of intraocular tissues from globes that are routinely immersion‐fixed can be prepared for epon embed­ ding and sectioning for electron microscopy, the subcellular details will be limited related to autolysis. Several fixation techniques are available. Most often these globes are immersed in cold fixative immediately after enucleation for several minutes, removed, and opened with a pars plana incision to enhance exposure of the intraocular tissues to other fixatives and buffers. For optimal outer segment and RPE fixation, osmium is often added to these protocols. These protocols provide excellent fixation and detail of the outer and inner retinal segments (Fig. 9.1F). Occasionally, methodologies such as histochemistry for lipids and immunohistochemistry require fresh tissue or special fixation and snap freezing. Preoperative communi­ cation between the clinician and pathologist to identify and address issues that surround specific projects is encouraged.

Fundamental Pathology The eye is a relatively closed system and injury to one ocular tissue often induces bystander injury to adjacent tissues. Many of the ocular tissues are postmitotic which limits the capacity for pristine repair. Most ocular tissues must adapt to injury in relatively limited ways, and many of these adapta­ tions are sequential. The adaptation and related responses of ocular tissues occur from development to maturity and include hypoplasia, atrophy, aplasia, dysplasia, hypertrophy, hyperplasia, metaplasia, necrosis, apoptosis, degeneration and calcification, and neoplasia. Hypoplasia is defined as diminished cell proliferation caused by inadequate cytokine stimulation, lack of progeni­ tor cells or specific cellular receptors, or yet undiscovered processes. Hypoplasia is most commonly associated with restricted development of an ocular tissue. The most com­ mon example occurs in subalbinotic animals where the uvea is hypoplastic. These blue‐eyed animals have less pigment and less blood supply throughout their entire uvea, and this is consistently present in dogs with Collie eye anomaly. Uveal hypoplasia is a consistent anomaly in some forms of anterior segment dysgenesis (ASD), especially those associ­ ated with glaucoma (Fig. 9.2). Aplasia is a lack of development of a tissue and reflects a complete lack of cellular development. Aplasia is usually

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483

Target

Stain

Result

General purpose

Hematoxylin and eosin

Proteins – pink Nucleic acid – purplish blue Calcium – blue

Basement membranes (mucopolysaccharides and glycoproteins)

Periodic acid‐Schiff (PAS)

Dark pink

Collagen/muscle

Masson’s trichrome

Collagen – blue

Acid mucopolysaccharides

Alcian blue

Blue

Muscle – red Colloidal iron

Blue

Mucin

Mucicarmine

Pink to red

Iron

Perl’s Prussian blue

Blue

Calcium

Von Kossa

Black

Alizarin red

Red

Myelin

Luxol fast blue

Aqua to blue

Axons

Bodian

Black

Lipid (fresh frozen tissue only)

Oil red‐O

Red

Sudan black

Black

Congo red

Red (yellow green birefringence with polarization)

Thioflavin T

Fluorescent white

Amyloid

Crystal violet

Violet to purple

Elastic tissue

Verhoeff‐Van Gieson

Black

Melanin

Fontana‐Masson

Black

Fungi and basement membranes

PAS

Purple‐pink

Fungi

Gomori methenamine silver

Black

Acid‐fast organisms

Ziehl‐Neelsen

Red

Fite‐Faraco

Red

Calcaflour white

Fluorescent white

Acridine orange

Fluorescent orange

Chlamydia

Giemsa

Pink inclusions

Mast cell granules

Duffy’s stain

Blue granules

Acanthomoeba

focal in ocular tissues. Absence of tissue creates a defect called a coloboma. Colobomas are only occasionally exam­ ined with light microscopy, because most of these do not affect ocular function and are incidental findings in globes submitted for other disorders (Fig. 9.3). Dysplasia by definition is atypical growth of a developing tissue. Dysplasia manifests as a morphologic abnormality in cell shape and organization. There are many examples of dysplasia in veterinary ophthalmology including photore­ ceptor, RPE, and retinal dysplasias (Fig. 9.4) (Rodarte‐Ahmeida et al., 2016). However, retinal dysplasia is occasionally an adaptational response to a virus, a toxin, or nutritional

deficiency which can induce necrosis or degeneration and inflammation of the affected tissues during development (Dombroski et al., 2016). Dystrophy is an abnormality that is initiated by faulty metabolism within mature cells. Several examples are inher­ ited mutations in specific breeds of dogs. The most common example is corneal dystrophy (Fig. 9.5). Atrophy is a reduction of tissue mass after the cells are mature. Etiologies are diverse and include ischemia, dener­ vation, inadequate nutrition, aging, and prolonged eleva­ tions of intraocular pressure. These conditions often induce degeneration, necrosis, or apoptosis and subsequently loss

SECTION II

Table 9.2  Common histochemical stains used in ophthalmic pathology.

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Section II: Foundations of Clinical Ophthalmology

SECTION II

Table 9.3  Common immunohistochemical and histochemical markers used in ophthalmic pathology. (Tagging the antibody with a red marker instead of the common brown marker enhances the examiner’s ability to identify positive labeling in the often heavily pigmented ocular tissues). Tissue

Antibody

Melanocytes

S‐100, melanin A, tyrosinase, HMSA 45

Glial cells

Glial fibrillary acidic protein (GFAP)

Vascular endothelium

Factor VII

Epithelial cells

Cytokeratin

Smooth muscle cells

Actin

Hematopoietic cells

Leucocyte common antigen

Mast cells and eosinophils

Duffy’s stain

B lymphocytes

CD79

T lymphocytes

CD3

Histiocytes

CD18

of tissue. Common examples include senile iris atrophy, glaucomatous uveal, retinal and optic nerve atrophy, and outer segment atrophy associated with retinal detachment (Fig. 9.6). Hypertrophy is an increase in cell size and therefore cel­ lular mass. A few ocular tissues adapt to varied conditions with hypertrophy, which is often a prelude to hyperplasia. A common example is RPE hypertrophy and subsequent hyperplasia that develops in response to retinal detachment (Fig. 9.7). Hyperplasia is an increase in the number of cells and this adaptational response develops secondary to multiple stress­ ors. Hyperplasia is an efficient adaptation response within ocular tissues that are capable of mitotic replication including

Figure 9.2  Ciliary hypoplasia and elongated ciliary processes are common and consistent features in globes from animals with glaucoma associated with ASD. (Hematoxylin and eosin stain.)

retinal pigment, lens, and corneal epithelia, and uveal melano­ cytes (Fig. 9.7C). Metaplasia is an adaptational response to stress where a mature tissue changes or transforms into another. This is an important response in the eye, and examples include fibrous or even osseous metaplasia within corneal, lens, uveal, and RPE tissues (Fig. 9.8). Perhaps the most spectacular example of metaplasia exists in birds where lens fibers occasionally develop within the retina. These adaptational and other cellular responses leave a footprint that is often unique in its appearance. These cellu­ lar responses facilitate the diagnosis by the ophthalmologist and confirmation of such by the pathologist. When the ocu­ lar cells or tissues can no longer adapt to the insult, cell death occurs by at least two basic mechanisms; necrosis or apoptosis. Necrosis is characterized with light microscopy by increased cellular cytoplasmic eosinophilia and nuclear

Figure 9.3  A gross section of a formalin-fixed eye from a blind Collie puppy. Note the peripapillary coloboma (C), staphyloma (S), and retinal detachment (RD).

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Figure 9.5  Inherited corneal dystrophy in an Alaskan Malamute. Note the opalescent circular ring in the cornea.

Figure 9.4  A section of retina from a Miniature Schnauzer with inherited retinal dysplasia. Note the prominent rosettes (R). The external limiting membrane was discontinuous centrally where the outer nuclear nuclei are displaced into the layer of inner segments of the photoreceptors. (Original magnification 60×. Toluidine blue stain.)

changes of pyknosis, karyolysis, and karyorrhexis. Different types of necrosis are recognized. With coagulative necrosis, the cell morphology is retained somewhat. Liquefactive necrosis occurs when enzymes destroy the cellular architec­ ture (Fig.  9.9A). Necrosis is usually accompanied by an inflammatory infiltrate.

A

In contrast, apoptosis is programmed cell death that often affects individual cells. Type I apoptosis is characterized by histomorphological clues including cell shrinkage, detach­ ment from neighboring cells, development of cell surface blebs, and frequently phagocytosis of the affected cell (Fig. 9.9B). Type II apoptosis is similar but is characterized by autophagy. Autophagy involves intracytoplasmic degen­ eration by cellular lysosomes. Both types I and II are recog­ nized as efficient methods of cell removal and remodeling of ocular tissues during development. Apoptosis is also a recognized part of both developmental ocular disorders (photoreceptor dysplasias) and acquired ocular disorders, including sudden acquired retinal degeneration, indolent corneal ulceration, and many neoplasms. An inflammatory infiltrate does not usually accompany apoptosis, in contrast to necrosis where inflammation is often present. In contrast to cell death and loss, neoplasia is uncontrolled persistent abnormal cellular proliferation. Neoplasms are

B

Figure 9.6  Optic nerve atrophy is a common lesion that develops secondary to glaucoma. Note the cavitation of the optic nerve in the gross (A), and histologic (B) section of a dog with chronic glaucoma.

Section II: Foundations of Clinical Ophthalmology

SECTION II

486

A

B

C

Figure 9.7  A. A histologic section of a chronically detached retina. Note the retinal detachment (RD), outer nuclear layer (ONL) is atrophied, and the retinal pigment epithelium (RPE) is hypertrophied and pigmented. The inner nuclear layer (INL) and ganglion cell layer (GCL) and nerve fiber layer (NFL) are relatively normal in this peripapillary section. (Original magnification 60×. Hematoxylin and eosin.) B. RPE hypertrophy is common and represents an acute adaptational response to retinal detachment in domestic animals. (Original magnification 100×. Toluidine blue stain, epon embedded.) C. A scanning electron micrograph of the RPE under a detached retina. The retina has been removed. Note the RPE hypertrophy and hyperplasia in a dog. (Bars = 0.1 mm.)

A

B

Figure 9.8  A. Osseous metaplasia (OM) of the anterior segment of a Guinea pig eye. (Original magnification 100×. Hematoxylin and eosin.) B. Posterior lens of a dog with a hypermature cataract. Note the wrinkled posterior lens capsule secondary to loss of lens cortical material and fibrous metaplasia and migration of lens epithelium under the posterior lens capsule. (Hematoxylin and eosin.).

487

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A

B

Figure 9.9  A. Choroiditis (C) and retinal necrosis (RN) in a septic bovine calf. The inflammatory infiltrate in these tissues is predominately neutrophilic. Note the thrombus present in the retinal blood vessel. (Original magnification 20×. Hematoxylin and eosin.) B. A transmitting electron micrograph of the outer segments of the photoreceptors of a middle-aged Collie with progressive retinal atrophy. Note the organelle swelling and shrinking cone nuclei exhibiting apoptotic change. (Magnification 3600×.)

benign or malignant. Benign ocular neoplasms contain well differentiated cells (Fig. 9.10A, B). Benign neoplasms are generally termed by adding the suffix “oma” to the cell of origin, i.e., melanocytoma, tarsal gland adenoma, etc. Benign neoplasms are slowly expansile, are usually encap­ sulated, and induce damage by compression of adjacent tissues. Malignant neoplasms are signified by attaching sarcoma or carcinoma to the tissue of origin, i.e., intraocular sarcoma

A

or squamous cell carcinoma. Malignant ocular neoplasms are categorized into four groups: carcinomas, sarcomas, mel­ anomas, and lymphoreticular (round cell) neoplasms. These neoplasms range from poorly to well‐differentiated and are characterized best by their invasion of tissues. Histologic features of malignant neoplasms include cellular pleomor­ phism, increased nucleocytoplasmic ratio, high mitotic index, atypical mitotic figures, necrosis, and destruction and invasion of cellular architecture (Fig. 9.10C).

B

C

Figure 9.10  A. Tarsal gland adenomas (TGA) are common benign eyelid neoplasms of dogs. Note the location on the eyelid margin and well-differentiated glandular structure on histologic section. (Original magnification 10×. Hematoxylin and eosin.). B. A well-differentiated ciliary adenoma (CA) within the posterior segment of a cat. Notice the characteristic endophytic growth and lack of ocular tissue invasion of this benign neoplasm. (Magnification 2×. Periodic acid-Schiff.). C. A subgross view of a malignant posttraumatic intraocular sarcoma (IS) in a cat. Note the complete invasion of the vitreous, choroid, ciliary body, and iris. Note the incomplete lens capsule (*), and the invasion of the uvea by this tumor. (Original magnification 2×. Periodic acid-Schiff.)

488

Section II: Foundations of Clinical Ophthalmology

SECTION II

Ocular Inflammation Ocular inflammation is the result of a variety of insults including accidental or surgical trauma, exposure to toxic substances, infectious agents, noninfectious immunogenic stimuli, physical agents, and neoplasia. The clinician dedi­ cates significant resources to temper ocular inflammation. The unique anatomic and physiologic properties of the eye render it exquisitely sensitive to inflammation and its seque­ lae. These properties include ocular functional dependence on transparency and precise intertissue physical relation­ ships. Inflammation resolves with fibrosis, and scars are not transparent and distort tissue relationships as they mature and contract. Likewise, the eye is largely composed of volu­ minous extracellular fluid compartments (anterior and pos­ terior chambers and vitreous) which allow chemical mediators and products of inflammation to exert an exagger­ ated and prolonged effect. Elsewhere in the body, products of inflammation are metabolized, diluted, and carried away by the vasculature in a more efficient manner. The eye is an immunologically privileged site related to the isolation and avascularity of many of its component tis­ sues and the absence of lymphatics. The conjunctiva does have lymphatics, and their presence in the orbit is somewhat controversial. These features largely dictate how a particular ocular tissue responds to inflammatory stimuli. Anterior chamber‐associated immune deviation (ACAID) has impli­ cations for the modulation of the ocular inflammatory response (see Chapter  6). Ocular inflammation should be regarded as a series of events occurring over time; the pathologist is thus limited to viewing a single frame. Inflammation is primarily regulated by a vast array of chem­ ical mediators. Most are endogenous, but some are exoge­ nous in origin, including venoms and microbial products. Acute inflammation is of rapid onset and of short duration, in terms of days. The initial events are vascular and exuda­ tive, mediated by plasma factors (kinin, clotting, and com­ plement systems) and tissue factors (vasoactive amines, prostaglandins, lysosomal, and lymphocyte products). Vascular changes include dilation with congestion and increased vascular permeability with disruption of the blood– ocular barriers and subsequent egress of intravascular fluid and protein into adjacent ocular tissues. Fibrin, the smallest of the plasma proteins, is the primary proteinaceous compo­ nent. Fibrinous inflammation is commonly associated with bacterial infection, septicemia, or surgical or accidental trauma. Clinically, these changes manifest as conjunctival and uveal edema, aqueous flare, and plasmoid vitreous. If these mediators compromise the RPE barrier, serous or exu­ dative retinal detachment often develops. If the tight inter­ cellular junctions of the ciliary epithelium remain intact, edema of the ciliary processes develops. This is a common and sensitive indicator of uveitis. Subsequent events are defined by the attraction and recruitment of inflammatory

Figure 9.11  Fine needle aspirate from the vitreous of a dog with septic endophthalmitis. Note the cluster of toxic neutrophils in the center of this field. They contain intracytoplasmic bacteria, and there are accompanying red blood cells and mononuclear cells. (Magnification 100×.Wrights Giemsa stain.)

cells. Neutrophils are the hallmark of acute inflammation (Fig.  9.11); note that this is the pathologists’ definition of acute, which may differ from that of the clinician. Neutrophils are produced in the bone marrow, are rapidly mobilized in response to injury, and have a short life span of 1–2 days in tissues. They are phagocytic cells whose granules contain substances that degrade nonviable substances. Neutrophils possess direct antimicrobial capacity. External degranulation can contribute to tissue damage. This is the case with the type III hypersensitivity reaction to canine adenovirus, type I, where the antigen‐antibody complexes that form within the corneal endothelium subsequently fix complement which is a neutrophil chemotaxin. If infiltra­ tion is accompanied by liquefactive necrosis, the inflamma­ tion is described as purulent and suppurative. In the anterior chamber, neutrophils gravitate inferiorly and are seen as hypopyon. Inflammation becomes chronic with persistence of the original stimulus, significant and prolonged tissue destruc­ tion, a foreign body, or an altered blood supply. Chronic inflammation is often exudative and proliferative, occurs over weeks, and is superimposed on the repair process. Lymphocyte and plasma cell infiltrates are the hallmark of chronic disease, with implications of an immune‐mediated process (Fig. 9.12). Lymphocytes are either thymus‐ (T‐lymphocytes) or non­ thymus‐derived lymphocytes (B‐lymphocytes). The former are involved with cell‐mediated immune responses and include subpopulations that are specifically cytotoxic, secretors of lymphokines, immunomodulatory, and carri­ ers of immune memory. B‐lymphocytes are capable of transforming into plasma cells, which secrete class‐specific antibodies to a specific antigen. Inspissation of plasma cells leads to the evolution of plasmacytoid and Russell body cells. Some lymphocytes lack both T and B characteristics

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Figure 9.12  A. This is a section of a part of the anterior segment of a cat’s eye with idiopathic lymphocytic plasmacytic uveitis. Note the diffuse infiltration of lymphocytes and the lymphoid follicle (LF) at the anterior base of the iris. (Original magnification 200×. Hematoxylin and eosin.) B. Lymphocytes, recognizable by their small size and scant cytoplasm and plasma cells with their pink cytoplasmic perinuclear halos are common inflammatory cells in uveitis, and these are both present within the ciliary processes of this horse with equine recurrent uveitis. (Magnification 60×. Hematoxylin and eosin.)

and are referred to as null cells and have cytotoxic capabili­ ties. In the anterior chamber, lymphocytes and plasma cells will adhere to the iris and corneal endothelium as fine granular precipitates. Lymphoplasmacytic inflammation is a common histopathologic diagnosis. Many infectious and immune‐mediated diseases present with such an infiltrate and additional diagnostic modalities (serology, culture, immunofluorescence assay, polymerase chain reaction) are often indicated. Eosinophils are produced in the bone marrow and are pre­ sent in both acute and chronic inflammation (Fig.  9.13); their granules contain arginine‐rich basic protein, peroxi­ dase, arylsulfatase, and phospholipase. They are attracted by antibody‐antigen complexes, modulate the inflammatory response by inhibiting mast cell products, and show a killer function toward parasites, and thus are associated with aller­ gic reactions and parasitic infestation. Mast cell granules contain heparin, histamine, and serotonin, among other fac­ tors (Fig. 9.14), are found in abundance in the conjunctiva and uvea, and play an initiating role in hypersensitivity responses. Cytoplasmic metachromatic granules, not seen on routinely stained preparations, are readily evident when stained with toluidine blue. The presence of a resistant or replicating stimulus leads to activation of the macrophage system, which is referred to as granulomatous inflammation and is always chronic. Seldom does the response contain only macrophages because neutrophils are often present. When their num­ bers are significant, the inflammation is pyogranuloma­ tous. Often diffuse or follicular collections of lymphocytes and plasma cells are also present. Granulomatous uveitis develops secondary to specific organisms, immunologic

Figure 9.13  Eosinophils and mast cells are readily identified by several histochemical stains including Duffy’s stain. Note the blue-stained mast cells and red stained eosinophils in this palpebral conjunctival biopsy from a cat with eosinophilic conjunctivitis. (Original magnification 200×. Duffy’s stain.)

reactions, or foreign bodies. Its hallmark is the epithelioid cell, a specialized histiocyte characterized by abundant cytoplasm and a large pale nucleus (with an appearance reminiscent of a squamous epithelial cell). Fusion of epi­ thelioid cells forms multinucleated giant cells. Foreign body giant cells possess multiple nuclei dispersed through­ out the cytoplasm. The nuclei of Langhans giant cells array around the periphery of the cell and are usually associated with infectious granulomas. Touton giant cells are encountered in xanthomatous and lipogranulomatous

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Figure 9.14  Mast cells are normal inhabitants of the conjunctival and episcleral tissues, and their prominent granules contain heparin, histamine, and serotonin. This cytological specimen was a fine needle aspirate from an episcleral lesion from a dog with a conjunctival mast cell tumor. (Magnification 400×. Toluidine blue stain.)

Discrete granulomas can form in virtually any of the ocular tissues and require distinction both clinically and histo­ pathologically from nodular or follicular lymphoplasmacytic infiltrates. In zonal granulomatous inflammation, the epi­ thelioid cells surround the stimulus; chalazion, phacoclastic uveitis (in some species), and scleritis exemplify, with seba­ ceous secretion, lens protein, and collagen, the respective stimuli (Alleaume et al., 2017). Epithelioid cells intermixed with lymphocytes and plasma cells are broadly distributed in diffuse granulomatous inflammation, with uveodermato­ logic syndrome providing a prototypic example. In the ante­ rior chamber, macrophages will congregate and adhere to the corneal endothelial surface as large “mutton‐fat” precipitates. Regardless, the pathologist attempts to identify what the cells are phagocytizing to arrive at an etiologic diagnosis, and stains for fungi, mycobacteria, and spirochetes (silver stains) are useful in this regard (see Table 9.2). Granulomatous inflammation can have an acute neutro­ philic component typical of mycotic infections (Fig.  9.16). Pyogranulomatous blepharitis (presumed an immune‐medi­ ated disease) and the pyogranulomatous uveitis that accom­ panies feline coronavirus infection are additional examples. Note that the terminology is not precise in that there is not necessarily necrosis and suppuration in these processes. Inflammation can be described as acute or chronic, as nongranulomatous or granulomatous, or suppurative or lymphocytic/plasmacytic based upon the nature of the cel­ lular infiltrate. Ocular inflammation can also be classified by the extent of involvement of the ocular tissues. Involvement of isolated or adjacent tissues is described with the suffix “itis”; if two or more tissues are involved, that which is most directly or primarily involved comes first in the terminology. If there is significant involvement of one of the large extra­

Figure 9.15  Multiple coalescing epithelioid macrophages (M) within a fibrovascular membrane on the iris of a dog with chronic retinal detachment and uveitis. Some of these giant cells have peripheral nuclei typical of Langerhans giant cells. It is unusual to have a granulomatous cellular infiltrate with retinal detachments, and special stains should be applied to rule out specific bacterial and fungal organisms. (Original magnification 400×. Hematoxylin and eosin.)

disease with cytoplasmic lipid vacuoles and the nuclei con­ centrically arranged in the mid‐periphery (Fig. 9.15). Granulomatous inflammation is described as discrete, zonal, or diffuse, dependent upon the organization of the macrophages. In the discrete form, distinct compact granu­ lomas develop; there may or may not be central necrosis.

Figure 9.16  Pyogranulomatous inflammation commonly accompanies fungal endophthalmitis such as noted in this dog with blastomycosis. (Magnification 400×. Hematoxylin and eosin.)

cellular fluid compartments  –  the anterior and posterior chambers or the vitreous  –  then endophthalmitis is the appropriate descriptor. Panophthalmitis implies extensive intraocular involvement as well as involvement of the fibrous coats – cornea and/or sclera – with extension to adja­ cent orbit and adnexa.

Repair of Ocular Tissues The principles of tissue healing and repair are the same within the eye as other tissues and are discussed in detail in the introduction to this chapter. However, in addition to the interdependence of the ocular tissues and the function of transparency, the limited mitotic potential of critical tissues (the corneal endothelium in most species and retinal neu­ rons) as well as the proliferative and metaplastic capabilities of the lens and neuroectodermal epithelium, dictate that functional repair is the exception rather than the rule.

Sequelae of Ocular inflammation In general, the sequelae and consequences of intraocular inflammation are proportional to its severity and duration. Fibrinous exudation develops acutely and subsequently forms the scaffolds for fibrous ingrowth, organization into fibrous adhesions, and membranogenesis. Adhesions can form between iris and cornea (anterior synechiae) and iris and lens (posterior synechiae) (Fig.  9.17A). Adhesions between iris root and peripheral cornea (peripheral anterior synechiae) result in iridocorneal angle closure. Ocular membranogenesis is an important sequelae to inflammation. Cyclitic membranes are membranes that organize around the lens and use the iris as a scaffold and induce pupillary occlusion or grow across a condensation of vitreous and incorporate the ciliary processes (Fig. 9.17B, C). They can be devastating by virtue of ciliary and retinal traction with resultant ciliary detachment, hypotony, trac­ tional retinal detachment, and often phthisis bulbi or buphthalmos secondary to chronic glaucoma. Vitreal and periretinal membranes, although less common in animal eyes compared with humans, also result in retinal detach­ ment as they mature and contract. Although these mem­ branes may be referred to as retrolental membranes, pupillary membranes, cyclitic membranes, and the like, they typically extend as an anatomic continuum along the surfaces of the anterior and posterior segment. Photographs of gross sections reveal their extent better than clinical examinations and histologic sections in the acute and chronic stages (Fig. 9.17D–F). These membranes can be caused by fibrous ingrowth through a corneal or scleral wound, organization of fibrin­ ous exudation or hemorrhage, granulation responses by the uveal tissue, or arise from metaplastic epithelium. Phacoclastic uveitis, which occurs after breach of the lens

capsule, is largely the result of the proliferation of metaplas­ tic lens epithelium. The formation of fibrovascular membranes on the ante­ rior iris (Fig. 9.17G), retina, or optic disc as a consequence of the effects of soluble vasogenic proteins (predominantly vascular endothelial growth factor) is common in domes­ tic animals. They often occur as a result of chronic retinal detachment, retinal ischemia from glaucoma or hyperten­ sion, chronic uveitis, and intraocular tumors. The source of the proteins could be retinal neurons, inflammatory cells, or neoplastic cells. In domestic animals, the iris is more commonly affected than the posterior segment ­tissues. Although clinically the process is described as rubeosis iridis, or “red iris”, in human eyes, clinical mani­ festations are more difficult to detect in animals and the term “pre‐iridal fibrovascular membranes (PIFMs)” is pre­ ferred (Peiffer et  al., 1990; Treadwell et  al., 2015). These membranes often proliferate over the pectinate ligaments and lead to iridocorneal angle closure or obstructive glau­ coma, bleed as a common cause of spontaneous hyphema, and extend as pupillary, retroiridal, or anterior lens capsu­ lar membranes. Secondary cataracts occur because of the effects on lens metabolism by the products of inflammation. The lens epi­ thelial cells respond with anterior subscapular fibrous plaques, and metaplastic epithelium can migrate along the posterior lens capsule. Bladder cell and Morgagnian globule formation are common. Membranes can adhere to the ante­ rior lens capsule causing focal cataracts. Inflammatory cells and products can weaken the zonules with resultant lens dislocation. Secondary glaucoma occurs commonly as a sequela of inflammation (Johnstone McLean et  al., 2008). Extensive peripheral anterior synechiae with angle closure occurs with or without iris bombé or pupillary membranes. As men­ tioned above, iridocorneal angle obstruction and/or closure can occur as a result of PIFMs or other anterior chamber membranes. In phacolytic glaucoma, lens protein escaping through the intact lens capsule is ingested by macrophages that are of significant dimension to physically obstruct the trabecular meshwork. In chronic lymphoplasmacytic uvei­ tis, notably in cats, accumulations of inflammatory cells within the ciliary cleft can block access to the trabecular meshwork. Lastly, the chemical by‐products of chronic inflammation might have a deleterious effect on trabecular endothelial cells. Retinal detachment often occurs as the result of exudation from the choroid as the RPE barrier is compromised (Fig. 9.18A), or as a result of traction by cyclitic, vitreal, or perilenticular membranes that induce retinal tears (Fig. 9.18B). Atrophy is a postinflammatory sequelae to cell and tissue loss and occurs in uvea, retina, and optic nerve (Fig.  9.6 and Fig.  9.19). Less significant uveal changes include a

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Figure 9.17  A. This Bouin’s fixed canine globe has panophthalmitis with plasmoid material in the vitreous, posterior and anterior chambers, and in the subretinal space as portions of the retina have detached. Iris bombé is evident and developed secondary to the anterior and posterior synechiae. B. Pupillary occlusion (PO) due to posterior synechiae. Note the fibrous adhesion (FA) of the iris leaflets and ciliary processes to the anterior lens capsule in this domestic chicken. (Original magnification 40×. Hematoxylin and eosin.) C. This is a section of the anterior chamber of a dog diagnosed clinically with uveitis. Note the fibrovascular adhesion of this iris leaflet and the cornea and the lymphocytic–plasmacytic inflammation. (Magnification 200×. Hematoxylin and eosin.) D. A ruptured feline lens capsule with perilenticular fibrous membranes also known as cyclitic membranes, or perilenticular membranes. FM, fibrous membrane. Asterisk, thickened iris and ciliary body. (Original magnification 2×. Periodic acid-Schiff.) E. In the early stages of endophthalmitis, fibrin and neutrophils collect within anterior and posterior segments and form a scaffold for fibrous membranes to grow upon. In this gross section the lens implant is visible and significant purulent debris is collecting around the lens capsule and within the anterior vitreous of this dog. F. With time the fibrous membranes stretch across the intraocular tissues and occlude the pupil and encircle the lens which is ruptured in this dog. These fibrous membranes are also lifting and tearing the retina in this globe. G. Ectropion uveae in a dog due to a preiridal fibrovascular membrane that envelops the iris leaflet and contracts with outward deviation of the sphincter muscle and iris margin. (Magnification 400×. Hematoxylin and eosin.)

A

melanocytic hyperplasia with resultant hyperpigmentation and the formation of inflammatory iridociliary cysts. Phthisis bulbi occurs when severe inflammation and its sequelae result in cessation of aqueous production (Fig.  9.20). The clinical appearance of this end‐stage pro­ cess is a shrunken eye. Histologically, the hallmarks are an atrophic and disorganized globe characterized by cyclitic membranes, folds in Descemet’s membrane and the cor­ nea, a thickened sclera, loss of the anterior and posterior chambers and vitreous cavity, and variable degrees of chronic inflammation. Fibrous or osseous metaplasia of the ocular epithelium is common and necessitates decalci­ fication prior to processing the globe.

Pathology of Congenital Disorders

B Figure 9.18  A. Gross section of canine eye with septic endophthalmitis. Note the opaque plasmoid aqueous (PA) and vitreous (PV), and exudative retinal detachment. B. Gross section of a formalin-fixed dog’s eye with a rhegmatogenous retinal detachment. Note the giant tears in the peripheral retina, and the retinal scrolling. Focal vitreous traction bands induced the scrolling and contraction of the retina. GRT, giant retinal tear.

Figure 9.19  Retinal and choroidal degeneration with intraretinal migration of retinal pigment epithelium cells (arrows). (Original magnification 300×. Hematoxylin and eosin.)

Congenital disorders manifest at birth or shortly thereafter. Although the etiologies are diverse and often unknown or idiopathic, they include genetic mutation(s) or exposure of the embryo to nutritional deficiencies, toxins, or infectious agents. Anomalies have been categorized as those that occur during organogenesis and those disorders of tissue differen­ tiation that develop subsequent to organogenesis and target specific ocular tissues (surface ectoderm, mesoderm, neural crest, and neuroectoderm). Normal embryologic ocular development is not reviewed here and readers are encour­ aged to review Chapter 1 of this text.

Defective Organogenesis Anophthalmos is a total absence of ocular tissue that occurs because of failure of the primary optical vesicle to develop or because of complete regression of the optic vesicle (Fulton et  al., 1977; Rothenburger et  al., 2017). The few reported natural cases are bilateral. Vitamin A deficiency is also asso­ ciated with anophthalmos and concurrent anomalies of skeletal and central nervous systems anomalies in swine (Bendixen, 1944; Hale, 1935; Leipold & Huston, 1968). Far more common is the clinical perception of anophthalmos with histologic evidence of a microphthalmic globe or other ocular primordial element. Cystic eyes are very rare and consist of spherical structures lined by a single layer of undifferentiated neuroectoderm. The ocular development arrested at the optic vesicle stage with failure of invagination to form the optic cup and failure of lens development and invagination of the neuroectoder­ mal tissues. Microphthalmia is a small globe that usually has multiple ocular anomalies including cataract, microphakia, uveal hypoplasia, and varied colobomas (Fig. 9.21) (Da Silva et al., 2015). When a small globe is otherwise normal and the entire globe is symmetrical, the term nanophthalmia is appropriate. Phthisis bulbi is the major differential diagnosis, and the

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Figure 9.20  Gross (A) and subgross (B) sections. Phthisis bulbi develops secondary to unrelenting endophthalmitis. The hallmarks are a shrunken globe with multiple folds in the fibrous tunic and signs of chronic inflammation as present in this canine globe with chronic phacoclastic uveitis. (Magnification 2×. Hematoxylin and eosin.).

A

B

Figure 9.21  A. Microphthalmia in a Siamese kitten. Lack of support by a normal globe allows passive prolapse of the third eyelid. B. This microphthalmic eye is from a puppy. Absence of cornea and lens indicates ASD, hypoplastic uveal-like tissue lines the entire fibrous tunic (sclera), and the retina is dysplastic and nonattached. (Magnification 2×. Hematoxylin and eosin.)

histologic footprints of inflammation and thickened sclera facilitate distinction. True cyclopia is an exceedingly rare congenital anomaly in domestic animals that manifests as single orbit and globe located centrally in the forehead (Fig.  9.22A). More typi­ cally, a midline anomaly represents fusion of the develop­ ing globes with partial or complete duplication of intraocular structures and is properly referred to as syn­ ophthalmos (Fig.  9.22B). Both conditions are usually accompanied by multiple midline anomalies including cleft palate, hydrancephaly, microcephaly, median probos­ cis, and cranioschisis. Cyclopia has been induced by feed­ ing ewes Veratum californica (Binns et al., 1959, 1965). This

plant contains steroid alkaloids that damage the neural groove of the fetal lamb exposed at gestational days 14 and 15. Similarly, synophthalmia has been induced in mice by exposure of pregnant dams to ochratoxin (Robinson et al., 1993). Griseofulvin toxicity induces cyclopia, anophthal­ mia, and aplastic optic nerves in kittens from medicated queens (Scott et al., 1974). Coloboma is an absence of ocular tissue. Colobomas are classified as typical (orientated along the embryonic fissure) and atypical (those that are orientated along all other planes). Typical colobomas develop because of incomplete fusion of the embryonic fissure whereas atypical colobomas develop because of a lack induction or impaired proliferation of the

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(ii)

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Figure 9.22  A. A bovine cyclops with a single central eye and lack of nasal and maxillary development. B. (i) Synophthalmos in a newborn kid. (ii) Sagittal section reveals paired lens, partial separation of the anterior segments, and sharing of a posterior segment. (Courtesy of Brian Wilcock.)

affected tissues. Colobomas can affect most ocular tissues; so‐called lens colobomas are misnamed, and they are a deformity manifesting as a consequence of ciliary body and zonular colobomas. Extensive scleral colobomas lead to thinning (ectasia) with outpouching of the uvea and retina (staphyloma). Scleral colobomas can give rise to orbital cysts, which are lined by anomalous neural crest and neuroectodermal tissues (Greenberg et al., 2016). Inherited choroidal and optic nerve colobomas are common in dogs with Collie eye anomaly (Fig. 9.3 and Fig. 9.23), and in Charlais cattle (Brown et al., 1979; Roberts, 1960; Roberts et al., 1966).

Defective Tissue Differentiation After the optic cup is formed, ocular development continues with differentiation of neuroectoderm into retina, ciliary, and iridal epithelia. Neural crest tissues migrate and develop into the uvea, whereas mesenchymal differentiation pro­ ceeds into the vascular and fibrous tunics of the eye. Surface ectoderm differentiates into the lens, corneal and conjuncti­ val epithelium, and lacrimal, eyelid and conjunctival glands. The congenital anomalies that develop during tissue differ­ entiation are reviewed by the originating tissue.

Defective Neuroectoderm Differentiation Retinal Dysplasia

Retinal dysplasia reflects disorganization of the neuronal lamellae. The quintessential histologic lesion of retinal dys­ plasia is the rosette (Fig. 9.24). Rosettes consist of a central lumen containing dysplastic photoreceptor inner and outer segments surrounded by mul­ tiple layers of neuroblasts and axons and a discontinuous external limiting membrane. The pathogenesis of retinal dysplasia is complex and largely unknown (Silverstein et al., 1971). Retinal dysplasia has multiple etiologies, the most com­ mon being genetic mutations. The mode of inheritance has been confirmed in multiple dog breeds, and multiple organ system involvement is occasionally reported (Carrig et  al., 1988; Grahn et al., 2004; Meyers et al., 1983; Whiteley, 1991). Retinal dysplasia can be induced by in utero virus infections in cattle, dogs, cats, and sheep. These lesions are characterized by cellular necrosis and scarring with rosettes. Incriminated agents include bovine virus diarrhea, feline panleukopenia, feline leukemia, canine herpes, and bovine blue tongue viruses (Albert et al., 1976; Bistner et al., 1970). The acute lesions are a nonsuppurative endophthal­ mitis with multifocal chorioretinal necrosis. Chronic lesions

Section II: Foundations of Clinical Ophthalmology

ciencies (vitamin A, zinc, taurine) (Barnett & Grimes, 1974; Bendixen, 1944; Paterson et al., 1999). Retinal folds represent uncoordinated growth of retina and the outer coats such that excess retina is present (Fig. 9.1F). Although folds can be encountered as a component of retinal dysplasia as a secondary consequence of altered growth rate, they are distinct in terms of pathogenesis and significance. The antithesis is a developing retina that grows less than normal with resultant stretching, peripheral tearing, and congenital nonattachment.

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Optic Nerve Hypoplasia and Ganglion Cell Hypoplasia

Figure 9.23  A peripapillary coloboma (C), staphyloma (S), retinal detachment (RD), and retinal dysplasia (rd) in a Collie puppy with collie eye anomaly. (Original magnification 100×. Hematoxylin and eosin.)

Optic nerve hypoplasia develops secondary to ganglion cell hypoplasia as the axons of these ganglion cells form the optic nerve. The clinical diagnosis of optic nerve hypoplasia is lim­ ited to morphologic estimation (Fig. 9.25). These conditions are likely inherited, and they all involve ganglion cell hypo­ plasia (Barnett & Grimes, 1974; da Silva et al., 2008; Ernest, 1976; Gelatt & Leipold, 1971; Kern & Riis, 1981). In utero optic nerve atrophy is difficult to distinguish from hypoplasia both clinically and histologically; the former is distinguished by gliosis. Optic nerve and ganglion cell atro­ phy are induced in young cattle by vitamin A deficiency. The pathogenesis includes failed remodeling of the optic fora­ men resulting in stenosis and optic nerve compression and atrophy (Hayes et  al., 1968). Vitamin A deficiency induces optic nerve hypoplasia, retinal dysplasia, and systemic anomalies in piglets (Bendixen, 1944; Hale, 1935) Griseofulvin toxicity induces cyclopia, anophthalmia, and aplastic optic nerves in kittens from medicated queens (Scott et al., 1974).

Figure 9.24  Retinal dysplasia in a dog. Note the outer nuclear rosettes (R) and complete disorganization of the retina. (Original magnification 300×. Hematoxylin and eosin.)

include multifocal chorioretinal scarring, atrophy, and reti­ nal rosettes. The RPE is commonly affected with multifocal hyperplasia and degeneration. It is commonly accompanied by cerebellar atrophy, hydrocephalus, and hydrancephaly. Retinal dysplasia also occurs secondary to maternal toxin exposure (Percy & Danylchuk, 1977) and nutritional defi­

Figure 9.25  Optic nerve hypoplasia manifests as a small optic nerve; the affected animal may have abnormal pupillary light reflexes and visual impairment.

Defective Neurocrest and Mesenchymal Differentiation

After the optic cup is formed and the lens vesicle separates from the surface ectoderm, the periocular mesenchyme and neural crest cells undergo a series of migrations, differentia­ tions, and atrophies, and perturbations give rise most notably to ASD. ASD includes multiple anomalies of the cornea, lens, and anterior uvea. Affected globes often have micro­ cornea, corneal edema and scarring, adhesion of lens to cor­ nea, microphakia, spherophakia, and cataract. The anterior uvea and filtration angle are usually hypoplastic and con­ genital glaucoma can result (Fig.  9.26A, B; Helanda et  al.,

1997). Often marked angle recession precludes filtration angle assessment. ASD is caused by a primary lack of induc­ tion and differentiation of neural crest tissues or surface ectoderm or physical obstruction to migration by delayed separation of lens from surface ectoderm (Fig. 9.26C, D). There is considerable confusion surrounding congenital and perinatal glaucoma associated with ASD and primary glaucoma of dogs. Briefly, these are completely different syn­ dromes. Congenital glaucoma and glaucoma associated with ASD are confirmed by documenting a bupthalmic globe with microphakia and a hypoplastic uvea from birth to approximately three years of age. The intraocular pressures

A

C

B

D

Figure 9.26  A. Congenital glaucoma in a llama (Llama glama) characterized by microphakia, corneal striae, and a dilated pupil. (Reprinted with permission, Cullen, C.L. & Grahn, B.H. (1997). Congenital glaucoma in a llama (Llama glama). Veterinary and Comparative Ophthalmology, 7, 253–257.) B. Subgross section of the llama eye in A demonstrates buphthalmia, uveal hypoplasia, and mild optic disc cupping. The microphakic lens was removed from the anterior chamber during sectioning. (Original magnification 2×. Periodic acidSchiff.) C. Filtration angle hypoplasia is a common anomaly associated with glaucoma associated with ASD. (Periodic acid-Schiff.). D. Ciliary hypoplasia is a consistent anomaly in dogs and cats with glaucoma that is associated with ASD. (Smooth muscle actin label.)

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Section II: Foundations of Clinical Ophthalmology

in these globes are variable. In contrast, primary glaucoma associated with goniodysgenesis or open angles are develop­ mental anomalies that usually manifest much later in life. Although the outflow pathway in ASD might be described as goniodysgenesis, distinction is made from the other changes associated with primary glaucoma. Uveal hypoplasia is a common anomaly. All animals with poorly pigmented uvea have a hypoplastic vascular tunic. The extreme of this hypoplasia is albinism where uveal and neuroectodermal pigment are absent. The tapetum is usu­ ally poorly developed or absent in animals with hypoplastic uvea. Blue‐eyed animals lack iris stromal pigment whereas the neuroectodermal pigment remains. It has been assumed the lack of neurocrest (melanocytic) cells are a significant factor that results in the thin uvea in this condition; how­ ever, research is lacking. Collie eye anomaly is a congenital condition in Collie and Collie‐related dogs. The basic defect is focal choroidal hypo­ plasia located temporal to the optic disc and is inherited as an autosomal recessive trait. The genetic mutation is a homozygous deletion of 7.8 kb from the NHEJI gene, an intronic deletion in a conserved binding domain that binds several developmentally important proteins (Parker et  al., 2007). This syndrome is also reported in Border Collies, Shetland Sheepdogs, Australian Shepherd dogs, and Nova Scotia Duck Tolling dogs. Ophthalmic and gross examination reveals a variety of ocular anomalies including microphthalmia, choroidal hypoplasia that is focal and located temporal to the optic disc, optic disc and peripapillary colobomas and scleral ecta­ sia, and retinal detachment (Fig.  9.3). Light microscopic examination confirms the focal choroidal hypoplasia mani­ festing with thinning and hypopigmentation and other lesions. Persistent pupillary membranes, persistent hyperplastic primary vitreous (PHPV), persistent hyperplastic tunica vas­ culosa lentis (PHTVL) and patent hyaloid artery have been categorized within the classification of retention of primi­ tive embryonic vasculature (PEV) (Fig. 9.27). Persistent (or dysplastic) pupillary membranes represent incomplete atrophy of the perilenticular vasculature. These remain as pigmented strands that arise and insert on the iris collarette and usually span the pupil. If the membrane inserts on the lens or cornea, not only is it persistent but also dysplastic because in normal development such relation­ ships do not occur. This condition is common and in some breeds of dogs is an inherited congenital condition (Rubin, 1989). Iris to iris persistent pupillary membranes are present in most if not all horses. PHPV, PHTVL, and patent hyaloid artery are disorders that involve persistence of the posterior segment vascular supply to the lens. During ocular development the hyaloid artery extends from the optic disc to the lens and anasto­ moses with a capillary net from the anterior uvea (tunica

vasculosa lentis). During normal development in domestic animals these vessels atrophy and only focal remnants commonly remain (Bergmeister’s papilla, Mittendorf’s dot, anterior lens capsule pigment). Retention of these vascular nets are often incidental idiopathic congenital conditions (Boillot et al., 2015), although PHPV and PHTVL are inher­ ited congenital conditions in Doberman dogs, Staffordshire Terriers, Bloodhounds, and Miniature Schnauzer dogs (Grahn et al., 2004; Leon et al., 1986; Rensburg et al., 1992; van der Linde‐Sipman et al., 1983; Venter et al., 1996). The light microscopic features of PHPV (a misnomer because the tissue is actually metaplastic as well) include retention of multiple blood vessels and primitive perilenticular mes­ oderm and neurocrest cells in a core that extends from the optic disc to the posterior lens capsule. Occasionally, chori­ ostomatous cartilaginous or adipose tissues are encoun­ tered. The lens is often cataractous, and the posterior lens capsule is usually thickened with spindle cells and melano­ cytes. The posterior lens capsule is occasionally incomplete, and vessels and fibrous and pigmented tissues extend into the posterior lens cortex. The light microscopic findings with patent hyaloid arteries are similar; however, they are milder and include only a patent blood vessel that extends from the optic disc to the posterior lens capsule. The light microscopic findings of PHTVL are somewhat similar; however, the majority of vessels, pigmented neurocrest, and mesodermal tissues extend from the iris around the lens and anastomose with the retained primary vitreous cone and extend to the optic disc. Congenital anomalies of extraocular muscles are docu­ mented occasionally in dogs (brachycephalic breeds) and cattle (Holsteins), but the extraocular muscles have not been examined histologically. The clinical manifestations are often a bilateral strabismus (usually exotropia). The neuro­ logic system is usually normal. There is speculation that the affected extraocular muscles are either hypoplastic or have displaced scleral insertions. Defective Surface Ectoderm Differentiation

The corneal epithelium, lens, eyelids, and adnexal tissues are derived predominantly from surface ectoderm, although neurocrest and mesenchymal tissues might also contribute to some of the associated anomalies. Congenital anomalies, although not rare clinically, are seldom examined by the pathologist. Eyelid colobomas, micropalpebrae, and macro­ palpebrae are examples of such, and they might accompany other ocular anomalies including microphthalmia, entro­ pion, and ectropion. Colobomas and micropalpebrae are examples of defective ectodermal induction and differentiation. Similarly, anomalies involving the cilia and tarsal glands of dogs are common but only occasionally examined histo­ logically. Ectopic cilia and distichiasis develop because of dysplasia of the tarsal glands (Fig. 9.28). They are inherited

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A

B

D

C

E

F

G

Figure 9.27  Persistent and dysplastic pupillary membranes occur in three variants: iris to iris (A), iris to cornea (B), and iris to lens (C). The gross and light microscopic findings include pigmented uveal tissue that envelops small often nonpatent embryonic blood vessels that originate from the iris (D, E). F. Spherophakia and persistent hyperplastic primary vitreous in a dog. Note the pigment patches on the protruding posterior lens capsule and the vascularized stalk that adheres to the posterior lenticonus. G. Persistent hyperplastic primary vitreous (PHPV) in a dog. Note the shrunken lens (LENS) and lens capsule folds. The posterior lens capsule is incomplete. (Original magnification 2×. Hematoxylin and eosin.) (Courtesy of Brian Wilcock.)

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500

Figure 9.28  Multiple dysplastic eyelid tarsal glands with ectopic cilia in a dog. Multiple ectopic cilia are present on the palpebral conjunctival surface. The yellow distended and impacted tarsal glands are the chalazia.

in some dogs. Trichiasis and trichomegaly are similar con­ genital anomalies of the eyelids that occur because of misdi­ rected normal hair follicles and excessively large cilia, respectively. Lacrimal gland and duct aplasia or hypoplasia are poten­ tial etiologies for congenital keratoconjunctivitis sicca. Ipsilateral micropalpebral fissure is commonly associated. Congenital lacrimal gland disorders probably develop because of a lack of induction of the gland or secondary to duct atresia. Punctal, canalicular, and nasolacrimal duct atresia occur in dogs, camelids, cattle, and horses, but histologic examina­ tion of these tissues is not reported. The etiology is atresia. Occasionally, ectopic and supernumerary nasolacrimal duct openings are reported. The etiology is usually unknown and the pathogenesis is thought to be a lack of development of the surface ectoderm into a patent duct. Dacryops, canaliculops, and orbital cysts are uncommon congenital anomalies of dogs, cats, and horses (Dawson et al., 2016; Gerding, 1991; Grahn & Mason, 1995; Sritrakoon et al., 2016). These arise from abnormal development of the lacrimal glands, glands of the third eyelid, nasolacrimal drainage ducts, and canaliculi. The clinical manifestations include a cystic mass in the periocular tissue in the first months of life. Light microscopic findings include a mon­ olayer of cuboidal epithelium with or without an outer layer of spindle‐shaped myofibroblasts surrounding a serous to hemorrhagic fluid (Fig. 9.29). Dermoids are congenital lesions of the superficial cornea, conjunctiva, and eyelid skin. Dermoids are choriostomas which are misplaced normal tissues (Fig. 9.30A). They most likely develop because of defective induction or differentia­ tion of surface ectoderm. Histologic examination reveals stratified squamous epithelium that is keratinized and vari­ ably pigmented. The associated dermis contains sebaceous

Figure 9.29  Dacryops in a dog. Note the primarily double layered cuboidal epithelium with submucosal fibrosis and a clear lumen (Hematoxylin and eosin.) (Courtesy of Diane Hendrix.)

and sweat glands, adipose tissue, and hair follicles (Fig.  9.30B). Occasionally cartilage and bone are encoun­ tered. The edges of the dermoid blend into the corneal and conjunctival epithelium and stroma. Microcornea and macrocornea are uncommon and have no apparent histologic abnormality. The etiology is likely defective induction of neurocrest and or surface ectoderm. Congenital corneal opacities are frequently diagnosed in domestic animals; however, they are seldom examined his­ tologically. Those that involve the endothelium and are white or pigmented are often remnants of the embryonic vasculature (see persistent pupillary membranes). Congenital anomalies of the lens include cataracts, apha­ kia, microphakia, spherophakia, lenticonus, incomplete or delayed separation from the cornea, and lenticular coloboma (Fig. 9.31 and Fig. 9.32). These disorders might be isolated; however, they are commonly associated with ASD, congeni­ tal glaucoma, and PEV. Most of these anomalies develop sec­ ondary to defective induction and differentiation of surface ectoderm with some contributions of neurocrest and mesen­ chymal tissues during development. Cataracts are the most common congenital lenticular anomaly. The light microscopic manifestations are nonspe­ cific and include lens fiber protein alteration, fiber cell mem­ branolysis, and lens epithelial cell dysplasia, hypertrophy, and posterior migration, and occasionally mineralization. Congenital cataracts are unilateral or bilateral and solitary or associated with microphakia, lenticonus, spherophakia, and ASD. Aphakia is complete absence of a lens and is rare (Peiffer, 1982). The failure of differentiation of a lens from surface ectoderm does occur and dysplastic lens remnants can be found embedded within or adherent to the cornea (Fig.  9.32C, D). Microphakia and aphakia are common accompaniments in cases of congenital glaucoma. Microphakia manifests as a primary congenital anomaly and

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B

Figure 9.30  A. A corneal dermoid in a puppy. B. Histologic section of a corneal dermoid of the dog in A after keratectomy. The dermal components include hair follicles (H), sebaceous glands (SG), adipose tissue (F), keratinized pigmented epithelium (K&E). (Original magnification 200×. Hematoxylin and eosin.)

Figure 9.31  Congenital cataract and lenticular pseudocoloboma (*) in a dog. The equator is flattened and zonules absent. Generalized nuclear and focal cortical cataracts are present.

is usually associated with cataracts or ASD. Many breeds of dog with microphakia also have microphthalmia, and the condition is bilateral and often inherited. Spherophakia and microphakia are indicative of cessation of lens growth prior to the formation of secondary lens fib­

ers. Lenticonus describes a misshapen lens with a posterior or more rarely an anterior protuberance that results from dysplastic basement membrane production by the primary lens fibers. Posterior lenticonus (Fig. 9.32A, B) is commonly associated with PEV and posterior lens capsule dysplasia. Anterior lenticonus is most often associated with ASD and occasionally congenital glaucoma and reflects delayed sepa­ ration of the lens vesicle from surface ectoderm (Fig. 9.32C, D). Light microscopy reveals lens capsule distortion in either an anterior or posterior direction and subcapsular cataract. When the condition is associated with developmental anom­ alies of the vitreous, a posterior retrolental fibovascular membrane is often present; often the posterior lens capsule is incomplete and these abnormal tissues extend into the lens cortex. Certain breeds of dog (notably terriers) have a heritable condition in which the zonules appear normal initially but are of reduced tensile strength and rupture easily (Farlas et al., 2010; Foster et al., 1986). Light microscopic examina­ tion of terriers and Shar Pei dogs with zonular dysplasia reveals distinctive lamellar and crosshatched zonular pat­ terns with positive PAS and Mason’s trichrome and negative elastin staining (Morris & Dubielzig, 2005). Lens colobomas are actually pseudocolobomas that occur secondary to zonular aplasia. These are rare anomalies which manifest as an equatorial lens flattening where the zonules are absent (Fig.  9.31). Other than the misshapen equator, lens morphology is normal. If multiple colobomas are present around the lens equator, lens subluxation can result because of lack of zonular support. The light micro­ scopic findings with this disorder include focal zonular

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A

C

B

D

Figure 9.32  A. Posterior lenticonus in a calf. This is a congenital protrusion of posterior lens cortex, and the lens capsule might be incomplete in this area. B. Anterior lenticonus in a bovine. C. Histologic section of a cornea of a puppy with ASD with congenital glaucoma, aphakia, and other ocular anomalies. A periodic acid-Schiff positive basement membrane of varied thickness is embedded in peripheral cornea (arrows). The epithelial cells within the membrane resemble lens epithelium, but misplaced corneal endothelium with Descemet’s membrane is also a consideration. (Original magnification 20×. Periodic acid-Schiff.) D. This microphakic lens has not separated from the cornea in this dog with ASD. (Magnification 40×. Hematoxylin and eosin.).

aplasia associated with ciliary body colobomas or focal cili­ ary hypoplasia.

Acquired Ocular Disorders The pathology of acquired ocular disorders is diverse. The following information has been organized so that each ocular tissue (orbita, conjunctiva, cornea, sclera, uvea, vitreous and retina, optic nerve, and glaucoma) is discussed individually within the broad topics of noninfectious ocular disorders, infectious ocular diseases, degenerative disorders, and con­ ditions presumed to be inherited. Then metabolic and

infectious diseases that commonly affect ocular tissues will be summarized, and then finally ocular neoplasia is reviewed. The topics covered in the degenerative sections have some nebulous overlap with the earlier sections on congenital and inherited developmental diseases. In this section “degenera­ tion” is defined broadly to include: those diseases associated with a nutritional or metabolic basis; toxic conditions; aging changes; changes that occur associated with systemic dis­ ease; and those diseases of unknown etiology that are sus­ pected to have a genetic basis but remain somewhat equivocal in regard to cause. Inherited ocular disorders can be congenital or developmental and manifest later in life. This inconsistency in age of initial presentation makes

9: Veterinary Ophthalmic Pathology

Table 9.4  Ocular lesions associated with accidental or surgical trauma. Orbit

Edema, hemorrhage Orbital bone fractures

Adnexa

Edema, hemorrhage Laceration

Globe

Corneoscleral perforation Epithelial or fibrous ingrowth (late)

Conjunctiva

Erythema, chemosis, and hemorrhage Laceration

Cornea

Epithelial erosion Blood staining (with hyphema, endothelial damage, elevated intraocular pressure) Penetration/perforation

Anterior uvea Hyphema Trabecular fracture Iris sphincter muscle rupture

Noninfectious Inflammatory Ocular Disease

Iridodialysis

Ocular Trauma

Iridoschisis (separation of pigmented epithelium)

Traumatic disease is almost always accompanied by inflam­ mation (Moore et  al., 2017; Welihozkiy et  al., 2011); the importance of the post‐traumatic inflammation varies tre­ mendously. Mechanical trauma includes: accidental perfo­ rating and penetrating wounds of the globe, with or without the introduction of microbes and foreign bodies; contusion injuries; and surgical trauma. Physical trauma includes chemical and thermal burns and those changes induced by electromagnetic radiation. A penetrating wound is one that extends only partway through the tissue of reference; a perforating wound has both an entrance and exit site in the tissue of reference (Fig. 9.33). Thus, a perforating injury to the cornea may be either a penetrating wound of the globe or perforating if the injury extends through the cornea and sclera. With either, the sudden decompression of the globe leads to breakdown of the blood–ocular barrier and protein exudation (Fig. 9.33B). Uveal tissue is drawn into the defect, which it might effectively seal; if not, extrusion of lens, vitreous, and retina can follow. Shearing of the ciliary vessels as they pass from sclera to choroid can occur leading to expulsive subcho­ roidal hemorrhage that hastens the extrusion of globe contents. Although small hemorrhages usually resorb without sig­ nificant sequelae, large and recurrent hemorrhages can stimulate synechiae and membranogenesis as they organize (Fig.  9.33D), lead to hemoglobin‐staining of the cornea in the presence of endothelial compromise and elevated intraocular pressure (IOP), and leave behind hemosiderin and cholesterol residues. The specific lesions that are related to trauma are listed in Table 9.4.

Postcontusion angle deformity Cyclodialysis Lens

Capsular rupture Luxation/subluxation with zonular disinsertion Cataract

Vitreous

Detachment Prolapse (if zonules ruptured) Hemorrhage (from retinal vessels)

Retina

Edema Hemorrhage Necrosis Tear/peripheral dialysis/detachment

Optic nerve

Avulsion

Acquired Orbital Disorders Idiopathic Orbital Inflammatory Syndrome

Historically described in the human ophthalmic pathology literature as “pseudotumor,” this process occurs rarely in animal species. By definition, it is a benign nongranuloma­ tous, noninfectious inflammatory process characterized by a diffuse lymphocytic plasmacytic orbital cellulitis and fibro­ sis with chronicity. Cases previously reported as orbital pseudotumor in cats would now most likely be diagnosed as feline restrictive orbital myofibroblastic sarcoma (Bell et  al., 2011; Billson et  al., 2006; Miller et  al., 2000). Histologic examination reveals orbital fibrosis and lymphocytic/plasmacytic orbital inflammation. This condition is progressive and manifests

SECTION II

classification of inherited congenital, inherited, or breed specific developmental disorders, and some acquired ocular conditions somewhat problematic. Accurate diagnosis of an inherited developmental disorder requires knowledge of breed predispositions, ages of onset, clinical manifestations and appreciation of the primary lesions, and changes that occur secondary to the primary lesion. Confirmation requires test breeding and a pedigree analysis to determine the mode of inheritance. Finally, examination of DNA, RNA, and proteins at a molecular level are required to document the mutation inducing the anomaly. Ophthalmologists cate­ gorize many disorders as inherited based on breed predispo­ sition and pedigree analysis because the basic research is often lacking. The descriptions here have been limited to a few disorders that have a unique breed predisposition, a con­ sistent bilateral clinical manifestation, and histologic exami­ nation findings that are most consistent with a developmental disorder.

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A

C

B

D

Figure 9.33  A. This cat eye sustained penetrating and perforating trauma. Note the thin discontinuous sclera with the uveal plug (UP), the ruptured lens (RL), and major disruption of the intraocular contents. B. Plant foreign bodies within the vitreous of this dog’s eye. Spear grass seeds (asterisks) will occasionally penetrate and then perforate the sclera and induce a fulminant endophthalmitis. C. Endophthalmitis and scleral perforation (SP) in a dog with penetrating trauma and septic endophthalmitis. Note the streaming of inflammatory exudates through the choroidal and scleral perforation. (Original magnification 200×. Hematoxylin and eosin.). D. Blunt ocular trauma often induces significant intraocular hemorrhage with disruption of most ocular tissues like this canine globe.

histologically with a diffuse spindle cell infiltration with vari­ able collagen accumulation around the episcleral tissues. Orbital Cellulitis/Abscess

Orbital cellulitis/abscess is a suppurative process with mul­ tiple causes including: sharp foreign bodies that penetrate

the oral cavity behind the upper last molars, the eyelids, or conjunctiva; foreign body migration (porcupine quills) (Grahn et  al., 1995b); self‐inflicted wounds (hedgehogs) (Wheler et al., 2002); cat bite wounds; hematogenous seed­ ing of bacteremia; or extension of diseased adjacent tissues (Grahn et al., 1995a). Although clinical signs and imaging

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505

inflammation predominate initially, with muscle atrophy a sequela in chronic cases.

are usually definitive, fine needle aspirates and orbital biopsies can be used to confirm the diagnosis. Acutely, this condition is largely neutrophilic; with time, the infiltrate will become mixed, with macrophages, lymphocytes, and plasma cells predominating.

Orbital and periorbital cysts occur in young animals and most commonly arise from dysplastic lacrimal tissue (Grahn & Mason, 1995; Martin et al., 1987). Light microscopic exam­ ination reveals thin‐walled cysts lined by a bilayered epithe­ lium containing serous fluid (Fig.  9.35). Zygomatic mucoceles are identified by nonencapsulated mucinous secretions dissecting through the orbit and periorbital soft tissues.

Masticatory Myositis

Masticatory and extraocular myositis occurs in large breeds of dogs (Allgoewer et  al., 2000; Carpenter et  al., 1989). Initially, exophthalmos is related to compression of the orbital contents by the inflamed muscles of mastication, and chronically enophthalmos results from atrophy of both muscle and orbital tissues. Histopathology reveals that the orbital tissues are edematous and infiltrated diffusely with lymphocytes, plasma cells, and eosinophils secondary to the masticatory myositis (Fig.  9.34). Muscle degeneration and

Degenerative Orbit Disorders

Enophthalmos secondary to atrophy of periorbital muscles/ adipose tissue is a common sequel to chronic extraocular myositis and orbital cellulitis, and also occurs with aging. Histopathologic alterations include atrophy and fibrosis of the orbital tissues including the extraocular muscles; seque­ lae to cases caused by myositis or cellulitis often have an inflammatory footprint. Presumed Inherited Orbital Conditions

Proptosed globes induce significant orbital cellulitis and extraocular myositis and most commonly occur in brachy­ cephalic dogs with shallow orbits and large eyelid fissures. This most likely has a multifactorial inheritance. Similarly, extraocular myositis of Golden Retrievers, eosinophilic masticatory myositis of German Shepherd dogs and Weimaraners, and craniomandibular osteopathy of West Highland and Scottish Terriers are bilateral immune‐ mediated predominantly breed‐specific conditions which most likely have a genetic etiology or predisposition. Diagnoses of eosinophilic myositis and extraocular myositis are confirmed by biopsy and light microscopic examination

Figure 9.34  Extraocular myositis in a young Golden Retriever. There are dense infiltrations of lymphocytes and plasma cells within the rectus muscles. (Original magnification 100×. Hematoxylin and eosin.)

A

B

Figure 9.35  A. Lacrimal gland cyst with a bilayered lining of cuboidal epithelial cells and fusiform myoeithelium. (Original magnification 200×. Hematoxylin and eosin.) B. Lacrimal gland cyst lining (C) that is fibrotic and infiltrated with numerous lymphocytes adjacent to the lacrimal gland (LG) from a dog. (Original magnification 200×. Hematoxylin and eosin.)

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Orbital Cysts and Mucoceles

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Section II: Foundations of Clinical Ophthalmology

which reveals eosinophilic and lymphocytic plasmacytic myositis, respectively, acutely. When the myositis is chronic, nonspecific fibrosis and atrophy of the affected muscles can be found. The pathogenesis of both disorders is largely unknown; antibodies against 2M muscle fibers have been detected.

Acquired Lacrimal Gland Disease Degenerative Lacrimal Gland Disorders

Lacrimal gland degeneration develops most commonly sec­ ondary to immune‐mediated or inflammatory adenitis, and less frequently from toxicities and denervation (Fig. 9.36A). Immune‐mediated adenitis is lymphoplasmacytic, with extension of neutrophils (Fig.  9.36B). Chronically, gland atrophy and fibrosis with smatterings of residual inflamma­ tory cells and keratoconjunctivitis sicca result (Kaswan et al., 1984, 1985; Kern et al., 1988; Martin et al., 1988).

Acquired Conjunctival Disorders Conjunctivitis

The conjunctiva serves as a mediator of inflammation of the anterior segment. A resident small population of lym­ phocytes and plasma cells and the occasional mast cell is commonly present. A diagnosis of “conjunctivitis” requires appreciation of other anterior segment changes to deter­ mine if the conjunctiva is primarily involved or simply reacting to what is happening with adjacent tissue. Conjunctivitis is characterized acutely by vascular dilation, edema, cellular infiltration, and exudation, which mani­ fests as ocular discharge (Fig. 9.37A). Rarely, pseudomem­ branes form and are composed of necrotic cells, protein,

A

and fibrin. True membranes result from epithelial necrosis, and removal results in an ulcerative, frequently hemor­ rhagic lesion. With chronicity, lymphoid follicles often form on the surface (Fig. 9.37B). Although there are diverse etiologies for conjunctivitis, light microscopic changes are generally nonspecific. However, conjunctival biopsies are readily harvested and are potentially useful. Eosinophilia is suggestive of a parasitic disease. In concert with cytology, infectious organisms such as mycoplasma and chlamydia may be identified. Eosinophilic Keratoconjunctivitis

Eosinophilic keratoconjunctivitis is an idiopathic chronic ocular condition of cats (Fig. 9.13) (Allgoewer et al., 2001) and horses (Lassaline‐Utter et al., 2014). The clinical mani­ festations include conjunctival hyperemia and nonulcera­ tive vascular keratitis with multifocal white to yellow surface granules. The diagnosis is confirmed with light microscopic examination of cytologic specimens or biopsy which reveals a mixed inflammatory infiltrate with variable but prominent numbers of eosinophils accompanied by lymphocytes, plasma cells, and mast cells. The surface granules are thought to represent concretions of mast cell products. A similar condition with identical histologic features can be found in horses. Lipogranulomatous Conjunctivitis

Multifocal gray to yellow nodules have been reported on the palpebral conjunctiva of cats (Kerlin & Dubielzig, 1997; Read & Lucas, 2001). These have light microscopic features of lipogranulomas with packets of free lipid delineated by pillars of giant cells, macrophages, and a sparse number of neutrophils and lymphocytes. The pathogenesis is not

B

Figure 9.36  A. Normal canine lacrimal gland. Note the acinar structure and occasional periacinar lymphocytes and plasma cells. (Original magnification 60×. Hematoxylin and eosin.) B. Lacrimal gland adenitis with neutrophil infiltration. (Original magnification 20×. Hematoxylin and eosin.)

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B

Figure 9.37  A. Acute conjunctivitis in a dog. Note the vasodilation congestion and neutrophilic infiltration. (Original magnification 200×. Hematoxylin and eosin.) B. Chronic conjunctivitis in a dog. Note the proteinaceous surface exudate, vasodilation, and diffuse mononuclear cell infiltrate (Original magnification 200×. Hematoxylin and eosin.)

known but speculated to be related to meibomian gland dys­ function and ultraviolet radiation. Miscellaneous Conjunctival Disorders Including Goblet Cell Atrophy, Conjunctival Overgrowth, and Conjunctival Sequestrae

Deficiency of tear film mucin has been reported in both dogs and cats (Cullen et al., 1999; Grahn et al., 2005; Moore et al., 1987). The clinical manifestations include conjunctivitis and keratitis. The light microscopic examination of bulbar con­ junctival biopsies typically reveals reduced numbers of gob­ let cells in all quadrants and a mild nonspecific lymphocytic plasmacytic conjunctivitis (Fig. 9.38). PAS sections facilitate goblet cell assessment, and normal ratios of goblet cells to

A

basal epithelial cells by quadrant have been reported (Cullen et al., 1999; Grahn et al., 2005). Conjunctival overgrowth is an unusual idiopathic condi­ tion of rabbits that manifests clinically with a fold of redun­ dant conjunctiva that develops circumferentially around the peripheral cornea (Fig.  9.39A). Light microscopic findings include a fold of conjunctiva that originates from the limbus and extends axially across the cornea. The epithelium on the leading edges of the overgrowth and the cornea is occasion­ ally noted to be hyperplastic (Fig.  9.39B). A mild lympho­ cytic plasmacytic cell infiltrate is often present but not considered significant. Sequestrae of the conjunctiva (including the third eye­ lid and conjunctival grafts) occur in cats and are similar

B

Figure 9.38  A. A conjunctival biopsy from the conjunctival fornix of a normal cat. (Original magnification 50×. Periodic acid-Schiff.) B. A conjunctival biopsy from a cat with goblet cell atrophy. Compare this photo with an age-matched control cat in A. (Original magnification 50×. Periodic acid-Schiff.) (Source: Reprinted with permission from Cullen, C.L., Njaa, B.L. & Grahn, B.H. (1999) Ulcerative keratitis associated with qualitative tear film abnormalities in cats. Veterinary Ophthalmology, 2, 197–204.)

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A

B

Figure 9.39  A. Conjunctival overgrowth in rabbit. B. Histologic appearance of conjunctival overgrowth (CO) in the rabbit noted in A. Note the plicated conjunctiva overlying the cornea (C) and hyperplastic corneal epithelium at the leading edge. (Original magnification 100×. Hematoxylin and eosin.)

histologically to corneal sequestrum; the reader is referred to the section on Corneal Sequestrae for a more complete description.

Conjunctival Disorders That Are Presumed Inherited Ligneous conjunctivitis is a manifestation of a suspected inherited disease of Doberman Pinscher dogs and Golden Retrievers (McLean et  al., 2008; Ramsey et  al., 1996). The clinical presentation is dramatic with thickening of the con­ junctiva with yellow‐gray membranes. Ulcerative lesions of other mucous membranes and proteinuria often occur con­ currently. The surface of the conjunctiva is often encased in

purulent debris and fibrin (Fig.  9.40) with an amorphous hyaline membrane in the substantia propria and diffuse lym­ phocyte infiltration. The condition is related to a plasmino­ gen deficiency, and the prognosis is poor (McLean et  al., 2008).

Acquired Conditions of the Cornea Keratitis

Inflammatory disease of the cornea is meaningfully classi­ fied as either ulcerative or nonulcerative and superficial or deep (stromal). Nonulcerative Keratitis

Acute inflammation is characterized by edema associated with loss of epithelial integrity and/or compromise of the limbal blood vessels. Neutrophilic infiltrate gains access from the conjunctiva via the tear film or migration from lim­ bal vessels. With chronicity, the nature of the infiltrate changes, neovascularization from limbal blood vessels occurs, and scarring and epithelial pigmentation often develop (Fig. 9.41). Ulcerative Keratitis

Figure 9.40  Ligneous conjunctivitis in a Doberman Pinscher. Note the hyperemic conjunctivitis and fibrinous conjunctival discharge. (Courtesy of Lynne Sandmeyer.)

Ulcerative keratitis can be classified as simple, indolent, and complex. As simple ulcers are superficial, they are seldom examined histologically unless they are incidental to another globe‐threatening disorder. The histologic findings include absence of epithelium with associated edema and sparse neutrophilic infiltrate. Indolent, or slow or nonhealing cor­ neal ulcers (superficial chronic corneal epithelial defects) are best categorized as primary (idiopathic) or secondary to

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Figure 9.41  A. Chronic keratitis in any species can induce chronic changes in the cornea to the extent that the cornea begins to resemble skin, or epidermalization. The epithelium thickens and rete peg projections develop. Dyskeratosis can occur. The underlying stroma demonstrates fibrovascular ingrowth, and there is a zonal lymphocytic and plasmacytic infiltrate. (Original magnification 100×. Hematoxylin and eosin.). B. Pigmentary keratitis that develops in a medial to temporal progression is common in brachycephalic dogs with shallow orbits and an enlarged palpebral fissure. Light microscopy reveals epithelial and subepithelial melanocyte hypertrophy and hyperplasia and subepithelial scarring and vascularization. (Original magnification 400×. Hematoxylin and eosin.)

a known cause, that is, tear film abnormality, conjunctival or eyelid foreign body or cilia, or breed associated (notably Boxer dogs). The epithelium at the margins is elevated off the stroma; cellular disorganization is manifested by loss of polarity and epithelial cellular eddies. The basement mem­ brane is often absent or thickened. An acellular zone is usu­ ally present on the denuded corneal surface (Fig.  9.42). Although the ulcer is focal (usually) the entire cornea is involved in the underlying condition. The pathogenesis is unknown, with possible origins including defects in epithe­ lial cell hemidesmosomes, basement membrane, or underly­

ing stroma (Bentley et  al 2001; Gelatt & Samuelson, 1982; Hempstead et al., 2014; Jegou & Tromeur, 2015; Kirschner et  al., 1989; La Croix et  al., 2001). Complex corneal ulcers typically involve loss of stroma, can have a robust neutro­ philic infiltration, and exhibit variable collagenolysis (Fig. 9.43); infectious agents are often identified with special stains. Progression to perforation and associated complica­ tions is a frequent finding in enucleated globes. Corneal Inclusion Cysts

Occasionally, corneal epithelium becomes displaced by trauma into the corneal or conjunctival stroma and rarely into the eye (Fig.  9.44). The epithelium then proliferates, resulting in an inclusion cyst. These cysts have a yellow‐gray appearance clinically and contain desquamated epithelial cells and are lined by corneal epithelium. The diagnosis is confirmed by light microscopic confirmation of an epithe­ lial‐lined cyst within the cornea or the presence of epithe­ lium growing across intraocular surfaces. Degenerative Corneal Disorders

Figure 9.42  An indolent corneal ulcer in a Boxer dog. Note the epithelial nonadherence, irregular thickened basement membrane (BM), corneal edema, and the relatively acellular subepithelial stromal layer (ASL). (Original magnification 100×. Hematoxylin and eosin.)

Degenerative corneal disease includes pigmentary keratitis (Fig.  9.41B), calcific degeneration (Fig.  9.45A), and lipid degeneration (Fig.  9.45B) and occurs in dogs, horses, and cats (Berryhill et al., 2017). The majority of corneal degen­ erations are the product of chronic keratitis (including that seen with exposure keratopathy or keratoconjunctivitis sicca), and the primary etiology might not be evident histopathologically.

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A

B

Figure 9.43  A. Collagenolysis of the cornea in dog. A large deep ulcer is present with a mucopurulent stream of liquefied collagen extending off the inferior edge. B. Histopathology of a melting cornea shows absence of corneal epithelium, neutrophilic infiltration throughout the corneal stroma, loss of corneal stroma (CS) secondary to collagenolysis, and plasmoid aqueous. (Original magnification 250×. Hematoxylin and eosin.)

A

B

Figure 9.44  A. A corneal epithelial inclusion cyst in a Miniature Poodle. B. Histologic section of corneal epithelial inclusion cyst noted in A. Epithelial inclusion cysts are lined by a nonkeratinized epithelium (E) and contain desquamated epithelial debris (ED). (Original magnification 100×. Hematoxylin and eosin.)

Corneal Sequestrae

Corneal sequestrae are common in cats. Variant lesions have rarely been described in horses and dogs. In cats, sequestrae manifest as a golden to dark brown discoloration of the cor­ neal stroma. Etiology is unknown; association with feline herpesvirus‐1 infection and corneal ulceration has been

hypothesized, and Persians and Himalayans are predisposed. Histologic features include a loss of keratocytes with stromal hyalinization and an amber pink coloration on hematoxylin and eosin‐stained sections (Fig.  9.46). The corneal lesion commonly involves the anterior stroma, but full‐thickness lesions including Descemet’s membrane occur. PAS stains

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SECTION II

C

C

C

A

C

C

B

Figure 9.45  A. Calcific corneal degeneration in a dog. Calcium appears as a red granular supbepithelial deposit. (Original magnification 250×. Alizarin red stain.) B. Lipid corneal degeneration in a dog. Note stromal clefts (C) where lipid was present before processing and the diffuse infiltration of lymphocytes and plasma cells and neutrophils. (Original magnification 250×. Periodic acid-Schiff.)

A

B

Figure 9.46  A. A feline corneal sequestrum (CS) with characteristic amber color and stromal acellularity and compaction. (Original magnification 50×. Hematoxylin and eosin.) B. The edge of the sequestrum in A with numerous degenerating neutrophils (N) invading the edge of and colonies of bacteria (arrows) present near the surface of this sequestrum. (Hematoxylin and eosin. Original magnification 200×.)

identify granules in the degenerate keratocytes and suggest an autolytic process. The source of the discoloration is not known (Featherstone et al., 2004; Newkirk et al., 2011). With chronicity, stromal vascularization and inflammatory infil­ trates encompass the sequestrum (Fig. 9.46B). Bullous Keratopathy in Cats

An idiopathic condition characterized by uni‐ or bilateral formation of large corneal stromal bullae occurs in cats. Histologically, stromal fibers are separated by clear fluid and the endothelium appears normal. Mild inflamma­ tory infiltrates are present with neutrophils the most common.

Inherited Corneal Disorders Corneal dystrophy occurs in many species. For example, corneal dystrophy in rabbits and rodents likely has a genetic basis; incidence varies depending on strain. Histologic fea­ tures include calcification of the basal lamina and an over­ lying epitheliopathy. The following discussion will focus on dogs. Corneal Stromal Dystrophies

Corneal stromal dystrophies are inherited stromal metabolic defects that result in the accumulation of extracellular and intracellular lipid in many breeds of dogs (Ekins et al., 1980;

Section II: Foundations of Clinical Ophthalmology

affected cornea stained with lipid stains, including oil red O, reveals extracellular and intracellular lipid. Differentiation from the morphologically similar lipid degeneration that occurs secondary to chronic keratitis, episcleritis, or at the corneal margin of a limbal melanocytoma is facilitated by identification of an initiating factor.

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Corneal Endothelial Dystrophy

Figure 9.47  Inherited corneal dystrophy in a young American Cocker Spaniel. A band of subepithelial clefts (C) are present where lipid that was dissolved during processing was present. This lesion is easily mistaken as stromal artifact; however, the lesion was bilaterally symmetric and the clefts larger than the artefactual separations of fixation. (Original magnification 50×. Periodic acid-Schiff.)

MacMillan et al., 1979; Martin & Dice, 1982; Morrin et al., 1982; Rubin, 1989; Spangler et al., 1982; Waring et al., 1986). The light microscopic findings are subtle with spherical to elliptical clefts situated between the collagen fibers in the superficial and mid stroma and less commonly in the deep stroma (Fig.  9.47). Stromal keratocytes in affected corneas appear degenerate, necrotic, or normal. Frozen sections of

A

Corneal endothelial dystrophy manifests as corneal edema. Predisposed breeds of dogs include the Boston Terrier, Poodle, Chihuahua, Dachshund, and Shih Tzu (Gwin, 1982; Rubin, 1989). Clinically, stromal and epithelial edema with bullae and ulceration, vascularization, and pigmentation are evident. The pathogenesis appears to involve endothelial apoptosis that allows the pressure gradient of IOP to over­ whelm the remaining endothelial pump function, and cor­ neal decompensation and edema develop. The edema often begins in the paracentral or temporal areas and progresses across the entire cornea. The histologic features include extensive corneal edema detected by the presence of intra‐ and intercellular edema and subepithelial bullae, thickening of the corneal stroma with dampening of tinctorial quality and notable decreases in common artefactual fixation‐ induced intercollagenous clefts, thickening of Descemet’s membrane by a retrocorneal membrane, and depletion and fibrous metaplasia of endothelial cells (Fig. 9.48). Corneal Subepithelial Dystrophy

Corneal subepithelial dystrophy is also known as epithelial erosion syndrome and superficial punctate keratopathy. This condition is likely inherited in Shetland Sheepdogs and

B

Figure 9.48  A. A Boston Terrier with endothelial dystrophy following corneal transplantation contrasting the central clear button with peripheral diffuse corneal edema. B. The diseased cornea of the dog in A was characterized by a depletion of endothelial cells. Fibrous metaplasia has formed a fibrous retrocorneal membrane. (Original magnification 300×. Hematoxylin and eosin.)

9: Veterinary Ophthalmic Pathology

Dachshunds (Rubin, 1989). The pathogenesis might involve a metabolic defect that induces multifocal punctate lipid deposits around and beneath the epithelial cells. This condi­ tion manifests with focal corneal rings and spots with white to yellow margins. The histologic manifestations have not been reported but likely include subepithelial lipid and min­ eral infiltrates.

513

Acquired Disorders of the Sclera Inflammation of the sclera and episclera is classified by location (anterior vs. posterior), as diffuse or nodular, as granulomatous or nongranulomatous, and as necrotizing or non‐necrotizing (Fig. 9.50). Scleritis typically is characterized by macrophages pali­ sading about degenerating collagen fibrils and may be accompanied by discrete uveal granulomas or extend to involve adjacent uvea in a diffuse inflammatory process (Breaux et  al., 2007; Day et  al., 2008; Denk et  al., 2012; Williams et  al., 2005). Scleral necrosis (degeneration is a more appropriate term) and malacia with perforation can occur and is considered pathognomonic for necrotic scleritis (Fig.  9.51). The majority of primary scleritis cases are immune‐mediated processes localized to the eye.

Chronic Superficial Keratitis (Pannus)

Chronic superficial keratitis (pannus) is a bilateral symmet­ rical immune‐mediated nonulcerative keratitis that may have a genetic component and manifests primarily in the German Shepherd dog, Greyhound, and several other large breed dogs (Rubin, 1989). In those rare instances when the cornea is examined histologically, there is edema, vasculari­ zation, pigmentation, and mineralization (Fig.  9.49). The inflammatory cell infiltrate is mixed and includes lympho­ cytes and plasma cells that array along the epithelial base­ ment membrane.

Presumed Inherited Episcleral Disorders Nodular episclerokeratitis (which may involve the conjunc­ tiva as well) is a bilateral inflammatory disorder that is unique to the Collie dog (Deykin et al., 1997; Paulsen et al., 1987). The clinical manifestations include bilateral nodular pink masses that commonly develop near the temporal lim­ bus, cornea, or third eyelid (Fig. 9.50A). Excisional biopsies reveal a diffuse mixed inflammatory infiltrate with lympho­ cytes, plasma cells, macrophages, and fibroblasts (Fig. 9.50B). The pathogenesis is assumed to be immune‐mediated based on the response to immunomodulators. Bilateral episcleritis is diagnosed commonly in American Cocker Spaniels. Light microscopy reveals a diffuse mixed inflammatory cell infiltrate that targets the episcleral tissues similar to nodular episclerokeratitis in Collies. It is assumed

Figure 9.49  Chronic superficial keratitis in a dog. Note the nonspecific epithelial hyperplasia (EH), pigmentation, and undulating epithelial basement membrane, and stromal vascularization (SV) and scarring. (Original magnification 100×. Hematoxylin and eosin.)

A Figure 9.50  A. Nodular episclerokeratitis in a Collie. B. The light microscopic manifestations are nonspecific and consistent with all forms of episcleritis and include a mixture of lymphocytes, plasma cells, macrophages, fibroblasts, and occasional neutrophils. (Magnification 200×. Hematoxylin and eosin.)

B

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Episcleritis and Scleritis

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A

B

Figure 9.51  A. Canine globe with necrotic scleritis. Note the extensive thickened sclera (S) and eosin-stained patches characteristic of collagen degeneration (*). (Original magnification 2×. Hematoxylin and eosin.) (Courtesy of Brian Wilcock.) B. Collagen degeneration in necrotic scleritis which is a nonspecific finding as it is also found in non-necrotizing scleritis cases. Note the eosinophilic staining of the scleral collagen fibers, the lack of sclera cells, and the bands of dark blue inflammatory cells near the edges. Examination at higher magnification revealed lymphocytes, plasma cells and macrophages, and occasional neutrophils. (Original magnification 100×. Hematoxylin and eosin.)

500 μm

Figure 9.52  Lymphoplasmacytic uveitis in a cat diagnosed with secondary glaucoma. Note the perivascular cellular infiltrate in the iris that extended into the trabecular meshwork. (Original magnification 200×. Hematoxylin and eosin.)

to be immune‐mediated based upon histology and response to immunosuppression.

Acquired Inflammatory Uveal Disorders Lymphoplasmacytic uveitis is a common nonspecific histo­ logic diagnosis in animals (Bergstrom et  al., 2017; Jinks

Figure 9.53  Equine recurrent uveitis. A fibrovascular membrane incorporates the ciliary processes and neutrophils and lymphocytes extend from the ciliary body into the vitreous which contains fibrin as well. (Original magnification 200×. Periodic acid-Schiff.)

et al., 2016). The classic histologic features include diffuse or nodular infiltrates of lymphocytes and plasma cells in the anterior (Fig.  9.52) and occasionally the posterior uvea (choroid). Granulomatous uveitis occurs infrequently (see Fig.  9.69A, B). Several accompanying ocular disorders include glaucoma, ulcerative and nonulcerative keratitis, hyalitis, vitreous degeneration, and cataract. Equine recurrent uveitis and feline lymphocytic uveitis are common idiopathic conditions characterized by lym­ phoplasmacytic uveitis (Fig. 9.53). Equine recurrent uveitis in its acute form manifests histologically as a predominantly

9: Veterinary Ophthalmic Pathology

Figure 9.54  Vasculitis in the retina of a cow with malignant catarrhal fever. Note the inflammatory infiltrate within the retinal arterial wall. (Original magnification 250×. Hematoxylin and eosin.)

are also seen (Fig. 9.54). The lymphoid cells often have fre­ quent mitoses. Conjunctiva, uvea, retina, and optic nerve meninges can be involved. The inflammation has been clas­ sified as a type IV hypersensitivity reaction. Lens-Induced Uveitis

Lens‐induced uveitis manifests in two forms, phacolytic and phacoclastic in all species. Phacolytic uveitis also has two variants: a mild lymphoplasmacytic uveitis and a severe granulomatous anterior uveitis (Fig. 9.55) (van Der Woerdt et  al., 1992; Wilcock & Peiffer, 1987). The pathogenesis of both is thought to be caused by liquefied cataractous lens proteins leaking through an intact capsule and initiating the inflammatory response. The light microscopic findings of the mild form include minimal anterior uvea lymphocytic plasmacytic infiltrate and a cataract. The granulomatous version also includes a cataractous lens; however, the uveitis is more severe, and the inflammatory infiltrate includes macrophages, lymphocytes, and neutrophils. The reason for the difference is unknown; the granulomatous variant occurs most commonly in diabetic cataracts with a predispo­ sition for Miniature Schnauzers. Phacoclastic uveitis presents most often as a granuloma­ tous lens‐induced uveitis that follows rupture of the lens capsule with resultant exposure of large amounts of lens protein (Fig. 9.56) (Wilcock & Peiffer, 1987). The capsular rupture occurs after blunt or penetrating (including surgi­ cal) trauma, spontaneously with an intumescent cataract (usually diabetic), or associated with infectious agents (Encepalitizoon caniculi). The nature of the response is dependent upon species, age, amount and nature of the lens protein exposed, the presence of concurrent microbial endophthalmitis, and duration. The resulting lesion repre­ sents a combination of the effects of the initial insult, the immunologic response to the released lens protein, a

Figure 9.55  Severe phacolytic uveitis in a dog. Note the keratic precipitates and hypopyon.

SECTION II

lymphocytic anterior uveal and peripapillary choroidal infiltrate with exudation into the aqueous and vitreous. With chronicity and recurrence, crystalline pro­ tein inclusions might be seen ultrastructurally within the ciliary epithelium, and the basal layer of the inverted non­ pigmented ciliary epithelial cells are enveloped by amyloid. An accompanying mononuclear perivascular infiltrate will be evident in uvea, retina, and optic nerve (Cooley et  al., 1990; Dubielzig et al., 1997). Heterochromic iridocyclitis has been reported in horses (Pinto et al., 2015), and it is characterized histologically as a lymphocytic uveitis with iridal pigment loss and endotheli­ alitis and keratitis. In feline lymphoplasmacytic uveitis, two variants, one with and the other without anterior uveal lymphoid nodules, exist (Davidson et al., 1991; Peiffer & Wilcock, 1991). These nodules are largely lymphocytic without follicular differentiation. Many cases will show a granulomatous component with “mutton fat” keratic precipitates that with chronicity can lead to endothelial damage and bullous keratopathy. Secondary glaucoma is common. Inflammatory cells and proteinaceous globules can localize retrolentally and within the peripheral anterior vitreous in a “snow banking” effect caused by cells migrating from the retina where mononuclear perivascular infiltrates are common. The condition has been associated with feline immunodeficiency virus, feline herpesvirus‐1, feline leukemia virus, toxoplasmosis, and bartonellosis, but many cases remain idiopathic and are presumed immune mediated in spite of exhaustive diagnostics. Bovine malignant catarrhal fever is characterized by the accumulation of lymphocytes and lymphoblasts within the subendothelial and adventitial regions of blood vessels. Arterial, arteriolar, and venular necrosis and hemorrhage

515

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A

B

Figure 9.56  A. Phacoclastic uveitis in a dog. Note the discontinuous lens capsule, keratitis, posterior and anterior synechiae, retinal detachment, and plasmoid aqueous and vitreous. These gross findings are usually synonymous with penetrating ocular trauma. (Original magnification 2×. Hematoxylin and eosin.) (Courtesy of Brian Wilcock.) B. An equatorial lens capsule rupture in a dog. Note the discontinuous and coiled lens capsule (LC), fibrous tissue (F), and inflammatory cells that span the capsular tear and envelop the lens (L). (Original magnification 250×. Periodic acid-Schiff.)

reparative fibrometaplastic proliferation of the lens epi­ thelium, membranogenesis of proximal tissues, sepsis, and not infrequently, secondary glaucoma. The inflamma­ tory response is zonal, being most severe at the site of cap­ sular rupture; the edges of the ruptured capsule are fimbriated, retracted, and/or coiled. Response in the dog eye is intense with a prominent neutrophil component acutely; the inflammation can extend throughout the eye. The response of the rabbit eye to capsular rupture is local­ ized, measured, and largely granulomatous, with the cat eye somewhere between. Spontaneous and small trau­ matic lens capsule ruptures in young animals of any spe­ cies often occur with minimal inflammatory response.

Degenerative Uveal Conditions Uveal Atrophy and Cysts

Uveal atrophy is nonspecific and occurs secondary to chronic glaucoma, uveitis, and aging. The iris, ciliary body, and cho­ roid decrease in thickness secondary to a loss of pigment, smooth muscle, and vascular tissues, and all of these are readily discernable on histologic examination.

Anterior uveal epithelial cysts are common accompani­ ments to many chronic degenerative ocular conditions. These likely develop secondary to epithelial alterations induced by the ocular disorder. Incidental anterior uveal cysts and iris atrophy are nonspecific findings and only need to be differentiated from inherited pigmentary/cystic glau­ coma of Golden Retrievers.

Inherited Uveal Conditions Melanocytosis of Dogs, Pigmentary/Cystic Glaucoma of Golden Retrievers, Uveal Cysts, and Uveodermatologic Syndrome

Melanocytosis, also known as pigmentary glaucoma and melanosis, is an inherited, intraocular melanocytic prolifera­ tion disorder of the Cairn Terrier (Gearhart et  al., 2008; Petersen‐Jones, 1991; Petersen‐Jones et al., 2007, 2008). This syndrome has also been reported in Boxers and Golden Retrievers (van de Sandt et al., 2003). Melanocytosis induces secondary glaucoma by the accumulation of pigment, mel­ anocytes, and pigment‐laden macrophages in the filtration angle and anterior uvea. Light microscopy reveals a diffusely

517

etiology, but some cysts appear to develop secondary to uvei­ tis (Corcoran & Koch, 1993). Uveodermatologic syndrome is an immune‐mediated condition of young dogs. Clinical signs include severe and relentless granulomatous panuveitis and depigmentation of the hair coat (poliosis), and skin (vitiligo), and/or mucus membrane ulceration. The skin lesions typically develop later than the panuveitis (Kern et al., 1985; Lindley et al., 1990). Akitas, Siberian Huskies, and Samoyeds appear pre­ disposed. Dispersion and phagocytosis of melanin is a his­ tologic feature of both dermal and ocular lesions, and if skin lesions are present, biopsy can confirm the ocular diagnosis. Extensive diffuse granulomatous panuveitis and exudative retinal detachment are frequent presenting fea­ tures, and glaucoma is a common blinding sequela (Fig. 9.58).

SECTION II

thickened uvea with an infiltrate primarily consisting of atypical polyhedral melanin‐laden melanocytes (Fig.  9.57). Remarkably similar cellular populations (melanocytoma cells) are encountered in limbal melanocytomas and uveal melanocytomas. These cells accumulate throughout the fil­ tration angle, uvea, anterior and posterior chambers, vitre­ ous, and around the episcleral collecting veins and within the episcleral tissues. Secondary ocular pathology is consist­ ent with sustained glaucoma. The etiology and pathogenesis are unknown. Pigmentary/cystic glaucoma in Golden Retrievers is an inherited slowly progressive disorder that manifests clini­ cally with multiple ciliary and iridal cysts that rupture and disperse pigment over the lens, iris, and cornea (Holly et al., 2016; Sapienza et  al., 2000). This condition is suspected to have an autosomal dominant mode of inheritance with par­ tial penetrance. The light microscopic findings are limited to minimal lymphocytic plasmacytic anterior uveal accumula­ tions, large thin‐walled asymmetrical epithelial cysts, and ocular changes consistent with secondary glaucoma. Uveal cysts are sporadically identified in many species. They manifest clinically as a round black to brown cyst that is either floating free in the anterior chamber or attached to any of the anterior chamber tissues. Light microscopic examination reveals variably pigmented fluid filled, epithe­ lial lined cysts (Spiess et al., 1998). They might have a genetic

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Acquired Retinal Disorders Retinal Detachment

The lateral junctions of the RPE (along with the tight endothelial junctions of the retinal vascular endothelium) form the posterior blood–aqueous barrier. When compro­ mised by inflammation or ischemia, the choroidal blood ves­ sels leak serous to protein‐rich fluid that collects in the potential space between the retina and RPE with resultant neurosensory retinal detachment (see Fig.  9.3, Fig.  9.7A, Fig.  9.17A, Fig.  9.18A, B, and 9.58A). Separated from the nutrition of the choriocapillaris and the metabolic support of the RPE, the outer segments will atrophy initially with the photoreceptors following. Exudative retinal detachment is a nonspecific response to infectious or noninfectious inflam­ matory diseases or ischemia of the RPE, as encountered in systemic hypertension. The neurosensory retina remains attached at the ora ciliaris retinae and the optic disc, with the fluid in the subretinal space varying from serous to protein‐ rich to hemorrhagic, and with or without inflammatory infiltrates dependent upon the causes of the primary disease process. Rhegmatogenous retinal detachments develop secondary to retinal holes or tears. Retinal tears develop secondary to trauma or vitreous traction. These detachments are often focal initially and then expand with time. Tractional retinal detachments occur secondary to con­ tractile disease processes within the vitreous. Sudden Acquired Retinal Degeneration Syndrome

Figure 9.57  Ocular melanocytosis in a Cairn terrier. Note the heavily pigmented irides and ciliary body with extension of pigment into the episcleral tissues around the aqueous collecting veins and choroid. Glaucoma is indicated by the thin sclera and was confirmed with light microscopic examination of the retina and optic nerve. (Original magnification 2×. Hematoxylin and eosin.)

Sudden acquired retinal degeneration syndrome (SARDS) is a retinal disorder in dogs characterized clinically by its acute onset, permanent blindness, and predisposition for middle‐aged often overweight dogs (Komaromy et  al., 2016; Leis et al., 2017b; Miller et al., 1998; van Der Woerdt et al., 1991). The light microscopic findings in SARDS are generalized photoreceptor apoptosis, with minimal inflam­

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A

B

Figure 9.58  A. Exudative retinal detachment (RD) in a dog with uveodermatologic syndrome. Note the diffuse inflammatory infiltrate in the choroid (C) and pars plana and the detached retina and retinal pigment epithelium (RPE) hypertrophy. (Original magnification 400×. Hematoxylin and eosin.) B. Uveodermatologic syndrome in a dog. Note the granulomatous choroiditis with macrophages that are targeting the choroidal melanocytes. The retina was detached and the RPE is hypertrophied. (Original magnification 400×. Hematoxylin and eosin.)

mation except a few macrophages that engulf the photore­ ceptor debris. The etiology and pathogenesis remain unknown. There is evidence that ongoing photoreceptor apoptosis occurs after blindness (Braus et al., 2008; Miller et al., 1998).

Inherited Conditions of the Retina and Vitreous Inherited retinopathies are common in dogs, cats, and rodents, and are uncommon in other species. This discus­ sion will be limited to those of the dog and cat because the gross, light, and electron microscopic changes are similar across species. Progressive Retinal Atrophy in Dogs

Progressive retinal atrophy (PRA) is a collective term for the multiple inherited retinopathies that occur in the dog and cat that manifest clinically in a similar fashion. Specific genetic mutations have been found in many breeds. Clinical diagnosis is often made with a history of nyctalopia, findings of diffuse retinal degeneration, and scotopic and photopic electroretinography. Light microscopic examination of affected eyes reveals outer and inner segment degeneration prior to maturation of these tissues at 8 weeks of age in the photoreceptor dyspla­ sias and later in life for photoreceptor degenerations (see Fig.  9.9B). The photoreceptor atrophy is accompanied by

apoptosis of the outer nuclear and outer plexiform layers, and eventually the inner nuclear and inner plexiform layers. Several variations include rod dysplasia, rod cone dysplasia, and cone dysplasia. Despite variations in the photoreceptor affected, light microscopic findings are similar, and with time, the retina is reduced to a glial scar. The RPE, which is responsible for phagocytosis of degenerating photoreceptors and neurons, is secondarily involved with hypertrophy, hyperplasia, and metaplasia. With time, retrograde changes occur, including vitreous liquefaction (syneresis) with clumped collagen strands suspended in the dependent pos­ terior segment. Cataracts develop, initially posterior subcap­ sular, presumably related to the release of photosensitizing ketones that are released by degenerating photoreceptors and diffuse across the vitreous. Rarely, zonular degeneration leads to lens luxation. PIFMs are also occasionally noted in globes affected with chronic photoreceptor dysplasia. The histologic confirmation of chronic PRA is difficult because the diffuse panretinal degeneration is nonspecific. The histo­ pathologic differential diagnoses that warrant consideration include nutritional deficiencies (taurine, vitamin E, vitamin A), toxins (numerous drugs including fluoroquinolones and aminoglycosides), plant toxicoses including bracken fern Pterdium sp. and locoweed (Astragulus sp.), phototoxicity, radiation, and SARDS (see acquired retinal diseases) (Buyukmichi, 1981; Jamieson et  al., 1991; Kuwabora & Gorn, 1968; Lanum, 1978; Miller et al., 1998; Peiffer et al.,

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519

1981; Roberts et al., 1987; Sadda et al., 1994; van der Woerdt et al., 1991).

Three early onset photoreceptor degenerations have been reported in cats: mixed breed retinal degeneration (West‐ Hyde & Buyukmichi, 1982); Persian retinal degeneration (Rubin & Lipton, 1973); and Abyssinian retinal dysplasia (Barnett & Curtis, 1985; Leon & Curtis, 1990). The Persian retinal degeneration is an autosomal recessive condition (Narfstrom & Nilsson, 1986), whereas the other two are autosomal dominant (Barnett & Curtis, 1985; West‐Hyde & Buyukmichi, 1982). These three rod cone degenerations all manifest with clinical signs of retinal thinning with tapetal hyperreflectivity and retinal vascular attenuation, within a few months of age (Narfstrom & Ekesten, 1999). Light microscopic examination confirms both rod and cone degen­ eration that extends from the outer segment to the inner seg­ ment and gradually throughout all the layers of the retina. Abyssinian cats with photoreceptor dysplasia fail to develop rod and cone outer segments, and there is incomplete synap­ togenesis; degeneration begins near the central retina and progresses to the periphery by about 7 months. Eventually, the RPE, choriocapillaris, and tapetum also atrophy. A late‐onset autosomal recessive photoreceptor degenera­ tion is also reported in Abyssinian cats (Narfstrom & Nilsson, 1986, 1989). Light microscopic examination reveals initial disorientation of the rod outer segments with subsequent degeneration of the outer segment by approximately 6 months of age. Over the next year, the rods, their axons and associated nuclei, and axons in the outer plexiform, inner nuclear, and inner plexiform layers degenerate (Fig.  9.59). The cones remain normal until the affected cats are 2–3 years of age. Retinal Pigment Epithelial Disorders

At least two inherited retinal degenerations of dogs are asso­ ciated with primary disease of the RPE: congenital station­ ary night blindness in Briard dogs and retinal pigment epithelial dystrophy as reported in several breeds of dog (Aguirre & Laties, 1976; Aguirre et al., 1998; Bedford, 1984). In addition, multifocal retinopathies are inherited in Great Pyrenees, Coton de Tulear, and Mastiff dogs and are directly related to mutations that alter RPE function. Congenital Stationary Night Blindness in Briard Dogs

Congenital stationary night blindness has been reported in the Briard dog. This disorder is a slowly progressive blinding disorder that is caused by a mutation in the RPE 65 gene (Aguirre et al., 1998). The gross manifestations include reti­ nal atrophy. Light microscopic abnormalities include RPE vacuoles and hyperpigmentation with apoptosis and degen­ eration of the photoreceptors and a progressive loss of the

SECTION II

Progressive Retinal Atrophy in Cats

Figure 9.59  Transmission electron micrograph of the retina of a 6-month-old Abyssinian cat with progressive retinal degeneration characterized by degenerating photoreceptor outer and inner segments. (Magnification 4000×.) (Courtesy of K. Narfstrom.)

nuclear and plexiform layers (Narfstrom, 1999; Narfstrom et al., 1989, 1994). Retinal Pigment Epithelial Dystrophy

Retinal pigment epithelial dystrophy (RPED) (also referred to as central PRA) is a rare disorder of dogs in North America, and multiple etiologies have been reported, including genetic mutations and nutritional deficiency of vitamin E (Barnett, 1967; Davidson et al., 1998; McLellan et al., 2002; Riis et al., 1981; Watson & Bedford, 1992). Some dog breeds manifest with central PRA because of mutations that alter vitamin E metabolism (Davidson et al., 1998). The hallmark histologic finding is lipofuscin accumulation within the RPE and degeneration of the outer and inner segments. If chronic, the outer and inner nuclear and associated plexiform layers will also be degenerate. Unlike PRA and photoreceptor dys­ plasia, secondary intraocular diseases such as cataracts and vitreous degeneration are uncommon. Multifocal Retinopathies in Dogs

Multifocal retinopathies develop most likely secondary to retinal pigment epithelial dysplasia that affects RPE func­ tion. These disorders are inherited in the Great Pyrenees,

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Coton de Tulear, and Bullmastiff dogs. They manifest as bul­ lous retinal detachments at approximately 11–17 weeks (Fig. 9.60A). There is progressive enlargement of focal reti­ nal and RPE detachments and development of new lesions until approximately 6–10 months of age. Light microscopic examinations confirm multifocal bullous retinal detach­ ments with associated RPE hypertrophy, hyperplasia, and hyperpigmentation (Grahn et  al., 1998, 1999, 2008) (Fig. 9.60B). In addition, there are focal areas of degenera­ tion of the outer nuclear and plexiform layers associated with each detachment. The RPE also develops focal detach­ ments from Bruch’s membrane in affected Great Pyrenees dogs (Fig. 9.60C). The mutations responsible for these multi­ focal retinopathies have been reported in the Bestrophin gene, and the pathogenesis relates to altered RPE fluid trans­ fer (Grahn & Cullen, 2001; Guziewicz et al., 2007).

Acquired Vitreous Disorders Although vitreous syneresis (liquefaction) and detachment are considered consequences of normal aging, they also

occur as a result of pathologic processes, including inflam­ mation and glaucoma that cause depolymerization of vitre­ ous hyaluronic acid and induce collagenolysis (Fig. 9.61A). Clinical diagnosis of either condition can be problematic; however, it is facilitated by posterior segment biomicro­ scopic examination. Syneresis is generally regarded as innoc­ uous. Posterior vitreous detachment can be diagnosed in paraffin‐embedded sections with optimal processing, with protein condensation delineating the posterior hyaloid membrane. Syneresis is a gross pathologic diagnosis made upon qualitative evaluation of vitreous viscosity upon open­ ing the globe. Asteroid hyalosis is the formation of 0.01–0.1 mm of roughly spherical bodies suspended within formed vitreous. Their nature is thought to be a calcium and phosphorous‐ containing lipid, and they could arise from degenerated vit­ reous collagen fibrils (Fig. 9.61B). Asteroid bodies are weakly basophilic with H&E and have the suggestion of a lamellar arrangement. They stain positively for lipid, although they resist fat solvents. They are mucopolysaccharide positive and hyaluronidase resistant. With polarized light, one

B

A C Figure 9.60  A. Inherited multifocal retinopathy of Great Pyrenees dogs. B. Retinal pigment epithelium hypertrophy, vacuolation, and pigmentation that developed near the edge of a focal inherited retinal detachment in a Great Pyrenees dog. (Original magnification 300×. Toluidine blue stain) C. Histologic section of the retina of a 4-month-old Great Pyrenees dog with inherited multifocal retinopathy. Note the focal retinal detachment (RD) and retinal pigment epithelial detachments (RPED). (Original magnification 200×. Hematoxylin and eosin.) (Source: Reprinted with permission from Grahn, B.H., Philibert, H., Cullen, C.L., Houston, D.M. & Schmutz, S. (1999) Multifocal retinopathy of Great Pyrenees. Veterinary Ophthalmology, 1, 211–221.)

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B

Figure 9.61  A. Vitreous degeneration (VD) in dog with secondary glaucoma and retinal detachment. The vitreous strands are congealed and therefore appear thickened and bunched together, and they are apposed to the inner limiting membrane in some areas of the ventral non-tapetal retina. Plasma proteins are also present around the thickened vitreous tendrils. Note the characteristic retinal degeneration of the inner retina (glaucoma) and loss of photoreceptors and outer nuclear layer (retinal detachment). (Original magnification 200×. Periodic acid-Schiff.) B. Asteroid hyalosis (AH) in a dog. Note the amorphous pink granular bodies associated with dark small hyalocyte nuclei. (Original magnification 400×. Periodic acid-Schiff.)

observes birefringent spicules. Asteroid hyalosis is not an uncommon finding in older dogs and has not been reported in cats or other domestic animals. It is unilateral or bilateral, and even in its densest presentation, does not seem to affect vision appreciably. Cholesterolosis bulbi is an uncommon condition that results from incomplete resolution of intraocular hemor­ rhage and syneresis. The refractile cholesterol crystals settle to the bottom of the vitreous chamber (and/or the anterior chamber in aphakic eyes) when the eye is at rest. Other sig­ nificant ocular lesions usually accompany the condition. In paraffin‐embedded sections, the cholesterol esters have been dissolved in processing. Their location can be identified as slit‐like spaces, occasionally with an associated granuloma­ tous inflammatory response, and hemosiderosis can be pre­ sent and is shown nicely with stains for iron.

Inherited Choroidal and Vitreous Anomalies Tapetal Degeneration in Dogs and Cats

Inherited tapetal degeneration in Beagles is an autosomal recessive condition where the number of tapetal cells is nor­ mal at birth. The clinical manifestations include loss of the normal reflective tapetum caused by progressive degenera­ tion which begins at approximately 2 months of age; by about 3 months, the tapetal cells have lost all their rodlets and are packed with membranous inclusions (Bellhorn et al., 1975; Wen et al., 1982a).

A similar disorder occurs in Siamese cats with Chediak– Higashi syndrome. The tapetum in these cats is likewise nor­ mal at birth and is completely degenerate by 2 months of age. Macrophages are absent in both of these disorders (Collier et al., 1985; Wen et al., 1982b). Borzoi Chorioretinopathy

Multifocal choroidal retinal lesions have been reported in Borzoi dogs (Fig.  9.62A) (Chaudieu, 1995; MacMillan & Scagliotti, 1977; Rubin, 1989; Storey et  al., 2005). The mode of inheritance is unknown. PRA has been excluded as part of this disorder by electroretinographic and light micro­ scopic examinations (Storey et  al., 2005). The light micro­ scopic findings of Borzoi retinopathy include focal choroidal atrophy, loss of choriocapillaris, focal hypertrophy and pig­ mentation of the RPE, and focal degeneration of associated photoreceptors (Fig. 9.62B). Inherited Vitreous Degeneration

Vitreous degeneration is suspected to be an inherited con­ dition in Whippets and Italian Greyhounds given the devel­ opment of syneresis and prolapse of tendrils of degenerate vitreous into the anterior chamber in young dogs (from 6 months to 4 years of age). Light microscopic diagnosis of vitreous degeneration is nonspecific in regard to etiology, and the lesions are subtle. Thorough light microscopic examination of the vitreous reveals condensed vitreous

Section II: Foundations of Clinical Ophthalmology

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A

B

Figure 9.62  A. A mature male Borzoi dog with Borzoi chorioretinopathy. Note the focal hyperreflective lesions with hyperpigmented foci located ventrally and dorsally in this fundic photograph. B. Histologic lesions include retinal pigment epithelium (RPE) hypertrophy, hyperplasia and pigmentation, and the outer nuclear layer (ONL) and inner segment photoreceptor (PRL) degeneration and loss of outer nuclear, outer plexiform, and inner nuclear (INL) layers. Occasional mononuclear cells are present within this focal lesion. The retina on either side of this lesion was normal morphologically. (Original magnification 400×. Toluidine blue stain.)

fibers and a lack of fine fibrillary vitreous collagen and detachment of these condensed fibers from the inner limit­ ing membrane.

Inherited Storage Disorders, Amino Acid, and Lipid Peroxidation Disorders Metabolic storage diseases are uncommon in animals. However, several have been investigated thoroughly in the research laboratory as models for similar human disorders. These storage disorders result from genetic defects in metab­ olism and are generally the result of a deficient degradory pathway. These metabolic defects result in accumulation of complex lipids, glycoproteins, or polysaccharides within specific types of cells within the eye and other organs. These cells include keratocytes, ganglion cells, or RPE. Histopathologic signs are subtle when the sole diagnostic examination is light microscopy; these systemic metabolic conditions are best defined by histochemistry and transmis­ sion electron microscopy. The typical clinical presentation is that of a young animal with neurologic and frequently ocu­ lar signs. Only the histologic findings found in the eyes are described here. Clinical findings and references can be found in respective chapters. Lysosomal storage diseases include gangliosidosis (Gm1 and Gm2) and mucopolysaccharidoses (MPSI VI, VII) and cause the accumulation of glycosamino­ glycans and glycoproteins within membranous inclusions in the corneal stromal keratocytes and endothelium. These

inclusions are identifiable by light and electron microscopy. Similarly, these metabolic by‐products accumulate in the retina and RPE and affect their function and can cause blindness. Fucosidosis has been reported in English Springer Spaniels with alpha‐L‐fucosidase deficiency and manifests histopathologically as vacuolated ganglion cells, astrocytes, and RPE. Ornithinuria, a deficiency of ornithinuria trans­ ferase, causes generalized histopathologic lesions including retinal, RPE, choriocapillaris, and choroidal atrophy. Choroidal vascular atrophy is the unique histologic finding with this disorder. The diagnosis is confirmed by document­ ing elevated levels of ornithine in the urine or plasma. Lipid peroxidation defects include neuronal ceroid lipofuscinoses which is caused by decreased peroxidase activity and is asso­ ciated with the intracellular accumulation of ceroid lipofus­ cin. Stacked membranous inclusions in RPE (Fig. 9.63) and ganglion cells are noted with light and electron microscopy and are accompanied by ophthalmoscopic lesions and visual dysfunction.

Degenerative Lenticular Disorders A basic discussion of cataractogenesis should reference the biochemical and metabolic changes that precede or accom­ pany the morphologic changes. Alterations in nutrition, metabolism, and osmotic balance can lead to alterations in cell membranes and/or proteins that define cataracts. The lens consists predominantly of water and protein, with

Figure 9.63  The inclusions that are characteristic of neuronal ceroid lipofuscinosis. (Courtesy of K. Narfstrom.)

minute amounts of inorganic ions, organic phosphates, nucleic acid, and lipid. The proteins include the soluble crys­ talline, insoluble albuminoids, mucoproteins, and nucleo­ proteins. Differentiation of lens epithelial cells into lens fiber cells is a life‐long process that occurs at the equator; these cells mediate transcapsular transport, provided by a Na+, K+‐ATPase‐dependent pump. Oxygen needs are mini­ mal, and anaerobic glycolysis, which converts glucose to lac­ tic acid, provides most of the energy required. Glucose enters the lens by both diffusion and facilitated transport; transport mechanisms play a role in cation and amino acid influx as well. Alterations in substrate or enzymatic activity can alter the homeostatic equilibrium of the lens with increased hydration and associated protein alterations. Cataracto­ genesis is also associated with increases in lens glutathione, insoluble proteins, and hydrolytic enzymes. There is increas­ ing evidence that oxidative damage is a common final path­ way for a variety of cataracts. Although the pathologist strives for an etiologic diagnosis, the nonspecificity of cataract morphology frequently limits diagnosis to morphologic description. Histopathologically, cataractogenesis is manifested by a limited number of mor­ phological alterations in the lens capsule, epithelial cells, and/ or lens fiber cells. These alterations represent the common end stage of a spectrum of insults, be they genetic, traumatic, toxic, or secondary to ocular or systemic disease (Thoresen

et  al. 2002). The histopathologist can readily classify these changes by location and morphology but in the absence of other clues may be hard pressed to determine etiology (Fig. 9.64). Distinction between artifact and real change can be chal­ lenging, especially in regard to cortical and nuclear altera­ tions. The lens is dense and sequestered within the globe; thus, fixatives penetrate poorly, and shattering and fragmen­ tation under the microtome blade occurs frequently. Both fixative and osmotic factors can distort size and shape and contribute to the appearance of vacuoles that can mimic pathologic alterations. Anterior capsular changes of delamination as seen with heat and/or infrared exposure and pseudoexfoliation have not been described in animal eyes; however, anterior capsu­ lar thickness might increase in response to excess basement membrane production by stressed lens epithelial cells. Capsular opacification associated with persistence of the fetal vasculature and spontaneous congenital capsular rup­ ture have been discussed in the section Pathology of Congenital Disorders, and the features of traumatic or spon­ taneous acquired capsular rupture in the paragraph on Phacoclastic Uveitis. Lesions affecting the lens epithelium involve the anterior or equatorial epithelial cells. These cells degenerate, develop fibrous metaplasia, migrate along the posterior lens capsule, hypertrophy, and/or become hyperplastic in response to disease. Epithelial cells can transform from cuboidal to flattened fusiform cells, frequently forming a multilayered plaque; although fibrous in appearance by light microscopy, ultrastructurally these cells maintain intercellular macula adherents and are surrounded by basement membrane, maintaining characteristics of epi­ thelial cells. When epithelial cells migrate posteriorly, they follow the capsule where they undergo metaplasia or migrate into the posterior cortex where they hypertrophy, perhaps as an abortive attempt at repair, with production of lens proteins. These spherical cells maintain their nuclei and are known as bladder cells. Cortical cataracts are characterized by changes in cell membranes, lens proteins, or both (Taylor et  al., 1997). Intercellular fluid accumulation manifests as vacuoles, clefts, and fissures between cells. Intracytoplasmic swelling imparts enlarged profiles and a granular cytoplasm; as lens proteins denature, they become more eosinophilic and homogeneous. Fiber cell membranolysis results in extracel­ lular pools or distinct spherules of altered protein; the latter is referred to as Morgagni globules. Increased fluid intake leads to swelling of the lens with stretching of the capsule (spontaneous rupture, usually of the posterior capsule, can occur). As the osmotic pressure with the aqueous humor equalizes across the lens capsule because of altered metabo­ lism and loss of transcapsular transport mechanisms, solu­ ble proteins will diffuse from the lens, with resultant

523

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SECTION II

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A

C

B

D

Figure 9.64  A. A mature cataract is present in this gross section of this dog’s eye. B. Fibrous metaplasia of lens epithelium under a folded anterior lens capsule of a dog. Note the capsular fold and lens epithelial cells that are scattered among collagen fibers. (Original magnification 250×. Hematoxylin and eosin.) C. Cortical liquefaction (L) is present under the anterior lens capsule (LC) of this dog. (Original magnification 200×. Hematoxylin and eosin.) D. Cortical liquefaction (L) is present under the posterior lens capsule in this dog. Arrows, posterior migration of lens epithelial cells. (Original magnification 200×. Hematoxylin and eosin.)

shrinkage and capsular wrinkling. Cholesterol deposits or dystrophic calcification can occur. The role of altered carbohydrate metabolism, in particular glucose and galactose, has been studied extensively. In dia­ betes mellitus, excessive levels of glucose enter the lens, the rate‐limiting enzymes of the Embden‐Meyerhoff pathway are saturated, and the sorbitol pathway and aldose reductase are activated, with the sugar being metabolized to polyalco­ hols with resultant osmotic imbalance and water influx (Beam et  al., 1999). Elevation of galactose levels related to excessive dietary intake or genetic enzymatic defects follows a similar pattern (Sato et al., 1991; Wyman et al., 1988); neo­ natal marsupials supplemented with cow’s milk, which is high in galactose that these animals are unable to properly metabolize, will develop cataracts. Low glucose levels can also lead to cataract formation and further reveals the piv­ otal role that glucose plays in lens metabolism. Hypocalcemia can cause cataracts in dogs and cats, and numerous toxins, chemicals, and pharmaceutical agents have been shown to cause both experimental and sponta­ neous disease. Glucocorticoids administered both topically

and systemically in humans can result in posterior subcap­ sular cataracts that continue to progress after treatment is discontinued; domestic species appear to be relatively resistant to steroid cataracts. Heavy metals including lead and silver can induce cataracts. A cholinesterase inhibitor used to control sea lice in Atlantic salmon has been impli­ cated in cataractogenesis. Dinitrophenol in dogs and hygro­ mycin B in swine have also been shown to be cataractogenic (Bunce et al., 1990; Glaze & Blanchard, 1983; Martin, 1975; Martin & Chambreau, 1982). Radiant energy can cause cataractogenesis; light energy might be cataractogenic in fish. The lens is quite sensitive to radiation, which results in increases in membrane permeability and alters protein synthesis and metabolism. Younger animals are more susceptible; birds are remarkably resistant. A period of latency follows exposure with vacuoles forming at the poste­ rior pole and progressing to cortical involvement (Brightman et al., 1984; Brown et al., 1972; Jamieson et al., 1991; Lipman et al., 1988; Peiffer et al., 1981; Roberts et al., 1987). Nutritional factors other than carbohydrates may be cata­ ractogenic, including amino acid deficiencies of tryptophan,

phenylalanine, valine, and histidine. Arginine deficiency causes cataracts in wolf pups (Anderson et al., 1988; Hughes et al., 1981; Ketola, 1979; Poston & Rusey, 1983; Poston et al., 1977; Vainisi et al., 1981). Other diseases such as uveitis, glaucoma, and retinal degeneration cause cataracts by altering the ocular milieu and thus lens nutrition. Turkeys and chickens with avian encephalomyelitis and Marek’s disease develop cataracts. In fish, phacotropism is demonstrated by trematode (diplosto­ mum) larvae with associated cataract, and encephalitizoon has been associated with cataract and lens capsule rupture primarily in rabbits (Shariff et al., 1980; Wolfer et al., 1993). In many cases, including cataracts in pinnepeds, etiologies remain undefined; various dietary, environmental, genetic, and traumatic factors have been postulated. Likewise, the cellular and subcellular mechanism of inherited cataracts in domestic animals is largely unknown.

Acquired Lens Luxation The lens is anchored by the zonular fibers which blend with the anterior and posterior lens capsule and extend to the cili­ ary body. Disruption usually occurs at the site of capsular insertion, with resultant subluxation or luxation (Fig. 9.65). Congenital abnormalities in zonular insertion and/or physi­ cal properties in connective tissue disorders predispose to dislocation, and bilateral lens luxation has been described in

Figure 9.65  A clinical photograph of an inherited posterior lens luxation in a Jack Russell Terrier. Note the prominent aphakic crescent (AC) and the equator of the inferiorly and posteriorly luxated lens.

a dog with Ehlers–Danlos syndrome. Heritable conditions in certain dog breeds (notably terriers) (Curtis, 1983; Curtis & Barnett, 1983; Gwin et  al., 1982; Kuchtey et  al., 2011; Lazarus et al., 1998) exist in which the zonules have reduced tensile strength and rupture easily and are discussed in the section on Inherited Developmental Disorders. Chronic inflammation will also result in zonulysis and lens luxation in both dogs and, more notably, cats and horses (Martin, 1978). Physical trauma to the globe of sufficient magnitude can dislodge the lens and, as described later, chronic glau­ coma with globe enlargement and zonular stretching to rup­ ture is a common finding. Posterior subluxation may be associated with elevated IOP if formed vitreous moves anteriorly to obstruct the pupil or outflow pathway; similar events can occur with posterior luxations, as well as perilenticular membranogenesis with resultant retinal traction. Anterior luxations in the dog are accompanied by glaucoma as the lens and/or adherent vitre­ ous obstruct the pupil and outflow pathway. Regardless of species, physical contact between lens and corneal endothe­ lium often compromises the latter.

Acquired Glaucoma Glaucoma is a generic term used to describe a variety of pathophysiological processes in which the IOP reaches a level sufficient to cause damage to the eye. In humans, glau­ coma can occur in individuals whose IOP falls in or close to normal range (normotensive glaucoma); alternatively, a population is recognized with IOP above normal values but without evidence of glaucomatous damage (ocular hyper­ tension). Neither of these conditions has been unequivocally reported to occur in eyes of other animal species. Pathologic elevation of the IOP is the consequence of obstruction or misdirection of aqueous flow or outflow anywhere along its course. In terms of classification, glaucoma should foremost be classified as being primary or secondary. The former is a genetic and bilateral (although not usually concurrently so) condition that occurs in the absence of antecedent ocular disease. The latter, in contrast, occurs as a direct result of antecedent or concurrent ocular disease that results in impaired aqueous circulation or outflow. Glaucoma that manifests at birth or shortly thereafter is best labeled “con­ genital,” and the reader is referred to section on Pathology of Congenital Disorders. This scheme is somewhat ambiguous; for example, the primary glaucoma most commonly encoun­ tered in the dog is associated with congenital goniodysgene­ sis, but manifests much later in life. Because of the unique morphology of the subprimate outflow pathway, a morphologic classification of glaucoma in animals should consider those changes that occur within the ciliary cleft (CC) distinct and separate from those that occur at the iridocorneal angle (ICA). With an open ICA,

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normal anatomic relationships exist between iris root, pec­ tinate ligament, and the inner surface of the peripheral cor­ nea. An ICA can be open but dysplastic, with abnormalities of the pectinate ligament (to be elaborated upon shortly). An ICA can be open but obstructed, for instance by the pro­ liferation of a fibrovascular membrane from the iris root across the face of the pectinate ligament. The ICA is closed when the anterior surface of the iris root is displaced ante­ riorly to come in contact with the anterior surface of the pectinate ligament and peripheral cornea, with resultant obstruction of aqueous access to the trabecular meshwork (TM) and the CC. The CC may be open, narrowed, or col­ lapsed. It is quite possible to have an open ICA with a col­ lapsed CC; in fact, this is the most common manifestation associated with both primary glaucoma and glaucoma associated with lens luxation in the dog. As the cleft col­ lapses, access of the aqueous fluid to the CC and TM is like­ wise impaired; outflow decreases, and the IOP increases and the anterior chamber becomes more shallow or deep­ ens depending on the type of glaucoma. Because of the anatomic relationships, angle closure is always associated with narrowing and collapse of the CC. Collapse of the CC could be the key event that leads to acute elevation of IOP in the majority of animal glaucoma cases; unfortunately, the mechanism(s) that maintain and control CC width have yet to be defined. Although determining shallowing of the anterior chamber related to anterior displacement of the iris leaflet can be problematic for the pathologist, both the status of the ICA and the width of the cleft can be assessed with reasonable accuracy in histopathologic sections. Gonioscopic appearance can readily be correlated with the above morphologic classification scheme; if the ICA is open, but the cleft collapsed, the iris root will be in direct apposi­ tion with the outer pigment band; the pectinate ligament and cleft will not be observable. With angle closure, the iris root is displaced anteriorly to obscure visualization of the outer pigmented band. Species Characteristics of Acquired Glaucoma Canine Acquired Glaucoma

In the dog, secondary glaucoma occurs two to three times as frequently as primary glaucoma. Congenital glaucoma occurs rarely, and when it does, it is usually associated with ASD (see the section on Pathology of Congenital Disorders). A recessively inherited primary open angle glaucoma in the Beagle dog has been investigated as a model for pri­ mary glaucoma in humans (Gelatt et  al., 1977; Gelatt & Gum, 1981; Gum et al., 1993; Samuelson et al., 1989b). There is no evidence of goniodysgenesis at the time of insidious elevation of IOP, which first is noted at about a year of age, and the ICA and CC are open at this stage. With chronicity, the cleft closes. The most common pri­ mary glaucoma seen in dogs is an inherited condition asso­

ciated with goniodysgenesis. Goniodysgenesis is a broad term that implies abnormal development of the pectinate ligament, CC, and/or TM. Primary Glaucoma and Goniodysgenesis in Purebred Dogs

Primary glaucoma associated with goniodysgenesis is reported in American Cocker Spaniels, Bouviers des Flanders, Siberian Huskies, Bassett Hounds, Shar Peis, and many other breeds of dogs, and is most likely inherited in all breeds (Gelatt & Mackay, 2004). This form of glaucoma is challenging to treat effectively, and to alleviate pain and dis­ comfort many eyes are enucleated or eviscerated because of blindness and lack of response to most therapies. There has been confusion regarding the classification of open and closed angles in veterinary medicine. To clarify this, the ICA is closed when the base of the iris is displaced anterior to overlie the pectinate ligament and the peripheral cornea. This occurs most commonly with peripheral ante­ rior synechiae and with expansive iridal and ciliary neo­ plasms, and these changes are accompanied by narrowing or closure of the CC. Goniodysgenesis includes failure of devel­ opment of the pectinate ligament, CC, and/or TM. Rarefaction of the primitive uveal neurocrest tissues to form the filtration angle occurs shortly after birth, but fails to do so in eyes affected with goniodysgenesis. The histologic fea­ tures of goniodysgenesis include nodular thickening of the termination of Descemet’s membrane, thickened and short­ ened pectinate ligaments with infrequent flow holes, and hypoplasia of the CC; it is difficult for the histopathologist to distinguish hypoplasia of the cleft from collapse. In dogs with primary glaucoma, PAS‐positive basement membrane material is identified within the TM (Fig.  9.66A) and is hypothesized to reflect dysplastic trabecular cells. Progressive deposition of this material can lead to physical obstruction of the TM and explains why the disease does not manifest until later in life. Pectinate ligament dysplasia is the only manifestation of goniodysgenesis readily evident to the clin­ ical ophthalmologist, and although in itself it does not play a role in the pathogenesis of primary glaucoma, it rather serves as a marker for the CC and trabecular changes in the aforementioned dog breeds. Pectinate ligament dysplasia by itself has little predictive value; many dogs will fail to develop glaucoma despite the smallest of flow holes in the dysplastic filtration angle. Light microscopic examination of eyes with primary glau­ coma and goniodysgenesis reveals a spectrum of intraocu­ lar pathology depending on the duration and severity of the glaucoma. Acute (10 years) (Fig. 9.72A). In any given tarsal gland neoplasm, either basal cells with very little sebaceous differentiation predominate (tarsal gland epithelioma) or fully differentiated glandular cells predominate (tarsal gland adenoma) (Fig. 9.72B, C). In the older literature, ductal adenomas were confused with basal cell carcinomas (Gelatt, 1971), which are rarely

encountered in domestic animals. Histologically, hemor­ rhage, necrosis, pigmentation, and chalazion are commonly noted within these tumors. The lipid secretion is often extruded from the tarsal gland during progressive neoplastic expansion and induces a significant granulomatous response. Rarely hyperchromatism and increased mitotic activity give rise to concerns; however, excision or ablation is curative. SCC is a common eyelid and conjunctival neoplasm of horses, cattle, and cats. Poorly pigmented eyelids, actinic exposure, and papilloma virus play a role in pathogenesis and predispose to precancerous changes including plaques, papillomas, keratin horns (Fig. 9.72D), and carcinoma in situ (Fig. 9.72E). These preneoplastic lesions are erythematous,

SECTION II

Table 9.9  Common eyelid and conjunctival neoplasms.

Section II: Foundations of Clinical Ophthalmology

SECTION II

536

A

B

C

Figure 9.72  A. Multiple tarsal gland adenomas on the eyelid margin of an aged American Cocker Spaniel. B. Subgross appearance of one tarsal gland adenoma depicts the marginal location with displacement of the eyelid skin and palpebral conjunctiva over the basophilic adenoidal tumor. (Original magnification 2×. Hematoxylin and eosin.). C. Histologic features of a tarsal gland adenoma include basophilic staining basal cells with focal sebaceous differentiation and a mild diffuse neutrophil and macrophage infiltration. This inflammatory cell infiltration is a common response to the lipid extrusion (clear vacuoles). (Original magnification 300×.Hematoxylin and eosin.) D. A keratin horn that was removed from the cornea near the temporal limbus of a Hereford bull. (Original magnification 200×. Hematoxylin and eosin.) E. Bovine squamous cell carcinoma (SCC) in situ in the perilimbal corneal epithelium. Tumor cells are confined to the epithelium and have not breached the basement membrane to invade the stroma. The surface is keratinized and contains a focal keratin pearl. (Original magnification 300×. Hematoxylin and eosin.) F. A well-differentiated SCC from the conjunctiva of a Hereford bull invades the subconjunctival tissues. Multiple keratin pearls are present. (Original magnification 300×. Hematoxylin and eosin.) G. Orbital biopsy with keratin pearls and diverse epithelial morphology confirms an invasive SCC in a horse. H. Histologic section of invasive SCC has replaced most of this bovine cornea in this cow. (Original magnification 300×. Hematoxylin and eosin.)

scaly, crusty, or even hornlike, and they can regress sponta­ neously or slowly develop into SCC. In horses, cattle, and cats, SCC manifests as a friable salmon pink placoid often‐ ulcerated lesion. Incisional biopsy is used to confirm the

increased mitotic figures. Broder’s classification can be uti­ lized to establish the prognosis; grade I SCCs are well differ­ entiated with large round epithelial cells with prominent intercellular bridges, abundant pink cytoplasm, ­homogenous

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D

F

E

G

H

Figure 9.72  (Continued)

nuclear patterns, and only a few mitotic figures. Keratin pearls are prominent features as are neutrophils within these well‐differentiated neoplasms (Fig.  9.72F). Grade II SCCs are similar; however, the mitotic index is higher. Grade III SCCs have fewer keratin pearls and there is evidence of tis­ sue invasion which creates multiple neoplastic islands (Fig. 9.72G). Grade IV tumors are poorly differentiated carci­ nomas with absence of keratin pearls and amphophilic cyto­ plasm with pleomorphic and hyperchromatic nuclei. The mitotic index is high, and tissue invasion is prominent (Fig. 9.72H). Metastatic potential increases with each grade of SCC, and although uncommon, these tumors can spread via the lymphatics to the regional lymph nodes (mandibular, retropharyngeal, and mediastinal). Papilloma virus plays a role in the development of some SCCs. Papillomas of the eyelids are common in dogs, horses, and ruminants (Fig. 9.73A, B). Papillomas are induced by papilloma viruses and manifest as multiple lesions in young animals ( 0.5 mm), transparent ocular structures such as the cornea become visible as a parallel‐piped “block of tissue” (Fig. 10.1.13). Corneal examination with such a broad slit can be helpful to visualize many opacities, but is less efficient than the creation of an optical section with a thin beam (0.1–0.2 mm), as it creates a variable amount of overlap between anterior and posterior corneal surface (Martonyi et al., 2007). Abnormalities of the deeper structures may therefore best be seen in sections using a broad beam, when examining the “trailing edge” of the parallel‐piped block (Fig. 10.1.14). In contrast, in the corneal section created with a thin beam of light, tear film, and epithelium, corneal stroma, and endothelium all become visible separately (Fig. 10.1.15). It is important that with the use of both broad and narrow beams, an appropriately wide angle between the slit‐ lamp microscope and illuminator (more than 45 degrees) is chosen, as the section collapses with too narrow an angle (Fig.  10.1.16; Martonyi et  al., 2007). Examination with a slit beam will also help to provide topographic information, both about the tissues examined as well as the relationship of ocular structures to each other (Martonyi et al., 2007). The slit beam is deflected away from the examiner with a depression and toward the examiner by an elevation. This is well illustrated by the

580

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Table 10.1.2  Overview of characteristics of commonly available portable slit-lamp models. Slit Options (mm width)

Light Source

Illumination Levels

KOWA SL 17® 10×, 16×

1×1 0.1, 0.2, 0.8 5.0 and 12.0 circle

LED

Keeler PSL classic®

10×, 16×

1 × 1; 0.15, 0.5, 0.8, LED 1.6, 12.0 circle

Hawkeye® (Dioptrix, Toulouse, France)

8×, 12.5×, 20× 1 × 1; 0.1, 0.2, 15.0

SECTION II

Model

Magnification

Reichert PSL® 10×, 16× (Depew, NY, USA)

0.15–11.0

LED

Photo/Video Port

Weight (kg)

Continuous Blue, white

Video (via iPhone adapter)

0.79

Continuous Red free, blue, neutral density, clear

Video (iPhone adapter)

0.93

Continuous Green (red free), cobalt blue

Photo and video (6 MPX integrated digital camera)

Inbuilt 1.5 (including holder for fundus camera) exam lenses

LED

Light Filters

Red free, blue color temperature conversion

Extras

0.68

LED, light-emitting diode; MPX, megapixel.

example of corneal ulceration, where the slit on the surface of the cornea will be deflected away from the examiner (Fig. 10.1.17), and by the example of an iris tumor, where the slit beam overlying the iris lesion is deviated toward the examiner (Fig. 10.1.18). The experienced examiner will also gain the ability to distinguish between normal thickness of ocular tissues and increased or decreased thickness of the tissues in their diseased state (see Fig. 10.1.13A, B; Fig. 10.1.17; and Fig. 10.1.18). With time, the experienced examiner is able to form a mental reference library of distances between ocular structures visible in the beam for the normal eye at any given angle, allowing for recognition and estimation of distances in the pathologic status. Typical examples are the shallow anterior chamber associated with lens intumescence, and the increased anterior chamber depth associated with largely resorbed hypermature cataract. The former is demonstrated on optical sectioning by a reduced distance between the slit image on the posterior corneal surface and the convex bright slit section on the anterior lens surface, while the latter is associated with an increase in the same distance, if examined at the same angle (Fig. 10.1.19). The usually tall or long slit beam used for optical sectioning can be reduced to a minimum height or even a pinpoint (1–2 mm) to allow checking for the Tyndall effect, indicating any deviations of the composition of the normally optically clear aqueous (Fig.  10.1.20). The phenomenon of specular reflection is also utilized in the ocular slit‐lamp biomicroscope examination, specifically during assessment of the integrity of the outer and inner corneal surfaces. A specular reflection is the creation of an image of the light source itself that can, according to Snellen’s law, only be seen from the correct position – as the angle of incidence equals the angle of reflection. To visualize the corneal specular reflection, the examiner must therefore place both illuminator and microscope at angles approximately 25–30 degrees to the midline,

and project the light onto the transparent ocular structure under scrutiny. The clarity and sharpness of the specular reflection depend on the smoothness and reflectivity of the surface on which it is created. With normal corneal surface health, the specular reflection will directly mirror the image of the light source (see Fig.  10.1.18A). Deficiencies of the precorneal tear film or epithelial irregularities will negatively affect the specular reflection from the corneal surface and result in a distorted and irregular image of the light source (see Fig. 10.1.6). The phenomenon of specular reflection can also be used to examine the integrity of the corneal endothelium. The surfaces of healthy corneal endothelial cells are usually smooth and highly reflective, whereas their borders are irregular, and thus highlighted by the absence of specular reflection, leading to the “honeycomb” appearance of the normal corneal endothelium on high‐magnification examination, as described above (Fig. 10.1.21). Pathology of endothelial cells will lead to loss of the normal specular reflection, visible as a dark “fill defect” in the normal endothelial pattern. Individual endothelial cells can only be appreciated, however, with magnification settings of 25–40×, which exceeds the ability of handheld biomicroscopes. Specular reflection can also be used to examine irregularities in the epithelial cells lining the anterior lens capsule, but the same requirement for magnification exists here. Both direct illumination and retroillumination are utilized during ocular slit‐lamp biomicroscopy. With direct illumination, the structure to be examined is illuminated by the light source itself, while in retroillumination, the structure of interest is illuminated by light reflected from a neighboring tissue (Berliner, 1943; Martin, 1969b; Martonyi et al., 2007). The same opacity within the clear ocular media may appear bright in direct illumination and dark on indirect illumination (Fig.  10.1.22). For this purpose, corneal changes are mostly examined by retroillumination from the iris, while iris and lens

581

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A

B

C

D

Figure 10.1.11  Magnification during use of the slit lamp for examination of the anterior ocular segment with a broad beam. A. Anterior segment in chronic anterior uveitis in a Domestic Shorthair, 12× magnification. B. Same patient as A, but increased detail visible on 25× magnification. C. Follicular conjunctivitis on 25× magnification. D. Chronic blepharitis on 25× magnification. (Courtesy of AHT, Newmarket, UK.)

Figure 10.1.12  On a slit setting with high levels of illumination, the slit lamp functions to section the transparent tissue of the anterior segment with a slab of light. Slit-lamp image of an elderly Labrador Retriever with nuclear sclerosis, showing the reflection of the slit beam on the cornea and lens. (Courtesy of AHT, Newmarket, UK.)

changes are routinely examined with the help of light reflected from the fundus. Iris transillumination can be achieved when the fundus is illuminated through a small pupil only and will highlight defects in iris pigmentation or tissue (Martonyi et al.,

2007). If mydriasis has been induced, fundic retroillumination can be created to allow corneal examination (Martonyi et al., 2007). To achieve optimal fundic retroillumination, the angle between the slit‐lamp biomicroscope illuminator and the microscope should be as narrow as possible. Retroillumination from the iris can be both direct and indirect (Fig. 10.1.23 and Fig. 10.1.24). With direct retroillumination, corneal anomalies are highlighted by light reflected from the iris immediately posterior to them (see Fig. 10.1.23 and Fig. 10.1.24). For this purpose, a moderately broad slit beam is placed onto the iris at an angle wide enough to avoid directly illuminating the area of cornea that is to be examined. Indirect retroillumination is created by scattering of light into areas of the cornea adjacent to those directly retroilluminated from the iris. Thus, the corneal area of interest is examined against a dark, nonilluminated iris background. Indirect retroillumination is used to highlight the most subtle changes within the cornea, whose degree of transparency only minimally deviates from that of the surrounding tissue and which would not be seen against an illuminated iris background (i.e., with direct retroillumination; see Fig. 10.1.23 and Fig. 10.1.24). To achieve optimal indirect retroillumination, the normally isocentric relationship between the slit‐lamp biomicroscope illuminator and

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A

B

C Figure 10.1.13  The use of a broad slit beam (> 0.5 cm) is demonstrated here on a patient with corneal edema. A. Corneal edema seen with the diffuse beam. B, C. The broad slit beam creates a parallel-piped corneal section, as seen in the same patient and depicted in the schematic diagram. (Courtesy of AHT, Newmarket, UK.)

the biomicroscope is uncoupled and the slit beam is placed tangentially to the axis of viewing (Martonyi et  al., 2007). Unfortunately, many handheld slit‐lamp biomicroscopes do not offer the option to decenter the light beam, and precise indirect retroillumination may be limited to the more sophisticated table‐mounted slit‐lamp biomicroscope models. Using direct retroillumination, three basic types of lesions can be defined (Fig.  10.1.25): obstructive, translucent, and refractile (Berliner, 1943). Obstructive lesions block the reflected light and stand out dark against a bright background. Examples of obstructive lesions include active corneal blood vessels, corneal pigmentation, blood clots in the anterior chamber, dense cataract, and tissue masses. Translucent lesions allow the passage of some light on retroillumination, but detailed examination through the lesion is not possible. Corneal edema, keratic precipitates, iris cysts, fibrin, incipient cataract, and thin scars all are examples of refractive lesions. Refractile lesions allow the passage of light on retroillumination and will take on the color of their background. They will refract the light, but will still allow more posterior structures to be examined in detail. Examples

of refractile lesions include lens vacuoles, lens capsular wrinkling, the distorted tear film, or interrupted epithelium and corneal bullae (Berliner, 1943). Practical Application of Slit-Lamp Biomicroscope Examination

At the start of slit‐lamp biomicroscopy, the oculars (eye pieces) should be adjusted to accommodate the interpupillary distance and to correct any refractive error of the examiner’s eyes (Berliner, 1943; Blumenthal, 1995; Schmidt, 1975). This is done by focusing on a target rod (i.e., focusing bar) that attaches to the instrument at a fixed distance from the objective (i.e., the focal distance of the slit beam) or on small print or small parallel lines present in the periphery of the viewing field, as seen through the slit‐lamp biomicroscope oculars (Blumenthal, 1995). The animal’s head is restrained by an assistant or with the examiner’s free hand (see Fig. 10.1.10). The light beam is angled at 20–45 degrees from the axis of the microscope, initially away from the muzzle, and the oculars are rested against the examiner’s brow. During the course of the examination, however, the light

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Figure 10.1.14  Keratic precipitates in a cat with chronic anterior uveitis. Due to the tissue overlap that occurs with the use of a broad beam, the deeper corneal structures are best examined at the trailing edge of the beam, allowing ideal location of the position of the precipitates to the corneal endothelium level. (Courtesy of N. Wallin Håkansson.)

beam should be alternated between sides to allow examination of the ocular structures with light reaching the eye at a variety of different angles. The focal distance of the instrument is 7–12 cm, at the intersection of the light beam axis with the microscope axis, and the fine focus is achieved by moving either toward or away from the eye within this range. The inexperienced examiner may at first find it difficult to orient him‐ or herself with respect to the position of the eye when looking through the oculars at the beginning of the examination. A helpful tip is for the examiner to approach the corneal surface with the slit‐lamp biomicroscope turned “on” until the circle of light observed with the naked eye has a sharp outline on the cornea or eyelids, before applying his or her eyes to the oculars. This way, the slit‐lamp biomicroscope is already at the correct focal position, avoiding an embarrassing “search for the eye.” Initially, the entire ocular surface is screened with the slit‐lamp biomicroscope using a diffuse, unfocused beam with a low intensity and low level of magnification. Some examiners also like to use focal illumination with a broad beam (> 0.8 mm) for this purpose, as the reduced light intensity might improve patient cooperation. The adnexa are first examined and any abnormalities noted. Specifically, the lids are examined for aberrant lashes and the eyelid margin is everted to allow visualization of ectopic cilia. Meibomian gland orifices are assessed, and the glands themselves can also be visualized through the palpebral conjunctiva at the everted eyelid margin. The status of palpebral and bulbar conjunctiva as well as the appearance of the nictitating membrane are noted. The nasolacrimal

Figure 10.1.15  Human cornea on examination with a thin slit beam. In the corneal section created with a thin beam of light, tear film and epithelium, corneal stroma, and endothelium all become visible separately. (Reproduced with permission from Martonyi, C.L., Bahn, C.F., & Meyer, R.F. (2007) Clinical Slit Lamp Biomicroscopy and Photo Slit Lamp Biomicrography. Ann Arbor, MI: Time One Ink.)

puncta can be identified and their shape and patency assessed. Diffuse illumination is specifically suited to reveal gross corneal pathology, such as the presence of foreign bodies, ulceration, pigmentation, active vascularization, or edema, and serves to note areas of interest to be subsequently examined with more selective methods and higher magnification. The specular reflection of the corneal surface, which represents the integrity of the precorneal tear film and corneal epithelium, can also be observed under diffuse lighting on low magnification, with the slit‐lamp biomicroscope illuminator and microscope positioned as described above. The anterior chamber and iris are also screened with the diffuse beam for obvious changes such as hypopyon, fibrin, hyphema, cysts, pigmentary changes, pupillary distortion, or mass effects. The presence of iridodonesis or vitreal herniation is noted. Examination of the lens with the diffuse beam prior to induction of mydriasis will be limited to confirming its correct anatomic position, as well as the presence of obvious anterior capsular anomalies and cataract. In the next step, focal illumination with a broad beam (0.5–1.5 mm) is employed to create a parallel‐piped section of the cornea, giving a three‐dimensional view of a block of corneal tissue. Specific attention is paid to the trailing edge of the beam, as deeper structures are visible here without an overlay from more anterior tissues. Once the observer has scanned the

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A

B

D

C

Figure 10.1.16  It is important that with both the use of broad and narrow beams, an appropriately wide angle between the slit-lamp microscope and illuminator (more than 45 degrees) is chosen, as the section collapses with too narrow an angle. A, C. Narrow angle between illuminator and biomicroscope. (Courtesy of AHT, Newmarket, UK.) B, D. Wide angle between illuminator and microscope.

A

B

Figure 10.1.17  Descemetocoele in a West Highland White Terrier with keratoconjunctivitis sicca. A. The slit image on the corneal surface deviates away from the examiner, indicating the presence of a corneal defect. The steep decline of the slit on the surface into the depth of the ulcer confirms the lesion to be deep stromal. B. On higher magnification, the examiner can appreciate that the slit image on the floor of the ulcerated area is gently bowing toward the examiner again, indicating the presence of a descemetocoele. (Courtesy of AHT, Newmarket, UK.)

585

SECTION II

10.1: Ophthalmic Examination and Diagnostics

A

B

Figure 10.1.18  Diffuse iris melanoma in a cat. A. Appearance of a lesion on slit-lamp examination with a diffuse beam. B. On examination with a slit beam, the iris lesion is deviated toward the examiner, indicating that the iris surface is raised. (Courtesy of AHT, Newmarket, UK.)

A

B

Figure 10.1.19  Distance estimation with the help of a slit beam. A. The close proximity of the slit beam image on cornea and iris surface indicates marked anterior chamber shallowing in this patient with diabetes with an intumescent cataract. B. The increased anterior chamber depth is made visible by the increased distance between the slit beam on the cornea and the wrinkled anterior lens capsule in this patient with a hypermature cataract. (Courtesy of AHT, Newmarket, UK.)

cornea with the broad slit for an overview, the beam is narrowed to allow optical sectioning of the transparent ocular media. For this purpose, a tall slit beam of approximately 0.1–0.2 mm diameter is focused onto the cornea, with an angle of at least 45 degrees between illuminator and microscope. The cornea is then sequentially sectioned as the slit beam is moved across its entirety. In the optical section of the healthy cornea examined at high magnification (25–40×), the tear film is seen as a bright, sharp line, underlain immediately by a dark zone representing the corneal epithelium (see Fig. 10.1.15). On lower magnifications (8–16×), as provided by most handheld units, it will not be possible to distinguish between tear film and epithelium, and the anterior corneal surface will appear as a bright line of reflection only. The corneal stroma is visible as

a diffusely gray zone, which is less intense toward the corneal endothelium, the latter standing out in the optical section as a gray line slightly less bright than that at the corneal surface (see Fig.  10.1.15). Loss of intensity and fragmentation of the usually bright leading line of reflection of the optical section of the cornea are typically seen in patients with tear film deficiencies, epithelial irregularities, or frank ulceration. Stromal lesions such as vascularization, ulceration and edema, deposition of aberrant metabolites, and tearing or disruption of Descemet’s membrane will all distort the normal, orderly, and well‐defined appearance of the corneal slit section. To best appreciate changes in the posterior aspect of the corneal slit section, the specular reflection of this area is utilized. In order to visualize the specular reflection of the

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586

A

B

C Figure 10.1.20  Examination of the anterior chamber for signs of aqueous flare. A. Absence of aqueous flare. B. Aqueous flare is visible as a faint haze in the light beam. C. Not only protein but also herniated vitreous and pigment can cause the Tyndall effect on examination with a slit beam, as seen here in an Italian Greyhound with vitreal degeneration. (Courtesy of AHT, Newmarket, UK.)

endothelial cells, the observer first centers and focuses on the brighter reflection of the corneal surface with a narrow beam and an angle of approximately 30 degrees between illuminator and microscope. At this point, the reflection from the corneal endothelium will become visible as a significantly less bright line. Once this is in sharp view, the examiner moves the focus onto the endothelial reflection by moving the slit‐lamp biomicroscope forward minimally – by a distance approximating the thickness of the corneal stroma. Individual endothelial cells may be appreciated by the help of their specular reflection in the typical honeycomb pattern at magnifications from 25× to 40×. Even at lower magnification levels, endothelial defects characterized by cell loss may become visible, as dark zones and endothe-

lial deposits such as keratic precipitates may be visible as highly reflective areas. Optical sectioning is also utilized to estimate corneal thickness. In corneal ulceration, the distance between anterior and posterior slit image will be narrowed, and the most proximal slit image will be deflected away from the examiner. The remaining thickness of illuminated stroma allows precise gauging of the depth of ulceration (see Fig. 10.1.17A). A complex image of the leading slit beam is seen in the presence of a descemetocoele, where the peripheral part of the slit beam is deflected away from the examiner and the deepest, central part of the section is deviated toward the examiner, indicating an outward bowing of Descemet’s membrane (see Fig.  10.1.17B). However, an increase in corneal thick-

ness, such as in corneal edema, will result in an increase of the thickness of the optical section compared with the normal cornea if the same angle between illuminator and microscope is chosen (see Fig. 10.1.13B). In bullous keratopathy associated with loss of endothelial cell function, areas of stromal fluid accumulation are seen as dark “fill defects” in the otherwise grayish stromal section, often accumulating subepithelially. In cases of tearing of Descemet’s membrane, the normally bright posterior aspect of the corneal slit section is distorted, and associated stromal edema is visible as fill defects in the increased stromal aspect of the corneal section. The level of blood vessels and position of sequestra or foreign bodies with regard to their depth within the cornea can also be determined by optical sectioning: if a lesion is visible one‐third within the optical section, it is positioned at one‐third of corneal depth (Fig. 10.1.26). The iris surface is also examined with a narrow slit beam and changes in surface texture and thickness are noted. The pupillary margin of the iris can be examined by retroillumination from the fundus, as can areas of iris hypoplasia. It must be remembered, however, that examination of the iris is two‐dimensional because of its nontransparent nature, and an optical slit section cannot be obtained (Berliner, 1943). Areas of changes in iris pigmentation must be specifically and carefully examined across their surface, as any deviation of the slit beam toward the examiner could indicate the presence of an iridal mass (see Fig. 10.1.18A, B). A slit projected onto the iris surface would also be deflected toward the examiner if the iris was distorted forward by a mass or cysts within the posterior chamber. In equine iris hypoplasia, the forward‐ bowed iris would elicit a deflection of the slit toward the examiner, but the absence of a mass lesion in this case would be eliminated by the translucency of the thinned iris tissue. Iris cysts present freely in the anterior chamber or attached to

Figure 10.1.21  Appearance of the human corneal endothelium by examination of its specular reflection on slit-lamp examination. The surfaces of healthy corneal endothelial cells are usually smooth and highly reflective, whereas their borders are irregular and thus highlighted by the absence of specular reflection, leading to the “honeycomb” appearance of the normal corneal endothelium on high-magnification examination, as previously described. Pathology of endothelial cells will lead to loss of the normal specular reflection – visible as a dark “fill defect” in the normal endothelial pattern. To visualize individual endothelial cells, magnification levels of 25–40× are required, which exceeds the scope of most handheld slit-lamp models. (Reproduced with permission from Martonyi, C.L., Bahn, C.F., & Meyer, R.F. (2007) Clinical Slit Lamp Biomicroscopy and Photo Slit Lamp Biomicrography. Ann Arbor, MI: Time One Ink.)

A

B

Figure 10.1.22  A posterior polar subcapsular cataract seen with the broad beam on direct illumination and on retroillumination, demonstrating that the form of illumination chosen will affect the appearance of an opacity in the visual pathways. A. On direct illumination, the cataract appears as a light-colored opacity. B. On retroillumination, the cataract stands out dark against the bright fundic reflex. (Courtesy of AHT, Newmarket, UK.)

587

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c

b

a

Figure 10.1.23  Subtle corneal changes are best examined with indirect methods of illumination. The photograph shows the appearance of keratic precipitates in direct illumination (a) and retroillumination from the iris (b, c). Retroillumination from the iris can be direct (b) and indirect (c), with the latter method being able to highlight even the most subtle corneal opacities by scattering of light against an otherwise dark background. (Courtesy of N. Wallin Håkansson.)

Figure 10.1.24  Illustration of the same changes as shown in Fig. 10.1.23.

the pupillary margin are distinguished from solid masses as they transilluminate when examined at an oblique angle with a bright and narrow light beam. In the next step, the anterior chamber is assessed for flare using a bright slit beam reduced to a minimal height (ideally pinpoint lighting). Protein, cells, or pigment dispersed within the anterior chamber are highlighted, as smoke would be if hit by a beam of light falling into an otherwise darkened room (see Fig. 10.1.20). The degree of aqueous flare observed should be noted and graded (Munger, 2002). Following this first part of the biomicroscopic examination, mydriasis is induced to allow complete assessment of the lens and, if desired, the fundus (Gelatt et al., 1973, 1995a, 1995b; Munger, 2002; Rubin & Wolfes, 1962). Diffuse illumination of the lens may reveal lentodonesis (phacodonesis). On optical sectioning, the lens is visible with a convex bright line of illumination representing the anterior lens capsule; a concave, less bright line of illumination representing the posterior lens capsule; and a diffuse, gray zone in between. In cases of aphakia or lens luxation, the above reflections are absent; in lens subluxation, only the very peripheral part of the reflected slit‐lamp biomicroscope beam on the lens may be missing, highlighting an aphakic crescent. Changes to the anterior lens capsule such as tears or wrinkling can be appreciated as distortions or loss of brightness of the anterior reflections. In adult dogs (at more than 1 year of age), it is possible to distinguish between two distant areas within the lens as cortex and nucleus, and with advancing age the dis-

tance from anterior lens capsule to nucleus will increase. Both anterior and posterior suture lines may be visible as thin white lines separated by a central dark line (Martin, 1969c, 1969d). Cataracts will be visible as bright opacities in the lens section and their position can be precisely identified and recorded (Fig.  10.1.27). Changes in lens volume will be reflected in the anterior chamber depth, as previously described. Changing focus to just behind the posterior lens capsule, the anterior vitreous can be examined on the slit section via a mydriatic pupil. The vitreo‐hyaloid ligament insertion, a normal physiologic structure, is visible in the dog as a small round opacity just beside and below the posterior lens pole. In the center of this opacity, the Mittendorf’s dot is visible as a small, white, pigtail‐like structure protruding into the anterior vitreous for 1–2 mm (Martin, 1969c, 1969d). In vitreal disease, the Tyndall phenomenon may highlight vitreal condensations, cellular infiltrates, blood, or pigment. With direct and indirect goniolenses, the slit‐lamp biomicroscope allows for a magnified and stereoscopic view of the ICA and CC (Schmidt, 1975). Special contact and noncontact lenses are also available for use with the slit‐lamp biomicroscope to allow visualization of the vitreous chamber, ciliary body, and fundus (Martonyi et al., 2007). Examples of such lenses are the Goldmann 3, Hruby, and Rosen lenses (Schmidt, 1975). Fundic examination of veterinary patients with handheld slit‐lamp biomicroscope models is technically challenging in the clinical setting, as the examiner has to use both hands to hold the instrument and condensing

589

SECTION II

10.1: Ophthalmic Examination and Diagnostics

A

B

D

E

C

F

Figure 10.1.25  Types of lesions observed with the slit-lamp biomicroscope. Using the direct and retroillumination methods, three basic methods of lesion can be defined: obstructive lesions (A; i.e., they block the light) such as pigment, blood clot, dense scar, dense cataract, and tissue masses, including ciliary body tumor (B); translucent lesions (C; i.e., some light may pass through the lesion but is scattered), such as corneal edema, keratic precipitates, fibrin, mild cataract, thin scars, and cysts, including ciliary body cysts (D); and refractile lesions (E; i.e., light passes freely through the lesion but is refracted), such as the lens equator, lens vacuoles (F), lens wrinkles, distorted tear film, and corneal bullae.

lens, and will rely entirely on the assistant to restrain the patient’s head and keep the eyelids open. Only few portable slit‐lamp biomicroscope models have integrated holders for condensing lenses at the front of the instrument, making the use of the slit‐lamp biomicroscope for fundic examination in veterinary patients a more viable option (see Table 10.1.2). The use of the slit‐lamp biomicroscope has also been described for examination of the precorneal tear film using polarized light in healthy cats and dogs, as well as in dogs with KCS (Carrington et al., 1987a, 1987b, 1987c) Given the significant cost of even the handheld slit‐lamp biomicroscope units, several manufacturers have made efforts to produce cost‐effective alternatives. For this purpose, manufacturers have developed either simplified handheld units or headpieces for the direct ophthalmoscope handle, which combine a bright light source that can be used both diffuse

(approximately 3–5 mm circle) or on a slit setting (0.3–0.4 mm) with a magnifying lens of 6× magnification at a 25–35 degree fixed angle. These instruments have obvious limitations when compared with the more versatile handheld slit‐lamp biomicroscopes previously described, but can still be useful to help with depth estimation of lesions in the anterior segment and lens, as well as with the detection of aqueous flare.

Direct Ophthalmoscopy In 1704, Méry described direct visualization of the feline ocular fundus when the eye was immersed in water (Albert & Edwards, 1996; Enbaugh, 1958). De la Hire later explained this phenomenon, stating that the water neutralized the reflective and refractive effects of the corneal curvature. In 1846, William Cumming reported his findings of the fundus

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590

Figure 10.1.26  The level of blood vessels and position of sequestra or foreign bodies with regard to their depth within the cornea can also be determined by optical sectioning. In this patient with immune-mediated keratitis, blood vessels can be located to the midstroma on slit-lamp examination. (Courtesy of AHT, Newmarket, UK.)

reflex in humans. Charles Babbage subsequently developed the first ophthalmoscope, using a mirror with a hole in its center. This crude device reflected light at the eye, with the central hole allowing visualization of the fundus by the examiner. In 1854, Thomas Wharton Jones publicized Babbage’s device, and Von Helmholtz reported his ophthalmoscope several years later (Albert & Edwards, 1996). Constructed out of pasteboard, cover glasses, and a lens, this device permitted visualization of an image of the patient’s ocular fundus. Reynat is credited as being the first to use direct ophthalmoscopy for veterinary ophthalmology in 1858 (Rubin, 1974). Van Biervliet and van Rooy in Belgium

A

and Guerineau in France subsequently reported equine ocular abnormalities observed by direct ophthalmoscopy in 1861. Three decades later, in 1892, Bayer of Vienna published the first atlas of comparative ophthalmoscopy. Ophthalmoscopy is a technique that requires extensive practice until it becomes a valuable and rapid diagnostic tool for the clinician. This is not only because of the actual difficulty of performing the procedure, but because of the huge variation in fundic appearance both between and within different species. It is only with considerable practice that it is possible to accumulate the vast “memory reference library” of fundic images that will enable the clinician to instantaneously distinguish between normal variations and signs of pathology. Direct ophthalmoscopy is the classic form of ophthalmoscopy with which most clinicians are familiar, because the direct ophthalmoscope is commonly available as part of a set with an otoscope. The direct ophthalmoscope consists of a power source and a halogen or LED coaxial optical system (Fig. 10.1.28). Light is directed via a mirror or prism into the patient’s eye and is reflected back through a lens in the ophthalmoscope to the examiner (Fig.  10.1.29; Ollivier et  al., 2007). Direct ophthalmoscopes take advantage of the refractive power of the patient’s cornea and lens. Therefore, refractive errors in both the patient and the examiner affect the ability to focus on the ocular fundus. Refractive errors of most animals appear to be reasonably static, with the exceptions of the nonhuman primate and the cat, in which some accommodation may occur. Most fundi are in focus at 0–2 diopters (D) if the examiner is emmetropic (Ollivier et  al., 2007). The resultant image is real, erect, and magnified several times, depending on the species being evaluated (Table  10.1.3). The size of the eye being examined, and

B

Figure 10.1.27  The position of a cataract can be located accurately on examination with the slit beam. A. Nuclear cataract with subtle cortical extensions in a Golden Retriever clearly visible on the slit section between slit image on anterior and posterior lens capsule. B. Posterior polar subcapsular cataract in a Labrador Retriever located just in front of the slit beam on the posterior lens capsule. (Courtesy of AHT, Newmarket, UK.)

591

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A

B

Figure 10.1.28  Direct ophthalmoscope head. A. Observer side with viewing aperture, lens dial, quick lens switch, and diopter indicator. B. Patient side with viewing hole and switches/dials allowing selection of beam size and shape as well as light filters.

Examiner

Mirror

Patient

Figure 10.1.29  Optics of direct ophthalmoscopy. The direct ophthalmoscope allows alignment of the observer’s visual axis with a light beam, which is reflected via a mirror to illuminate the patient’s fundus. Light rays emanating from the patient’s eye form a real image on the observer’s retina.

therefore the working distance between the examiner and the lesion of interest, will affect magnification, so it is important to compare any lesion(s) with the size or diameter of the optic disc, rather than with any units of measurement. In order for the clinician to perform direct ophthalmoscopy, animals must be either reasonably cooperative or adequately restrained. Most small animals can be gently restrained on the examination table by the owner or an assistant; some fractious animals or large animals require some form of sedation and/or an auriculopalpebral nerve block. Before examination, the pupils are usually dilated with a

short‐acting mydriatic such as 0.5%–1% tropicamide (Klauss & Constantinescu, 2004; Munger, 2002). Eyes with dark‐colored irides may require repeat application of the mydriatic agent compared with eyes with lighter colored irides, and frequently take longer to dilate (Ollivier et al., 2007). The fundi of large animals such as the horse can often be visualized without dilation, but mydriasis will ensure a thorough examination. Following induction of adequate mydriasis, the examiner rests the direct ophthalmoscope against his or her brow and identifies the patient’s fundic reflex from approximately arm’s length (Fig. 10.1.30).

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Table 10.1.3  Optical changes of direct ophthalmoscopy in animals: Change in millimeters with 1 D change in focus with the direct ophthalmoscope.

Species

Fundus Equivalent/ Diopter Change

Magnification (mm)

Dog

17.2

0.28

Cat

19.5

0.22

Horse

7.9

1.33

Cow

10.6

0.74

Sheep

13.9

0.43

Pig

15.2

0.36

Rabbit

25.3

0.13

Rat

77.2

0.01

Iguana

38.8

0.06

Great Horned Owl Pigeon

9.6

0.90

31.6

0.08

Monkey

20.7

0.19

Human

14.7

0.39

Source: Modified from Murphy, C.J. & Howland, H.C. (1987) The optics of comparative ophthalmoscopy. Vision Research, 27, 599.

Figure 10.1.30  Distant direct ophthalmoscopy. The patient’s fundic reflex is picked up at arm’s length and any opacities in the clear ocular media will stand out dark against the bright background. This test is also helpful to check for anisocoria if both fundic reflexes are compared.

Ideally, the examiner’s right eye should be used to examine the patient’s right eye and vice versa. This is especially important in patients with frontal eyes and long noses, because this position minimizes contact between the examiner’s nose and the patient’s muzzle. Alternating eyes, however, does require practice, because most people have a dominant eye that they prefer to use.

Figure 10.1.31  Close direct ophthalmoscopy. The examiner must be as close as possible to obtain an optimal image with direct ophthalmoscopy. To achieve this, the examiner ideally should use the right eye to examine the patient’s right eye and vice versa.

Once the fundic reflex is identified, the examiner moves toward the patient to a point approximately 2–3 cm from the eye. The closer the examiner is to the patient’s eye, the wider the angle of view will be (Fig. 10.1.31). If the direct ophthalmoscope is positioned too far from the cornea, the entire fundus cannot be visualized, and even the slightest movement will cause most of the fundic image to be lost. The constant head and eye movements of veterinary patients will frequently cause the examiner to lose the image. If this happens, the quickest way to regain alignment is to step back, find the tapetal reflection again, and then move in close. Once the fundus is visualized, ophthalmoscopy should proceed in a timely and orderly fashion. It is important for each examiner to establish an order or pattern for the fundic examination to ensure that no features are missed. The optic nerve is typically identified and examined first. Afterward, the remainder of the fundus is thoroughly examined in quadrants, making sure that the tapetal regions of the fundus, the atapetal regions of the fundus, the fundic periphery, and the retinal vasculature are closely examined. A circular dial on the direct ophthalmoscope holds a series of concave and convex lenses that can be rotated through the viewing aperture (see Fig.  10.1.28A; Barnett, 1967; Bistner, 1983; Bunce, 1955; Catcott, 1952). Green or black numbers on the circular dial represent convex or converging lenses (positive), while red numbers represent concave or diverging lenses (negative). A separate dial or switch adjusts the size, shape, and color of the light beam (see Fig. 10.1.28B). Possible options include large and small spots, slit, graticule, red‐free filter (which appears green), and cobalt blue filter. The red‐ free light is used to evaluate retinal vessels and the nerve fiber layer. It is also useful for differentiating hemorrhage, which appears black, from normal pigment and pigmented lesions

such as melanomas, which appear brown. The graticule consists of a grid (often of 16 squares) used to estimate the size of fundic lesions. This is most useful for ophthalmologists examining human eyes, which are of very similar size. The cobalt blue filter can also be used to examine the nerve fiber layer of the retina and to highlight the presence of fluorescein dye. The slit beam aids in detection of elevations or depressions in the ocular fundus. Distances between the normal retina and the surface of such abnormalities can be estimated by changing the dioptric power of the ophthalmoscope. For example, if the retina is in focus at 0 D, and the surface of a lesion is in focus at +3 D (green or black), the lesion is elevated. If, however, the surface of the lesion is in focus at −3 D (red), it is depressed. The diopter equivalent is the actual distance (in millimeters) that the focal plane moves anteriorly or posteriorly with each diopter, and it varies with the species examined (Table 10.1.4; Murphy & Howland, 1987). The size of the circular spot of white light should be adjusted to the patient’s pupil size to minimize light reflections from the corneal surface. The intensity of the illuminating light is

c­ ontrolled by a rheostat and is generally adjusted as low as possible to allow a good view for the comfort of both the patient and the examiner. If for some reason the pupil is not dilated, it is best to have the illuminating light dim to minimize the pupillary constriction that will result when the light is directed on the eye. It is also important to perform fundic examination in a darkened room to optimize the conditions for a thorough and complete examination. The direct ophthalmoscope can also be used to pick up any central opacities in the clear media anterior to the fundus by retroillumination. Once the fundic reflex is identified by the examiner looking through the ophthalmoscope at a distance (“distant direct ophthalmoscopy”; see Fig.  10.1.30), a dark spot detected against the fundus reflection indicates that an opacity is blocking the return of light to the observer. Ideally, the presence of this opacity is noted and its exact depth (whether it is in the cornea, anterior chamber, lens, or vitreous) will be determined subsequently with slit‐lamp biomicroscope examination. However, in the absence of access to a slit‐lamp biomicroscope, it is possible to determine whether

Table 10.1.4  Lateral and axial magnification in indirect ophthalmoscopy. Lateral Magnification Species

14 D Lens

20 D Lens

30 D Lens

Axial Magnification 40 D Lens

14 D Lens

20 D Lens

30 D Lens

40 D Lens

Dog

2.57

1.72

1.11

0.82

8.85

3.97

1.65

0.90

Cat

2.91

1.95

1.26

0.93

11.31

5.08

2.11

1.15

Horse

1.18

0.79

0.51

0.38

1.86

0.84

0.35

0.19

Cow

1.58

1.06

0.68

0.50

3.34

1.50

0.62

0.34

Sheep

2.07

1.39

0.90

0.66

5.74

2.58

1.07

0.58

Great Horned Owl

1.43

0.96

0.62

0.46

2.75

1.23

0.51

0.28

Tawny Owl

2.16

1.45

0.94

0.69

6.26

2.81

1.17

0.64

Pigeon

4.72

3.16

2.04

1.51

29.84

13.40

5.58

3.04

Pig

2.26

1.52

0.98

0.72

6.83

3.07

1.28

0.70

Human

2.19

1.47

0.95

0.70

6.39

2.87

1.19

0.65

Monkey

3.09

2.07

1.34

0.99

12.79

5.74

2.39

1.30

Rabbit

3.77

2.53

1.63

1.20

18.99

8.53

3.55

1.93

Gecko

4.19

2.81

1.81

1.34

23.48

10.54

4.39

2.39

Iguana

5.79

3.88

2.50

1.85

44.71

20.07

8.35

4.55

Flying Fox

5.38

3.60

2.32

1.72

38.62

17.34

7.22

3.93

Opossum

7.30

4.89

3.16

2.33

71.24

31.98

13.31

7.25

Frog

9.15

6.13

3.95

2.92

50.24

20.91

11.39

Rat

11.52

7.72

4.98

3.68

177.44

79.65

33.15

Bat

36.23

24.27

15.66

11.56

1753.33

787.07

327.60

111.9

18.06 178

Source: Murphy, C.J. & Howland, H.C. (1985). Optics of comparative ophthalmoscopy. Transactions of the Sixteenth Annual Scientific Program of the College of Veterinary Ophthalmologists, 1985, 132–157.

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the identified opacity is anterior or posterior to the lens nucleus with the help of the phenomenon of parallax. Opacities located anterior to the lens nucleus will move away from the observer and light source, and those located posterior to the lens nucleus will move with the observer and light source during lateral motion of the observer. The advantages of direct versus indirect ophthalmoscopy include greater magnification, availability of options such as the slit and grid, and ability to alter the dioptric power of the ophthalmoscope. Disadvantages include a small field of view that can result in lesions being missed, short working distance between examiner and patient, lack of stereopsis, difficulty in examining the peripheral fundus, and greater distortion when the visual axis is not completely transparent (Fig. 10.1.32).

Indirect Ophthalmoscopy Ruete first conceived of the indirect ophthalmoscope in 1853 (Albert & Edwards, 1996). Despite several advantages over direct ophthalmoscopy, it did not gain wide acceptance in

the United States until 1947, when Schepens and Bahn (1950) developed a high‐intensity light that improved visualization of the fundus. In 1960, Rubin (Rubin, 1960) published the first study describing indirect ophthalmoscopy in dogs; this was closely followed by Vierheller’s clinical experiences with the device (Vierheller, 1966). Indirect ophthalmoscopy has since become a routine part of the veterinary ophthalmic examination. Indirect ophthalmoscopy, in contrast to direct ophthalmoscopy, allows the clinician to view a larger portion of the fundus (larger field of view) at one time and to do so from a greater and safer working distance from the patient (Fig. 10.1.33 and Fig. 10.1.34). The image generated with indirect ophthalmoscopy may initially be confusing to the novice examiner because it is inverted and reversed (upside down and backward), but once the technique is mastered, it is an indispensable tool for a thorough evaluation (see Fig. 10.1.32; Havener & O’Dair, 1963). Because there is much less magnification of the image perceived with indirect ophthalmoscopy than with direct ophthalmoscopy, a better overview of the

A

B

C Indirect

Direct

D

Panoptic

E

F

Figure 10.1.32  Comparison of direct, panoptic, and indirect ophthalmoscopy. These photographs illustrate the different appearances in terms of magnification and orientation of the canine and equine ocular fundus with each of the three methods of ophthalmoscopy: direct (A, D), panoptic (B, E), and indirect (C, F) ophthalmoscopy.

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Figure 10.1.33  Binocular indirect ophthalmoscopy. In this technique, the observer does not only have stereopsis, but also has one hand free to hold the patient’s head.

Figure 10.1.34  Monocular indirect ophthalmoscopy. The technique can be carried out with minimal equipment, but stereopsis is lost and the observer relies on the help of an assistant to stabilize the patient’s head.

fundus can be achieved (see Fig.  10.1.32 and Table  10.1.4; Murphy & Howland, 1987). The two methods often complement each other, particularly if a lesion detected with the indirect method is then examined more closely, at greater magnification, with the direct method (Murphy & Howland, 1987). The necessary components of indirect ophthalmoscopy are a strong, focal light source and a converging lens. Indirect ophthalmoscopy has additional advantages over direct ophthalmoscopy when a binocular indirect ophthalmoscope is utilized, including stereopsis and the ability to use both hands for patient manipulation. Binocular indirect ophthalmoscopy uses a halogen, xenon, or LED light source, a mirror to direct light into the patient’s eye, a handheld converging lens to magnify the reflected image, and two prisms to split the reflected light so that it can be directed into both of the examiner’s eyes, thereby permitting stereopsis (Fig. 10.1.35). The ophthalmoscope and light source are fitted onto a headband or spectacle frame that can be adjusted to comfortably fit the examiner (Fig. 10.1.36). Eyepieces are

adjusted to match the distance between the examiner’s eyes and light intensity is altered with a rheostat. Most binocular indirect ophthalmoscopes have interchangeable apertures and filters, as well as permanent or detachable teaching mirrors. The headset provides the light necessary for the examination, frees the operator’s hands to hold the lens and position the patient’s head (frequently without the aid of an assistant; see Fig. 10.1.33), and optically narrows the examiner’s interpupillary distance to permit a binocular view and stereopsis. Newer, head‐mounted indirect ophthalmoscopes enable the observer’s interpupillary distance to be optically reduced to a minimal setting to allow retinal examination through small pupils, in situations where mydriasis is undesired or cannot be induced while still preserving stereopsis. If a binocular headset is unavailable or cost prohibitive, indirect ophthalmoscopy can be performed quite adequately without it. Monocular indirect ophthalmoscopy employs only a bright, handheld light source (e.g., transilluminator, direct ophthalmoscope or strong otoscope, fiberoptic bundle,

Examiner

Aerial image of retina

Condenser

Patient

Figure 10.1.35  Optics in binocular indirect ophthalmoscopy. In this technique, the light returning from the patient’s fundus is split via a prism into both of the observer’s eyes, allowing stereopsis. The image created is virtual and inverted.

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A

B

Figure 10.1.36  A. Keeler (Broomall, PA, USA and Windsor, UK) Vantage indirect head-mounted ophthalmoscope and Volk (Mentor, OH, USA) 20 D, 30 D, 90 D, and 2.2 Pan-retinal condensing lenses. The halogen ophthalmoscope is powered by a battery included into the headband and is thus ideal for examination of all veterinary patients. B. The panoptic ophthalmoscope is a good compromise between the direct and indirect methods of ophthalmoscopy, proving a real image (neither inverted nor reversed) and intermediate in magnifications between the two.

penlight) and a handheld lens (see Fig. 10.1.34). This method does not provide stereopsis and requires an assistant to restrain the patient and position the head, but nonetheless gives an overall view of the fundus. To perform the fundic examination following induction of mydriasis, the examiner grasps the patient’s muzzle with one hand and stabilizes the head. The other hand is used both to hold the eyelids open and to position the lens 2–4 cm in front of the patient’s cornea. When a binocular headset is unavailable, an assistant positions the head and holds the eyelids open, while the examiner uses one hand to hold the light source against his or her temple so that both the head and the light source move as a unit, and the other hand to hold and position the lens. The lens is held with the thumb and forefinger and positioned so that the strongest convex surface is facing the examiner (or flatter surface toward patient) for the best image. From a distance of approximately 0.50–0.75 m (at arm’s length), the examiner then directs the light into the patient’s eye and identifies the fundic reflex. The light should be adjusted so that its intensity permits adequate, but not excessive, illumination of the ocular fundus. Excessively bright light can obscure details and cause patient discomfort and thus lack of cooperation. Many indirect head‐mounted ophthalmoscopes will offer the option of a light diffuser, which provides softer light to make the examination more comfortable for the patient. Another benefit of diffuse light is the elimination of shadows on the edge of the condensing light, which allows a significantly increased view of the peripheral retina. Anesthetized patients that cannot move may develop retinal burns when the light utilized for the examination is too strong. Light‐ induced retinal damage can also be caused by ophthalmoscopic examination in canine patients with T4R RHO retinal degeneration (Cideciyan et  al., 2005; Gu et  al., 2007).

Following indirect ophthalmoscopy, an increased interval of at least 60 minutes of light adaptation has been recommended before performing ERG (Tuntivanich et al., 2005). In animals that have a tapetum, the light should be decreased for examination of that region and may need to be increased for examination of the atapetal fundus (Martin, 2005). Reflections from the surface of the handheld lens occasionally obscure part of the fundic image, but these can be easily eliminated by slightly tilting the lens. Once the fundic reflex is identified, opacities of the cornea, lens, and vitreous can be seen as dark areas highlighted against the fundic reflection, as in distant direct ophthalmoscopy. Again, as with distant direct ophthalmoscopy, lesions can be approximately localized in an anteroposterior direction with the help of the phenomenon of parallax (see the previous section). Opacities in the anterior chamber or vitreous may oscillate or float with eye movement. Lesions anterior to the retina or optic nerve (e.g., persistent hyaloid artery) will change position with respect to their background when viewed from a different angle, an example of the parallax phenomenon. Slight manipulations of the handheld lens itself can reveal subtle hyperreflectivity or streaking in the tapetal fundus. Examination of the fundus with indirect ophthalmoscopy should proceed in an orderly fashion, as with direct ophthalmoscopy, taking care to examine the optic nerve, the retinal vasculature, and the tapetal and nontapetal fundus and the periphery. The extreme peripheral retina at the ora ciliaris can be visualized with practice and good mydriasis, especially ventrally and temporally. There are many different lenses available for use with indirect ophthalmoscopy, ranging in diopter strength from +5.5 D to +90 D (see Fig. 10.1.36). The choice of lens will vary depending on the required magnification, field of view, stereopsis, and the size of the patient’s pupil. Fundic magnification varies

with lens and species (see Table 10.1.4; Murphy & Howland, 1987). The magnification of the image is equal to the diopter strength of the eye divided by the diopter strength of the lens (Goldbaum et al., 1980; Martin, 2005), so the smaller the diopter rating of the lens, the greater the magnification of the image (smaller number, larger image). It is important to take into account that additional magnification is built into the binocular headset, so that the image perceived with its use will be even more magnified than with the lens alone. The strength of the lens also affects the depth perception of the examiner. The higher the diopter strength of the lens, the less stereopsis there will be (larger number, less stereopsis; Martin, 2005). It is also important to consider the size of the animal’s pupil when selecting a lens. The higher the diopter strength of the lens, the easier it will be for the examiner to see through a small pupil (smaller pupil, higher number; Goldbaum et al., 1980). In general, a high diopter strength lens results in a smaller image but a larger field of view, less stereopsis, and easier examination through a smaller pupil (Goldbaum et al., 1980; Martin, 2005). The 2.2 panretinal lens is the most versatile lens for the clinician who wishes to only acquire one lens, as it provides the best compromise between magnification and field of view (Snead et al., 1992). Various models of binocular indirect ophthalmoscopes are available from Heine, Keeler, Propper, Topcon, Xonix, and Zeiss. Camera and video attachments are available for some models, thus allowing the examiner to display and record findings for teaching and research purposes. Commercial monocular indirect ophthalmoscopes are manufactured by Reichert and the American Optical Corporation. These instruments use an internal lens to magnify the reflected fundic image. The American Optical monocular scope is useful for looking through small pupils and produces an erect image. The panoptic ophthalmoscope presents a good compromise between the direct and indirect ophthalmoscopes. The image is real and intermediate in magnification between the two types (Fig. 10.1.35B). Indirect ophthalmoscopy can also be used to semiqualify the refractive error of an animal. By slowly withdrawing the handheld lens from the eye and observing any change in magnification of the image, the clinician can roughly estimate the refractive power of the patient. If the fundic image becomes larger, then the animal is somewhat myopic; if it becomes smaller, then the patient is hyperopic; and if the size of the image remains static, then the animal is emmetropic (Rubin, 1960). Indirect ophthalmoscopy is an essential technique, and its main disadvantage is the cost of the head‐mounted binocular equipment.

Magnification in Ophthalmoscopy In both direct and indirect ophthalmoscopy, lateral and axial magnification have to be considered when interpreting fundic lesions. Lateral magnification describes the magnifica-

tion of an area across an axis perpendicular to the observer’s view, for example in a lateral‐to‐medial and dorsal‐to‐ventral direction with regard to the fundus. Lateral magnification can be exemplified by the action of a slide projector throwing an image onto a screen. Axial magnification describes magnification along the axis of viewing; that is, in depth. In particular, axial magnification describes the ratio of the distance along the optical axis between two corresponding points in object space. Axial magnification is useful when considering an image in its three dimensions. Clinically, it is important when assessing the thickness of retinal or fundic lesions (Murphy & Howland, 1987). In both direct and indirect ophthalmoscopy, lateral magnification varies inversely with the focal length of the eye and axial magnification varies with the inverse square of the focal length (Murphy & Howland, 1987). Given the large variation of eye size in veterinary patients, this has significant implications when performing fundoscopy in the different species. Small eyes (which have high dioptric power) usually have high lateral and axial magnification, in contrast to large eyes (which have low dioptric power) with low lateral and axial magnification. As a result, ophthalmoscopically visible elevations of retina or disc margin in an equine fundus should be given more significance as a clinical finding than in a canine or feline eye (see Table 10.1.4; Murphy & Howland, 1987).

Retinoscopy Retinoscopy, also known as skiascopy, is the objective determination of the dioptric state or refractive error of the eye. Commonly used in human ophthalmology and optometry, this technique has also found use in veterinary ophthalmology, particularly to define the normal, pathologic, and surgically induced refractive state of eyes and in the evaluation and improvement of intraocular lens implants (Davidson, 1997; Davidson et al., 1993; Gaiddon et al., 1996; Gift et al., 2009; Grinninger et al., 2010; Kubai et al., 2008; McMullen et  al., 2010; Millichamp & Dziezyc, 2000; Murphy et  al., 1992, 1997; Mutti et al., 1999; Pollet, 1982; Roberts, 1992). When light rays are projected onto an eye from infinity, they emerge from an emmetropic eye as parallel rays, from a myopic eye as converging rays, and from a hyperopic eye as diverging rays. The location at which these emergent light rays form a focal point or plane is called the far point. The far point is at infinity, in front of infinity, and beyond infinity for the emmetropic, myopic, and hyperopic eye, respectively (Davidson, 1997). The procedure of retinoscopy utilizes a lens placed in front of the eye to modify the image produced (Fig. 10.1.37). The power of the lens that corrects the image, or neutralizes the movement of the fundic reflex, permits an estimation of the dioptric power of the patient’s eye and its difference from emmetropia. Retinoscopy allows veterinary ophthalmologists to quantitatively determine the refractive

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Figure 10.1.37  Retinoscopy carried out in a dog. Note the working distance of 67 cm between examiner and patient. The skiascopy bar or rack is positioned in front of the dog’s eye; it contains a series of plus and minus spherical lenses in increments of 0.5–1.0 D to quantify the eye’s refractive error.

error of the eye to within 0.25–0.50 D of its true refractive state (Davidson, 1997). The retinoscope, either streak or spot, consists of a tungsten bulb filament, a condensing lens, a circular or linear aperture, and an angulated plane mirror (Fig.  10.1.38). Streak retinoscopes produce a linear band of light, whereas spot retinoscopes produce a circular beam; newer models combine both options. Streak retinoscopes are more commonly employed in veterinary ophthalmology. A sleeve in the handle of the streak retinoscope is moved up and down to change the orientation of the mirror and bulb, thus affecting the vergence of the emitted light. Rotating the sleeve clockwise or counterclockwise affects the orientation of the streak itself. Both streak and spot retinoscopes are available from Copeland, Heine, Keeler, Propper, Reichert, and Welch Allyn. Plus or minus spherical lenses, which are available in increments of 0.25 D, are placed between the retinoscope and the patient to quantitate the refractive error of the eye. A skiascopy bar or rack, which contains a series of plus and minus spherical lenses in increments of 0.5–1.0 D, is a simple, convenient, and inexpensive tool for quantifying the refractive error of an animal’s eye. In the United States, positive lenses are usually marked black, while negative lenses are marked red, and it may be important for the examiner to know that this is the exact opposite in Europe. As most domestic animals have limited accommodative ability, the cycloplegia afforded by the mydriatic agents is not necessary (Murphy et al., 1992), and it has been shown in dogs and horses that the induction of cycloplegia does not significantly alter the results of streak retinoscopy from the noncyclopleged eye (Groth et  al., 2013; McMullen et  al., 2014; Rull‐Cotrina et al., 2013). The induction of mydriasis prior to streak retinoscopy may even make the procedure more difficult, due to blurry or reversing streak reflexes following the application of topical tropicamide (McMullen et al., 2014). With the retinoscope resting against the brow,

Figure 10.1.38  Keeler streak retinoscope®.

the examiner is positioned 0.67 m (about arm’s length) from the patient’s eye (a measured 0.67 m string attached to the retinoscope is useful for maintaining this working distance; see Fig. 10.1.37). The sleeve is moved either down (i.e., Heine and Welch Allyn retinoscopes, Welch Allyn, Scaneateles Falls, NY, USA) or up (i.e., Copeland retinoscope) such that the projected light rays are very slightly divergent (i.e., plane mirror effect) and the streak is positioned vertically. Purkinje images from the patient’s cornea and lens are superimposed, and the streak is swept horizontally across the animal’s pupil. The streak is then rotated horizontally and is swept vertically across the pupil. Finally, a trial lens or skiascopy bar is placed 1–2 cm from the patient’s cornea, and the process is repeated. As the streak is slowly swept across the pupil, the fundic reflex will move in either the same or the opposite direction, depending on the refractive error of the patient. With no refractive lens, the fundic reflex will move in the same direction as the sweep with emmetropic and hyperopic eyes (“with motion”), and in the opposite direction to the sweep with less than 1.5 D myopic eyes (“against motion”). If a “with motion” is observed, plus lenses of increasing dioptric strength are placed in front of the patient’s eye until an “against motion” is observed or neutralization is reached. Neutralization is characterized by a fundic reflex that completely fills the pupil without any notable direction of movement. If an “against motion” is observed, minus lenses of increasing dioptric strength are used to achieve neutrality. At a working distance of 0.67 m, a

+1.5 D lens is needed to achieve neutralization with an emmetropic eye; therefore, the refractive error of an eye is determined by subtracting 1.5 D from the gross refraction needed to achieve neutrality (Davidson, 1997). Retinoscopy in the canine reveals that most phakic dogs are within 1.0 D of emmetropia (Kubai et al., 2008; Murphy et  al., 1992; Pollet, 1982). One study of 14,400 adult dogs revealed anisometropia in only 6% of all dogs (Kubai et al., 2008). Attempts to correlate refractive error with animal size and environment have yielded variable results. Results of one study suggest that indoor dogs and small to medium breeds show a tendency toward myopia, whereas outdoor and large‐breed dogs show a tendency toward hyperopia (Gaiddon et al., 1996). However, a familial predisposition to slight myopia has also been reported in some populations of large working dogs, including the German Shepherd, the Rottweiler, and the Labrador Retriever (Kubai et  al., 2008; Murphy et al., 1992; Mutti et al., 1999). The degree of myopia was found to increase with increasing age across all breeds (Kubai et  al., 2008). Astigmatism is reported to be rare in dogs, with only 1% of 1440 adults dogs affected in one study, and only the German Shepherd Dog appeared to be predisposed, with 3% of the examined 90 dogs affected (Kubai et al., 2008). Retinoscopic results of aphakic canine eyes suggest that the mean refractive error ranges from +14.0 D to +15.2 D, and that a +41.5 D lens will usually correct this error to within 1.2 D of emmetropia (Davidson et al., 1993; Gaiddon et al., 1991, 1996; Gift et al., 2009; Pollet, 1982). At the same dioptric strength, however, lens material and design may have an impact on the refractive state of canine patients after cataract surgery (Gift et  al., 2009). In domestic cats of all ages, the mean refractive state ranged from –0.78 D to +1.37 D. The mean refractive error in cats changed significantly as a function of age, with kittens under the age of 4 months ranging from –2.45 D to +1.75 D, while in adult cats it measured from –0.39 D to +0.85 D (Konrade et al., 2012). Refractive error in normal horses has been reported to range from −3 to +3 D, but most appear to be within 1 D of emmetropia (Bracun et al., 2014; Grinninger et al., 2010; Roberts, 1992; Rull‐Cotrina et  al., 2013). A further study surveying 333 horses and ponies showed that 83.63% of eyes were emmetropic, with 68.5% of horses being emmetropic in both eyes (Bracun et  al., 2014). In the same study, only 2.7% of eyes showed ametropia greater than 1.5 D, with 54% of affected eyes being hyperopic and 46% of eyes being myopic. Anisometropia was found in 30.3% of horses. Horses affected with multiple congenital ocular anomalies due to being homozygous for the Silver mutation were found with myopia of –2 D or more, while horses heterozygous for the mutation were only showing an increased tendency to myopia once over 16 years of age (Johansson et al., 2017). After cataract surgery, the aphakic equine eye has been reported to be hyperopic at +9.94 D (Millichamp & Dziezyc, 2000). A 30 D

strength lens implant has been suggested to be able to correct hyperopia after equine cataract surgery, based on calculations using biometry and keratometry results obtained in the normal horse (McMullen & Gilger, 2006; McMullen & Utter, 2010). However, implantation of a 30 D lens in enucleated equine globes and a 25 D lens in the adult equine eye following phacoemulsification still resulted in overcorrection of refractive error by −2.47 D and −3.94 D, respectively (McMullen et al., 2010). Retinoscopy is also readily applicable in avian patients, and a 13.8 D lens implant corrected aphakia in a Great Horned Owl to within −0.75 D of emmetropia following phacoemulsification (Carter et al., 2007). Retinoscopy in 10 healthy rabbits revealed the majority of rabbits to be within 0.5 D of emmetropia (Sanchez et  al., 2017). In four pet rabbits, placement of a 58 D posterior chamber lens implant resulted in streak refraction values from –1.5 D to +1 D (Sanchez et al., 2017, 2018). Retinoscopy has become a firmly established procedure in clinical veterinary ophthalmology. However, considerable practice is necessary to produce consistent results with retinoscopy in animals. For that reason, model eyes are available for teaching and practice purposes (Wessels et al., 1995). With increased use, retinoscopy will not only continue to improve our selection of intraocular lens implants for patients undergoing cataract surgery, but also assist with evaluating performance problems associated with ametropia in working animals (Murphy et al., 1997).

Corneal Esthesiometry The corneal reflex is one of the most sensitive reflexes in the body and its purpose is to protect the eye. The corneal reflex is assessed by touching the peripheral cornea, to avoid a menace response, with a noninjurious object, such as a wisp of cotton wool, swab tip, or fiber from an esthesiometer. The expected result is retraction of the globe, protraction of the nictitating membrane, and closure of the eyelids (Fig.  10.1.39). The afferent arm of the corneal reflex is the ophthalmic branch of cranial nerve V, and the efferent arm is mediated by cranial nerves VI (globe retraction) and VII (eyelid closure). Corneal esthesiometry uses the corneal reflex to quantitatively evaluate corneal sensitivity and thereby indirectly assess corneal innervation. Different types of corneal esthesiometers include Cochet–Bonnet, Larson–Millodot (Luneau USA, Westport, CT, USA), and noncontact air jet esthesiometers (Golebiowski et  al., 2011; Millodot & Larson, 1969). The Cochet–Bonnet esthesiometer is used most commonly in veterinary ophthalmology (see Fig. 10.1.39A). It consists of a nylon filament that is 0.12 mm in diameter and has a variable length of 0.5–6 cm (the filament is platinum in the Larson–Millodot esthesiometer). A change in filament length relates to a change in pressure exerted on the cornea by the filament tip; shorter filament lengths apply more

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600

A

B Figure 10.1.39  A. Cochet–Bonnet esthesiometer®. B. Corneal sensation can be assessed quantitatively by a Cochet–Bonnet esthesiometer. (Courtesy of N. Hamzianpour and R. Pinheiro de Lacerda, Willows Referral Service, UK.)

pressure to the cornea and vice versa. The pressure ranges from 5 to 180 mg/0.0113 mm (0.4–15.9 g/mm). Corneal esthesiometry should be performed in a quiet environment with minimal restraint to the head and eyelids. The instrument is held perpendicular to the cornea, with the filament extended to its maximum length and advanced until the filament contacts the cornea, creating a slight bend in the fiber (Fig.  10.1.39B). The corneal touch threshold (CTT) is the degree of corneal stimulation that is required to elicit a blink reflex. Corneal sensitivity and CTT are inversely proportional. The CTT is defined as the pressure at which the majority of touch stimuli elicit a blink; this is quantified in most studies. For example, when more than 50% of the attempts result in a blink reflex, the filament is shortened by 0.5 cm decrements. The CTT in centimeters is converted to pressure in milligrams per S (S = 0.0113 mm2 sectional area of the filament) and grams per square millimeter using the conversion table provided by the esthesiometer manufacturer. Sensitivity can be assessed in different regions, for example central, dorsal, temporal, ventral, and nasal regions.

Numerous factors influence corneal sensitivity and include species, age, skull shape, region of cornea, systemic disease, and topical anesthetic agents. It is difficult and potentially inaccurate to compare results from different studies because multiple measuring units have been reported, some nonidentifiable, and the nylon filament of the Cochet–Bonnet esthesiometer and conversion table were changed by the manufacturer (Western Ophthalmics, Lynwood, WA, USA) between 1990 and 2010. Furthermore, there is no available corrective formula for deviations from the recommended ambient temperature and humidity (Wieser et al., 2012). Ambient humidity influences results, with a longer filament length eliciting a blink response at a lower humidity (Dorbandt et al., 2017). Results from different studies can only be compared if the filament strength used and units of applied pressure (mg/0.0113 mm2 or g/mm2) are uniform. When comparing studies that reported values in mg/0.0113 mm2, the order of most sensitive to least sensitive is cria (Rankin et  al., 2011a), human (Millodot, 1977), adult alpaca (Rankin et  al., 2011a), cat (Chan‐Ling, 1989), pigmented rabbit (Millodot, 1978), albino rabbit (Millodot, 1978), and nonbrachycephalic dog (Barrett et al., 1991). When comparing studies that reported values in g/mm2, the order of most sensitive to least sensitive is cria (Rankin et  al., 2011a), chinchilla (Lima et  al., 2010; Müller et al., 2010), sheep (Wieser et al., 2012), horse (Wieser et al., 2012), calf (Wieser et al., 2012), goat (Wieser et  al., 2012), normoglycemic dog (Good et  al., 2003), cow (Wieser et al., 2012), Domestic Shorthaired Cat (Blocker & van der Woerdt, 2001), dog with diabetes (Good et  al., 2003), adult alpaca (Rankin et al., 2011a), guinea pig (Trost et  al., 2007), and brachycephalic cat (Blocker & van der Woerdt, 2001). Brachycephalic cats and dogs have reduced corneal sensitivity compared with nonbrachycephalic breeds (Barrett et al., 1991; Blocker & van der Woerdt, 2001). Age influences corneal sensitivity in several species, including the horse (Brooks et  al., 2000b; Miller et  al., 2013), alpaca (Rankin et  al., 2011a), cattle (Tofflemire et  al., 2014), and birds (Lacerda et al., 2014). Corneal sensitivity is higher in neonatal foals, crias, calves, and fledglings (Athene noctua and Strix aluco) than in their adult counterparts (Brooks et al., 2000b; Lacerda et al., 2014; Miller et al., 2013; Rankin et al., 2011a; Tofflemire et  al., 2014). Human corneal sensitivity has been shown to vary with age, gender, and iris pigmentation (Acosta et al., 2006; Millodot, 1977). The central cornea is usually the most sensitive region in many species, including the dog (Barrett et al., 1991; Good et  al., 2003), cat (Blocker & van der Woerdt, 2001), horse (Brooks et al., 2000b; Kaps et al., 2003), alpaca (Rankin et al., 2011a; Welihozkiy et al., 2011), and guinea pig (Trost et al., 2007), although the difference is not always significant. In dogs (Barrett et  al., 1991), cats (Chan‐Ling, 1989), and

­ onhuman primates (Zander & Weddell, 1951), the maxin mum sensitivity of the central cornea correlates to the highest density of nerve fibers. The dorsal region of the cornea is typically less sensitive than other regions, and this has been hypothesized, in humans, to be a result of desensitization from contact with the upper eyelid (Millodot & Larson, 1969). The effect of surgical procedures for canine glaucoma on corneal sensitivity has been studied (Blocker et al., 2007; Weigt et  al., 2002). Neodymium : yttrium‐aluminum‐garnet (Nd : YAG) laser therapy reduces both the corneal sensitivity and the number of major corneal nerve bundles in treated eyes (Weigt et al., 2002). Sensitivity of the central cornea is lower in buphthalmic glaucomatous eyes than in normal eyes, but is not reduced further by the dorsal scleral incision required for evisceration and placement of an intrascleral prosthesis (Blocker et al., 2007). In horses, corneal sensation is reduced in eyes with keratitis as compared to eyes with other ocular disease (Knickelbein et  al., 2018). Corneal esthesiometry has been used to objectively measure the effect of different agents (Arnold et  al., 2014; Binder & Herring, 2006; Chen & Powell, 2015; Dorbandt et al., 2016; Douet et al., 2013; Giudici et al., 2015; Gordon et al., 2018; Herring et al., 2005; Kalf et al., 2008; Kim et al., 2013; Pucket et al., 2013; Sharrow‐Reabe & Townsend, 2012; Venturi et al., 2017; Wotman & Utter, 2010).

Tear Tests The tear film can be assessed in quantitative and qualitative terms. Three quantitative tests are described in this section: the Schirmer tear test (STT), the phenol red thread (PRT) tear test, and the most recent, endodontic absorbent paper point test (EAPTT; see later Fig.  10.1.41). The tear film breakup time (TBUT), a qualitative test, is described under “External Ophthalmic Dyes.”

first 10 mm and then 7 mm beyond (van der Woerdt & Adamcak, 2000). The STT was first described in the dog in 1962 (Roberts & Erickson, 1962), followed by several reports over the next decade (Gelatt et al., 1975; Hamor et al., 2000; Harker, 1970; Roberts & Erickson, 1962; Rubin et al., 1965), and in the cat in 1970 (Veith et  al., 1970). Despite criticism of its poor repeatability and inconsistencies, the STT remains the standard method for quantifying aqueous tear production in veterinary ophthalmology (Hawkins & Murphy, 1986). It has been used extensively to establish normal values in domestic and nondomestic species (Table 10.1.5) to determine the relative contributions of aqueous from the lacrimal and nictitans glands, and to assess the influence of different factors such as signalment, environment, and drugs on tear production (Hartley et al., 2006; McLaughlin et al., 1988; Saito et al., 2001; Williams et al., 1979). The STT should be performed early in the ophthalmic examination to minimize the effect of reflex tearing from eyelid manipulation and before any topical agents are applied to the eye. The strips are supplied in sterile packs of two. The strip should be bent slightly at the notch before removal from the pack; it is preferable to avoid touching the short end of the strip to maintain sterility, and because skin lipid may interfere with aqueous tear absorption. The short folded end is placed in the lateral half of the lower conjunctival sac so that the notch is at the level of the lid margin and the strip is in contact with the cornea (Fig. 10.1.40). The strip is left in place for 1 min and tears are measured immediately upon removal. It has long been accepted that the eyelids can be open or held closed, but a recent study in normal horses showed that STT values were significantly lower when the eyelids were open (Trbolova & Ghaffari, 2017). Premature

Schirmer Tear Test

The STT quantifies production of the aqueous component of the tear film. First described by Schirmer in 1903, a standardized strip of filter paper is placed in the conjunctival sac to measure wetting in millimeters over 1 min (mm/min). Schirmer I (STT I), without topical anesthesia, measures basal and reflex tearing. Schirmer II (STT II), performed after topical anesthesia, measures only basal tearing. In 1961, Halberg and Berens (1961) introduced a standardized 5 × 35 mm strip of Whatman no. 41 filter paper with a rounded tip and a notch 5 mm from the end for bending. Commercial strips have a millimeter scale and may be impregnated with blue dye at the 5 mm point to highlight tear fluid migration (Hirsh & Kaswan, 1995; Wyman et al., 1995). The use of a modified strip has been described in the dog; the strip is 5 mm wide for the

Figure 10.1.40  Aqueous tear production can be accessed by the Schirmer tear test. The short folded end of the paper strip is placed in the lateral half of the lower conjunctival sac so that it is in direct contact with the cornea, in order to measure both basal and reflex tear reproduction.

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Table 10.1.5A  Values for tear production and intraocular pressure in domesticated mammals. EAPTT (mm/min)

IOP Mean ± SD (mmHg)

STT (mm/min)

PRT (mm/15 s)

Cat

18.4 ± 0.5 (TP-XL, TP-Vet) 20.74 ± 0.5 (TV)

18 (9–34)

29 (15–37)

Dog

11.7 ± 2.5 (7-20) (TP-XL) 14.3 ± 4.0 (8-25) (AcP) 15.6 ± 4.2 (6-25) (TP‐XL) 15.0 ± 3.2 (7‐22) (TV) 19.2 ±3.1 (11‐25) (TV Plus) 12.8 ± 2.9 (6‐19) (TP‐Avia)

18.64 ± 4.47 to 23.90 ± 5.12

Tofflemire et al. (2017) Refer to text – multiple studies  Kato (2014)   Ben‐Shlomo & Muirhead (2020)   Refer to text – multiple studies

Horse

23.2 ± 6.89 (7‐37) (TP)

20.6 ± 6.5 to 24.8 ± 4.8

Miller et al. (1990, 1991) Refer to text – multiple studies

Cow

23 (12‐40) (TV) 16 (8‐27) (TP‐Avia)

24.18 ± 6.5 mm/30 s

Whitley & Moore (1984) Peche & Eule (2018)

Calf (dairy)

15.2 ± 5.2 (TV)

20.4 ± 5.0

Tofflemire et al. (2015)

Sheep

11 (7‐20) (TV) 10 (5‐18) (TV‐Avia)

SECTION II

Species

Pig Llama

Passaglia et al. (2004) Rusanen et al. (2010) McLellan & Miller (2011) Sebbag et al. (2015) Refer to text – multiple studies

Peche & Eule (2018) 15.6 ± 3.7 (10–22)

Trbolova & Ghaffari (2012)

13.10 ± 0.35 (TP)

Willis et al. (2000)

16.96 ± 3.51 (TP)

Nuhsbaum et al. (2000) 20.30 ± 2.96

Alpaca

Pigatto et al. (2010b)

14.85 ± 0.45 (TP)

Willis et al. (2000)

16.14 ± 3.74 (TP)

Nuhsbaum et al. (2000)

14.21 ± 2.73 (TV) 12.51 ± 2.78 (TP‐XL)

McDonald et al. (2017)

Rabbit

4.85

20.88

Angora

5.4 ± 1.6

25.0 ± 2.7

18.8 ± 2.1

Dutch

4.6 ± 1.2

23.6 ± 2.3

16.9 ± 1.7

New Zealand

7.58 ± 2.3

Biricik et al. (2005)

13.8 ± 1.5

5.30 ± 2.96 Guinea pig

0.36 ± 1.09 6.81 ± 1.41 (TV)

Rajaei et al. (2016c) Rajaei et al. (2016c) Whittaker & Williams (2015)

5.2 ± 1.0

Rat

Authors

Lima et al. (2015) Abrams et al. (1990)

16 ± 4.7 14.33 ± 1.35

17.30 ± 5.25 (TP)

Mouse

Trost et al. (2007) 8.54 ± 1.08

Rajaei et al. (2016a)

6.18 ± 2.06

Mermoud et al. (1994) Lange et al. (2014)

4.39 ± 1.45

Lange et al. (2014)

Ferret

14.50 ± 3.27 (TP)

5.31 ± 1.32

Montiani‐Ferreira et al. (2006)

Chinchilla

17.71 ± 4.17 (TP‐XL)

1.07 ± 0.54

Lima et al. (2010)

2.9 ± 1.8 (TV)

Unreliable

ex vivo

9.7 ± 2.5 (TV; “d” setting)

14.6 ± 3.5

Müller et al. (2010) Snyder et al. (2017)

10.1: Ophthalmic Examination and Diagnostics

603

STT (mm/min)

PRT (mm/15 s)

EAPTT (mm/min)

Authors

6.8 ± 2.3   5.57 ± 1.51

    4.52 ± 1.55

Rajaei et al. (2013)   Rajaei et al. (2016b)

Species

IOP Mean ± SD (mmHg)

Hamster

  4.55 ± 1.33 (TV)

Hedgehog

20.4 ± 4.0 (TP) 12.6 ± 1.8 (TV)

Williams et al. (2017)

Goat

23 (9‐37) (TV) 13 (4‐25) (TVP‐Avia)

Peche & Eule (2018)

Pygmy goat

10.8 (8–14) (TP‐XL)

1.7 ± 1.2 (range 0–4)

15.8 (range 10–30)

11.8 (9–14) (TV‐D) 17.8 ± 3.7 (13.5–24.5) (TP)

Broadwater et al. (2007) Broadwater et al. (2007)

7.9 Donkey

Ghaffari and Hajikhani (2011)

Broadwater et al. (2007) 22.1 ± 6.9 (range 13–35)

Ghaffari et al. (2017)

AcP, Accupen; EAPTT, endodontic absorbent paper point test; IOP, intraocular pressure; PRT, phenol red thread; SD, standard deviation; STT, Schirmer tear test; TP, Tono‐Pen; TP‐XL, Tono‐Pen XL; TV, TonoVet; TV‐D, TonoVet (dog); TV‐Plus, TonoVet Plus.

loss of the strip is probably less likely if the eyelids are held closed. The STT is considered to be well tolerated, but a recent study in rabbits quantified an increase in corneal sensitivity for up to 16 min following the STT (Lima et al., 2015). This highlights the fundamental principle of the test, which is to measure reflex lacrimation as well as the tear film meniscus and basal lacrimation. STT I values in the normal adult dog vary from 18.64 ± 4.47 mm/min to 23.90 ± 5.12 mm/min (Gelatt et  al., 1975; Hamor et  al., 2000; Harker, 1970; Hirsh & Kaswan, 1995; Saito & Kotani, 2001; Wyman et al., 1995). In the dog, values less than 5 mm/min are considered to be diagnostic for KCS, and values less than 10 mm/min are suspicious if combined with characteristic clinical signs. STT I values in the normal adult cat vary from 14.3 ± 4.7 mm/min to 16.92 ± 5.73 mm/ min (Arnett et al., 1984; Cullen et al., 2005b; Margadant et al., 2003; McLaughlin et  al., 1988; Veith et  al., 1970). Low STT values in the cat must be carefully interpreted together with the clinical signs, because the range of values in normal cats is wide; in one study of 76 cats, STT I values ranged from 1 to 33 mm/min (Waters, 1994). In a recent study of selected tear film tests in 135 cats, the median STT I value was 18 mm/min (range 9–34 mm/min; Sebbag et al., 2015). Tear production in the horse is greater than in the dog and cat and may overwhelm commercial strips in less than the standard 1 min period (Beech et  al., 2003; Brightman et  al., 1983; Crispin, 2000; Harling, 1988; Marts et al., 1977). STT I values in the normal adult horse, using a standard 5 × 35 mm test strip, vary from 20.6 ± 6.5 mm/min to 24.8 ± 4.8 mm/min (Beech

et  al., 2003; Brightman et  al., 1983; Harling, 1988; Regnier, 2002). Two additional studies present STT I values more broadly as 11 to more than 30 mm/min and 15–20 mm/30 s (Marts et al., 1977; Moore, 1992). In the horse, STT I values of less than 10 mm/min are diagnostic for KCS (Crispin, 2000). The STT I value in the normal adult cow is 24.18 ± 6.5 mm/30 s (Whitley & Moore, 1984), and in the pig is 15.6 ± 3.7 mm/min (range, 10–22 mm/min; Trbolova & Ghaffari, 2012). Tear absorption has been shown to be nonlinear in dogs (Williams, 2005) and horses (Cutler, 2002). Because of the initial rapid absorption of tear fluid, it has been suggested that temporal examination of the STT may be more precise than the standard method (Williams, 2005). STT II measures only basal tear production, because reflex tear production is eliminated by topical anesthesia. The STT II test is used more widely in humans, where high reflex tear production may mask low basal tear production. One drop of topical anesthetic is applied to the eye and the excess is blotted away with a swab or cotton‐tipped applicator; a few minutes are allowed to elapse. The test is then performed as for STT I. Reported STT II values in the normal adult dog are 6.2 ± 3.1 mm/min (Gelatt et al., 1975), 9.52 ± 4.55 mm/min (Saito & Kotani, 2001), and 11.6 ± 6.1 mm/min (Hamor et al., 2000). The STT II value in the normal adult cat is 13.2 ± 3.4 mm/min, approximately 80% of the STT I result in the same study (McLaughlin et al., 1988). As in the dog and cat, the mean STT II values are lower than the STT I values in other species, including the pig (Trbolova & Ghaffari, 2012) and the camel (Marzok et  al., 2017), but not in the horse

SECTION II

Table 10.1.5A  (Continued )

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SECTION II

Table 10.1.5B  Values for tear production and intraocular pressure in nondomesticated (zoo) mammals.

Species

IOP Mean ± SD (mmHg)

STT (mm/min)

PRT (mm/15s)

Prairie dog

7.7 ± 2.2 (TV)

1.2 ± 0.9 (modified)

13.6 ± 7.8

EAPTT (mm/min)

Authors

Meekins et al. (2015b)

Camel Calf

14–18

Marzok et al. (2017)

Immature

> 32.5 (TP)

22–26

Marzok et al. (2015, 2017)

Mature

> 28.5 (TP)

30–34

Marzok et al. (2015, 2017)

African giant pouched rat

7.7 ± 2.9 (TV)

Capybara

18.4 ± 3.8 (TP‐XL)

14.9 ± 5.1

Heller et al. (2017) Montiani‐Ferreira et al. (2008b)

4.10 ± 0.44

Balthazar da Silveira et al. (2017)

Paca

6.34 ± 0.43 (TP‐Vet)

Beaver

17.95 (TP‐XL)

Cullen (2003)

Grant’s Zebra

25.30 ± 3.06 (Sch)

Ofri et al. (1998b)

29.47 ± 3.43 (TP)

Ofri et al. (1998b)

Burchell’s zebra

23.4 ± 3.4

Nubian Ibex

17.95 ± 4.78 (Sch)

Arabian Oryx

22.68 ± 8.15 (Sch)

Ofri et al. (1999a) Ofri et al. (1998b)

13.2 ± 5.1

Ofri et al. (1999a) Ofri et al. (1998b)

11.76 ± 3.43 (Sch)

Ofri et al. (1998b) 12.7 ± 4.8

Ofri et al. (1999a)

Eland

14.6 ± 4.0 (app)

18.7 ± 5.9

Ofri et al. (2001)

Fallow Deer

11.9 ± 3.3 (app)

10.5 ± 6.5

Ofri et al. (2001)

14.1 ± 2.48

17.8 ± 3.16

Kvapil et al. (2018)

Thomson’s Gazelle

7.6 ± 1.6 (TP‐XL)

Ofri et al. (2000)

Addax Antelope

11.2 ± 3.2 (TP‐XL)

28.8 ± 8.3

Ofri et al. (2002a)

Impala

8.0 ± 1.2 (TP‐XL)

18.8 ± 1.8

Ofri et al. (2002a)

Wildebeest

15.5 ± 3.7 (TP‐XL)

19.3 ± 4.6

Oryx

15.8 ± 1.5 (TP‐XL)

Ofri et al. (2002a) Ofri et al. (2002a)

Sambar deer

11.4 ± 2.8 (TP‐XL)

18.8 ± 4.7

Oriá et al. (2015a)

Mouflon

14.9 ± 2.20

17.9 ± 3.87

Kvapil et al. (2018)

Ibex

13.1 ± 2.43

11.7 ± 3.87

Kvapil et al. (2018)

Chamois

10.2 ± 2.5

14.5 ± 3.0

Kvapil et al. (2018)

Rhinoceros

32.1 ± 10.4 (TP‐XL)

17.6 ± 3.1

Ofri et al. (2002a)

31.2 ± 6.62 (app)

18.2 ± 3.49

Bapodra & Wolfe (2014)

Capuchin Monkey

18.4 ± 3.8 (TP)

Marmoset Lemur (gray mouse)

14.9 ± 5.1 –0.46 ± 3.41

20.3 ± 2.8 (TV/TP)

Montiani‐Ferreira et al. (2008a) 13.27 ± 5.41

Lange et al. (2012) Dubicanac et al. (2016)

Koala Conscious

15.3 ± 5.1 (TP‐Vet)

10.3 ± 3.6

Grundon et al. (2011)

Anesthetized

13.8 ± 3.4 (TP‐Vet)

3.8 ± 4.0

Grundon et al. (2011)

Lion Male

24.9 ± 2.0 (Sch)

Ofri et al. (1998b)

Female

20.9 ± 2.4 (Sch)

Ofri et al. (1998b)

1 year

12.8 ± 4.1 (TP)

Ofri et al. (2008)

> 1 year

23.9 ± 4.1 (TP)

Ofri et al. (2008)

10.1: Ophthalmic Examination and Diagnostics

605

Table 10.1.5B  (Continued ) IOP Mean ± SD (mmHg)

STT (mm/min)

PRT (mm/15s)

EAPTT (mm/min)

Authors

Luteal female

27.07 ± 2.15 (Sch)

Ofri et al. (1999b)

Nonluteal female

21.61 ± 2.70 (Sch)

Ofri et al. (1999b)

SECTION II

Species

Fruit bat Hanging

19.38 ± 0.77 (TV)

Upright

13.95 ± 0.60 (TV)

23 ± 1.28

Blackwood et al. (2010) Blackwood et al. (2010)

Source: app, applanation; EAPTT, endodontic absorbent paper point test; IOP, intraocular pressure; PRT, phenol red thread; Sch, Schiøtz; SD, standard deviation; STT, Schirmer tear test; TP, Tono‐Pen; TP‐Vet, Tono‐Pen Vet; TP‐XL, Tono‐Pen XL; TV, TonoVet.

(Beech et al., 2003; Williams et al., 1979). Reflex tear production may not exist in the guinea pig, because there is no significant difference between the mean STT 1 and STT II values (Trost et  al., 2007). The correlation between reflex tear production and corneal sensitivity was assessed in several species, with inconclusive results (Wieser et al., 2012). The PRT tear test also quantifies production of the aqueous component of the tear film (Brown et al., 1996; Sakamoto et al., 1993). Kurihashi et al. first described the use of thread to measure tear production in 1975. The method was refined by Hamano et al. in 1982 by impregnating the thread with phenol red, a pH‐sensitive indicator. The standardized cotton thread is 75 mm long with a fold 3 mm from one end (Menicon, Clovis, CA, USA). The folded end is placed in the lower conjunctival fornix for 15 s. As the slightly alkaline tears wick along the thread, the pale yellow thread turns orange (Fig.  10.1.41A). The length of color change in millimeters is read from the end of the thread (not the bend), immediately upon removal from the eye. PRT tear test values are 34.15 ± 4.45 mm and 23.04 ± 2.23 mm in the dog and cat, respectively (Brown et al., 1996, 1997). A recent study in the horse provided PRT tear test values of 30.22 ± 0.99 mm and 31.00 ± 1.4 mm in the Arabian and Thoroughbred Horse, respectively (Sindak et al., 2010). The main advantage of the PRT tear test in veterinary ophthalmology is that it can be used in small eyes and is therefore appropriate for many nondomestic species (see the next section). The EAPPT was first reported in marmosets by Lange in 2012. Like the STT and the PRT test, the EAPPT quantifies the aqueous portion of tears. Like the PRT test, the EAPTT is particularly suitable for eyes with very low tear production and/or for very small eyes. The suitability for small eyes is highlighted by results from a seed finch weighing 20 g with a palpebral length of 4.46 ± 0.09 mm (the width of a standard STT strip is 5 mm; Lange et  al., 2014). The strip is used in dentistry and is highly absorptive and sterile. The standard length is 28 mm and the diameter of the conical tip varies from 0.15 to 0.80 mm, making it highly applicable to species with small eyes. The Lange marmoset study used a 0.3 mm

A

B Figure 10.1.41  A. Aqueous tear production can be assessed quantitatively by the phenol red thread tear test in a guinea pig. The folded end of the thread is placed in the lower conjunctival fornix. The pale yellow thread turns orange as the slightly alkaline tears wick along it. (Reproduced with permission from Walde, I., Nell, B., Schäffer, E. et al. (2008) Augenheilkunde, 3rd ed. Stuttgart: Schattauer, p. 765.) B. Aqueous tear production can be assessed quantitatively by the endodontic absorbent paper tear test. The result in this rabbit is 13 mm/min. (Courtesy of Leandro Lima and Fabiano Montiani-Ferreira, Comparative Ophthalmology Lab – Laboratório de Oftalmologia Comparada da Universidade Federal do Paraná, Curitiba-PR, Brazil.)

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SECTION II

Table 10.1.5C  Values for tear production and intraocular pressure in avian species.

Species

IOP Mean ± SD (mmHg)

Chicken

17.51 ± 0.13 (TV)

Prashar et al. (2007)

Pigeon

11.7 ± 1.6 (TV)

Park et al. (2017)

Red‐Tailed Hawk

20.6 ± 3.4 (app)

Stiles et al. (1994)

Swainson’s Hawk

20.8 ± 2.3 (app)

Stiles et al. (1994)

Golden Eagle

21.5 ± 3.0 (app)

Stiles et al. (1994)

Bald Eagle

20.6 ± 2.0 (app)

Stiles et al. (1994)

Great Horned Owl

10.8 ± 3.6 (app)

Stiles et al. (1994)

Screech Owl

11 ± 1.9 (TP‐XL)

STT (mm/min)

2 (2–6)

PRT (mm/15 s)

EAPTT (mm/min)

15 ± 4.3

Harris et al. (2008)

14 ± 2.4 (TV‐D) Eurasian Eagle Owl

Authors

Harris et al. (2008)

9.35 ± 1.81 (TP‐XL)

Jeong et al. (2007)

Psittaciformes

3.2 ±.7 to 7.5 ± 2.6

Korbel & Leitenstorfer (1998)

Falconiformes

4.1 ± 2.7 to 14.4 ± 7.2

Korbel & Leitenstorfer (1998) 30.6 ± 4.2

Smith et al. (2015)

Accipitriformes

10.7 ± 4.0 to 11.5 ±5.4

Korbel & Leitenstorfer (1998)

Strigiformes

50 cm long

11.6 ± 0.5 (app)

Whittaker et al. (1995)

Caiman Broad‐Snouted Yacare

12.9 ± 6.2 (TP‐XL)

3.4 ± 3.6

17.1 ± 2.5

9.56 ± 2.69 (TP‐XL)

Oriá et al. (2015c) Ruiz et al. (2015)

Red‐Footed Tortoise Male, DV

11.5 ± 2.8 (TP‐XL)

12.0 ± 3.5

Oriá et al. (2015b)

Female, DV

14.0 ± 3.5 (TP‐XL)

Oriá et al. (2015b)

Male, VD

18.0 ± 3.2 (TP‐XL)

Oriá et al. (2015b)

Female, VD

24.1 ± 3.0 (TP‐XL)

Red‐Eared Slider Turtle

5.42 ± 1.7 (TV)

Oriá et al. (2015b) 15.9 ± 0.7 @ 32°C 15.4 ± 0.4 @ 18°C

    Oriá et al. (2015b)

8.79 ± 0.38

Delgado et al. (2014) Lange et al. (2014)

2.55 ± 3.4 (modified)

11.32 ± 1.7 (TV)

Somma et al. (2014)

Yellow‐Footed Tortoise

14.2 ± 1.2 (TP)

Selmi et al. (2003)

Hermann’s Tortoise

15.74 ± 0.20 (TV)

Selleri et al. (2012)

Kemp’s Ridley Turtle

6.5 ± 1.0 (TV; “h” setting)

Gornik et al. (2016)

Sea Turtle DV/VD

5/7

Chittick & Harms (2001)

Head‐down

23 (TP‐XL)

Chittick & Harms (2001)

Gulf Coast Turtle

6.7 ± 1.4 (TV)

Espinheira Gomes et al. (2016)

Three‐Toed Turtle

8.3 ± 1.5 (TV)

Espinheira Gomes et al. (2016)

Koi Fish

4.9 (TV)

Lynch et al. (2007)

Bullfrog

4 (TV) 16 (TP‐AVIA)

Cannizzo et al. (2017)

Bearded Dragon

6.16 (TV)

Schuster et al. (2015)

Source: app, applanation; DV, dorsoventral; EAPTT, endodontic absorbent paper point test; IOP, intraocular pressure; PRT, phenol red thread; SD, standard deviation; STT, Schirmer tear test; TP, Tono‐Pen; TP‐AVIA, Tono‐Pen AVIA; TP‐XL, Tono‐Pen XL; TV, TonoVet; VD, ventrodorsal.

tip (Sterile Roeko Top Color, size 30, Roeko, Langenau, Germany). The strip is placed in the lower conjunctival fornix for 1 min. After removal, the length of wetting is measured in millimeters. The authors found the test easier to perform, even with a single examiner, than the modified STT I and PRT. Furthermore, there was less variation in the data obtained from the EAPPT compared to the modified STT and PRT data. A study in New Zealand rabbits showed objectively that the EAPPT was well tolerated; there was no difference in the CTT between control rabbits and EAPTT rabbits,

whereas corneal sensitivity increased for 16 min following a standard STT (Lima et  al., 2015). Values for EAPPT have since been published in several species, including the rabbit (Lima et  al., 2015; Rajaei et  al., 2016c), guinea pig (Rajaei et  al., 2016a), caiman (Oriá et  al., 2015c), Syrian hamster (Rajaei et al., 2016b), red‐footed tortoise (Oriá et al., 2015b), and the finch, mouse, and rat (Lange et al., 2014). Multiple factors influence tear production. The influence of signalment (age, gender, and breed) has been studied in several species. Age has been shown to affect tear production in

SECTION II

Alligator

SECTION II

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the dog, cat, horse, pig, and camel. As a general rule, there is a positive correlation between tear production and age (as compared to a negative correlation between IOP and age). However, conflicting results have been found in different studies in dogs. An early study in the dog showed that age had no effect (Hamor et  al., 2000), whereas a subsequent study showed that tear production decreased with increasing age at a rate of 0.44 mm/year (Hartley et  al., 2006). Three more recent studies have shown that tear production in the dog increases with age, as in most other species (Broadwater et al., 2010; da Silva et  al., 2013; Verboven et  al., 2014). The Broadwater study looked specifically at juvenile dogs (less than 6 months old) and found that age and weight had a significant effect on tear production, as STT I values increased by 0.15 mm/min for each 1 day increase in age, and by 0.84 mm/ min for each 1 kg increase in bodyweight; adult values were reached by 9–10 weeks of age (Broadwater et al., 2010). STT II values were significantly lower in cats less than 1 year old compared to those more than 1 year old (Waters, 1994). Neonatal foals, both sick and healthy, have lower tear production than adult horses (Brooks et  al., 2000b). Sick neonatal foals, healthy neonatal foals, and healthy adult horses have STT I values of 14.2 ± 1 mm/min, 12.8 ± 2.4 mm/min, and 18.3 ± 2.1 mm/min, respectively (Brooks et al., 2000b). STT I and II values are lower in the juvenile pig than in the adult pig (Trbolova & Ghaffari, 2012). Tear production in camels increased with age, being 14–18 mm/min in the calf and 30–34 mm/min in the mature camel (Marzok et al., 2017). The effect of gender on tear production has been described in dogs, horses, and Syrian hamsters. Gender affects tear production in the juvenile dog (Hartley et al., 2006), but not in the adult dog (Hamor et al., 2000). The influence of gender in the adult horse is inconsistent (Beech et  al., 2003; Piccione et al., 2008; Regnier, 2002). Tear production is significantly higher in the female Syrian hamster compared to the male (Rajaei et al., 2016b). Diurnal rhythm has been shown to have a significant effect on tear production in the dog (Berger & King, 1998; Giannetto et al., 2009; Hakanson & Arnesson, 1997), whereas the results in the horse were variable (Beech et al., 2003; Piccione et al., 2008; Regnier, 2002). Early studies in the horse found no daily fluctuations or seasonal effects (Beech et  al., 2003; Regnier, 2002), in contrast to the circadian rhythm in tear production described more recently (Piccione et  al., 2008). The variability in tear production between eyes in the same horse has also been found to be inconsistent (Beech et  al., 2003; Piccione et al., 2008; Regnier, 2002). STT values were significantly lower in nocturnal species of raptors as compared to diurnal species (Beckwith‐Cohen et al., 2015). The effect of topical tropicamide 1% on tear production varies with species. It had no effect in the dog (Margadant et  al., 2003), but significantly reduced tear production at 1 hour in both the treated and untreated eye in the cat

(Margadant et al., 2003), and only at 4 hours in just the treated eye in the horse (Ghaffari et  al., 2009). Topical atropine reduced tear production in the dog, exerting its maximum effect at 120 min and returning to baseline at 300 min, but also affected both eyes (Hollingsworth et al., 1992). Systemic atropine sulfate has been shown to reduce tear production in the cat and the dog (Arnett et al., 1984; Ludders & Heavner, 1979). In contrast, topical 1% cyclopentolate hydrochloride had no effect on tear production (nor IOP) in normal dogs (Costa et al., 2016). The potential for systemic sulfonamides to cause KCS in the dog, as a result of toxicity to the glandular tissue, has been known since the early 1990s (Berger et al., 1995; Diehl & Roberts, 1991). Recent studies found that trimethoprim‐ sulfamethoxazole significantly reduced tear production in the New Zealand white rabbit (Shirani et al., 2010) and the Syrian hamster (Rajaei et al., 2015), whereas trimethoprim‐ sulfadiazine had no effect in the horse (Rothschild et  al., 2004) or the guinea pig (Asadi et  al., 2016). The effect of numerous drugs on tear parameters in the dog has been studied. Oral diphenhydramine (antihistamine) did not affect tear production in dogs (Montgomery et al., 2011), but did reduce tear film stability and increase corneal sensitivity (Evans et al., 2012). Topical 0.3% naltrexone (Arnold et al., 2014), and oral propranolol (Ghaffari et  al., 2011) had no effect on tear production in dogs. Glycopyrrolate (anticholinergic) caused reduced STT values, but had no effect on IOP in dogs (Doering et al., 2016). Several studies evaluated the effect of sedation and general anesthesia on tear production in different species, including the dog (Biricik et  al., 2004; Costa et  al., 2015; Dodam et al., 1998; Komnenou et al., 2013; Sanchez et al., 2006), cat (Arnett et  al., 1984; Peche et  al., 2015), horse (Brightman et al., 1983), lion (Ofri et al., 1998a), and koala (Grundon et al., 2011). Tear production is usually reduced by sedation and/or general anesthesia. General anesthesia has been shown to reduce tear production in the dog (Herring et al., 2000), horse (Brightman et al., 1983), cat (Peche et al., 2015), and koala (Grundon et al., 2011). General anesthesia lowered tear production in the dog for up to 24 hours and the return to normal was prolonged when the duration of anesthesia was more than 2 hours (Herring et al., 2000). Another study showed that tear production was reduced for up to 10 hours irrespective of the duration of the anesthesia (1–4 hours; Shepard et al., 2011). Dogs hospitalized in intensive care units had reduced tear production (Chandler et al., 2013). Several studies, mostly in dogs, have assessed the effect of both individual agents and multiagent protocols. The combination of pethidine and fentanyl caused a significant reduction in tear production in dogs; the STT I value fell to 5 mm/min in one dog and less than 10 mm/min in two dogs (Biricik et  al., 2004). Intravenous medetomidine or medetomidine‐butorphanol in dogs caused a significant

decrease in tear production 15 min after sedation; readings returned close to the baseline within 15 min of reversal with atipamazole in most dogs (Sanchez et al., 2006). Alfaxalone reduced tear production at 10 and 20 mins, in contrast to propofol, which had no effect (Costa et al., 2015). Tear production was reduced in dogs receiving medetomidine, propofol, carprofen, and halothane (Komnenou et al., 2013), and morphine, alfaxalone, midazolam, and sevoflurane (Mayordomo‐Febrer et al., 2017), but was unaffected by acepromazine maleate, morphine, and sevoflurane (Mouney et al., 2011). In a study comparing several sedative and opioid drugs, the combination of xylazine and butorphanol had the maximum effect on lowering tear production in normal dogs (Dodam et  al., 1998). In contrast, sedation with xylazine did not affect tear production in the horse (Brightman et al., 1983). Sedation with acepromazine, xylazine, or ketamine reduced tear production in cats (Arnett et  al., 1984; Ghaffari et al., 2010a). Anesthesia with medetomidine‐ketamine in normal cats caused a significant decrease in tear production, but the STT I values returned nearly to preanesthetic values within 15 min after reversal with atipamezole, whereas the STT I values for the control group were still low at that point (Di Pietro et al., 2016). As would be expected, tear levels can be affected by changes involving tear production and tear drainage. Removal of the TEL gland in the dog resulted in a 26% reduction in tear production within 3–7 months, but it almost recovered by 1 year (Saito et al., 2001). New Zealand rabbits developed clinical signs of dry eye without a reduction in STT values following removal of the nictitating membrane, the Harderian gland, and the main lacrimal gland (Bhattacharya et al., 2015). The placement of upper and/or lower punctal plugs has limited effect on STT values in normal dogs, but has been shown to increase STT readings significantly in patients with KCS (Gelatt et al., 2006; Williams, 2002). Tear production is significantly lower in dogs with endocrine disease (diabetes mellitus, hypothyroidism, hyperadrenocorticism; Cullen et  al., 2005a; Gemensky‐Metzler et al., 2015; Williams et al., 2007). Surgical procedures that have been associated with reduced tear production in dogs include placement of an intrascleral prosthesis for glaucoma (Blocker et al., 2007) and phacoemulsification (Gemensky‐ Metzler et al., 2015). STT values increased in cats experimentally infected with feline herpesvirus‐1 (FHV‐1), but the increase remained within the reference range and did not differ from the control group (Lim et al., 2009). In cats with conjunctivitis, there was poor correlation between STT and TBUT (Lim & Cullen, 2005). Dogs with unilateral ulcerative keratitis had increased STT values and reduced IOP values (Williams & Burg, 2017). Tear production has been assessed in many nondomestic species using either the standard or modified STT, the PRT

tear test, or, more recently, the EAPPT (Lange et  al., 2012; Table 10.1.5). The highest reported tear production is in the addax antelope (28.8 ± 8.3 mm/min; Ofri et al., 2002a). By comparison, the lowest reported STT I value is in the guinea pig (0.36 ± 1.09 mm/min; Trost et al., 2007), although a negative value was reported in the marmoset (Lange et al., 2012). The first publication of a range of normal values for tear production in birds (42 species, 7 orders) was produced from Germany in 1998 (Korbel & Leitenstorfer, 1998). A standardized 5 mm wide strip was used in most birds, but the small palpebral fissure in some species necessitated the strips to be trimmed to 2 or 4 mm wide (modified STT). Schirmer values were less than 3 mm/min in the owl (Strigiformes), a species known to have no lacrimal gland. The authors also described an additional assessment test, Schirmer III, under gaseous anesthesia. A later study found the PRT tear test to be a practical method for measuring tear production in large Psittaciformes, although adaptations to the established technique were necessary to overcome anatomic differences between species (Holt et al., 2006). There was poor repeatability between tests, but geographic location appeared to significantly influence results. Tear production, before and after topical anesthesia, has also been determined by Schirmer and PRT tear tests in Hispaniolan Amazon Parrots (Storey et al., 2009). Both methods were found to be practical, in accordance with the earlier studies (Korbel & Leitenstorfer, 1998). Topical anesthesia significantly reduced the STT values (i.e., mean STT II value was lower than mean STT I value), as found in the original German study, but had no significant effect on the PRT tear test values (Korbel & Leitenstorfer, 1998). The modified STT has been described in several studies, but is not standardized. The PRT test and the EAPPT are more appropriate in species with very low tear production and/or small eyes, and this is reflected in the increasing number of studies (see Table 10.1.5). Other Tear Tests

The Schirmer and PRT tear tests are relatively invasive and modify the very parameter they are designed to measure. Noninvasive or minimally invasive tests aim to overcome this problem and provide more reproducible and objective data. They have been developed extensively in humans and are beginning to be adopted in veterinary ophthalmology (Yokoi & Komuro, 2004; Yokoi et  al., 2005). Techniques include meniscometry (indirect assessment of tear volume by measurement of the tear meniscus radius), interferometry (assessment of tear film thickness and analysis of the lipid layer), and meibometry (quantification of the amount of meibomian lipid on the lid margin; Dogru et  al., 2006; Hosaka et al., 2011; Ibrahim et al., 2011; Yokoi et al., 2005). The first study on meibometry performed in healthy dogs was reported in 2007 (Ofri et al., 2007). The study established

609

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Section II: Foundations of Clinical Ophthalmology

that the technique could be readily performed in conscious dogs and provided baseline values for reference. The mean meibomian level in 84 eyes was 179 ± 60 MU (meibometer units). The results were not affected by age, gender, or laterality (Ofri et al., 2007). A subsequent study evaluated the precision of the Meibometer MB550 (Courage‐Khazaka Electronic, Cologne, Germany) in 20 eyes of healthy dogs (Benz et  al., 2008). The mean meibomian lipid level was 211 ± 48 MU and 205 ± 41 MU in the right and left eyes, respectively. In accordance with the first study, the results were not affected by gender or laterality. However, there was a broad distribution in values; there was a significant difference between the two examiners and between the set of measurements performed in the first 5 days compared with those in the following 5 days (Benz et al., 2008). The first meibometry study in healthy cats was reported in 2015 (Sebbag et al., 2015). The median meibomian level was 32 MU. Direct visual examination of meibomian gland structure by noncontact infrared meibography has been described in dogs and cats (Endo et al., 2012). Tear film osmolarity has been assessed in cats (Davis & Townsend, 2011; Sebbag et al., 2015) and dogs (Sebbag et al., 2017) using the Tear Lab™ Osmolarity System (TearLab Corporation, San Diego, CA, USA). In general, the system was easy to use and well tolerated, but required multiple readings to be informative. The median tear osmolarity of normal cats was similar in both studies: 322 mOsm/L (Sebbag et al., 2015) and 328.5 mOsm/L (Davis & Townsend, 2011) and was not significantly different from cats with conjunctivitis (Davis & Townsend, 2011). The mean tear osmolarity in normal dogs was 337.4 mOsm/L and was lower at 306.2 mOsm/L in dogs with untreated KCS (Sebbag et  al., 2017). Tear film osmolality was performed in horses and the mean value was 283.51 (9.33) mmol/kg (Best et al., 2015). Strip meniscometry (SM) was performed in normal adult dogs, cats, and rabbits to establish normal values and to compare the results with STT I (Rajaei et  al., 2017). Mean SM values for dogs, cats, and rabbits were 9.66 ± 2.15 mm/5 s, 10.50 ± 0.7 mm/5 s, and 4.72 ± 1.20 mm/5 s, respectively. There was correlation between SM and STT I values in the dog only. Interferometry in pinnipeds revealed the absence of a lipid layer in the outer tear film (Kelleher Davis et al., 2013), consistent with living in an aquatic environment. The tear ferning test (TFT) has been described in dogs (Oriá et  al., 2018) and horses (Silva et  al., 2017). The TFT provides important information about the gross biochemical composition of the tear film. It is a simple and low‐cost diagnostic test that complements evaluation of the ocular surface in conjunction with standard tests such as STT. In brief, a tear sample is obtained, for example from an STT paper strip, and dried onto a microscope slide. The ferning pattern is observed under a polarized light microscope and classified according to the Rolando and Masmali grading scales, which divide the pattern into normal and abnormal.

Examination after Topical Anesthetic Application At this stage in the examination, it may be necessary to examine the posterior (bulbar) surface of the TEL. Indications include suspected foreign body and examination of the lymphoid follicles. Topical anesthetic (e.g., proparacaine) is instilled prior to protraction of the TEL with atraumatic forceps (e.g., von Graefe forceps, Sklar Surgical Instruments, West Chester, PA, USA; Bennett cilia forceps, John Weiss, Milton Keynes, UK; Miltex, Plainsboro, NJ, USA; Fig. 10.1.42). To minimize the risk of iatrogenic trauma to the TEL, the animal’s head must be adequately restrained and the forceps should grasp the TEL away from its free edge and overlying the TEL T‐shaped cartilage.

Laboratory Sampling The eye and adnexa are unusual in that they allow a detailed and direct visual examination, more so than any other body structure other than the skin. Laboratory tests are therefore often unnecessary. If they are required, the clinician must be well informed with regard to the appropriate laboratory test for the suspected disease process, the correct method of sample collection and handling, and interpretation of the results. Close communication with the laboratory will facilitate and further define these aspects. For further detail, see Chapter 7, “Clinical Microbiology and Parasitology.” Corneoconjunctival Culture

Corneal and conjunctival culture can aid in the diagnosis and determination of appropriate antimicrobial therapy in many ocular diseases. Sampling is quick and straightforward and is tolerated without topical anesthesia in most compliant animals. However, if the eye is very painful, sedation and regional nerve blocks may be necessary, and this applies in particular to the horse. To obtain a sample, the eyelids are gently retracted and the sampling tool is applied to the area of interest. A sample for culture can be collected by either a swab or a scraping. Swabs are available in different materials (e.g., cotton, Dacron, rayon), but of most importance is the selection of a swab that is designated for either microbiology or virology, as required; any swab type can be used for polymerase chain reaction (PCR). Standard and minitip swabs are available and the latter is helpful for small eyes or delicate areas, for example deep corneal ulcer (Fig. 10.1.43A). The swab can be premoistened with sterile saline to improve the yield of viable organisms, and to make the procedure more comfortable. A scraping can be made using either a sterile surgical blade or a Kimura spatula (Storz, St. Louis, MO, USA), a specific instrument for the procedure. The choice of sampling tool depends on the area of interest and examiner preference.

611

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10.1: Ophthalmic Examination and Diagnostics

A

B

C

Figure 10.1.42  A. Examination of the posterior (bulbar) surface of the third eyelid is performed following topical anesthesia and with the aid of atraumatic forceps, for example Bennett’s cilia forceps. B. Bennett’s cilia forceps. C. Atraumatic, smooth, cupped tips of Bennett’s cilia forceps.

To obtain a corneal sample using a swab, the swab is gently rubbed or rolled over the lesion; for a conjunctival sample, the swab is rolled in the lower conjunctival sac anterior to the TEL (facilitated by retropulsion to protrude the TEL; Fig.  10.1.43B). To obtain corneal material by scraping, the blunt end of a sterile surgical blade or a Kimura spatula is used in a scraping motion, ideally in one direction to create a “pile of cells.” The material is then transferred onto a sterile swab tip. Conjunctival scrapings can be performed in the same way, but are less commonly done because conjunctiva is freely movable. Care should be taken not to contaminate the sample by inadvertently touching the eyelid margins, hair, skin, and other nearby structures. Specimens for culture should be taken as early as possible in the examination, and ideally before the administration of topical agents. This is because many topical ophthalmic preparations contain preservatives that may impair culture results, and some topical agents (e.g., proparacaine, tetracaine, ophthalmic dyes) have themselves been shown to inhibit organism growth (Kleinfeld & Ellis, 1966, 1967; Storey et al., 2002). In contrast to fluorescein, which

can support bacterial growth and virus viability, Rose Bengal and lissamine green are both bacteriocidal and virucidal (Cello & Lasmanis, 1958; Seitzman et al., 2006; Storey et al., 2002). In humans, Rose Bengal and lissamine green have been shown to inhibit the detection of herpes simplex virus by PCR (Stroop et al., 2000). The effect of commonly used topical agents in cats with ocular surface disease on PCR assays for Chlamydophila felis and FHV‐1 was assessed in vitro (Segarra et  al., 2011). Proxymetacaine (proparacaine) and fluorescein did not interfere with the PCR assay; fusidic acid (a commonly used topical antibiotic in small animals in Europe) caused a small inhibitory effect of doubtful clinical significance (Segarra et al., 2011). In the clinical setting, it is considered acceptable to apply a topical anesthetic agent prior to sampling painful eyes and in uncooperative animals. This view is supported further by one study, which specifically demonstrated that a single application of a topical anesthetic drug is unlikely to inhibit culture results (Champagne & Pickett, 1995). Sampling should, however, be performed prior to the application of ophthalmic dyes.

Section II: Foundations of Clinical Ophthalmology

SECTION II

612

A

B Figure 10.1.43  A. Standard and minitip swabs. Minitip swabs are useful for taking samples from small eyes and delicate areas, for example deep corneal ulcer. B. To obtain a conjunctival sample, for either microbiology or cytology, the swab is gently rolled in the lower conjunctival sac anterior to the third eyelid (TEL). This is facilitated by retropulsion to protrude the TEL. Care must be taken to ensure that the swab touches only the area of interest to avoid contamination from nearby structures, for example eyelids.

Bacteriology samples should ideally be collected before antibiotic therapy is started, but organisms that persist with concurrent antibiotic therapy are relevant. In general terms, samples taken from the ocular surface should be submitted for aerobic culture, whereas those from deeper tissues, such as the orbit, should be submitted for both aerobic and anaerobic culture. Anaerobic bacteria do however occur on the ocular surface; in a study of 330 domestic animals (dog, cat, horse, alpaca) with ulcerative keratitis, anaerobic bacteria were isolated from 13.0% of corneal samples and the majority of infections were mixed (aerobic and anaerobic), unless antimicrobial therapy had been administered prior to presentation (Ledbetter & Scarlett, 2008). Bacteria, chlamydiae, mycoplasma, fungi, and viruses have different culture requirements in terms of transport medium, storage, and transport conditions (Table  10.1.6). Two general but important guidelines are that the designated laboratory should be contacted in advance for advice and to obtain the appropriate required materials; and the

delay between sampling, shipping, and arrival at the ­laboratory should always be minimized. Swabs for microbiology (bacteriology or fungal culture) can be placed in a dry sterile tube or into gel or charcoal medium; refrigeration until shipping is beneficial but not essential (Allen, 2011). Virus isolation is especially dependent on optimal collection and transport conditions. A swab dedicated for virology (i.e., not a plain swab or a microbiology swab) should be used and placed into virus transport medium (a buffered medium containing antibiotic to prevent bacterial overgrowth). Shipping on ice or with a freezer pack is ideal, but is not essential; freezing should be avoided because the freeze– thaw process may damage the virus (Erles, 2011). One disadvantage of corneoconjunctival culture is the inherent unavoidable delay in results. In clinical ophthalmology, immediate therapy is required in eyes with serious and/or rapidly progressive ocular surface disease, for example keratomalacia (melting ulcer) or suspected mycotic keratitis. Corneoconjunctival cytology should be considered, as it may provide immediate information about the causative organism(s). Culture is nevertheless more sensitive than cytology and is often essential to successful case management. For example, in 10 equine eyes with keratomycosis, fungal infection was diagnosed by cytology in 4 out of 9 eyes and by culture in 8 out of 10 eyes (Galan et al., 2009). Corneoconjunctival Cytology

Corneoconjunctival cytology is a quick and simple method to characterize, and in some cases diagnose, the disease process involving the ocular surface. It can be used either alone or in combination with culture to provide rapid results that may influence the immediate course of therapy (Bourges‐ Abella et al., 2007; Gerding et al., 1988; Jegou & Liotet, 1993; Lavach et  al., 1977; Murphy, 1988; Willis et  al., 1997). Although less sensitive than culture, exfoliative cytology is a very rewarding tool in clinical ophthalmology. It can identify organisms (e.g., bacteria, fungal hyphae, yeast bodies) and provide information in terms of morphology (e.g., rods/ cocci), staining characteristics (Gram‐positive or ‐negative), number, and location (intracellular/extracellular). Excessive surface debris and mucus should be removed before cytology, and samples for culture should be taken first, because cytologic techniques could alter the population of microorganisms present. The ideal sample provides a monolayer of an adequate number of cells with unaltered structure. Additionally, sample collection should produce minimal irritation to the animal. Instruments for collecting cytologic samples include those used for culture: swab (standard or minitip) and the blunt end of a sterile surgical blade, as well as specialized tools (e.g., cytobrush, Kimura spatula; Fig. 10.1.44). Topical anesthetic, microscope slides, stain(s), and a microscope are also required.

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613

Test

Sampling Tool

Transport Medium

Shipping Conditions

Bacteriology

Designated microbiology swab

Gel or charcoal medium

Refrigerate until shipping, normal post

Fungal culture

Designated microbiology swab

Gel or charcoal medium

Refrigerate until shipping, normal post

Virus isolation

Designated virology swab

Virus transport medium

Refrigerate until shipping, normal post

Polymerase chain reaction

Swab (any swab type)

Dry tube

Normal post

Scraping

Freeze in sterile saline or transfer material to swab tip (as above)

Ship on ice or normal post

Tissue biopsy

Dry tube or in sterile saline or in moist gauze swab

Normal post

Swab (any swab type)

Roll gently onto microscope slide

Normal post

Scraping (spatula/ scalpel blade)

Transfer to microscope slide

Normal post

Cytobrush

Roll gently onto microscope slide

Normal post

Impression smear

Transfer to microscope slide

Normal post

Forceps/scissors

10% formalin

Normal post

Cytology

Histopathology

The swab is the least traumatic method to the eye for sample collection (Bauer et  al., 1996). This technique is recommended when excessive manipulation is contraindicated, for example deep corneal ulcer and keratomalacia. Swabs preserve cellular integrity, but the number of cells collected is often too low to make a diagnosis. Samples should be gently rolled (not rubbed) onto glass slides to minimize cell damage (Villiers & Dunn, 1998). Swabs are more commonly used for the collection of samples for microbiology than for cytology.

The Kimura spatula provides a more precise method of collecting cells from specific areas, and greater numbers of deeper cells are usually obtained. This technique remains the standard in diagnostic veterinary ophthalmology. However, this method may lead to greater damage to both the sample (overlapping cells and crushing artifact) and the eye (Bauer et al., 1996; Willis et al., 1997). The blunt end of a scalpel blade functions similarly to a spatula, but with a slightly greater risk of trauma to the eye.

A

B

Figure 10.1.44  A. Instruments for corneoconjunctival cytology include Kimura spatula (top), cytobrush (middle), and scalpel blade (bottom). B. Impression cytology of the dorsal bulbar conjunctiva using a strip of Millipore paper. (Courtesy of J.L. Laus and A.A. Bolzan.)

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Table 10.1.6  Recommendations for laboratory sampling.

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The cytobrush has proved to be superior for all cytologic parameters studied when compared to cotton‐tipped swabs and two different spatulas in dogs, cats, sheep, goats, cattle, and horses (see Fig. 10.1.44B; Bauer et al., 1996; Bourges‐ Abella et  al., 2007; Willis et  al., 1997). The advantages of this technique include an increase in sample cellularity, acquisition of cells from deeper layers with less intervention, and improved morphologic appearance of each cell because of reduced cell overlap (i.e., a good monolayer; Willis et al., 1997). The nylon‐bristled brush is an 8 cm long plastic instrument with a tapered tip containing a nest of nonabsorbent, soft nylon bristles (3–4 mm long) at one end. The large size of the cytobrush is a disadvantage in small animals, but not in the large equine eye, where it successfully diagnosed Histoplasma spp. in a case of equine keratitis (Richter et al., 2003). Topical anesthetic is required in all techniques except perhaps for a swab. Care must be taken with all samples during collection and transfer to the slides to minimize cell damage and to create a monolayer. The examiner should roll rather than rub the swab, roll rather than spin the cytobrush, and use a needle to tease material off a blade/spatula, or use the blade like a paintbrush to form a smear (Bauer et al., 1996; Villiers & Dunn, 1998). Impression cytology relies on cells that exfoliate easily and is therefore most readily applied to the investigation of superficial conjunctival disease. It can be performed with a clean glass slide, cellulose acetate strip, Biopore membrane device (EMD Millipore Corporation, Billerica, MA, USA), or asymmetric strips of Millipore paper (Millipore HAWP04700, Millipore, São Paulo, Brazil; see Fig. 10.1.44C; Bolzan et al., 2005; McKelvie, 2003). Impression cytology provides a good

A

number of cells, but cell clumping is common. Eördögh et  al. (2015) studied different methods for conjunctival impression cytology in the cat. Biopore membrane (0.4 μm) held within the intended device, applied to the dorsal bulbar conjunctiva following topical anesthetic drops and drying, yielded the best samples in terms of cellularity and quality, and also caused the least discomfort. Impression cytology was shown to cause significantly less irritation than cytobrush sampling in horses with and without ocular surface disease (Braus et al., 2017). The material on the slide needs to be fixed immediately to prevent cellular degeneration. A simple practical method for rapid fixing is to apply heat from a hairdryer to the underside of the slide. A special cytologic fixative spray can also be applied immediately, while the sample is wet. Rapid staining kits (e.g., Diff‐Quik, Polysciences, Warrington, PA, USA) have a fixative incorporated into the staining process (Villiers & Dunn, 1998). If possible, several slides with adequate sample material should be prepared to permit the use of different stains if needed. Commonly used stains include the Gram stain and various Romanowsky‐type stains (e.g., Diff‐Quik, modified Wright–Giemsa stain). The Romanowsky‐type stains are excellent for nuclear and cytoplasmic detail and are generally adequate for the detection of bacteria, fungal hyphae, yeast bodies, inclusion bodies (viral, mycoplasmal, or chlamydial), and inflammatory and neoplastic cells (Fig.  10.1.45; Villiers & Dunn, 1998). The Gram stain provides further information about any identified bacteria. Fungal hyphae may be difficult to identify on routine staining, and more specialized stains for fungal elements include periodic acid‐Schiff and Gomori’s methenamine silver (see Fig. 10.1.45B; Forster et al., 1976).

B

Figure 10.1.45  A. Corneal cytology from a cat reveals a moderate number of eosinophils interspersed with sheets of epithelial cells, indicative of eosinophilic keratitis (modified Wright–Giemsa stain, 400×). B. Fungal hyphae of Aspergillus sp. are highlighted black with Gomori’s methenamine-silver stain (200×). (Courtesy of Emma Scurrell.)

The types of cells commonly encountered from a healthy conjunctiva are sheets of squamous and columnar epithelial cells and goblet cells. Occasional bacteria may be present, and lymphocytes, polymorphonuclear cells, monocytes, and plasma cells are rarely seen; mast cells and eosinophils are absent (Gerding et  al., 1988; Giuliano & Moore, 2002; Lavach et  al., 1977; Murphy, 1988; Prasse & Winston, 1999; Raskin, 2001). The types of cells commonly encountered in a healthy cornea are nonkeratinized epithelial cells (squamous and intermediate), lymphocytes, and polymorphonuclear cells. Nuclei, keratin debris, mucus, and bacteria are also observed; mast cells and eosinophils are absent. In bacterial keratitis, polymorphonuclear cells are the predominant cells and bacteria are present (Gerding et al., 1988; Giuliano & Moore, 2002; Murphy, 1988; Prasse & Winston, 1999; Raskin, 2001). Additional Tests

Additional tests that can be performed on corneal and conjunctival samples include PCR and immunofluorescent antibody (IFA) tests for C. felis, FHV‐1, equine herpesvirus (EHV‐1, EHV‐2, EHV‐4), and fungal DNA (Vengayil et  al., 2009). In PCR testing (the detection of organism DNA or RNA), nucleic acid can be affected by heat, ultraviolet light, and enzymes from damaged tissue. Any type of swab can be used for sample collection, unlike for microbiology (designated microbiology swab). The swab tip should be placed in a dry, plain tube without any sort of medium. Alternatively, the swab can be frozen and shipped on dry ice, but this is not essential and is rarely performed for clinical work (Erles, 2011). Samples for IFA testing should be collected before staining with fluorescein to prevent false‐positive results (da Silva Curiel et al., 1991). For PCR, a highly cellular sample is most likely to yield positive results. In other words, a positive result is more likely to be obtained from, in decreasing order, a biopsy sample, a scraping, and lastly a swab. In support of this, corneal tissue was found to be more helpful than a corneal swab for the detection of FHV‐1 DNA in cats with sequestra (Volopich et al., 2005). However, conjunctival swabs were significantly better at obtaining viral DNA samples than conjunctival biopsy in horses with keratoconjunctivitis (Hollingsworth et al., 2015). A swab for PCR is nonetheless often submitted from clinical cases (e.g., C. felis, FHV‐1) because sample collection is very quick and simple. The benefit of performing more than one sampling technique has been demonstrated in the cat and horse (Massa et  al., 1999; Volopich et  al., 2005; Zeiss et  al., 2013). In 48 horses with ulcerative keratitis, infection was identified in 35 eyes using cytology, culture, or both, as opposed to 26 and 29 eyes by cytology or culture alone, respectively (Massa et  al., 1999). In the horse, a comparison of

c­ onjunctival cytology (cytobrush technique) and conjunctival histopathology provided information that was considered similar to that in the dog (Bourges‐Abella et al., 2007). In equine ulcerative keratitis, nested PCR identified a greater spectrum of agents than either culture or quantitative PCR (Zeiss et al., 2013). Conjunctival Histology

Conjunctival biopsy can be readily performed on most animals without sedation. The area of conjunctiva to be sampled is anesthetized by the application of one or two drops of local anesthetic, for example proparacaine/proxymetacaine. Given the highly vascular nature of the conjunctiva, a more sustained application of topical anesthetic agent may be helpful. This is achieved by soaking a cotton‐tipped applicator or swab in the local anesthetic agent and applying it to the area of interest for 20–30 s. While an assistant restrains the animal’s head and everts the eyelid, a small piece of conjunctiva is delicately elevated using fine‐toothed forceps, for example Bishop‐Harmon forceps. A small snip biopsy is harvested by cutting across the base of the tented conjunctiva using small tenotomy scissors. Hemorrhage is minimal and can usually be controlled with gentle digital pressure; no sutures are required. Multiple samples, typically two to three, can be obtained from the same eye. Conjunctival tissue is usually submitted for histopathology, but can also be submitted for PCR testing. The sample should be placed in 10% formalin for routine histopathology. Given the small size of the samples attained, it is helpful to place them within a net inside a small cassette, which is then placed into the formalin container. For PCR, the sample can be submitted in a dry sterile tube, in sterile saline, or wrapped in gauze moistened with sterile saline. Although it is relatively straightforward to obtain a conjunctival biopsy, conjunctival histopathology may be unrewarding in cases of chronic conjunctivitis; it is not uncommon for the histopathologist to report nonspecific lymphoplasmacytic inflammation of unknown etiology. Conjunctival histopathology can, however, be very helpful to detect neoplasia (e.g., lymphoma, mast cell; Fife et al., 2011), proliferative conjunctivitis (Allgoewer et  al., 2001), infectious organisms (e.g., leishmaniasis; Peña et  al., 2008), onchocerciasis (Schmidt et al., 1982), and to aid in the diagnosis of qualitative tear film disorders (Cullen et  al., 1999; Grahn et al., 2005; Moore, 1990). For the latter, the quantification of conjunctival goblet and epithelial cells determines the goblet cell index (ratio of goblet cells to epithelial cells) and provides information on mucin deficiencies and ocular surface conditions (Cullen et  al., 1999; Evans et  al., 2012; Grahn et  al., 2005; Lim et  al., 2009; Moore, 1990; Sebbag et  al., 2016; Thomasy et  al., 2011). The goblet cell index was  assessed in cats with and without sequestra and no

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s­ ignificant difference was found (Grahn et al., 2005). A more recent study evaluated goblet cell density (GCD) and distribution in cats without clinical evidence of ocular surface disease and without histologic evidence of conjunctival disease. The mean GCD ranged widely by region: 48.8% from the anterior surface of the TEL, 47.0% from the fornices, 38.5% from the palpebral regions, 19.6% from the bulbar regions, and 12.6% from the posterior surface of the TEL. The anterior surface of the TEL is the recommended site for sampling because of the high GCD and its accessibility. In a study on tear ferning patterns in the horse, the mean goblet cell values were 50 ± 11.4 cells/field (Silva et al., 2017).

A

EXTERNAL OPHTHALMIC DYES External ophthalmic dyes are routinely used in veterinary medicine to aid in the diagnosis of corneal, conjunctival, lacrimal, and nasolacrimal diseases. The most commonly used dye is fluorescein, but Rose Bengal and trypan blue are also used by veterinary ophthalmologists (Brooks et  al., 2000a; Feenstra & Tseng, 1992; Gelatt, 1972; Herring, 2007; Laroche & Campbell, 1988; Slatter, 1973). Other ophthalmic stains include lissamine green, Alcian blue, and methylene blue (Kim, 2000; Slatter, 1973). Fluorescein Dye

The most common use for topical sodium fluorescein is in the detection of corneal ulceration (Fig. 10.1.46, Fig. 10.1.47, and Fig. 10.1.48). It is also used to detect conjunctival epithelial defects, aqueous humor leakage (Seidel test), qualitative tear film abnormalities (TBUT), and to assess tear film dynamics and the physiologic flow of the nasolacrimal system (Jones test). The dilution of tear fluorescein was assessed in normal dogs to evaluate the effect of lacrimal punctal plugs (Gelatt et al., 2006). Tear film dynamics was assessed in normal horses (Chen & Ward, 2010). Less common but important uses include some methods of applanation tonometry, fluorophotometry (e.g., determination of aqueous humor flow rate), angiography, tear film studies, and pharmacology studies (e.g., topical ophthalmic drug delivery device in the horse; Alario et  al., 2013a, 2013b; Allbaugh et  al., 2011; Bellhorn et  al., 2017; Chen & Ward, 2010; Crumley et al., 2012; Gelatt et al., 2006; Jones & Ward, 2012; LoPinto et  al., 2017; Miller et  al., 2012; Myrna & Herring, 2006; Pirie & Alario, 2015; Pirie et  al., 2012; Ward et  al., 2001). Sodium fluorescein is a water‐soluble weak dibasic acid of the xanthene group that is detectable in solution at concentrations as low as 1 ppm. Its absorption spectrum peaks at 490 nm (i.e., blue light). Sodium fluorescein converts almost 100% of absorbed light to emitted fluorescent light with a peak wavelength of 520 nm (i.e., green light). Fluorescence is most intense at alkaline pH (e.g., saline solution or the tear film); at acid pH, sodium fluorescein appears yellow or

B Figure 10.1.46  Ophthalmic stains. A. Fluorescein dye is available as a sterile impregnated paper strip and can be made into a solution by mixing with sterile water, saline, or eyewash. B. Fluorescein dye stains the exposed hydrophilic corneal stroma in a large superficial ulcer in a cat.

Figure 10.1.47  Application of fluorescein dye. The fluoresceinimpregnated strip is moistened with, for example, sterile saline or eyewash, and then gently touched once to the dorsal bulbar conjunctiva, with the upper lid retracted. The eyelids are then closed or the animal allowed to blink to distribute the fluorescein across the ocular surface.

orange. Fluorescein is available as a 2.0% alkaline solution or as an impregnated paper strip (Kimura, 1951). Only disposable sources (e.g., impregnated paper strips, single‐dose vials) should be used for topical application, because multidose solutions have been associated with bacterial contamination (Cello & Lasmanis, 1958). Common preservatives

such as benzalkonium chloride and chlorobutanol are inactivated by fluorescein, and ocular infection caused by Pseudomonas aeruginosa has been reported in the dog (Cello & Lasmanis, 1958). Viruses can also survive in fluorescein solution: feline calicivirus (a nonenveloped virus) remained viable in a multidose bottle of fluorescein for up to 7 days (Storey et  al., 2002). In the same study, two enveloped viruses, EHV‐4 and FHV‐1, were not detected at 1 hour. In small animals, the strip should be moistened with sterile normal saline or eyewash and gently touched once to the dorsal bulbar conjunctiva (see Fig.  10.1.47). Alternatively, one drop of fluorescein solution can be applied to each eye. In large animals, for example horses, the easiest method of application is to squirt fluorescein solution directly from a 3 mL syringe through the hub of a 25‐gauge needle that has been manually broken off. Care must be taken to ensure that the needle hub is firmly attached to the syringe. To create the solution of fluorescein, a strip can be placed in the empty syringe prior to drawing up the irrigating solution (Gilger & Stoppini, 2011). After application, regardless of the method used, the eyelids should be closed or the animal allowed to blink to distribute the fluorescein across the ocular surface. The eye is then irrigated (if tolerated) with additional saline or eyewash to remove excess dye from the ocular surface. This important step reduces the potential to make a false‐ positive diagnosis of a corneal ulcer (see Fig. 10.1.48). Fluorescein is highly lipophobic and hydrophilic. Thus, when applied to the surface of the eye, it does not remain in contact with the lipid‐containing cell membranes of the ­epithelium (conjunctival and corneal), but adheres to, and is absorbed by, any exposed stroma. It also stains intercellular spaces because of exposed hydrophilic substance, and

A

t­ herefore assists in the detection of corneal erosions (which by definition do not penetrate the basement membrane of the epithelium). Fluorescein does not stain Descemet’s membrane (see Fig.  10.1.48B). Interpretation is usually straightforward, but false‐positive results can occur. Direct contact between the paper strip and the cornea may leave a mark that resembles a corneal defect, especially if viewed with slit‐lamp biomicroscopy; topical anesthetic agents are epitheliotoxic and sometimes create subtle fluorescein‐positive staining in a punctate pattern; fluorescein solution can “pool” in surface irregularities, for example epithelial facet (a stromal ulcer that has re‐epithelialized). The use of magnification and/or an ultraviolet or blue light, usually available on a direct ophthalmoscope or a slit‐lamp biomicroscope, improves visualization of the dye, but is not usually necessary. Fluorescein may also be used to detect the leakage of aqueous humor through the cornea (Seidel test). To perform the Seidel test, fluorescein is applied to the cornea without subsequent flushing. The resulting high concentration of dye causes it to fluoresce at wavelengths closer to the yellow and orange spectra. If the corneal integrity is compromised, aqueous humor leakage locally dilutes the fluorescein as it exits the corneal defect, and makes the dye appear green. A positive Seidel test is most easily observed with some form of magnification, for example a slit‐lamp biomicroscope. While the aforementioned description is theoretically correct, a more practical description is: a positive Seidel test typically appears as a dark area, representing an exiting wave of aqueous humor, which rapidly increases in size and flows downward over the cornea as the leak continues, pushing the fluorescein solution away as an advancing green band (Fig. 10.1.49).

B

Figure 10.1.48  It is important to irrigate excess fluorescein dye from the ocular surface to reduce the risk of making a false-positive diagnosis. A. The entire surface of the focal, well-demarcated lesion in the paraxial cornea appears to stain with fluorescein dye; the lesion would be interpreted as a stromal ulcer. Fluorescein dye also adheres to a strand of mucus and a hair on the cornea and the dorsal limbus; it forms a prominent tear meniscus, which has spread onto periocular hair. B. The same eye is depicted immediately after irrigation of the ocular surface. The corneal lesion is accurately interpreted as a descemetocele because its base does not stain with fluorescein dye.

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Figure 10.1.49  Positive Seidel test depicts a leaking corneal wound at 12 o’clock.

Fluorescein is used to evaluate the stability of the tear film by measurement of the TBUT. The TBUT indirectly evaluates the mucin and/or lipid layers of the tear film by measuring the time it takes for fluorescein dye, and hence the tear film, to dissociate from the corneal surface (Cullen et  al., 2005b; Moore, 1990). It is a provocative test insofar as fluorescein shortens the normal TBUT. To perform this test, fluorescein solution is applied to the eye, the animal is allowed to blink, and the eyelids are then held open until the tear film begins to dissociate from the corneal surface. Dissociation results in the formation of a dry spot, which appears as a dark round area within the fluorescent tear film. Observation is facilitated by slit‐lamp biomicroscopy using a cobalt blue filter. In the dog, the mean TBUT ranges from 19.7 ± 5 to 21.53 ± 7.42 seconds (Beagle; Moore, 1990; Saito & Kotani, 2001). Oral diphenhydramine decreased TBUT in healthy adult dogs, but the effect was not clinically significant (Evans et al., 2012). Values for the mean TBUT in the cat are 16.7 (± 4.5) seconds in the juvenile cat (Cullen et al., 2005b), and vary from 12.4 seconds (Sebbag et al., 2015) to 21 (± 12) seconds in the adult cat (Grahn et al., 2005). TBUT is reduced (accelerated) in cats with conjunctivitis, ulcerative keratitis, and experimental infection with FHV‐1 (Cullen et  al., 1999; Davis & Townsend, 2011; Lim & Cullen, 2005; Lim et  al., 2009). TBUT is also reduced in eyes with sequestra (14 ± 13 seconds), but the difference is not significant from that in normal eyes (Grahn et  al., 2005). In the cats experimentally infected with FHV‐1, TBUT provided a reasonable estimate of the GCD, but did not correlate with aqueous tear production (STT values) in cats with conjunctivitis (Lim et  al., 2009). Two reports for TBUT values in the horse provide mean values from 8.3 ± 1.3 seconds to more than 13 seconds (Harling, 1988; Monclin et al., 2011). In the more recent of the two studies, TBUT was reduced by topical tetracaine hydrochloride (Monclin et al., 2011). In a rabbit model of dry eye, topical liposome‐bound tetracycline was found to

improve tear quantity and quality, respectively determined by STT and TBUT tests (Shafaa et al., 2011). The fluorescein drainage test (Jones test) assesses the entire mechanism of tear drainage by determining both the anatomic and physiologic patency of the nasolacrimal system. It does so without altering the natural state of the nasolacrimal system, in contrast to nasolacrimal flushing (see later section). Fluorescein is applied to the eye as described previously, but without subsequent rinsing. The Jones test is the timing of the passage of fluorescein through the system to the ipsilateral nares (Jones, 1961). The test is performed on both sides and the times compared (Fig.  10.1.50). The reported values for normal passage times in different species are highly variable. In dogs and cats, the following values have been reported: 30–60 seconds in the dog; from 30 seconds to 5 minutes in dogs and from 15 seconds to 1 minute in cats; within 5 minutes in dogs and cats; and up to 5–10 minutes in clinically normal dogs (Maggs, 2008; Martin, 2005; Ollivier et al., 2007). In the horse, the normal passage time is less than 5 minutes, but may be up to 20 minutes (Gilger & Stoppini, 2011; Harling, 1988). Binder and Herring (2010) performed an objective evaluation of fluorescein nasolacrimal transit time in normal dogs and nonbrachycephalic cats using two methods for the Jones test (impregnated strip and 0.2% fluorescein solution). In dogs, the median transit time following dye transfer by a moistened fluorescein strip was 248 seconds (approximately 4 minutes) and 48 seconds by fluorescein solution; in cats, the times were 46 seconds and 7 seconds, respectively. Thus, in both dogs and cats, transit times were faster with fluorescein solution than with the fluorescein strip, and were also highly variable. In dogs, several variables had a significant effect on transit time, including cephalic conformation (skull shape), snout length, age, and reproductive status. The test was not considered to be clinically useful in brachycephalic dogs. Similarly, another study in cats showed that breeds with severe brachycephalia have reduced tear drainage, because the nasolacrimal duct is forced to follow a steep V‐shaped course around the canine tooth, as determined by computed tomography (CT) and CT‐dacryocystography (Schlueter et al., 2009). A positive result is definitive for a patent duct, but does not confirm that the system is anatomically normal. A negative result is only suggestive of a problem, because there are several reasons that can give a false‐negative result. Practical variables include the amount of fluorescein applied and head position; a negative result will occur if the volume of dye applied is less than the volume capacity of the drainage system, particularly in the horse (Dziezyc, 1992; Latimer et al., 1984). In small animals, it is important to observe the dye as it emerges from the external nares before licking spreads the dye over both sides or removes visible traces completely. An early study found that approximately 40% of dogs have an additional communication between the duct and the ventral nasal meatus at the level of the canine tooth

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A

B

C

D

Figure 10.1.50  Jones test (fluorescein dye passage test) in a 1-year-old Labrador Retriever with a swelling ventral to the medial canthus of the right eye. A. Fluorescein dye flows onto the skin at the medial canthus of the right eye. B. An absence of fluorescein dye at the medial canthus of the left eye suggests that the dye has entered the nasolacrimal drainage apparatus. C. A positive Jones test result at the left nostril confirms nasolacrimal patency on that side. A negative result on the right side suggests that the ipsilateral nasolacrimal duct is blocked or partially blocked. (Reproduced with permission from Featherstone, H., & Holt, E. (2011) Small Animal Ophthalmology: What’s Your Diagnosis? Chichester: Wiley-Blackwell, Fig. 4.1c, p. 63.) D. A positive Jones result at the right nostril in a horse.

root (Michel, 1955). Many authors state that brachycephalic dogs have anomalous tear drainage into the caudal nasal cavity and then into the nasopharynx (Grahn & Sandmeyer, 2007; Kern, 1986; Ollivier et al., 2007). The same situation is believed to be true in brachycephalic cats (Breit et al., 2003; Kern, 1986). In theory, this may be observed as dye in the oropharynx or on the tongue, but is not always practical (Binder & Herring, 2010). Jones testing was performed by subspectacular injection of fluorescein in a study of the lacrimal system in snakes (Souza et al., 2015). Despite its inherent problems, the Jones test is a quick and simple diagnostic procedure and is the most common test for nasolacrimal patency. If the Jones test is negative and the clinical signs suggest a problem with tear drainage, further investigations are indicated, usually in the form of a nasolacrimal flush and imaging techniques (CT and dacryocystorhinography; see the section “Nasolacrimal Flush” and Chapter  10.2; Nykamp et  al., 2004; Rached et  al., 2011; Schlueter et al., 2009).

Rose Bengal

Rose Bengal is used in veterinary medicine to aid in the diagnosis of tear film disorders and superficial corneal epithelial abnormalities (Fig. 10.1.51; Gelatt, 1972). Rose Bengal is not a vital dye. It is toxic to normal healthy corneal epithelial cells in a dose‐dependent manner, which includes routine concentrations (Feenstra & Tseng, 1992; Kim, 2000; Kim & Foulks, 1999). Negative stain uptake is a result of normal tear film components, such as mucin and albumin, protecting the epithelial cells from the dye; positive stain uptake therefore represents a tear film abnormality (Feenstra & Tseng, 1992; Kim, 2000). This is different from the previous belief that Rose Bengal simply stains dead and degenerating cells and mucus. Rose Bengal (tetrachloro‐tetra‐iodo‐fluorescein) is a dark pink dye. Like fluorescein, it is available as a solution and as an impregnated paper strip (Gelatt, 1972; Slatter, 1973). Use of the 0.5% or lower concentrations can reduce the irritancy associated with the 1.0% solution (Slatter, 1973). The

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A

B Figure 10.1.51  A. Rose Bengal dye is available as a sterile impregnated paper strip and can be made into a dark pink solution by mixing with sterile water, saline, or eyewash. B. Rose Bengal dye stains superficial irregular linear corneal erosions in the dorsal cornea of a cat with feline herpesvirus-1 infection. Note the fluorescein dye within the tear meniscus, showing that fluorescein had been applied immediately prior to the Rose Bengal and had not highlighted the lesions.

dye is applied to the ocular surface in the same way as that described for fluorescein. It can be applied before or after fluorescein application, or even at the same time because the stain properties are unaffected by mixing (Korb et al., 2008; Slatter, 1973). In addition to its use in tear film assessment, Rose Bengal can demonstrate superficial corneal erosions or early ulcers that may not stain with fluorescein, for example punctate keratitis, herpetic keratitis, and early keratomycosis (Brooks et  al., 2000a; Brooks et  al., 2013; Ledbetter et al., 2009). Other Ophthalmic Dyes

Lissamine green is an organic acid dye. It is used widely in human ophthalmology, but its use in veterinary ophthalmology is mostly limited to those countries in which Rose Bengal is not available (Gerriets et  al., 2012; Kim, 2000; Norn, 1973; Oriá et al., 2018; Silva et al., 2017). It has been characterized as a true vital dye because it does not stain healthy cells, even in the absence of the tear film (unlike Rose Bengal; Chodosh et al., 1994). Despite this difference, lissamine green has a similar staining pattern to Rose Bengal and has been used in cases of KCS (Machado et al.,

2009; Manning et al., 1995; Yoon et al., 2011). At concentrations of 0.5% and 1%, lissamine green is less toxic than Rose Bengal and is less irritant (Kim, 2000; Machado et al., 2009; Manning et  al., 1995). As previously mentioned, different dyes can be applied alone, sequentially, or at the same time as mixing, and this does not affect staining properties (Korb et al., 2008; Slatter, 1973). In humans, fluorescein has traditionally been considered the premier dye for corneal staining and, similarly, Rose Bengal for conjunctival staining. However, in a study that assessed the efficacy of fluorescein, Rose Bengal, and lissamine green, the mixture of 2% fluorescein and 1% lissamine green was found to offer excellent simultaneous corneal and bulbar conjunctival staining and was well tolerated (Korb et al., 2008). Trypan blue, an azo dye, has been used extensively in human cataract surgery over the last decade, and its utilization has been extended to other anterior segment surgeries including trabeculectomy and corneal transplantation (Jhanji et  al., 2011; Norn, 1973). Trypan blue stains the anterior lens capsule and thus aids in its visualization during capsulorrhexis; it is used by many veterinary ophthalmologists for this purpose (Jacob et al., 2002; Pigatto et al., 2010a). Trypan blue is also used in research in both human and veterinary fields. Two recent studies have involved work on the equine cornea: an in vitro model for corneal scarring and a novel method of gene delivery (Buss et al., 2010a, 2010b). Topical ophthalmic dyes can interfere with the detection of infectious agents by culture and PCR, and, more specifically, fluorescein can cause false‐positive results in IFA testing (da Silva Curiel et al., 1991). In contrast to fluorescein, which can support bacterial growth and virus viability, Rose Bengal and lissamine green are bacteriocidal and virucidal (Cello & Lasmanis, 1958; Seitzman et al., 2006; Storey et al., 2002). Although fluorescein did not interfere with the PCR assay for C. felis and FHV‐1 (an in vitro study), Rose Bengal and lissamine green inhibited the detection of herpes simplex virus by PCR (Segarra et al., 2011; Seitzman et al., 2006; Stroop et al., 2000). In summary, sample collection for infectious agents should ideally be performed prior to the topical application of ophthalmic dyes if possible.

Tonometry Tonometry is the measurement of IOP and is an essential diagnostic procedure for a thorough ophthalmic examination. Direct tonometry via a manometer is the most accurate method, but is invasive and therefore impractical for clinical use. Indirect tonometry, the measurement of corneal tension, is the technique used to determine IOP in clinical ophthalmology. It is a quick, simple, and noninvasive procedure that can be performed with minimal discomfort to the patient, and the results determine not only the diagnosis, but the prognosis and treatment options. Tonometry should not

10.1: Ophthalmic Examination and Diagnostics

Digital Tonometry

Digital tonometry is the estimation of IOP by digital palpation. It was reported as early as pre‐Hippocratic times, and it is still practiced by some human and veterinary ophthalmologists. To perform this technique, the forefinger is placed on the closed upper eyelid, over the globe, and slight pressure is applied to estimate how hard the eye feels. This is ideally performed simultaneously on both eyes for comparison. Digital tonometry is a crude technique and basically differentiates between very soft and very hard eyes. It is of no value in monitoring IOP once therapy has been started, because it is too insensitive. Its use in humans is generally limited to patients who do not have access to specialized eye care, such as in rural areas or underdeveloped countries. Experience has been shown to be an important factor if any level of accuracy is to be achieved: a study using a cadaveric cornea eye model showed that an experienced examiner could estimate IOP within 5 mmHg 100% of the time, as compared with 62% for an inexperienced examiner (Birnbach & Leen, 1998). In a study comparing digital tonometry with Goldmann applanation tonometry, glaucoma specialists were able to digitally identify most eyes with an IOP of greater than 30 mmHg (Baum et al., 1995).

Instrumental Tonometry

The ideal tonometer should be easy to use, atraumatic, require minimal restraint, and provide accurate and repeatable estimates of IOP in both normal and diseased eyes. Tonometers designed for use in veterinary medicine should also be accurate across a wide range of species with different ocular anatomy. Instrumental tonometry includes certain assumptions about various physical factors such as corneal thickness and curvature, corneal and scleral rigidity, tear film viscosity, temperature, and the effects of any topical medications that might be present. Indentation Tonometry

The first indentation tonometer was reported by von Graefe in 1862 (Kronfeld, 1996). This was followed by reports of a similar device from Donders in 1863. In 1905, Schiøtz developed and described an indentation tonometer, the Schiøtz tonometer, which became widely used. In this method, a standard force is applied with a weighted plunger to the anesthetized cornea. The instrument measures the amount of corneal indentation produced by a given weight. The degree of corneal indentation is inversely proportional to the IOP (Fig. 10.1.52). Various models are available, but the fundamental design comprises three parts: footplate, plunger, and handle (holding bracket and recording scale; Fig.  10.1.53). The convex corneal footplate is attached to a 3 mm diameter, low‐friction, jewel‐mounted plunger (metal rod) within a holding bracket attached to a recording scale. The footplate approximates the curvature of the human cornea, and the metal rod protrudes slightly from its concave surface. The plunger weighs 5.5 g; weights of 7.5, 10.0, or 15.0 g can be added to the system. The greater the weight applied to the eye at a given IOP, the greater the indentation of the rod. Depending on the corneal rigidity, the metal rod indents the cornea variably, such that each 0.05 mm of indentation moves the recording needle one scale unit. Scale readings are converted to mmHg via the instrument’s calibration or conversion table. Although conversion tables have been calculated for the dog and the cat from invasive manometry, these tables are less accurate than the human calibration table supplied with the instrument, perhaps because of differences in ocular rigidity (Gelatt & Gum, 1995; Miller & Pickett, 1992a, 1992b; Peiffer et  al., 1977, 1988). The data are recorded as scale reading/weight/IOP, for example 5.0 units/5.5 g/21 mmHg. Before use, the tonometer should be calibrated using the stainless‐steel dome provided with the instrument. It is also important to check that the plunger assembly is clean, because an accumulation of debris will prevent free movement of the metal rod and cause inaccurate results. Following the topical administration of an anesthetic eye drop, the instrument, which relies on gravity, is placed vertically on the central horizontal cornea (see Fig. 10.1.53B). This means

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be restricted to the diagnosis of glaucoma; it should be used in the assessment of a red eye (e.g., conjunctivitis, keratitis, episcleritis, scleritis, anterior uveitis), focal or diffuse corneal edema, orbital disease, and a history of glaucoma or lens luxation in the opposite eye. Tonometry should also not be restricted to making the initial diagnosis and it is an essential part of good ongoing case management. Although tonometry in the outpatient clinic provides only a “snapshot” measurement of IOP, repeat tonometry is invaluable for effective monitoring of the disease itself and response to therapy. The range of normal IOP in most animals is somewhere between 15 and 25 mmHg because of the conservation between species. The mean IOP and range for an individual species varies with different studies, but general values in common domestic species are 15–18 mmHg (dog), 17–19 mmHg (cat), 15–20 mmHg (rabbit), and 17–28 mmHg (horse; Gum et al., 2007). The highest mean IOP recorded in any species is 32.1 ± 10.4 mmHg in the rhinoceros (Ofri et al., 2002a), and the lowest is 3 mmHg in the chinchilla (Müller et  al., 2010). Generally, the difference in IOP between fellow eyes should be less than 8 mmHg (Lovekin, 1964). If this is not the case, a thorough examination of both eyes should be performed to identify any relevant pathology. Indirect tonometry is performed by digital palpation or instrumental tonometry, of which three techniques are used in veterinary medicine: indentation, applanation, and rebound tonometry.

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Figure 10.1.52  Indentation tonometry: the degree of indentation by the metal rod is inversely proportional to the intraocular pressure (IOP). A. The metal rod protrudes slightly from the curved corneal footplate when used on an eye with a normal or raised IOP. B. The metal rod protrudes more in an eye with hypotony (low IOP). (Illustration by H. Featherstone and Simon Scurrell.)

that the animal must be restrained in such a way as to elevate the nose so that the cornea lies in a horizontal plane. The eyelids are gently retracted, avoiding pressure on the globe itself, to allow the footplate to sit on the cornea. The footplate must be placed away from the TEL. Three separate readings are taken, and the closest two results are averaged. Because of the weight of the instrument pressing on the globe, consecutive readings may become progressively lower. There are several disadvantages with a Schiøtz tonometer. Indentation tonometry is inherently subject to some degree

A

of inaccuracy. The main practical problems include difficulty in restraint of the animal in order to achieve the correct head and eye position and prevent movement, and correct alignment of the instrument on the cornea while avoiding the TEL (the footplate can be slipped under the leading edge of the TEL, or forceps can be used for gentle retraction). It should not be used after recent corneal and intraocular surgery and corneal pathology may give inaccurate results. The footplate is designed to match the curvature of the human cornea and its accuracy may vary in veterinary patients: large eyes with “flat” corneas generally give falsely low readings, whereas small eyes with greater corneal curvature tend to give falsely high readings (Strubbe & Gelatt, 1999). The diameter of the footplate is approximately 9 mm, so use in very small eyes is impossible. Ocular rigidity is variable and may affect the accuracy of indentation tonometry. Ocular rigidity is the resistance offered by the fibrous tunics of the eye (sclera and cornea) to a change in intraocular volume. It is a constant characteristic of each eye, but varies with IOP. The dog and cat have greater scleral elasticity than the adult human and therefore present less resistance to indentation tonometry. Readings taken at the limbus give higher values than those from the central cornea, which is considered more accurate (Khan et al., 1991). A simple assessment of the influence of ocular rigidity can be performed by measuring the IOP with two different weights, using the lighter weight first: if the IOP results are similar, the influence of ocular rigidity is small, and vice versa. Any procedure that alters the rigidity of the ocular fibrous coat may affect accu-

B

Figure 10.1.53  Indentation tonometry. A. Schiøtz tonometer with 7.5 and 10.0 g weights. B. Schiøtz tonometer in use on a cat.

racy (e.g., scleral buckling, glaucoma filtration procedures). It is however interesting that the Schiøtz tonometer was more accurate in human eyes with a sutured keratoprosthesis than applanation tonometry and digital manometry (Estrovich et al., 2015). Schiøtz tonometry is impractical in the horse and other large species with laterally positioned globes without general anesthesia (lateral recumbency; Gilger & Stoppini, 2011). However, normal values for the Schiøtz tonometer in the horse have been reported as between 14 and 22 mmHg (Severin, 1976). Mean IOP values obtained by Schiøtz tonometry have been reported in three large wildlife herbivores (Nubian Ibex, Grant Zebra, and Arabian Oryx; Table 10.1.5; Ofri et al., 1998b). Despite the potential for inaccuracy, results of studies comparing the Schiøtz instrument (5.5 and 7.5 g weights) and the Mackay–Marg or Tono‐Pen applanation tonometers suggest that reasonable correlations are possible (Miller & Pickett, 1992a, 1992b). It can provide a reasonable estimation of IOP (probably ± 4 to 5 mmHg), but is less accurate than applanation and rebound tonometry and harder to use. Applanation Tonometry

Maklakoff engineered the first applanation tonometer in 1885, and a modification of this device (Tonomat) was created by Posner and Inglima in 1964 (Albert & Edwards, 1996). Verhoeff developed the Souter applanation tonometer in 1916, reporting its use for optical estimations of IOP, and in 1954 Goldmann developed a slit‐lamp biomicroscope‐ mounted applanation tonometer, which has become the standard for applanation tonometry in human ophthalmology. Applanation tonometers measure the force required to flatten, or applanate, a constant area of cornea (pressure = force/area; Fig.  10.1.54). Applanation tonometry works on the principle of Goldmann’s Imbert‐Fick “law”: “The pressure in a sphere filled with liquid and surrounded by an infinitely thin membrane is measured by the counter‐pressure which just flattens the membrane.” The force required to flatten a known area of the cornea provides an estimate of the IOP. There is a variety of applanation tonometers: Goldmann (Veach Ophthalmic Instruments, Tempe, AZ, USA), Draeger, Perkins (Haag‐Streit USA, Mason, OH, USA), Halberg, Maklakoff, Mackay–Marg, Tono‐Pen® (Reichert, Buffalo, NY, USA), AccuPen (Accutome, Malvern, PA, USA), and pneumatonograph tonometers. A feature common to all is a contact probe with a 3–4 mm diameter planosurface that flattens a corresponding area of the cornea. At this diameter, the resistance of the cornea to flattening is counterbalanced by the capillary attraction of the tear film meniscus for the tonometer head. The force used is evaluated either optically (with a split‐field prism and fluorescein) or electronically (linear transducer, gas‐suspended probe, or air‐pulse noncontact sensor). The Goldmann, Draeger, Perkins, and Halberg applanation tonometers esti-

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Figure 10.1.54  Applanation tonometry: the force required to flatten, or applanate, a constant area of cornea is measured (pressure = force/area). (Illustration by H. Featherstone and Simon Scurrell.)

mate IOP by aligning a corneal contact prism with a hand dial or small motor to calculate the force of applanation. A common requirement is that the eye must remain stationary for several seconds to obtain an accurate reading. The Goldmann tonometer is fixed to a table‐mounted slit‐lamp biomicroscope and is the most accurate applanation tonometer in human ophthalmology; the Draeger, Perkins, and Halberg applanation tonometers are handheld instruments. Although these instruments are not widely used in veterinary ophthalmology, the Perkins tonometer has recently been evaluated in the dog, cat, horse, and cow (Andrade et al., 2009, 2011). In all four species, there was excellent correlation between the Perkins tonometer and direct tonometry. Its use has also been described in sedated rabbits (Lim et al., 2005). Electronic applanation tonometers are available as countertop or handheld instruments. The Mackay–Marg is a countertop tonometer which uses a ceramic actuating rod suspended within the tip of a stainless‐steel probe to activate a position transducer. The high‐frequency, alternating current supplied to the transducer by an amplifier–recorder unit is subsequently modified and returned to the recorder. The lowest repeatable measurements represent the IOP. The Mackay–Marg tonometer produced reliable results in comparison with direct tonometry in the dog, rabbit, and horse (Cohen & Reinke, 1970; Gelatt et  al., 1977b, 1981; Priehs et al., 1990). It underestimates higher IOPs in the cat (Miller et al., 1991). The Tono‐Pen is a digital handheld applanation tonometer based on the Mackay–Marg tonometer (Fig.  10.1.55). It is battery operated and portable. The footplate of the instrument contains a central, pressure‐sensitive tip, which protrudes from and is surrounded by an insensitive ring (see Fig. 10.1.55B). When the tip makes contact with the cornea, the tip applanates or flattens the predetermined area of the cornea; the point of applanation is read electronically (amplified, digitized, and passed through a single‐chip microprocessor). A degree of indentation occurs with con-

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C

D Figure 10.1.55  Applanation tonometry. A. Tono-Pen Vet. B. The footplate contains a central pressure-sensitive tip, which protrudes from and is surrounded by an insensitive ring. C. The tip is covered by a disposable latex membrane that protects the sensitive plunger and prevents disease transmission. D. Tono-Pen Vet in use on a dog.

tinued advancement of the tip, but the true IOP is determined only by the moment of applanation. The tip is covered by a disposable latex membrane that protects the sensitive plunger and prevents disease transmission (see Fig.  10.1.55C). Following topical anesthesia, the eyelids are gently retracted with the nondominant hand, taking care to avoid pressure on the globe. Using the dominant hand, the instrument is held perpendicular to the cornea so that the flat tip is parallel to the cornea (see Fig. 10.1.55D). The tip is tapped very lightly on the central cornea multiple times without causing a visible indentation. Readings taken

from the central two‐thirds of the cornea are most accurate (Khan et  al., 1991). IOP measurements are displayed on a liquid crystal screen. Brief clicks indicate when individual readings have been recorded, and a sustained tone indicates when a mean IOP has been calculated. The mean IOP is then displayed along with the coefficient of variance (i.e., 5%, 10%, 20%, or more than 20%). If the coefficient of variance is more than 5%, tonometry should be repeated. Because of its ease of use, portability, reliability, and cost, the Tono‐Pen has become a popular tonometer among veterinary ophthalmologists. The design has been modified over the years (Tono‐ Pen, Tono‐Pen 2, Tono‐Pen XL, Tono‐Pen Vet, Tono‐Pen Avia), but the basic utility is unchanged. The Tono‐Pen has been used in a variety of domestic and nondomestic species (see Table 10.1.5; Abrams et  al., 1996; Balthazar da Silveira et al., 2017; Barsotti et al, 2013; Bito et al., 1979; Dziezyc et  al., 1992; Gelatt et  al., 1977b; Kotani et  al., 1993; McDonald et  al., 2017; Mermoud et  al., 1995; Miller et al., 1988, 1990, 1991; Ofri et al., 2000, 2001; Oriá et al., 2015a, 2015b, 2015c; Passaglia et al., 2004; Peterson et al., 1996; Priehs et al., 1990; Stoiber et al., 2006; Tofflemire et al., 2017). The calibration of the Tono‐Pen is based mainly on IOPs within the normal range and up to about 30 mmHg, and therefore it will yield lower readings than actual IOP when IOP climbs into range of 40–50 mmHg or more! The majority of humans with early primary open‐angle glaucoma present with IOP levels less than 30 mmHg. Recent studies report a mean IOP of 11.7 ± 2.9 mmHg (Tofflemire et al., 2017) and 15.6 ± 4.2 mmHg (Kato, 2014) when normal canine eyes were evaluated by means of the Tono‐Pen XL. The reported mean IOP for the Tono‐Pen Avia (which is similar to the Tono‐Pen Avia Vet), the newest model of the Tono‐Pen, is 12.8 ± 2.9 mmHg (Ben-Shlomo & Muirhead, 2020). Using a Tono‐Pen, the mean IOP in the cat was 19.7 ± 5.6 mmHg and the mean IOP in the horse was 23.3 ± 6.89 mmHg (Miller et al., 1990, 1991). The reported mean IOP in dogs estimated by the AccuPen, a relatively new applanation tonometer, is 14.3 ± 4.0 mmHg in one study (Tofflemire et  al., 2017) and 13.4 ± 4.7 mmHg in another (Kato, 2014). Mean IOP values for some domestic and nondomestic species are provided in Table 10.1.5. The pneumatonograph is an applanation tonometer– tonographer that measures IOP via a gas‐suspended plunger. Compressed air is directed into a sensor housing that contains a hollow, metal plunger with a silicone sensor membrane at its tip. Part of the gas supports the plunger, thereby allowing it to move in a near‐frictionless state; the rest of the gas passes through the plunger (i.e., measurement chamber), gently pressing the sensor against the cornea during applanation. Pressure from the eye restricts the flow of gas between the sensor membrane and the plunger tip, thus increasing the pressure within the measurement chamber. To record IOP with the pneumatonograph, the cornea is anesthetized and the eyelids are gently retracted. With the

10.1: Ophthalmic Examination and Diagnostics

A

Rebound Tonometry

Rebound (impact or dynamic) tonometry uses a different mechanical principle to measure IOP. A small probe (such as a metal pin with a rounded end) is rapidly and electromagnetically propelled, from a fixed distance from the cornea, to contact the cornea before returning (rebounding) to the instrument (Fig.  10.1.56 and Fig.  10.1.57). The instrument assesses the rebound characteristics (probe deceleration): eyes with a higher IOP cause a slower deceleration of the probe and shorter return time to the instrument than those with a lower IOP. The technique is affected by ocular surface tension and should ideally be performed before the applica-

Figure 10.1.56  Rebound tonometry: a small probe is rapidly propelled from a fixed distance to contact the cornea before returning (rebounding) to the instrument. The rebound characteristics, including probe deceleration, are assessed to determine the intraocular pressure. (Illustration by H. Featherstone and Simon Scurrell.)

B

Figure 10.1.57  Rebound tonometry. A. TonoVet. B. Small metal pin with rounded plastic tip. C. TonoVet in use on a dog.

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plunger extended, the silicone footplate contacts the central cornea. Pressure is then applied until the plunger is depressed approximately halfway into the sensor housing, as indicated by red and green marks on the plunger, and contact is maintained for 3–5 seconds. In the cat, the pneumatonograph underestimates higher IOPs (more than 20 mmHg) and overestimates lower IOPs (less than 15 mmHg; Stoiber et al., 2006); it may underestimate IOP in the horse and the cow (Kotani et al., 1993). Only the pneumatonograph is commercially available and performs tonography in addition to tonometry. The different types of applanation tonometers have been compared within and between species (Boothe et al., 1988; Dziezyc et  al., 1992; Gorig et  al., 2006; Gum et  al., 1998; McLellan et al., 2013; Miller et al., 1988, 1990, 1991; Passaglia et al., 2004; Priehs et al., 1990; Stoiber et al., 2006; Tofflemire et al., 2017). The Tono‐Pen is very accurate in the physiologic range, but tends to overestimate IOP in the low range and underestimate IOP in the high range in dogs (Priehs et al., 1990), cats (McLellan et al., 2009; Stoiber et al., 2006), and humans (Boothe et al., 1988). In the dog and cat, there was strong correlation between the IOP values obtained by direct manometry, Tono‐Pen XL, and Perkins tonometers (Andrade et al., 2012). The Tono‐Pen XL underestimates IOP in the cat, cow, and sheep (McLellan et al., 2009; Passaglia et al., 2004). The pneumatonograph and the MMAC‐II (Professional Technologies, Redding, CA, USA) gave significantly different IOP values from MacKay–Marg and Tono‐Pen XL tonometers in a study of four different applanation tonometers in the dog (Gelatt & MacKay, 1998). In both the cat and the horse, Tono‐Pen and Mackay–Marg applanation tonometers underestimate IOP when compared to direct manometry, but do so in a predictable manner; the linear regression is easily corrected to enable IOP in the live animal to be measured accurately (Miller et al., 1990, 1991). The Tono‐Pen and Mackay–Marg tonometers correlate well in the horse and in the dairy cow (Tono‐Pen XL; Gum et al., 1998).

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tion of any topical medications, including topical anesthetic. Despite this recommendation, studies found that the IOP results were unaffected by topical anesthesia (Gorig et  al., 2006; Kim et al., 2013; Rusanen et al., 2010; Schuster et al., 2015; Tofflemire et al., 2017). Advantages of the rebound tonometer are that topical anesthesia is not necessary; a very small probe tip (1.3– 1.8 mm) makes it suitable for very small eyes, as in many exotic species, and in the presence of significant corneal disease; and the tip is disposable (see Fig. 10.1.57B). One disadvantage is that the instrument must be held upright during measurement so that the probe is propelled horizontally; this may make its use difficult in recalcitrant or recumbent patients (see Fig.  10.1.57C). Common types of alignment errors that can occur with rebound tonometry were simulated and assessed in the chicken (in vivo and in vitro; Prashar et al., 2007). Accuracy was unaffected by a variation in the probe‐to‐cornea distance over the range 3–5 mm and by lateral displacement of the probe from the visual over the range 0–2 mm. Although there was slightly more effect if the probe was angled away from the visual axis over the range 0–20 degrees, none of the alignment errors was considered to be clinically relevant in conscious birds. The TonoVet rebound tonometer is becoming increasingly popular in veterinary ophthalmology. A strong linear correlation between rebound tonometry and direct manometry has been demonstrated in the dog, cat, and horse (Knollinger et  al., 2005; McLellan et  al., 2013; Rusanen et  al., 2010; Tofflemire et  al., 2017). In contrast, rebound tonometry underestimated the IOP by 37%–60% in enucleated rabbit eyes and 17%–63% in enucleated porcine eyes, as compared to direct manometry (Lobler et al., 2011). When compared to the Tono‐PenVet, rebound tonometry underestimated the IOP by an average of 2 mmHg in the dog (Knollinger et al., 2005) and overestimated the IOP by 1 mmHg in the horse (Knollinger et  al., 2005). In the cat, the TonoVet is more accurate than the Tono‐Pen XL in normal and glaucomatous eyes (McLellan et al., 2013). In the pig (ex vivo porcine eyes), the TonoVet was more accurate than the Tono‐Pen Vet (Lewin & Miller, 2017). The TonoVet in “d” (dog) setting was found to be the most accurate of three tonometers in the ex vivo chinchilla eye (Snyder et al., 2017). Rebound tonometry has also been reported in the prairie dog (Meekins et  al., 2015a), alpaca (McDonald et  al., 2017), pygmy goat (Broadwater et al., 2007), rabbit (Pereira et al., 2011), dairy calf (Tofflemire et al., 2015), birds of prey (Harris et al., 2008; Jeong et  al., 2007; Labelle et al., 2012; Reuter et al., 2010), chicken (Prashar et  al., 2007), pigeon (Park et  al., 2017), ducks and geese (Ansari Mood et al., 2017), murres (guillemot; Freeman et al., 2018), chinchilla (Müller et al., 2010), African giant pouched rat (Heller et  al., 2018), turtle (Delgado et al., 2014; Espinheira Gomes et al., 2016; Somma et  al., 2014), gray mouse lemur (Dubicanac et  al., 2018), Yacare caiman (Ruiz et al., 2015), penguin (Bliss et al., 2015;

Gonzalez‐Alonso‐Alegre et  al., 2015; Sheldon et  al., 2017), American bullfrog (Cannizzo et  al., 2017), and koi fish (Lynch et al., 2007). The TonoVet Plus, a new model of the TonoVet, has been recently introduced. Together with improved user interphase and ergonomics, the device has been recalibrated for four species including the dog, cat, horse, and rabbit. The IOP values in normal canine eyes were reported to be 19.2 ± 3.1 mmHg, significantly higher than with the TonoVet and TonoPen Avia (Ben‐Shlomo & Muirhead, 2020). A manometry study suggests that the TonoVet Plus trends towards increased accuracy and precision when compared to the TonoVet, Tono‐Pen Avia, and Tono‐Pen XL (Minella et al., 2019). The IOP values obtained by the human‐calibrated rebound tonometer ICare® (Tiolat, Helsinki, Finland) were significantly lower than those for the Tono‐Pen XL in normal dog eyes (Leiva et al., 2006). Given this, and the results of other studies (Knollinger et  al., 2005; Rusanen et  al., 2010), the TonoVet has been calibrated for dogs, cats, and horses. The TonoLab rebound tonometer is specifically designed for performing tonometry in rodents (rat/mouse; Kim et al., 2013). The TonoLab was more accurate than the TonoVet when used in red‐eared slider turtles (Delgado et al., 2014). In the Kemp’s Ridley sea turtle, the mean IOP measured by the rebound tonometer on the “h” (horse) setting was approximately twice that for the “P” (nonspecified) setting (Gornik et  al., 2016). It is thus important to select the correct software, when known, for each species before performing tonometry. The aforementioned studies were performed in clinically normal animals, with the exception of the study in cats (McLellan et al., 2013). There are several studies that describe the use of tonometry in glaucomatous canine and feline eyes (Gorig et al., 2006; McLellan et al., 2013; Slack et al., 2011; von Spiessen et al., 2015). Both the TonoVet and Tono‐Pen XL provide reproducible IOP measurements in cats, but the TonoVet is more accurate in normal cats and for the detection of ocular hypertension and/or glaucoma in cats in a clinical setting (McLellan et al., 2013). In the dog, there was a 1 : 1 relationship between the TonoVet and the MacKay– Marg tonometer (Gorig et al., 2006), in contrast to an overestimation of IOP by the TonoVet compared with the TonoVet‐XL (Slack et al., 2011; Tofflemire et al., 2017). Factors That Influence Tonometry

Multiple factors can influence tonometric readings. Some factors are inherent to the type of tonometer (e.g., size of probe on a cornea with extensive pathology) and to the technique (e.g., head position), whereas others are beyond the control of the examiner (e.g., age, gender, season). In the clinical setting, tonometry can usually be performed in most common domestic species in conscious animals with minimal restraint. In cooperative patients, the main factors that influence the IOP results include improper or inexperienced

use of equipment or a disease process affecting one or both globes. In large species such as the horse, and when an eye is painful, adjunctive methods are required for reliable tonometry and can affect the IOP results. These include sedation, general anesthesia, and regional nerve blocks. The method of restraint (physical or chemical) and body and head position can also have a dramatic effect. The importance of striving to perform tonometry on an eye with minimal influencing factors has been demonstrated in a mouse model for glaucoma: tonometry results were more consistent and reliable in mice that had undergone successful behavioral training to accept tonometry conscious, than in mice that were placed in a restrainer device (Ding et al., 2011). It is important to try to perform tonometry before the application of topical mydriatic agents because of their potential effect on IOP. This includes short‐acting agents such as tropicamide, which is widely and routinely used for diagnostic purposes. Topical tropicamide 1% has been shown to cause a substantial increase in IOP (up to 6–7 mmHg) in both normal and glaucomatous cats (Gomes et al., 2011; Stadtbaumer et al., 2002, 2006). In contrast to the cat, topical tropicamide 1% has less effect on IOP in the dog, although clinically relevant increases (13.6 mmHg) in individual animals (Hacker & Farver, 1988) and interbreed variations have been recognized (Taylor et al., 2007). Topical and intramuscular atropine (0.06 mg/kg) both caused a significant increase in the IOP in healthy dogs (Kovalcuka et  al., 2015). In contrast, topical cyclopentolate did not affect IOP (or tear production) and could therefore be considered when a cycloplegic drug is needed without adverse effects on those parameters (Costa et al., 2016). The effect of sedation and general anesthesia on IOP is an important consideration when performing tonometry on eyes with corneal trauma, glaucoma, or those undergoing intraocular surgery. In the horse, IOP is reduced by xylazine alone (by up to 23%; van der Woerdt et al., 1995) and by the combination of acepromazine and xylazine (McClure et al., 1976), but not by the combination of ketamine and xylazine (Smith et al., 1990; Trim et al., 1985). Romifidine caused a significant decrease in IOP in the horse in two studies (Marzok et al., 2014; Stine et al., 2014). In the dog, ketamine alone causes a significant and clinically important increase in IOP (Hofmeister et  al., 2006a). Such an increase can be avoided, however, with concurrent use of diazepam or midazolam (Ghaffari et  al., 2010b; Hofmeister et  al., 2006a). Sedation with medetomidine and atipamezole in healthy Golden Retrievers undergoing routine health screening had no effect on IOP (Wallin‐Hakanson & Wallin‐Hakanson, 2001). Sedation with dexmedetomidine did not affect the IOP in dogs until 20 minutes, when it caused a reduction (Artigas et al., 2012). Propofol has shown conflicting effects on IOP in dogs in different studies. Dogs induced with intravenous propofol developed a significant increase in IOP before intubation and the increase was not prevented by

administering higher doses (Hofmeister et  al., 2009). This increase was also seen when propofol was compared to thiopental (Hofmeister et al., 2008). An increase in IOP was also seen with the combination of midazolam‐propofol and midazolam‐etomidate (Gunderson et al., 2013). However, in a more recent study, propofol and alfaxalone both decreased the IOP in dogs at 2 minutes following induction and were therefore considered appropriate induction agents for intraocular surgery (Costa et  al., 2015). The use of nitrous oxide did not affect IOP in dogs induced by propofol and maintained with desflurane (Almeida et al., 2008). IOP was increased in dogs receiving morphine, alfaxalone, midazolam, and sevoflurane, and the authors advised against this protocol for intraocular surgery (Mayordomo‐Febrer et  al., 2017). The combination of tiletamine and zolazepam had no effect on IOP in healthy dogs (Jang et al., 2015). It has long been recognized that pressure on the jugular veins from excessive restraint or a tight‐fitting collar may falsely elevate the IOP, particularly in brachycephalic dogs. These and related factors have been objectively assessed by two studies. IOP in dogs is significantly increased by applying neck pressure via a collar but not via a harness (Pauli et al., 2006). The effect of eyelid manipulation and manual compression of the jugular vein(s) on applanation tonometry in normal dogs was assessed (H.E. Klein et al., 2011). The greatest increase in IOP occurred with simultaneous bilateral jugular vein compression and lateral eyelid extension (increase of 17.6 mmHg), and lateral eyelid extension alone (16.5 mmHg). It has been suggested that horses without an auriculopalpebral nerve block may have an elevated IOP (Trim et al., 1985), but this has not been supported by two other studies (Miller et al., 1990; van der Woerdt et al., 1995). For reliable tonometry in the clinical setting, the use of an auriculopalpebral nerve block is recommended in the horse (Gilger & Stoppini, 2011). Different methods of manual head restraint were compared in the red‐eared turtle (Delgado et al., 2014). Rostral head restraint is preferred because it did not affect IOP, in contrast to neck restraint, which significantly increased IOP. The effect of body position on IOP was assessed using applanation tonometry in healthy dogs without glaucoma (Broadwater et  al., 2008). Three different body positions were compared (sternal recumbency, dorsal recumbency, and sitting position) and were found to affect IOP. During the 5‐minute examination, IOP decreased significantly in dogs that were dorsally recumbent or sitting, but did not change significantly in dogs that were sternally recumbent. The effect of body position on IOP has also been assessed in the mouse, together with the effect on episcleral venous pressure (EVP; Aihara et  al., 2003). Both IOP and EVP increased with a head‐down body position (16.5 ± 0.6, 18.2 ± 0.6, and 19.5 ± 1.8 mmHg for the horizontal/awake position, 30 degree head‐down position, and 60 degree head‐down position, respectively). In contrast to these studies in the dog

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and mouse, the IOP was unaffected by body position in young healthy calves in lateral recumbency, as compared to a normal standing position (Kurt et al., 2018). Head position was also found to have a significant effect on IOP in normal horses (Komáromy et al., 2006). Two different head positions, above and below heart level, were assessed following sedation (intravenous detomidine), auriculopalpebral nerve block, and topical corneal anesthesia. The IOP was increased in 87% of eyes when the head was below heart level, and there was a significant difference from the mean IOP when the head was above (17.5 ± 0.8 mmHg) or below (25.7 ± 1.2 mmHg) heart level. The effect on IOP of different head and body positions (sitting, recumbent, and hyperextension of the head) has been evaluated in humans using three different tonometers. The IOP of recumbent patients was only slightly higher than for sitting patients, but was significantly higher when the head was hyperextended using the Tono‐Pen (A. Klein et  al., 2011). Head and body position affects IOP in the fruit bat and in the loggerhead sea turtle (Blackwood et al., 2010; Chittick & Harms, 2001). The IOP in the upright fruit bat is lower than when hanging (Blackwood et al., 2010). The IOP in the sea turtle is significantly higher when suspended in a head‐down position, as compared with dorsoventral and ventrodorsal positions (positions commonly used for restraint for medical and surgical procedures; Chittick & Harms, 2001). The IOP in the red‐footed tortoise is also affected by different body positions, with higher values in the ventrodorsal position as compared to the dorsoventral position (Oriá et al., 2015b). A major advantage of the handheld electronic applanation tonometer (Tono‐Pen models, AccuPen) is that it can be used with the animal in any position. In contrast, the rebound tonometer probe must be horizontal (parallel to the floor), as mentioned previously (Takenaka et al., 2011). The need for the cornea to be horizontal is an obvious disadvantage for the Schiøtz tonometer. The effects of corneal thickness and corneal pathology have varied with different studies. Corneal thickness has been shown to affect IOP results with both the TonoVet and the Tono‐Pen XL (Park et  al., 2011). For every 100 μm increase in corneal thickness, the IOP increases by 1 mmHg for the Tono‐Pen XL and 2 mmHg for the TonoVet. However, a later study found that the IOP was not affected by central corneal thickness with two different applanation tonometers (Tono‐Pen XL and AccuPen; Kato, 2014). Another study showed that IOP values obtained by the AccuPen applanation tonometer in dogs underestimated the true IOP (obtained by manometry), and when corrected for central corneal thickness (which is a feature of the AccuPen), the calculated IOP further decreased compared to manometry. Hence, it was concluded that when using the AccuPen in dogs, the AccuPen default CCT setting should be used without further adjustment for the true CCT (Tofflemire et  al., 2017). Von Spiessen et al. (2015) found that corneal pathol-

ogy affected IOP values with both the TonoVet and the Tono‐ Pen Vet. If corneal pathology is present, it is prudent to take readings from the most normal part of the cornea. This factor is affected by the size of the footplate of the tonometer: the small area of the rebound tonometer probe (1.3 mm) and Tono‐Pen tip (approximately 3 mm) are more advantageous than the large footplate of the Schiøtz tonometer. Despite the influence of corneal pathology on IOP, the presence of a therapeutic soft contact lens has no clinically significant effect on IOP in humans (A. Klein et al., 2011) and by applanation tonometry (MacKay–Marg) in the dog (Miller & Murphy, 1995). A more recent study in the dog showed that measurements were more reliable in the presence of a soft contact lens with the Tono‐Pen XL than with the TonoVet rebound tonometer (Ahn et al., 2012). The effect of age on IOP has been reported in several species, including the dog (Gelatt & MacKay, 1998; Mughannam et al., 2004; Verboven et al., 2014), domestic cat (Kroll et al., 2001), lion (Ofri et al., 2008), camel (Marzok & El‐khodery, 2015), and sambar deer (Oriá et al., 2015a). As a general rule, there is a negative association between age and IOP (in contrast to a positive association between age and tear production). This is true for the dog, cat, and camel, but not for the lion (Ofri et al., 2008) and sambar deer (Oriá et al., 2015a). Several studies have demonstrated changes in IOP during maturation, in addition to changes from a mature adult to a geriatric animal. The IOP increased significantly in Beagle puppies from 2 weeks old (Verboven et  al., 2014), but was unaffected in Labrador Retrievers during maturation from 6 weeks to 1 year old (Mughannam et al., 2004). IOP in the dog declines by 2–4 mmHg as age increases from less than 2 years to greater than 6 years (Gelatt & MacKay, 1998). IOP is considerably lower in geriatric cats than in young cats; higher in adolescent than in adult cats; and lower in young kittens within the first few weeks of life than in adolescent cats (Kroll et al., 2001). In cats in which IOP was measured on multiple occasions over time, IOP decreased progressively, and it was not unusual for aged cats to have very low IOPs ( 7 mmHg) in the absence of any signs of anterior uveitis. This reduction in IOP may reflect reduction in active secretion of aqueous humor associated with declining systemic health. In the lion, IOP increases with age during the first 20 months of life, plateaus until approximately 40 months, and then gradually declines (Ofri et  al., 2008). In sambar deer, IOP was significantly higher in older animals (Oriá et al., 2015a). Although most studies have shown that gender has no effect on IOP, it has a significant effect on IOP in the lion: IOP in the male lion is significantly higher than in the female (Ofri et al., 1998a). Reproductive status was shown to have a significant effect in both the domestic cat and in the lion: the IOP was higher in cats in estrus and in lions in luteal phase (elevated progesterone) compared with those that were not (Ofri et al., 1999b, 2002b).

Circadian rhythm affects the IOP in the dog, cat, and horse (Bertolucci et al., 2009; Del Sole et al., 2007; Giannetto et al., 2009), and probably other species. In the dog there is a diurnal acrophase (left eye: 09:33 ± 00:50 hours; right eye: 09:25 ± 00:22 hours; Giannetto et al., 2009). The IOP (and central corneal thickness) was lower in the afternoon/evening in normal dogs (Garzón‐Ariza et al., 2018). In the cat, maximal IOP values were detected at night (by about 4–5 mmHg) and a gradual decline in IOP occurred during the day (with IOP in mid to late afternoon about 1–1.5 mmHg lower than morning values; Del Sole et al., 2007). In the horse, IOP was low during the dark phase and high during the light phase, with a peak at the end of the light phase (Bertolucci et al., 2009). The mouse has a biphasic 24‐hour pattern in IOP (Aihara et al., 2003). The IOP is lower during the day than at night in the New Zealand white rabbit (Wang et al., 2013). The relationship between IOP and body length has been studied in the American alligator and the red‐footed tortoise (Selmi et  al., 2002; Whittaker et  al., 1995). IOP and body length are related in the alligator but not in the tortoise. The IOP was significantly higher in alligators shorter than or equal to 50 cm in length compared with those longer than 50 cm; the relationship was nonlinear. In contrast, there was no relationship between carapace length and IOP in the red‐ footed tortoise (Selmi et al., 2002). Collating the results of the various studies, the examiner should be consistent when recording IOP values in terms of instrument used, time of day, head/body position, method of restraint (physical and chemical), sedation, and the use of an auriculopalpebral nerve block. This is especially important in monitoring for small changes by serial tonometry in the same animal.

TONOGRAPHY Tonography is the use of continuous tonometry to noninvasively estimate the pressure‐sensitive facility of conventional aqueous humor outflow. In this technique, a tonometer is allowed to rest on the cornea for a set time period, usually 2–4 minutes. In theory, the weight of the tonographic probe on the cornea increases the rate of aqueous humor outflow, without changing the rate of aqueous humor production, and hence decreases the IOP. The subsequent decline in IOP (decay curve) allows an estimation in μl/mmHg/minute of the conventional outflow (corneoscleral trabecular outflow). The unconventional (uveoscleral) outflow is pressure independent and therefore cannot be estimated by tonography. Schiøtz first described reduction of IOP through repeated tonometry in 1905, noting that pressure reduction occurred to a greater degree in normal than in glaucomatous eyes (Albert & Edwards, 1996). In 1911, Polak‐van Gelda reported similar results using intermittent Schiøtz tonometry over a period of 1–2 minutes. The following year, Schoenberg

described the application of continuous tonometry on the human eye, recording the decay curve for both normal and glaucomatous eyes. By the 1960s, tonography had become a routine part of the diagnostic regimen for human glaucoma. Sole reliance on tonography to detect glaucoma should be avoided, however, because misinterpretation and misdiagnosis may occur as a result of some overlap between the facility of aqueous outflow in normal versus early glaucomatous eyes (Hetland‐Eriksen & Odberg, 1975). Tonography remains an important, noninvasive, and repeatable clinical diagnostic procedure for the estimation of conventional aqueous humor outflow. The results of tonography have been reported in the rabbit, cat, dog, horse, and nonhuman primates (Bill & Barany, 1966; Eakins, 1969; Helper, 1974; Kornbluth & Linner, 1955; Zhao et  al., 2010). It has further been used to compare the facility of aqueous humor outflow in normal and glaucomatous Beagles (Gelatt et  al., 1977a, 1996). Tonography has established that there is increased resistance to aqueous humor outflow in dogs with glaucoma (Gelatt et  al., 1977a, 1996). The technique appears to be very accurate when compared with the traditional, invasive, constant‐pressure, and two‐step perfusion techniques of measuring aqueous humor outflow (Peiffer et al., 1976). The typical tonogram waveform is a gradually descending line with only slight fluctuations, which reflect pulse and respiration. The descending line represents decreasing IOP. The slope of the line is greater with normal than with glaucomatous eyes. Human tonography tables have been used to calculate the coefficient of aqueous humor outflow in the dog, cat, and horse. Using either the Schiøtz tonograph or the pneumatonograph, the facility of aqueous humor outflow (C‐value) is from 0.24 ± 0.07 μL/mmHg/min to 0.297 ± 0.149 μL/mmHg/min for the normal dog eye, from 0.27 to 0.32 μL/mmHg/min for the normal cat eye, and 0.88 ± 0.65 μL/mmHg/min for the normal horse eye (Gelatt et al., 1996; Smith et al., 1990; Toris et al., 1995). Two types of tonographs are available: those that utilize indentation and those that utilize applanation to estimate changes in IOP. The Schiøtz tonograph is an indentation‐type instrument, consisting of an electronic Schiøtz tonometer connected to a transducer. Readings are displayed on a console. The Schiøtz probe is large, covering most of the corneal surface, and has all the mechanical problems associated with this type of tonometer. It is not available as a new instrument. Applanation tonography is performed with a pneumatonograph or a modified Mackay–Marg tonometer. The pneumatonograph uses a compressed air–supported, silicone‐tipped plunger to flatten or applanate a focal area of the cornea, thus displaying both digital and waveform results in a manner similar to the Schiøtz tonograph. The pneumatonograph probe® (Reichert, Buffalo, NY, USA) is smaller than the Schiøtz instrument and is more easily maintained on the center of the cornea.

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Sedation or general anesthesia is necessary when performing tonography because the eye must be immobile for 2–4 minutes during the procedure, and most veterinary patients are unwilling or unable to cooperate for that long without pharmacologic restraint. The two most important requirements are constant blood pressure and an immobile eye in a normal position so that the cornea is vertical. The agents for sedation or anesthesia must be chosen carefully, however, because many drugs can cause significant changes in venous blood pressure, IOP, and pupil size, and thereby potentially affect the facility of aqueous humor outflow. Gelatt et  al. (1977a, 1996) described a protocol using acepromazine (0.5 mg/kg intravenously) followed 5 minutes later by ketamine (10 mg/kg intramuscularly). The use of halothane anesthesia has also been reported for patient anesthesia prior to pneumatonography (Glover et al., 1995; Spiess, 1995), and seems not to affect outflow results. Gaseous anesthesia is now generally more accessible and familiar, but the general health status of each individual patient must be considered carefully before choosing any one particular protocol. Topical anesthetic is applied to the cornea, and if necessary to permit probe placement and prevent blinking; an auriculopalpebral nerve block may be performed. Regardless of the method of restraint, the patient is placed in dorsal recumbency, and the eyelids are held open manually or with an eyelid speculum. The speculum should not be so tight fitting as to put direct pressure on the globe, and the cornea should be kept moist to avoid damage to the epithelium. The contact surface of the tonograph probe is carefully placed against the central cornea, and measurements are continuously recorded for a period of 2–4 minutes. During this time, the contact probe should remain in a fixed position to minimize artifacts, which may result from probe movement, probe malfunction, nystagmus, blinking, sneezing, and hyperventilation. Tonography is not commonly utilized in clinical veterinary ophthalmology. Lack of consistency and the difficulties associated with recording data in untrained animals and the need for either heavy sedation or anesthesia make this tool most useful in the research setting. In the latter, tonography is routinely used in the assessment of antiglaucoma medications and their mechanisms of action, and surgical techniques. Additional information on tonography can be found in Chapters 3 (“Physiology of the Eye”) and 20 (“The Canine Glaucomas”).

GONIOSCOPY Gonioscopy describes the technique that allows examination of the anterior face of the iridocorneal angle (ICA) and ciliary cleft (CC). The clinical examination of this region is an integral part of the evaluation of the aqueous outflow pathways and may provide insight into the pathogenesis of a glaucomatous state (Bedford, 1975, 1980a, 1980b; Gelatt & Ladds, 1971; Grozdanic et al., 2010; Lovekin, 1964).

Dellaporta (1975) provides a detailed history of gonioscopy. Trantas first reported direct visualization of the human ICA in 1907 with the help of a direct ophthalmoscope, digital pressure on the sclera, and a +4 D to +15 D lens, and he published his first paper specifically describing the clinical examination of the ICA and Schlemm’s canal in 1918. Salzmann later constructed the first goniolens from a modified Fick keratoconus contact lens (Dellaporta, 1975). Between 1919 and 1920, Koeppe described gonioscopy using a slit‐lamp biomicroscope and a special steeper contact lens. Troncoso modified the Koeppe goniolens in 1920, using a monocular instrument called a gonioscope to magnify the angle by a power of 13–21. In 1938, Barkan described gonioscopy as a diagnostic aid for human primary glaucoma (Becker, 1972), and in that same year Goldmann introduced the indirect goniolens, which allowed visualization of all 360 degrees of the ICA simply by rotating the mirror of the goniolens. In 1942, Troncoso introduced the binocular gonioscope, which was a handheld instrument allowing stereoscopic visualization of the ICA (Troncoso, 1948). In 1936, Troncoso and Castroviejo published the comparative gonioscopic anatomy of the rabbit, pig, cat, dog, and nonhuman primate. In 1960, Calkins published a phylogenetic study of the ICA in a variety of species, and Magrane (1957) and Lovekin (1964) also briefly described gonioscopy. Lescure (1963) photographed the canine ICA and CC using the Goldmann lens. Gelatt and Bedford published photographs of the normal canine ICA and CC using the Koeppe (Ocular Instruments, Bellevue, WA, USA) and Barkan lenses (Medical Works Ocular Instruments, Bellevue, WA, USA) and KOWA fundus camera (KOWA Optimed, Torrance, CA, USA; Bedford, 1973). The ICA of most animals and humans cannot be directly visualized because it is obscured by the scleral shelf (Troncoso, 1948). This is in contrast to other structures in the anterior chamber, which are visible without instrumental aid because light rays returning from them to the examiner’s eye are largely refracted and only partially internally reflected along their passage from aqueous humor and cornea to air (Fig. 10.1.58). Light rays directed at the ICA do not return to the examiner’s eye even if viewed obliquely, as they are totally internally reflected. The phenomenon of total internal reflection occurs when light rays exceed a “critical angle” as they attempt to pass from a medium of higher refractive index (1.376 for cornea) to one of lower refractive index (1.00 for air). The application of a contact lens to the eye can overcome this problem by removing the cornea‐to‐air interface and creating a new contact lens‐to‐ air interface instead (see Fig.  10.1.58C; Martin, 1969a; Troncoso, 1948). Only a few animals with very large and deep anterior chambers, such as felids, have ICAs and C s that are somewhat visible to the unaided eye (McLellan & Miller, 2011). The examination of the feline ICA is thus possible without a gonioscopy lens, using a focal light source or an indirect ophthalmoscope and a condensing

n1

n1

n2

n2 Light

Critical angle

Critical angle

Light

Density of the optical media: n2 > n1

Density of the optical media: n2 > n1

A

B

goniolens n1 n2 Light

Critical angle

Density of the optical media: n2 > n1

C Figure 10.1.58  Phenomenon of total internal reflection. A. When a light beam passes from a medium of higher refractive index (n2) to one of lower refractive index (n1) – in the case of the anterior chamber aqueous to air – it is partially refracted and partially reflected. B. If the angle at which the light beam hits the interphase between the two media is greater than the so-called critical angle, the beam is completely reflected. C. With the application of a contact lens, this problem can be overcome by creating a new interphase between the different media (in this case, creating an aqueous-to-contact lens and contact lens-to-air interphase).

lens at an extreme angle (McLellan & Miller, 2011; Samuelson et al., 1989) or a standard glass slide to flatten the cornea. In the adult horse, it is possible to directly visualize the entrance to the ICA without any instrumental aid in the lateral and medial regions where the scleral shelf is absent (Samuelson et al., 1989). Many different designs of goniolens are available commercially, but all fall into two categories: direct or indirect (Fig. 10.1.59). Direct goniolenses are very convex to avoid reaching the critical angle and allow the examiner to look obliquely across the anterior chamber to the opposite ICA

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segment (see Fig.  10.1.59A). The image in direct gonioscopy is real and magnified 1.5–3×, but the examiner must change positions to examine the entire 360 degrees (Martin, 1969a; Troncoso, 1948). The Koeppe and Lovac‐Barkan lenses are both direct gonioscopy lenses that are commonly used in the dog (Fig. 10.1.60). The Koeppe lens is held in place by a combination of the vacuum created by pressing the lens onto the anesthetized corneal surface and the small “flange” placed into the conjunctival fornices, whereas the Lovac‐Barkan lens is held in place by a vacuum created via a syringe and a silicone tube attachment

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A

B

Figure 10.1.59  Gonioscopy lenses can be divided into direct and indirect. A. Direct gonioscopy lenses allow examination of the iridocorneal angle opposite to the viewing position of the examiner and create a real image. B. Indirect goniolenses for gonioprisms form a virtual image that the observer examines from a frontal position.

Figure 10.1.60  Direct gonioscopy lenses provide a magnified image, as demonstrated here by the Koeppe (left) and LovacBarkan (right) lenses.

(Fig. 10.1.61 and Fig. 10.1.62). Other less commonly used direct gonioscopy lenses include the Cardona and Swan‐ Jacob models (Ocular Instruments), which are useful in small eyes, as well as the Franklin and Troncoso models, which have silicone flanges and tube handles, respectively. Indirect gonioscopy lenses use single or multiple mirrors or prisms that reflect the light rays emanating from the ICA through a plano anterior contact lens, ensuring that the critical angle is not reached (Fig. 10.1.63). Indirect lenses allow the ICA and opening of the CC to be visualized from directly in front of the patient. The entire circumference of the angle can thus be observed simply by minimal rotation of the lens or by changing focus from mirror to mirror. However, indirect goniolenses or prisms are designed for human corneas, which are significantly smaller and have a more acute curvature than canine corneas, and can result in some image distortion. Indirect gonioscopy lenses do not provide magnification, unlike the direct ones.

Figure 10.1.61  Koeppe lens in situ. The lens is retained by suction on the corneal surface, freeing the examiner’s hands.

Figure 10.1.62  Lovac-Barkan lens in situ. The lens is retained in place with a vacuum created by a fluid column in the attached tube, which is free hanging. It is not necessary for additional vacuum to be created by aspiration with a syringe at the end of the tubing during the procedure.

Figure 10.1.63  Posner indirect gonioprism. The observer can assess multiple quadrants of the iridocorneal angle at the same time from a frontal position, but no magnification is provided and the prism must be held in place by the observer.

Furthermore, indirect goniolenses are more difficult to use in the conscious patient, because they will not adhere to the eye via a vacuum mechanism, but require active application to the cornea with one of the examiner’s hands via a handle or a tube extension. However, some examiners prefer the use of indirect goniolenses, and the ICA is easier to photograph through the flat surface (Miller & Bentley 2015). The Karickhoff diagnostic lens, Posner gonioprisms (Ocular Instruments), and Sussman gonioscope (Ocular Instruments) are examples of indirect gonioscopy lenses. There are various other single‐, two‐, and three‐mirrored forms as well, some of which allow concurrent examination of the ICA and the ocular fundus via separate mirrors. Practical Application of Gonioscopy

Gonioscopy can usually be performed in the conscious patient following topical anesthesia; sedation is only required in a few uncooperative patients (Bedford, 1973, 1977a, 1977b). Restraint of the patient’s head should ideally be provided by a trained assistant, as the examiner will require both hands for the procedure. Both sitting and lateral recumbent positions have been described for canine gonioscopy (Martin, 1969a; Bedford, 1973, 1977b). Examination under sedation or anesthesia may be necessary if a lesion is within a less accessible area, for example the 12 o’clock position. Proparacaine (proxymetacaine) is a suitable local anesthetic in veterinary patients (Bedford, 1973). Gonioscopy lenses should be cleaned between patients by means of a 5‐minute soak with 3% hydrogen peroxide to prevent the transmission of infectious diseases. The use of alcohol wipes may not be adequate and may cause material damage (Neubauer et al., 2009). It is important to flush the lens thoroughly prior to use to remove all traces of disinfectant. After the topical anesthetic is instilled, 0.5%–2.5% methylcellulose solution is placed on the concave contact

surface of the gonioscopy lens, which is then applied to the cornea by the examiner with one hand while the other hand keeps the eyelids open. The patient’s head should be tilted slightly laterally or “nose down” by the assistant and the inferior edge of the lens is placed first, which will both prevent loss of the coupling agent and will help to displace the TEL. When applying a direct contact lens such as the Koeppe lens, initial gentle pressure onto the lens is required to create a vacuum, which will then allow retention of the lens on the cornea without further manual support for the remainder of the examination. The continued application of pressure to the globe via the contact lens should be avoided, as this might distort the relationship of the ICA structures, unless dynamic gonioscopy is actually required to screen for temporary peripheral adhesions (see the next section). Less viscous solutions, such as 0.9% saline, are not as effective at preventing air entering between the lens and the cornea. Air bubbles should be avoided, as they will prevent adequate visualization of the ICA. An exception with regard to the coupling medium is made, however, when a Lovac‐Barkan lens is used. Here, the silicone tubing attached to the lens is flushed with sterile saline until the small well on the concave side of the lens is filled with fluid. The lens is then applied to the eye as previously described and the eyelids are closed firmly over the lens while further saline is flushed through the silicone tube via an attached syringe (Bedford, 1973). Once all air bubbles have been displaced between the lens and the cornea, the syringe is detached and the silicone tube is left to hang freely, creating gentle suction, which secures the lens on the corneal surface without additional manual support (see Fig. 10.1.62). When using indirect gonioscopy lenses, no coupling medium may be required or 0.5% methylcellulose is used. After the lens is in place, a light source is required to illuminate the region of the ICA. A portable slit‐lamp biomicroscope is ideal for providing magnification and stereopsis, but a handheld fundus camera can also provide good magnification and will allow photodocumentation of the ICA entrance (Bedford, 1973). Some examiners traditionally use an otoscope with the speculum removed, which obviously affords less magnification (Bjerkas et al., 2002). With direct gonioscopy lenses, the examiner must look into the lens from all four quadrants to obtain a complete image of the ICA, with the dorsal and lateral quadrants being the least accessible in the awake and upright patient. When performing indirect gonioscopy, the examiner must remember that the area of ICA visualized is opposite the position of the mirror (James, 2007). Gonioscopy is performed after routine intraocular examination because the coupling agent will obscure the view. Most manufacturers recommend extensive cleaning protocols for the use of gonioscopy lenses between patients, which in practice are rarely adhered to, but even with limited cleaning protocols there appears to be a very small risk

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of transfer of bacterial infection between canine eyes (Grundon et al., 2018). The entire ICA and opening of the CC are systematically evaluated, with special attention given to angle width and pectinate ligament conformation. The normal canine pectinate ligament consists of fine strands of tissue that originate as solitary or “tent‐like” structures from the iris base, traverse the CC, often interweaving, and insert onto the corneal endothelial surface (Fig.  10.1.64 and Fig.  10.1.65; Bedford, 1973, 1977b; Martin, 1969a; Troncoso, 1948; Wyman, 1973). The insertion line is somewhat variable in thickness and pigmentation, but can be seen in most pigmented dogs and is referred to as the deep pigmented line (Martin, 1969a; Wyman, 1973). A less densely pigmented line is visible in most dogs extending superficially and more axially along the cornea. This area, referred to as the superficial pigment line,

represents the pigmentation at the corneoscleral limbus (see Fig. 10.1.64 and Fig. 10.1.65; Martin, 1969a; Wyman, 1973). The presence of both the superficial and deep pigment lines varies even between different quadrants of the same eye (Martin, 1969a). The canine pectinate ligament is less “comb like” than that of the ungulate, but not as thin and delicate as in the feline, and has been described as “trees in a forest” (McLellan & Miller, 2011; Troncoso, 1948). The appearance of the canine pectinate ligament varies both between breeds and within individual animals (Bedford, 1977b). Dogs with dark irides usually have darkly pigmented pectinate ligaments, although even in such individuals, the degree of pigmentation may vary, not only between eyes, but also in different quadrants within the same eye (Bedford, 1977b). In dogs with reduced iris pigment, the pectinate ligaments can be extremely fine and difficult to visualize (see Fig. 10.1.64).

Cornea Light (limbal) pigment band Dark pigment band Pectinate ligament fibers Iris

Pupil

Figure 10.1.64  Normal iridocorneal angle in a Flat-Coated Retriever. (Courtesy of S. Ellis.)

Cornea Sclera and limbus

Pectinate ligament fibers Iris Pupil

Husky - albinotic

Figure 10.1.65  Normal iridocorneal angle in a blue-eyed Siberian Husky. (Courtesy of S. Ellis.)

A small percentage of broader fibers (also termed fibrae latae) is considered a normal variation (Fig.  10.1.66), as opposed to the extensive abnormal and thickened fibers or sheets of tissue that characterize pectinate ligament dysplasia (PLD; Fig. 10.1.67). However, the percentage of “normal” focally dysplastic pectinate fibers proposed by investigators ranges from 6% to 12.5% to 25% of angle circumference (Bjerkas et al., 2002; Ekesten & Narfstrom, 1991; Read et al., 1998; Wood et  al., 2001). The presence of synechia (especially peripheral anterior synechia), peripheral iris cysts, foreign bodies, neoplasia, granulomas, traumatic iridal dialyses or other injuries, and anterior segment colobomas should also be noted (Bedford, 1977b; Gelatt & Ladds, 1971; Lovekin, 1964; Martin, 1969a; Vainisi, 1970; Wyman, 1973). Gonioscopy has been used to identify intraocular extension of limbal masses such as melanomas (Featherstone et  al., 2009; Gelatt & Ladds, 1971) and to define the extent of intraocular neoplasia, for example uveal neoplasia (Cook & Wilkie, 1999; Gelatt & Ladds, 1971; Gwin et al., 1982). Indentation or dynamic gonioscopy may differentiate reversible ICA apposition from angle closure associated with peripheral anterior synechiae by the application of slight pressure at the peripheral cornea to try for separation (James, 2007). This method is not routinely applied in veterinary ophthalmology and may require sedation or anesthesia. Gonioscopy is most commonly performed in the dog as an essential tool in the management of glaucoma (the ICA and CC may change as the disease progresses) and to distinguish between open‐ and closed‐angle glaucoma (Bedford, 1975, 1977a; Bjerkas et al., 2002; Ekesten & Narfstrom, 1991; Gelatt & Ladds, 1971; Kato et al., 2006a, 2006b; van de Sandt et al.,

2003; Wood et  al., 2001). Canine patients presenting with unilateral glaucoma often have marked corneal pathology in the affected eye because of the elevated IOP, and it may not be possible to visualize the face of the ICA. Gonioscopic evaluation of the entrance to the ICA in the fellow eye is used in this situation to extrapolate information about the etiology of the glaucoma in the affected eye (Bedford, 1975). The appearance of the entrance to the ICA not only helps to elucidate the etiology of the glaucoma, but also is a possible predictor for the heritability of primary closed‐angle glaucoma associated with goniodysgenesis (Bjerkas et al., 2002; Read et  al., 1998; Wood et  al., 1998, 2001). Key criteria to evaluate the entrance to the ICA include the morphology of the pectinate ligament 360° and angle–CC width (Bedford, 1975, 1977a, 1977b, 1980a, 1980b; Bjerkas et  al., 2002; Cottrell & Barnett, 1988; Ekesten & Narfstrom, 1991; Gelatt & Ladds, 1971; Kato et al., 2006a; Wood et al., 1998, 2001). PLD has been proposed as a marker for primary closed‐ angle glaucoma in a number of studies (Bjerkas et al., 2002; Ekesten & Narfstrom, 1991; Kato et  al., 2006a; Read et  al., 1998; Wood et al., 1998, 2001). Recently, it has been brought into question whether PLD is truly a congenital condition as progression of PLD has been described (Pearl et al., 2015), and instead of a one‐off examination, it is recommended that gonioscopy is carried out at regular intervals to identify changes commensurate with PLD in predisposed dogs as they age. The width of the entrance to the ICA has also been investigated in correlation with IOP and primary closed‐angle glaucoma in the dog (Bjerkas et al., 2002; Ekesten & Narfstrom, 1991). Subjectively, the ICA can be described as open, narrow, or closed. An attempt to make an objective assessment of the

Figure 10.1.66  Focal fibrae latae in an otherwise normal iridocorneal angle of a Flat-Coated Retriever. (Courtesy of S. Ellis.)

Figure 10.1.67  Severely dysplastic pectinal ligament visible on gonioscopy in a Flat-Coated Retriever. (Courtesy of S. Ellis.)

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ICA entrance has been made by Ekesten and Narfstrom (1991) by estimation of the relative width of the ciliary cleft. In this method, the ratio between the anterior width of the CC (length of pectinate ligament from origin at iris base to its insertion at the deep limbal pigment band) and the total distance of the pectinate ligament from origin to the inner corneal surface is determined with the help of measurements obtained from goniophotographs. The ratio for the two variables is calculated and used to establish a grading system of angle width with five grades (closed, narrow, slightly narrow, open, and wide open; Ekesten & Narfstrom, 1991). When performing gonioscopy, the examiner must remember the possible limitations of the technique and, in particular, that the examined area is limited to the entrance of the ICA (Gibson et al., 1998). In cases of extensive PLD, visual assessment of the deeper structures of the CC is not possible with gonioscopy. This means that an at least partially open CC may be present behind solid sheets of dysplastic pectinate ligament (van der Linde‐Sipman, 1987). Additional diagnostic aids such as high‐resolution ultrasound and ultrasound biomicroscopy may eclipse gonioscopy, as they will be able to provide a more complete picture of the ICA and CC (Bentley et al., 2005; Gibson et al., 1998).

Nasolacrimal Flush Nasolacrimal flush is the manual irrigation of the nasolacrimal system to determine anatomic patency. Indications include delayed or absent fluorescein passage from the eye to the ipsilateral distal punctum (negative Jones test), epiphora without an identified cause, mucopurulent ocular or nasal punctal discharge (the latter in the horse), and dacryohemorrhea. The flush can be performed in either a normograde (orthograde; from the eyelid or lacrimal puncta) or retrograde (from the nasal punctum) direction; the choice depends on the species and the clinical signs. With the exception of the

A

horse, normograde irrigation is routine in most species because identification and cannulation of the small nasal punctum are difficult; in the horse, the distal nasal punctum is large and easy to identify. The level of restraint required varies between species and individuals. The technique can be performed conscious in many dogs, rabbits, and cattle, whereas horses usually require sedation and cats usually require sedation or general anesthesia (because the puncta are very small and difficult to cannulate). Topical anesthesia is achieved by topical anesthetic eye drops applied to the conjunctival sac (for a normograde flush) and by lidocaine gel to the nares (for a retrograde flush). With the aid of illumination and magnification (depending on the species), the upper and lower puncta are identified. The lacrimal puncta are slit‐like openings in most species, but are round in the cat. In the dog, the slit‐like puncta are 1 mm long by 0.3 mm wide and are located 2–5 mm lateral to the medial canthus, on the palpebral conjunctiva, where the line of meibomian glands end (Grahn & Sandmeyer, 2007). In the horse, the 2 mm slit‐like puncta are located 8–9 mm lateral to the medial canthus (Latimer et al., 1984). The rabbit has a single lower punctum and the pig has a single upper punctum. In some animals, identification of the lacrimal puncta may be facilitated by a small amount of surrounding pigment. Cannulation of the upper lacrimal punctum first is recommended to avoid damage to the lower punctum (which is responsible for the majority of tear drainage) and because it is usually easier in terms of manual dexterity. A metal or Portex lacrimal cannula (e.g., Smiths Medical International, Brisbane, Australia) or intravenous catheter (without metal stylet) is appropriate for irrigation in the rabbit, cat (24‐ to 25‐gauge), and dog (22‐ to 24‐gauge; Fig.  10.1.68). Cannulation with a plastic cannula is made easier by cutting the end short and at an oblique angle (see Fig. 10.1.68B). A 2–5 mL syringe of sterile saline or eyewash is attached to the cannula prior to cannulation.

B

Figure 10.1.68  A. Selection of plastic and metal lacrimal cannulas suitable for performing a nasolacrimal flush in a small animal, for example a dog or cat. B. Cannulation with a plastic cannula is made easier by cutting the end short and at an oblique angle.

With the upper lid everted to expose the upper punctum, the cannula is inserted in a ventromedial direction, following the line of the upper canaliculus (Fig. 10.1.69A, B). Fluid is slowly irrigated until it exits the lower punctum. This establishes patency of the upper and lower puncta, upper and lower canaliculi, and lacrimal sac. Digital pressure is then applied to occlude the lower punctum, diverting the irrigating fluid into the nasolacrimal duct. Fluid exiting from the ipsilateral nasal punctum establishes patency of the nasolacrimal duct. The muzzle should be directed ventrally to minimize fluid draining into the nasopharynx. Expelled debris may be collected for cytology, and culture and sensitivity if indicated. If necessary, the lower punctum can also be cannulated (Fig.  10.1.69C). If a normograde flush from either the upper or the lower punctum is unsuccessful, a retrograde flush can be performed under general anesthesia (conscious in the horse). Illumination and some form of speculum (e.g., vaginal speculum, otoscope head) are required to visualize the distal nasal punctum, which, in the dog, is ventrolateral near the alar fold. A Jackson’s tomcat catheter is useful for cannulation of the nasal punctum in small animals; rigidity provided by the metal style facilitates initial cannulation. In the horse, a retrograde flush is most commonly performed first (Crispin, 1988). The distal nasal punctum is large (3–4 mm in diameter) and therefore easily identified inside the external nares at the ventral mucocutaneous junction (Fig. 10.1.70A; Latimer et al., 1984). Suitable catheters are 4–6 Fr canine urinary catheter, 5 Fr feeding tube, or polyethylene tubing (Latimer et al., 1984). The tip of the catheter, coated with lidocaine gel, is inserted into the punctum for a distance of at least 5 cm (Fig.  10.1.70B).

A

Gentle digital pressure should be applied to the surrounding area to minimize normograde fluid loss. A 10–20 mL syringe, filled with irrigating fluid (eyewash, sterile saline), is attached and gentle irrigation is continued until fluid exits the proximal puncta. Sneezing is common and may be violent. Each lacrimal punctum can be evaluated separately by occluding the opposite punctum with digital pressure. If retrograde irrigation is unsuccessful, normograde irrigation should be attempted, as previously described for small animals but with a larger cannula (e.g., open‐ended tomcat catheter, teat tube syringe). Gentle pulse pressure may be necessary to unblock an obstructed duct. However, excessive force, either during cannulation or irrigation, should be avoided to prevent iatrogenic trauma to the nasolacrimal system. Imaging in the form of plain and contrast skull radiography (dacryocystorhinography) and/or CT should be performed if irrigation is not possible (Noller et  al., 2006; Nykamp et  al., 2004; Rached et al., 2011; Schlueter et al., 2009).

PARACENTESIS Paracentesis, the aspiration of fluid from a body cavity using a needle, can be performed on the eye for both diagnostic and therapeutic purposes. Aqueous and vitreous paracentesis requires some expertise and familiarity with ocular anatomy, and should only be used where its potential contribution to the management of the case is clearly understood. Aqueous Paracentesis (Keratocentesis)

Aqueous paracentesis, the aspiration of a small amount of aqueous humor from the anterior chamber, has both diag-

B

Figure 10.1.69  Nasolacrimal flush in a dog. A. With a 2–5 mL syringe of sterile saline or eye wash attached to the cannula, and the upper lid everted to expose the upper punctum, the cannula is inserted into the punctum in a ventromedial direction, following the line of the upper canaliculus. (Reproduced with permission from Featherstone, H., & Holt, E. (2011) Small Animal Ophthalmology: What’s Your Diagnosis? Chichester: Wiley-Blackwell, Fig. 2.2d (B), p. 35.) B. Cannulation of the lower punctum.

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638

A

B

Figure 10.1.70  Nasolacrimal flush in a horse. A. The distal punctum is large (3–4 mm in diameter) and easily identified inside the external nares at the ventral mucocutaneous junction. B. The tip of a catheter, coated with, for example, lidocaine gel, is inserted into the punctum and directed proximally for several centimeters.

nostic and therapeutic purposes (Hazel et  al., 1985; Olin, 1977). The procedure is relatively quick and simple if performed by someone with appropriate training and experience, but complications can occur. The procedure can be performed either with sedation and topical anesthesia or under short‐acting general anesthesia. If performed in the standing horse under sedation, retrobulbar and auriculopalpebral nerve blocks should also be performed. Some clinicians perform aqueous paracentesis with only topical anesthesia, but the risk of complications is greater. The conjunctival sac, and most importantly the bulbar conjunctiva, should be cleaned with a dilute (5%) povidone–iodine solution followed by sterile saline solution or eyewash. Topical anesthetic eye drops are applied to the ocular surface; a cotton‐tipped applicator soaked with the topical anesthetic agent can be pressed on the site of needle insertion to improve the level of anesthesia. Subconjunctival mepivacaine also facilitates the procedure in conscious or sedated animals. An eyelid speculum is placed. In theory, the needle can be inserted at any point on the limbus circumference, but the dorsolateral quadrant tends to be practical to avoid the TEL and for comfortable hand placement. Furthermore, in large herbivores such as the horse, the dorsal to dorsolateral limbus is preferred to take advantage of the scleral extension beyond the iris base. The bulbar conjunctiva is grasped with small forceps near the site of entry, and a 27‐ to 30‐gauge needle is inserted (bevel up) through the clear cornea immediately adjacent to the limbus or the subconjunctival limbus (Allbaugh et al., 2011). A gentle drilling and tunneling motion facilities passage through the sclera or cornea, and may facilitate rapid formation of a seal after the needle is withdrawn. The needle must enter the anterior chamber anterior to the iris and be directed parallel with the iris (Fig.  10.1.71A). The tip of the needle

should be visualized all the time to avoid lacerating the iris or anterior lens capsule. Although not essential, some form of magnification (e.g., loupes) is helpful, particularly in small animals. The volume of the anterior chamber varies between species: 0.3 mL (rabbit), 0.4–0.77 mL (dog), 0.6 mL (cat), and 2.4–3 mL (horse; Gilger et  al., 2005; Gum et  al., 2007). A small volume (0.1–0.5 mL) of aqueous humor can be removed by one of several methods. A syringe may be attached to the needle, either before or after the needle has entered the anterior chamber, to slowly aspirate the aqueous humor. Alternatively, the aqueous humor that fills the needle hub may be collected into a capillary tube, without the need for a syringe. The latter is less awkward and offers better control over the needle (May & Noll, 1988). The use of a compact suction pipette has been described to reduce instrumentation and minimize needle dead space (O’Rourke et al., 1991, 2004). To prevent the profound hypotony post‐paracentesis, an equal volume of saline or balanced salt solution can be injected, and IOP measured. Possible complications of aqueous paracentesis include hyphema, anterior lens capsule rupture with subsequent phacoclastic uveitis, corneal edema associated with endothelial damage, anterior uveitis, endophthalmitis, choroidal edema, and hemorrhage. The technique is more challenging if the cornea is opaque and in the presence of iris thickening or displacement (e.g., iris bombé). Anterior uveitis will always develop following paracentesis, even if the technique is rapid and straightforward, and is detected as an increase in the prostaglandin and protein levels in the aqueous humor (Rankin et al., 2002, 2011b; Regnier et al., 1995; Ward, 1996; Ward et al., 1992). Inflammation can be minimized by using the appropriate needle gauge, very slow removal of aqueous humor, injecting an equal amount of sterile normal saline or balanced salt solution into the

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10 mm (horse) 5–7 mm (dog)

A

B

Figure 10.1.71  Paracentesis. A. Aqueous paracentesis. The needle is inserted (bevel up) through the clear cornea immediately adjacent to the limbus or the subconjunctival limbus. A tunneling motion facilitates passage through the sclera or cornea. The needle must enter the anterior chamber anterior to the iris and be directed parallel with the iris. B. Vitreous paracentesis. The needle is inserted posterior to the limbus (5–7 mm in the dog and 10–12 mm in the horse) and firmly tunneled through the sclera and pars plana of the ciliary body. The needle must be directed toward the posterior pole to avoid the lens. (Illustration by H. Featherstone and Simon Scurrell.)

anterior chamber (unless the aim of paracentesis was to reduce IOP), and not exceeding the appropriate volume for the species (Gilger & Stoppini, 2011; Strubbe & Gelatt, 1999). The effect of different needle sizes for aqueous paracentesis in normal dogs has been evaluated by tonometry and fluorophotometry (Allbaugh et al., 2011). Of the three sizes used, the largest (25‐gauge) caused a significant increase in blood–aqueous barrier breakdown and transient ocular hypertension at 20 minutes, compared with the two smaller sizes (27‐ and 30‐gauge). Furthermore, there was evidence of breakdown of the blood–aqueous barrier in the contralateral eye in all dogs and with all needle sizes. Diagnostic tests for aqueous humor samples obtained by aqueous paracentesis include cytology, culture and sensitivity, protein measurement, PCR, and antibody titers (e.g., Leptospira spp., Toxoplasma gondii, Bartonella spp.; Chavkin et al., 1994; Faber et al., 2000; Gilger et al., 2008; Halliwell & Hines, 1985; Halliwell et  al., 1985; Krohne et al., 1995; Lappin et al., 2000; Maggs et al., 1999; Matthews & Poulter, 1986; Olin, 1977; Powell et  al., 2010; Wurster et  al., 1982). Antibody titers can be used to calculate the Goldmann–Witmer coefficient (C‐value), which compares the antibody titer in aqueous humor with that in the serum in order to establish the presence or absence of local antibody production (Chavkin et al., 1994). Aqueous paracentesis is also used extensively in research to determine drug levels in aqueous humor and other pharmacokinetic

parameters (Clode et  al., 2006, 2010, 2011; Gilger et  al., 2000a, 2000b; Gilmour et  al., 2005; Norcross et  al., 2010; Regnier et  al., 2003, 2008; Westermeyer et  al., 2011; Yu‐ Speight et al., 2005). There are several therapeutic indications for aqueous paracentesis. It can provide immediate relief of ocular hypertension (e.g., postoperative hypertension following phacoemulsification), which is useful when intravenous mannitol cannot be used or if topical therapy has been ineffective. It allows the intracameral injection of drugs, for example tissue plasminogen activator in eyes with postsurgical or traumatic hyphema and/or fibrin clots (Gerding et  al., 1992). The procedure can also be used to aspirate uveal cysts. Vitreous Paracentesis

Vitreous paracentesis (hyalocentesis) is the aspiration of small amounts of vitreous humor for both diagnostic and therapeutic purposes. Vitreous paracentesis is usually performed with the patient under short‐acting general anesthesia or heavy sedation. Preparation is the same as for aqueous paracentesis in terms of aseptic preparation of the ocular surface and placement of an eyelid speculum. Visualization of the posterior segment is aided by inducing mydriasis with a short‐acting mydriatic (e.g., tropicamide) if the anterior segment is clear. The site of needle entry is very important and varies with species. In the dog, the general recommendation is 5–7 mm posterior to the limbus, but the distance

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varies with the ocular quadrant and globe size. In the medium‐sized mesaticephalic dog, the distances posterior to the limbus for safe needle entry are 7 mm (dorsolateral quadrant), 6 mm (ventrolateral quadrant), 5 mm (ventromedial quadrant), and 4–5 mm (dorsomedial quadrant; Fig. 10.1.71B; Smith et al., 1997). These sites are likely to be more posterior in larger dogs with larger eyes (Smith et  al., 1997). In the horse, the recommended site is 10–12 mm posterior to the limbus in the dorsolateral quadrant (Miller et  al., 2001; Stoppini & Gilger, 2017). The needle size varies from 26‐ gauge (dog, cat) to 23‐ to 25‐gauge (horse). The globe is stabilized by grasping the bulbar conjunctiva with forceps adjacent to the site of needle entry. The needle is gently but firmly tunneled through the sclera and pars plana of the ciliary body, directed toward the posterior pole to avoid the lens. Using a syringe attached to the needle, 0.1–0.3 mL of fluid is slowly aspirated (sometimes more in the end‐stage, glaucomatous eye). The volume of the vitreous varies between species: 1.5 mL (rabbit), 1.7–3.2 mL (dog), 2.8 mL (cat), and 26–28.8 mL (horse; Gilger et al., 2005; Gum et al., 2007). The needle may need to be repositioned to find areas of liquefied vitreous or gently flushed if the tip appears blocked. Normal vitreous and granulomatous or neoplastic material may require more aggressive aspiration and, in some cases, a larger‐gauge needle. This procedure can also be performed with magnification, for example loupes or operating microscope, or with ultrasound guidance to improve the accuracy of needle placement. Possible complications of vitreous paracentesis include intraocular hemorrhage, retinal tear or detachment, lens subluxation, cataract formation, uveitis, and endophthalmitis. The incidence of lens damage in humans is very low, 0.009% (2/21,653), when the technique is performed by experienced personnel (Meyer et al., 2010). As for aqueous humor, diagnostic tests for vitreous humor samples obtained by paracentesis include cytology, culture and sensitivity, protein measurement, antibody titers (e.g., Leptospira spp.), and PCR (Wollanke et al., 2001). Vitreous paracentesis is also used extensively in research to determine drug levels in vitreous humor and drug pharmacokinetics (Gilger et  al., 2000a, 2000b; Gilmour et  al., 2005; Norcross et al., 2010; Regnier et al., 2008).

than 2000 cells/μL), and is prepared by immediate cytocentrifugation (cytospin). If cytospin equipment is not available, a direct smear is still beneficial for fluids of low cellularity as well as for other body fluids. Both direct and sediment smears should be submitted unstained. In clinical ophthalmology, microbiology and cytology are the most commonly required tests for aqueous and vitreous humor samples. The sample should be divided into the following submissions: fluid in a plain tube (for microbiology); fluid in a pediatric EDTA tube and an unstained sediment smear prepared by cytospin (for cytology; see Table 10.1.7). An unstained direct smear can also be submitted if cytospin is unavailable, but is most likely to be diagnostic if the humor is grossly turbid. Like cerebrospinal fluid, samples of aqueous and vitreous humors are low volume and usually of low cellularity. The following points further help the clinician to achieve a diagnostic sample: discuss the test(s) required with the chosen laboratory prior to sampling; use pediatric tubes if possible; and use a same‐day courier to expedite arrival at the laboratory (to maximize cell preservation). Given the risks of paracentesis, the examiner must consider the risk–benefit ratio before proceeding. In clinical practice, aqueous humor cytology is often not rewarding, with the exception of diagnosing intraocular lymphoma (Finger et al., 2006; Linn‐Pearl et al., 2015). Linn‐Pearl and colleagues (2015) assessed the validity of aqueocentesis as a component of the investigations in dogs and cats with anterior uveitis. The technique was primarily useful to diagnosis lymphoma in both species; aqueous humor cytology alone was not diagnostic in nonneoplastic cases, but supplemented other diagnostic tests. Other molecular techniques such as Table 10.1.7  Recommendations for aqueous and vitreous samples. Test

Transport Medium

Shipping Conditions

Cytology

Unstained sediment smear prepared by cytospin

Same‐day courier

Pediatric EDTA tube (plain tube if unavailable) (Unstained direct smear if humor grossly turbid)

Same‐day courier

Bacteriology

Plain tube (not EDTA) or designated microbiology swab

Refrigerate until shipping, normal post

Fungal culture

Plain tube (not EDTA) or designated microbiology swab

Refrigerate until shipping, normal post

Polymerase chain reaction

Plain tube

Normal post

Aqueous and Vitreous Humor Samples

The general recommendation for cytology and culture of body fluids is to place the sample in an ethylenediaminetetraacetic acid (EDTA) tube and a sterile plain tube, respectively (culture cannot be performed from fluid from an EDTA tube; Table  10.1.7; Prasse & Winston, 1999; Raskin, 2001). A direct smear should also be submitted to enable the clinical pathologist to compare the cellularity of the sample and the appearance of the cells at the time of collection with that of the fluid received in the tube(s). A sediment smear is preferable to a direct smear for fluids of low cellularity (less

EDTA, ethylenediaminetetraacetic acid.

10.1: Ophthalmic Examination and Diagnostics

confirmed FIP (Felten et al., 2017). False‐positive results and an overall accuracy of 69.4% showed the limited benefit to this test. For endophthalmitis, diagnostic vitreous paracentesis is considered to have a higher sensitivity than aqueous paracentesis (Brightman et al., 1986; Martin, 2005). SECTION II

PCR for antigen receptor rearrangement can be used for further diagnostics (Pate et  al., 2011). In contrast, aqueous humor testing was unhelpful in the diagnosis of feline infectious peritonitis (FIP). The utility of an immunocytochemical assay using aqueous humor was evaluated in 26 cats with

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10.1: Ophthalmic Examination and Diagnostics

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Journal of the American Veterinary Medical Association, 219, 795–800. Wood, J.L., Lakhani, K.H., Mason, I.K., & Barnett, K.C. (2001) Relationship of the degree of goniodysgenesis and other ocular measurements to glaucoma in Great Danes. American Jourmal of Veterinary Research, 62, 1493–1499. Wood, J.L., Lakhani, K.H., & Read, R.A. (1998) Pectinate ligament dysplasia and glaucoma in Flat Coated Retrievers. II. Assessment of prevalence and heritability. Veterinary Ophthalmology, 1, 91–99. Wotman, K.L. & Utter, M.E. (2010) Effect of treatment with a topical ophthalmic preparation of 1% nalbuphine solution on corneal sensitivity in clinically normal horses. American Journal of Veterinary Research, 71, 223–228. Wurster, U., Riese, K., & Hoffmann, K. (1982) Enzyme activities and protein concentration in the intraocular fluids of ten mammals. Acta Ophthalmologica, 60, 729–741. Wyman, M. (1973) Applied anatomy and physiology of the anterior chamber angle. Veterinary Clinics of North America, 3, 439–451. Wyman, M., Gilger, B., Mueller, P., & Norris, K. (1995) Clinical evaluation of a new Schirmer tear test in the dog. Veterinary & Comparative Ophthalmology, 5, 211–214. Yeh, C.Y., Goldstein, O., Kukekova, A.V., et al. (2013) Genomic deletion of CNGB3 is identified by descent in multiple canine breeds and causes achromatopsia. BMC Genetics, 14, 27. Yeh, C.Y., Koehl, K.L., Harman, C.D., et al. (2017) Assessment of rod, cone, and intrinsically photosensitive retinal ganglion cell contributions to the canine chromatic pupillary response. Investigative Ophthalmology & Visual Science, 58, 65–78. Yokoi, N. & Komuro, A. (2004) Non‐invasive methods of assessing the tear film. Experimetal Eye Research, 78, 399–407. Yokoi, N., Komuro, A., Maruyama, K., & Kinoshita, S. (2005) New instruments for dry eye diagnosis. Seminars in Ophthalmology, 20, 63–70. Yoon, K.C., Im, S.K., Kim, H.G., & You, I.C. (2011) Usefulness of double vital staining with 1% fluorescein and 1% lissamine green in patients with dry eye syndrome. Cornea, 30, 972–976. Yu‐Speight, A.W., Kern, T.J., & Erb, H.N. (2005) Ciprofloxacin and ofloxacin aqueous humor concentrations after topical administration in dogs undergoing cataract surgery. Veterinary Ophthalmology, 8, 181–187. Zander, E. & Weddell, G. (1951) Observations on the innervation of the cornea. Journal of Anatomy, 85, 68–99. Zeiss, C., Neaderland, M., Yang, F.C., et al. (2013) Fungal polymerase chain reaction testing in equine ulcerative keratitis. Veterinary Ophthalmology, 16, 341–351. Zhao, M., Hejkal, J.J., Camras, C.B., & Toris, C.B. (2010) Aqueous humor dynamics during the day and night in juvenile and adult rabbits. Investigative Ophthalmology & Visual Science, 51, 3145–3151.

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10.2 Ophthalmic Examination and Diagnostics Part 2: Ocular Imaging David Donaldson and Claudia Hartley Langford Vets, University of Bristol Veterinary School, Langford, Bristol, UK

Role of Conventional Radiography

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In human medicine the role of the traditional skull or orbital radiograph has been supplanted in the modern era by crosssectional imaging techniques, including computed tomography (CT) and magnetic resonance imaging (MRI; Lee et al., 2009; Moseley, 1991; Sanders et al., 1994). In veterinary ophthalmology the relative economy and availability of routine radiography when compared to cross-sectional imaging techniques ensures an ongoing role for this technique in the investigation of many cases of orbital and neuro-ophthalmic disease. Although the complex nature of the skull, the superimposition of tissues, and the poor ability to differentiate orbital soft tissues all impair radiographic assessment, important information can still be obtained with conventional radiographs. The main utility of conventional radiography in veterinary ophthalmology is to evaluate the bony orbit for evidence of osteolysis, bone remodeling, or fracture; to assess the nasal cavity, frontal sinuses, and maxillary dental arcades for pathology; and to assist in identification of radiodense foreign bodies. It should be noted that in some situations such as trauma with bony fracture and dental disease, conventional radiography may be superior to cross‐ sectional imaging techniques (Burk & Feeney, 2003). When an orbital or ocular malignancy is suspected, survey radiology of the thorax and abdomen, as well as abdominal ultrasound, is often performed at the time of orbital imaging, to help rule out metastatic disease.

Optimizing Conventional Radiographic Studies Obtaining useful diagnostic information from conventional skull and orbital radiographs is challenging. To optimize the information obtained from conventional radiography, the following steps are necessary:

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Select appropriate radiographic views Obtain diagnostic radiographs Interpretation of the radiographs

Select Appropriate Radiographic Views Selection of the most appropriate radiographic views for a specific disease presentation requires a good knowledge of basic and more topographically specific radiographic views available for the skull. A series of views is necessary to thoroughly assess the dorsal, medial, and lateral bony margins of the canine orbit. Both orbits are always imaged so that a comparison can be made of the two sides. A routine study should include lateral and dorsoventral (DV) and sometimes DV intraoral radiographs, which provides finer detail of the nasal cavity, maxillary recess, and medial orbital wall (Dennis, 2000). Radiographic projections that are more topographically specific may be used to assess the orbit, nasal cavity and sinuses, maxillary molar teeth, and tympanic bullae. The recommended radiographic projections based on the region of the skull being investigated are reported for small animals (Burk & Feeney, 2003; Ferrell et al., 2007; Johnston & Feeney, 1980) and the horse (Ferrell et al., 2007; Park, 1993; Pease, 2007). In the dog the lateral and lateral oblique projections are used to provide information regarding the cranial, dorsal, and lateral bony orbit, as well as the sinuses, nasal cavity, and maxillary dental arcades (Johnston & Feeney, 1980). The rostrocaudal (frontal) tangential projection is used to evaluate the frontal sinus, while the rostrocaudal open‐mouthed projection delineates the tympanic bullae (Burk & Feeney, 2003; Ferrell et al., 2007). The rostrocaudal views also image the medial and lateral bony orbit (Johnston & Feeney, 1980) and are useful in identifying frontal bone osteolysis in cases of orbital neoplastic disease (Dennis, 2000). The ventrodorsal (VD) open‐mouthed view is essential for evaluating the

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

nasal cavity and frontal sinuses, and is also useful for evaluation of the maxillary teeth (Burk & Feeney, 2003) and the rostral extremity of the bony orbit (Johnston & Feeney, 1980). Improvised skyline views may be used to image any region of pathology identified on the skull’s surface, and may provide information not discernible on routine orthogonal projections.

Obtain Diagnostic Radiographs To obtain diagnostic radiographs, strict adherence to good basic radiographic technique is required. Full immobilization under general anesthesia is essential for high‐quality diagnostic skull radiographs and to reduce operator exposure. Patient positioning is particularly critical for the skull, as rotation or tilting in any plane will severely compromise the interpretability of the radiographs. It is necessary to use various facial features (e.g., medial canthii or palpebral fissures) and palpable landmarks (e.g., frontal processes of zygomatic bones) to align certain planes precisely in relation to the film plane. Radiolucent foam pads and wedges are used to position the patient’s head. Inaccurate positioning compromises symmetry, which is so important in the interpretation of skull radiographs (Ferrell et al., 2007).

Interpretation of the Radiographs A good knowledge of the skull’s complex gross and radiographic anatomy is essential for radiographic interpretation. Numerous publications are available describing and illustrating the radiographic anatomy of dogs and cats (Coulson & Lewis, 2002; Schebitz & Wilkens, 2004, 2005a; Smallwood & Spaulding, 2007), horses (Schebitz & Wilkens, 2005b; Smallwood & Spaulding, 2007), and a range of exotic species (Silverman & Tell, 2005), and access to such reference material while interpreting skull radiographs is recommended. A systematic approach to analysis of a radiographic skull study is needed and various topographic or regional systems have been described (Burke & Feeney, 2003; Ferrell et al., 2007). The bilateral symmetry of the skull allows direct comparison of the right and left sides on VD/DV projections for differences in structure or opacity (Ferrell et  al., 2007). The main aim of radiographic assessment of orbital disease is to identify bony pathology, including fractures, osteolysis, and osteoproliferative lesions. It is important to note that although bone lysis is highly suggestive of malignancy in dogs and cats (Boroffka et al., 2007; Calia et al., 1994; Dennis, 2000; Hendrix & Gelatt, 2000), a tissue diagnosis is still required to rule out infectious processes, in particular fungal disease (Calia et  al., 1994; Halenda & Reed, 1997). Furthermore, orbital radiography may not be highly sensitive in detecting orbital bone pathology. In a study comparing MRI and radiography in small animals with orbital

diseases, 11 of 16 cases with confirmed orbital disease had no radiologically apparent orbital bony changes, despite the fact that in 4 of the 11 cases MRI showed minor extension of the tumor beyond the orbit (Dennis, 2000). From this it was concluded that radiography was helpful only in cases in which neoplastic disease extended markedly beyond the confines of the orbit into the nasal chamber and paranasal sinuses (Dennis, 2000). Diseases of structures adjacent to the orbit, including the sinuses, nasal cavity, and maxillary premolar and molar teeth, may be radiographically apparent. Other pathology, including orbital and periorbital emphysema and calcification of soft tissues, may also be identified. Orbital emphysema may follow infection or trauma (Johnston & Feeney, 1980) or be a complication of enucleation (Bedford, 1979; Martin, 1971). Calcification of the ocular and orbital tissues may be dystrophic or metastatic (Dutton, 2010a). Although soft tissue calcification may be apparent on conventional radiographs (Sundheim & Lapayowker, 1976), this pathology is best evaluated on computed tomography (Dutton, 2010a). In humans, ocular calcification has been described in optic nerve drusen, scleral plaques, phthisis bulbi, osteoma, and retinoblastoma, and has been associated with lacrimal gland epithelial tumors, meningiomas, gliomas, schwannomas, fibro‐osseous tumors, epithelial cysts, dermoid cysts. and inflammatory diseases (Aviv & Miszkiel, 2005; Dutton, 2010a; Sundheim & Lapayowker, 1976; LeBedis & Sakai, 2008). Conventional radiographs may be used to screen for radiodense foreign bodies. For accurate localization two orthogonal views are needed. Screening of patients to rule out intraorbital metallic foreign bodies prior to MRI may be indicated in some cases. Movement of such foreign bodies in the magnetic field may result in injury to the globe or other soft tissues within the skull (Lee et al., 2009).

Contrast Radiography Contrast Radiography for Orbital Disease Contrast radiographic techniques described for the investigation of orbital disease have included zygomatic sialography (Johnston & Feeney, 1980), positive and negative contrast orbitography (Burk & Feeney, 2003), venography (Burk & Feeney, 2003), angiography (Burk & Feeney, 2003; Gelatt et al., 1970), and optic thecography (Burk & Feeney, 2003). The aim of these techniques is to improve the ability to differentiate orbital soft tissue structures compared to standard radiographs, and potentially delineate tumors or inflammatory lesions. These techniques have not become established for the routine investigation of orbital disease and in the modern era they have been supplanted by cross‐ sectional imaging techniques.

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Zygomatic Sialography Zygomatic sialography is the only contrast radiographic technique that is still utilized occasionally for the evaluation of orbital disease in dogs. Zygomatic sialography involves the retrograde instillation of a nonionic iodinated contrast medium into the zygomatic salivary gland duct. Lateral and DV radiographs are obtained to ensure correct exposures prior to contrast instillation. The zygomatic papilla is located lateral and caudal to the last upper molar tooth. The papilla is cannulated using a 22–25 gauge cannula and the contrast medium is instilled at 0.5–1 ml per 10 kg; instillation may be repeated prior to each exposure (Harvey, 1969; Wallack, 2003). Prior to instillation of contrast media, samples of saliva should be collected for cytology and culture and sensitivity testing. The sialoadenogram reveals the zygomatic salivary gland to be large, single lobed, and positioned ventral to the rostral end of the zygomatic arch (Harvey, 1969). Radiographic abnormalities may include filling defects, enlargement of the nasolacrimal duct, formation of fistulae, and displacement of the gland (Johnston & Feeney, 1980).

Dacryocystorhinography Dacryocystorhinography (DCRG) is a contrast radiographic procedure that may be used to assess diseases affecting any level of the nasolacrimal system. The technique for performing clinical DCRG in the dog has been described (Johnston & Feeney, 1980; Gelatt et al., 1972; Yakely & Alexander, 1971). DCRG is performed with the patient under general anesthesia. Lateral and DV radiographs are obtained to ensure correct exposures prior to contrast instillation. The patient is

A

positioned for a lateral radiograph with the affected side uppermost and the nose slightly lowered to prevent retrograde flow of contrast medium into the nasal cavity. The upper punctum is cannulated and the nasolacrimal system flushed with 0.9% saline. An iodinated contrast medium agent is injected via the upper punctum while digital pressure or forceps occlude the lower punctum. The volume of contrast medium needed for the DCRG varies from 0.5– 1.0 mL in the dog, cat, and rabbit to 3.0–5.0 mL in the horse, cow, and llama (Källberg, 2007). The contrast medium is injected continuously until a few drops appear at the external nares, or reflux occurs from the upper punctum around the cannula, at which stage the radiograph is taken (Fig.  10.2.1A). Additional radiographic projections including DV and oblique views are obtained as required to characterize any pathology identified. Additional contrast medium should be instilled if incomplete filling of the nasolacrimal system is evident during the DCRG study. Gross anatomic studies and DCRG have been used to study the normal anatomy of the nasolacrimal system in the dog (Gelatt et  al., 1972; Johnston & Feeney, 1980; Yakely & Alexander, 1971), cat (Gelatt et al., 1972), horse (Latimer et al., 1984), llama (Sapienza et al., 1992), sheep (Gilanpour, 1979), goat (Shadkhast et  al., 2008), one‐humped camel (Shokry et al., 1987), and rabbit (Marini et al., 1996). Clinically DCRG has been used to study a variety of congenital nasolacrimal system anomalies, including nasolacrimal duct atresia in the alpaca (Mangan et  al., 2008; Sandmeyer et  al., 2011), llama (Sapienza et al., 1996), horse (Latimer et al., 1984; Lundvall & Carter, 1971), and cattle (Heider et al., 1975); anomalous nasolacrimal duct openings (McLaughlin et  al., 1985; Wilkie & Rings, 1990) and dysplastic lacrimal puncta (van der Woerdt

B

Figure 10.2.1  A. Dacryocystorhinogram of the normal nasolacrimal duct system of a 9-year-old West Highland White Terrier. The cannula placed via the upper puncta into the lacrimal sac is visible (small arrow). Contrast medium is present at the nares and refluxing into the nasal cavity (large arrow). Note that the metallic pulse oximetry device is superimposed over the rostral nares and maxillary region. B. Dacryocystorhinogram of a 3-year-old Labrador Retriever with chronic dacryocystitis affecting the right side. Obstruction of contrast is evident at the level of the third upper premolar tooth (arrow). Proximal to the obstruction there is an irregular cystic dilation of the duct. No contrast is visible distal (rostral) to the obstruction. Magnetic resonance imaging in this case revealed a cystic dilation of the nasolacrimal duct within the maxillary bone.

et al., 1996) in cattle; and congenital lacrimal gland cyst (dacryops) in the dog (Cullen & Grahn, 2003; Grahn & Mason, 1995; Ota et al., 2009). Acquired nasolacrimal diseases may arise from the nasolacrimal duct or contiguous structures, including the nasal cavity, frontal sinuses, and maxillary dentition. Primary or secondary nasolacrimal duct pathology due to trauma or neoplastic or inflammatory diseases may be recognized on DCRG as complete or partial obstruction, deviation, cystic dilatation, and/or irregularities of the nasolacrimal duct (Johnston & Feeney, 1980). DCRG is integral to the surgical treatment of nasolacrimal disorders, providing information regarding the nature and location of pathology. An abnormal dacryocystorhinogram with obstruction and an irregular cystic dilation of the nasolacrimal duct in a dog with chronic dacryocystitis is shown in Fig. 10.2.1B. DCRG in cases of dacryocystitis in the dog have revealed cystic dilations of the nasolacrimal duct (Lussier & Carrier, 2004; Singh et  al., 2004; van der Woerdt et  al., 1996), periductal osteolysis (Yakely & Alexander, 1971), distention of the nasolacrimal sac associated with granuloma formation (Giuliano et al., 2006), and plant seed foreign bodies (Yakely & Alexander, 1971). In some cases of dacryocystitis, DCRG has facilitated surgical planning of drainage procedures in which communications are created between the cystic or dilated regions of the nasolacrimal duct and the nasal cavity (Giuliano et  al., 2006; Lussier & Carrier, 2004; van der Woerdt et al., 1997). In cases of epiphora in the dog, DCRG has identified nasolacrimal duct obstruction due to dental disease (Gelatt et  al., 1972; Yakely & Alexander, 1971) and nasal cavity neoplasia (Gelatt et  al., 1972). In the horse, DCRG has been used to evaluate purulent dacryocystitis secondary to periapical tooth root infection (Ramzan & Payne, 2005), obstruction of the nasolacrimal duct with secondary epiphora due to lacrimomaxillary suture exostosis (Carslake, 2009), and posttraumatic injury (Cruz et al., 1997; Wilson & Levine, 1991). Computed tomography dacryocystorhinography (CT‐DCRG) provides superior imaging of the nasolacrimal system and may have a role in the evaluation of more complex nasolacrimal disorders in veterinary patients (see later section).

Cross-Sectional Imaging Techniques: Computed Tomography and Magnetic Resonance Imaging The cross‐sectional imaging techniques of CT and MRI have greatly improved the diagnosis and management of a diverse range of ocular, orbital, and neuro‐ophthalmic conditions. In order to maximize the information gained from an imaging study, it is important for the clinician to understand the

basic mechanics, indications, and contraindications of the specific imaging modality, and the specific sequences used in neuro‐ophthalmic and orbital imaging (Lee et al., 2009). Furthermore, discussion with imaging colleagues regarding the reason for imaging the patient and the suspected nature and location of pathology will allow selection of the most appropriate imaging study. The advantages of MRI over CT include the absence of ionizing radiation, direct multiplanar imaging that does not require changing the position of the patient in the gantry, enhanced anatomic detail, and soft tissue characterization. MRI is considered superior to CT for most neuro‐ophthalmic indications, with better assessment of both the intra‐ and extraorbital optic nerve (Lee et al., 2009; Morgan et al., 1994; Penninck et al., 2001). The advantages of CT over MRI include shorter data acquisition time, decreased slice thickness and greater special resolution, more precise imaging of cortical bone and soft tissue mineralization, more precise imaging of acute hemorrhage, and the ability to image when magnetic foreign bodies are present (Lee et al., 2009; Morgan et al., 1994; Penninck et al., 2001). MRI and CT are therefore complementary and when combined often provide a more complete picture of the nature of disease.

Computed Tomography Basic Principles and Physics

CT imaging utilizes the variable attenuation of X‐ray photons by tissues of different densities to generate cross‐sectional images of the body (Dutton, 2010b; Tidwell, 2007). The frame of the CT machine that houses the X‐ray tube, collimators, and detectors is referred to as a gantry. The gantry has a large opening into which the patient is placed for CT imaging. Within the gantry of the CT machine an X‐ray tube emits a thin, collimated, fan‐ shaped beam of X‐rays that are attenuated as they pass through the patient. The transmitted X‐rays are subsequently detected by an arc of detectors positioned on the opposite side of the gantry. The most recent generation of CT scanners utilize a helical (or spiral) technology in which the X‐ray source rotates continuously in one direction as the patient moves forward at a constant rate, so the X‐ray beam describes a spiral path around the body (Kalender et al., 1990). The continuous acquisition of data as the patient moves through the gantry reduces the imaging time, motion artifacts, and overall radiation exposure. Multislice or multidetector‐slice CT scanners utilize the principles of helical scanners, but incorporate multiple rows of detectors that can therefore acquire multiple imaging slices per rotation of the X‐ray tube, increasing the area scanned in a given time by the X‐ray beam (Flohr et  al., 2005). The X‐ray attenuation data collected by the detectors (from the multiple X‐ray beam projection angles through the patient) are analyzed using a computer, and the density, or

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attenuation value, of each unit of tissue (voxel) within the slice is calculated. Using this attenuation value, a CT number for each voxel of tissue is calculated. The value of the CT number is expressed in Hounsfield units (HU) in honor of Sir Godfrey Hounsfield, who in 1967 developed the first modern CT scanner (Goldman, 2007). Hounsfield units represent an arbitrary scale in which the attenuation of water is assigned 0 HU, cortical bone +1000 HU (white on final image), and air –1000 HU (black on final image; Dutton, 2010b). To generate a CT image the CT number of each voxel within a slice is assigned to a specific shade of gray. This shade of gray is assigned to the corresponding picture element (pixel) within the reconstructed CT image matrix. The resultant CT image represents the voxel densities of tissues within the scanned slice of tissue, and therefore is displayed without the superimposition of overlying tissues, such as occurs with conventional radiography. The range of CT numbers, from –1000 HU for air to +1000 HU for bone, which can potentially be represented as shades of gray, far exceeds that which is visually discernible (perhaps fewer than 100), and modern CT images are typically displayed using about 250 gray levels (Goldman, 2007). The simultaneous display of all gray‐scale levels (i.e., the entire range of CT numbers) would mean that many soft tissue structures would be displayed with the same gray level as their surroundings, and thus would not be visible. This problem is solved by windowing, in which the radiologist interactively manipulates the gray scale to enhance the subtle differences between tissues of interest. This involves setting the window width (WW) and window level (WL). The WW is the range of CT numbers displayed as distinct gray levels; this varies with the tissues being examined, but is usually in the range of 350–400 HU. The WL is the level on which this range is centered (e.g., for orbital soft tissue a WL of +50 may be chosen; Dutton, 2010b), and should be set as close as possible to the mean density level of the tissue to be examined (Goldman, 2007). With respect to orbital imaging, the two most common gray‐scale adjustments used are the bone and soft tissue windows (Penninck et al., 2001). As an example, consider a typical orbital soft tissue window with a WW of 400 HU and a WL of +50 HU. The image will display all CT numbers between –150 HU and +250 HU on a gray scale from black to white. All tissues with a CT number of –150 HU or less will be displayed as black, while all tissue with CT numbers of +250 HU or more will be displayed as white. The operator is able to switch between different windows while viewing different regions of interest on the CT image by using a mouse or tracker ball (Goldman, 2007). Slice thickness is the thickness of tissue scanned, and this may vary from 1 to 10 mm (Naik et al., 2002). The use of thinner slices increases spatial resolution (Boroffka & Voorhout, 1999). With the latest CT scanners, slice thickness may be less than 1 mm, with slices as thin as 0.7 mm recommended

for orbital scans in humans (Lee et  al., 2009). Considering the longer scanning time and increased radiation doses required for thinner‐slice CT scans, some authors recommend 2 mm slices as an optimal compromise for general imaging of the human eye and orbit, except in special situations such as evaluation of the orbital apex, in which thinner slices (1 mm) can be more informative (Naik et  al., 2002). The concern regarding low‐dose radiation exposure relates to the increase in future cancer risk, particularly in children needing multiple or sequential imaging studies (Brenner & Hall, 2007; Lee et al., 2009) and is not relevant to veterinary patients, where sequential imaging studies are uncommonly performed. Unlike MRI, in which direct multiplanar imaging is possible without special positioning of the patient, direct image formation from a CT scan can only be formed in the plane parallel to the X‐ray beam. Therefore, to obtain direct imaging for a particular scan plane (e.g., the dorsal plane of the orbit), the patient’s head needs to be repositioned so the anatomic plane of interest is aligned parallel to the X‐ray beam. As a result, the number of potential direct scan planes is limited by the ability to position the animal’s head in relation to the X‐ray beam. For example, direct CT imaging of the equine skull is limited to the transverse plane because of the size of the skull and limited diameter of the CT gantry (Ramirez & Tucker, 2004). In the modern setting patients are not repositioned for direct multiplanar imaging; typically the patient is positioned in sternal recumbency for direct transverse imaging. With the latest generation of CT scanners, the multiplanar constructions from these transverse images are of such high quality that direct multiplanar imaging is rarely considered necessary (Lee et al., 2004). Any degradation in image quality can be somewhat offset in modern CT scanners by using thin scans to acquire the data set (Lee et  al., 2009). A routine series of the orbits should include transverse, dorsal oblique, and/or sagittal oblique image planes (Penninck et al., 2001). For localization purposes, it is important to view orbital anatomy and lesions in at least two orthogonal planes (Lee et  al., 2009). Transverse views are often used as a survey examination and display the anatomic relationships between the extraocular muscles, optic nerve, and surrounding osseous structures very well. Evaluation of the optic nerve and extraocular muscles is optimized when the image plane is parallel to the optic nerve (Boroffka & Voorhout, 1999). Contrast Studies

The contrast media utilized for CT scanning are usually iodine based and given intravenously. These contrast media increase the attenuation value of the vascular system and therefore of certain organs and tissues (Dutton, 2010b). Prior allergic reaction to iodinated contrast media or a history of renal failure may be contraindications to using contrast in CT (Lee et  al., 2000; Morcos & Thomsen, 2001; Zagoria,

1994). Although the intrinsic background contrast provided by orbital fat allows visualization of most orbital pathology (see below), the use of contrast media has been advocated for most ophthalmic conditions in humans, as it generally improves the sensitivity and specificity of CT scan interpretation (Lee et al., 2000, 2009). Although it has been reported that the use of contrast‐enhanced CT scans does not typically provide additional diagnostic information for orbital lesions in dogs (LeCouteur et al., 1982), in practice contrast is routinely used in orbital studies in veterinary patients. In some situations such as trauma and orbital or intracranial foreign bodies, contrast material adds little to the examination (Lee et al., 2009). The noncontrast study is superior for assessing the hyperdensity of acute blood and therefore a CT scan that is being performed for acute intracranial or intraorbital hemorrhage does not require the use of a contrast medium (Lee et al., 2009). Three-Dimensional CT

Many new CT systems incorporate computers that can perform three‐dimensional (3D) reconstructions, which can demonstrate superbly the anatomic relationships between osseous defects and sinus, orbital, or intracranial disease (Lee et al., 2009). A postcontrast 3D reformatted CT image of the skull of a dog showing the normal arterial vascular anatomy of the skull is illustrated in Fig. 10.2.2. To ensure optimal quality of the reconstructed images, all image slices should be thin and overlapping (Penninck et al., 2001). The use of 3D reconstructions is especially useful to evaluate head trauma and skull deformity, and to delineate tumor int & ext ophthalmic aa optic disc

maxillary a ext ethmoidal a

Figure 10.2.2  This postcontrast three-dimensional reformatted computed tomography image of the skull of a 5-year-old Golden Retriever shows the normal arterial vascular anatomy of the skull. The zygomatic arch has been removed to reveal the optic disc, the internal and external ophthalmic arteries, the maxillary artery, and the external ethmoidal artery. The dog and cat have no equivalent to the central retinal artery of humans. (Courtesy of Paul Mahoney, Willows Veterinary Centre & Referral Service, Solihull, UK.)

borders when planning surgery (Penninck et  al., 2001). However, caution has been advised against using 3D reconstructions exclusively, as the software involved in producing these images tends to smooth over abnormalities and may hide subtle pathology, such as a minimally displaced fracture (Lee et  al., 2009). The two‐dimensional (2D) source images should always be examined along with the 3D reconstructions. Orbital CT: Normal Anatomy

The normal CT appearance of the globe and orbit and the effect of using either bone or soft tissue windows are illustrated in Fig. 10.2.3. The excellent contrast provided by the retrobulbar fat during CT imaging of the orbit facilitates differentiation of anatomic structures including the globe, extraocular muscles, optic nerve, and cortical bone (Fike et al., 1984). The normal CT anatomy of the orbit of the dog (Boroffka & Voorhout, 1999; Fike et  al., 1984), the cranial nerve emergence and associated skull foramina in cats (Gomes et al., 2009) and dogs (Couturier et  al., 2005), and the skull of the dog (George & Smallwood, 1992), cat (Shojaei et  al., 2003), and horse (Kinns & Pease, 2009; Smallwood et al., 2002; Solano & Brawer, 2004; Tucker & Farrell, 2001) have been described. CT allows the confines of the orbit to be clearly defined with good delineation of dorsal (frontal bone, frontal sinus, and dorsal bony orbital rim), medial (frontal bone and palatine bone), ventral (medial pterygoid muscle, zygomatic salivary gland, and ventral fat cushion), and lateral (zygomatic arch and temporal muscle) borders (Boroffka & Voorhout, 1999). All extraocular muscles can be identified on CT imaging (Boroffka & Voorhout, 1999). The levator palpebrae superioris muscle cannot be distinguished from the dorsal rectus muscle (Boroffka & Voorhout, 1999). The optic nerve appears as an oval structure on transverse images, and on dorsal oblique and sagittal oblique images as a linear structure, surrounded by hypoattenuating fat (Boroffka & Voorhout, 1999). The region of the orbital apex is poorly imaged with CT (Boroffka & Voorhout, 1999) and thinner CT slices may be useful to increase information obtained when this area is studied (Naik et al., 2002). Immediately rostral and lateral to the optic foramen the optic nerves are closely surrounded by extraocular muscles, and neither the optic nerve nor individual extraocular muscles can be imaged as separate structures (Boroffka & Voorhout, 1999). Orbital CT: Pathologic Anatomy

Modern multislice CT imaging is associated with such rapid acquisition times that the whole head is typically imaged in small animals. The specific reconstructions needed for investigation of orbital and/or brain pathology are subsequently obtained from this data set. Other considerations include the

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Figure 10.2.3  A, B. Postcontrast reformatted computed tomography (CT) sagittal oblique images through the globe and retrobulbar space of a 5-year-old Boxer dog, viewed with (A) a bone window (width [W] 2000, length [L] 400) and (B) a soft tissue window (W 426, L 55). B. The normal optic nerve can be followed along its path from the optic disc through the optic canal. C. This postcontrast reformatted transverse CT image through the retrobulbar area of the same dog shows the larger outer rectus muscles and the smaller inner fascicule of the retractor bulbi muscle surrounding the centrally located optic nerve. The zygomatic salivary gland can be seen ventral to the retrobulbar muscles on all three images. D, E. Reformatted sagittal CT images of the normal feline globe seen in (D) a soft tissue window (W 426, L 55) and (E) a bone window (W 2000, L 400) for comparison. (Courtesy of Paul Mahoney, Willows Veterinary Centre & Referral Service, Solihull, UK.)

slice thickness, imaging planes, tissue windows, use of contrast enhancement, and potential 3D reconstructions. Although MRI is considered the examination of choice for most orbital and neurophthalmic conditions due to its superior soft tissue discrimination, there are situations in which CT has particular utility in demonstrating osseous pathology and tissue mineralization, and ruling out radiodense foreign bodies. In reality, although the pros and cons of MRI versus CT for different diseases are often discussed, the two modalities are complementary, and in many situations combining the two can provide a more complete picture of the nature of a lesion than either study alone (Lee et al., 2009). Human studies correlating the results of imaging studies (CT and MRI) to known orbital tissue diagnoses have led to the proposal of guidelines aimed at reducing the number of overall differential diagnoses under consideration and helping to establish appropriate management plans for patients with orbital disease (Aviv & Miszkiel, 2005; Ben Simon et al., 2005; Goh et al., 2008). The compartmental approach divides the orbital space into specific anatomic compartments, including sinus, bone, extraconal space, muscle cone, intraconal space, optic nerve, globe, and lacrimal fossa, and attempts to localize orbital pathology. Given that these compartments contain different tissues from which disease may arise or evolve, the number of differential diagnoses may be significantly reduced (Aviv & Miszkiel, 2005; Goh et  al., 2008). There are only a small number of studies and case reports in which CT has been used in the evaluation of veterinary ophthalmic patients, including orbital disease in dogs (Attali‐Soussay et al., 2001; Boroffka et al., 2007; Calia et al., 1994; LeCouteur et al., 1982) and cats (Attali‐Soussay et al., 2001; Calia et al., 1994; Zemljic et al., 2011). Individual case reports describe findings in a dog with cavernous sinus enlargement and unilateral exophthalmos (Tidwell et  al., 1997), and a cat with fungal sinusitis (Halenda & Reed, 1997). The correlation between orbital CT findings and specific diseases in animals is generally limited to the differentiation between neoplastic versus non‐neoplastic disease. In one study, the CT imaging features detected significantly more frequently in neoplastic versus non‐neoplastic diseases in dogs included focal mass effect, clearly delineated margins, bony involvement, and extraorbital extension (Boroffka et  al., 2007). In this study the compartmental approach to interpreting orbital CT studies had limited value in differentiating neoplastic and non‐neoplastic disease. CT is very sensitive for identifying bone lysis, which is highly suggestive of orbital malignancy in the cat and dog (Boroffka et  al., 2007; Calia et  al., 1994; Dennis, 2000; Hendrix & Gelatt, 2000), although a tissue diagnosis is still required to rule out infectious processes, in particular fungal disease (Calia et al., 1994; Halenda & Reed, 1997). CT evidence of bony lysis has been reported in 82% of cats with

orbital malignancy (Calia et al., 1994) and 48% of dogs with orbital neoplastic disease (Boroffka et al., 2007). Lysis of the medial bony orbital wall associated with an invasive nasal tumor is illustrated in Fig.  10.2.4). Orbital bone lysis in humans is occasionally seen as the result of chronic compression in benign conditions such as an orbital dermoid, epidermoid inclusion cysts, and fibrous dysplasia (Aviv & Miszkiel, 2005; Chung et al., 2007). Mineralization may be a prominent feature in certain ophthalmic diseases in humans, including meningioma and retinoblastoma, and CT identification of this change may assist when considering differential diagnoses (Aviv & Miszkiel, 2005; Lee et al., 2009; Naik et al., 2002). Although CT imaging has identified mineralization of orbital tumors in dogs (Boroffka et  al., 2007; Calia et  al., 1994), no correlation between mineralization and specific tissue diagnoses of tumors has been reported. In cases of orbital malignancy in dogs, exenteration is generally considered to be the treatment of choice (Boroffka et al., 2007). The ability of CT, particularly 3D CT, to accurately define the tumor boundaries and encroachment on other orbital structures and to assess the presence of extent and bone involvement makes it a valuable part of the presurgical assessment (Leib, 1994; Penninck et al., 2001). In orbital inflammation an increased radiodensity of the orbital tissues is expected. Fluid and cellular infiltrate increase the normally low X‐ray attenuation value of retrobulbar fat, which reduces the image contrast, obscuring visualization of the extraocular muscles, the optic nerve, and the globe. Although changes in the X‐ray attenuation of the orbital tissues (both before and after contrast enhancement) are a prominent feature of orbital inflammation, this in isolation does not allow differentiating inflammatory from neoplastic orbital disease (Boroffka et  al., 2007). In the same study (Boroffka et al., 2007), delineation of the margin of the lesion was shown to be the most important discriminator from cases of neoplastic orbital disease, with the margins of the inflammatory lesions being more ill‐defined on postcontrast‐enhanced CT. CT is important in determining the location of orbital infection in humans (Hirsch & Lifshitz, 1988; LeBedis & Sakai, 2008; Naik et  al., 2000). The location of an orbital infection is described with respect to the orbital septum, as either preseptal (periorbital) or postseptal (orbital; LeBedis & Sakai, 2008). The clinical staging of orbital cellulitis can be difficult and identification of postseptal disease is critical due to the potentially devastating complications, including cavernous sinus thrombosis and meningitis (LeBedis & Sakai, 2008). CT imaging of preseptal cellulitis reveals soft tissue thickening anterior to the orbital septum (LeBedis & Sakai, 2008). The earliest change associated with postseptal orbital involvement is a slight increase in the density of the orbital fat, which is followed by the development of discrete densities within the fat and extraocular muscle thickening as

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Figure 10.2.4  Aggressive osteolytic soft tissue nasal tumor invading the right orbit in a 9-year-old Dachshund. The computed tomography images show invasion through the medial bony orbital wall in (A) a soft tissue and (B) a bone window for comparison. (Courtesy of Paul Mahoney, Willows Veterinary Centre & Referral Service, Solihull, UK.)

the infection progresses (Naik et al., 2000). Although the use of CT to differentiate pre‐ and postseptal orbital cellulitis has not been described in veterinary species, it is likely to have similar utility for this condition. The CT appearance of an orbital abscess in a dog is illustrated in Fig. 10.2.5. CT has particular utility in the evaluation of orbital trauma (Penninck et al., 2001), allowing detailed assessment of bony lesions with simultaneous evaluation of soft tissues, globe, orbit, and brain. The use of CT to establish the nature of orbital fractures in horses has been reported (Gilger & Stoppini, 2011). Orbital fractures are often complex and the use of 3D reconstruction is particularly useful in planning the surgical realignment of displaced fracture fragments in these cases (Fig. 10.2.6). CT may also be useful in the identification of radiodense foreign material such as glass or metal, but in animals where pieces of plant material are usually the cause of orbital inflammation, such foreign bodies may be missed by CT imaging (Boroffka et al., 2007). CT Dacryocystorhinography

CT‐DCRG provides superior imaging of the nasolacrimal system, with better delineation of the adjacent soft tissues and bony structures when compared to conventional DCRG, CT, or MRI (Ashenhurst et  al., 1991; Freitag et  al., 2002; Udhay et  al., 2008). The use of connectivity algorithms

allows 3D CT‐DCRG color‐enhanced reconstructions, which facilitate understanding of complex pathology involving the nasolacrimal system, the relationships to the adjacent orbital and facial skeleton, and surgical planning (Freitag et  al., 2002; Udhay et al., 2008). CT‐dacryocystography (CT‐DCG) has been used to study the nasolacrimal system in the normal cat (Noeller et  al., 2006; Schlueter et  al., 2009) and dog (Rached et  al., 2008, 2011). CT‐DCRG may have a role in the evaluation of more complex nasolacrimal disorders in veterinary patients. CT‐ DCRG investigation of nasolacrimal disease has been described in the dog (Giuliano et  al., 2006; Nykamp et  al., 2004), horse (Nykamp et al., 2007), and donkey (Cleary et al., 2011). CT‐DCG and 3D CT‐DCRG in a case of chronic dacryocystitis in a dog are illustrated in Fig. 10.2.7. CT-Guided Percutaneous Biopsy

The ability of CT to provide excellent imaging of orbital and skull topography, and detailed delineation of orbital tumor location and boundaries, makes it a valuable technique for aspiration biopsy guidance (Penninck et al., 2001). The technique for CT‐guided percutaneous biopsy of orbital pathology in dogs has been described (Tidwell & Johnson, 1998). The technique has been recommended for lesions judged to be inaccessible (due to location or poor resolution) using other imaging techniques, including ultrasonography and

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Figure 10.2.5  Orbital abscessation in a 4-year-old Dalmatian. Reformatted dorsolateral-ventromedial sagittal oblique computed tomography images through the globe and retrobulbar region (A) precontrast and (B) postcontrast administration. The postcontrast image (B) shows a teardrop-shaped region of nonenhancement, surrounded by an enhancing rim that extends caudally into the retrobulbar space. The lesion appears to be associated with indentation of the dorsolateral margin of the left globe, and most likely represents inflammation of the dorsolateral orbital soft tissue structures and abscess formation. The region was surgically explored and a grass seed was removed. (Courtesy of Paul Mahoney, Willows Veterinary Centre & Referral Service, Solihull, UK.)

fluoroscopy, or when CT is needed to provide additional information regarding diagnosis, staging, or therapy planning (Tidwell & Johnson, 1998).

Magnetic Resonance Imaging Basic Principles and Physics

MRI is a technique for creating a cross‐sectional image of the body based on the magnetic resonance (MR) of atomic nuclei. The physics of medical MRI has been comprehensibly reviewed (Dutton, 2010b; Pooley, 2005; Tidwell & Johnson, 1994; Weishaupt et  al., 2008). The hydrogen nucleus is used for medical MRI because it is abundant in biologic tissue, being found in water and lipid molecules. The hydrogen nucleus is a proton and it is the resonance of these hydrogen protons in living tissues that is used to generate medical MR images. When a tissue is placed inside a powerful static magnetic field, some of its protons become aligned with the direction of the field (z‐axis), producing a small amount of spin polarization, and as a result overall magnetization of the tissue. If a strong radiofrequency (RF) field of a certain frequency (known as resonance or Larmor frequency) is imposed at right angles to the static magnetic field, energy is absorbed that flips the spin of the aligned protons briefly into a higher energy state. In this state the axial alignment of the protons is parallel to the RF field (90 degrees to the static magnetic field). A second effect of

the applied RF field is that the phase of the proton spins become synchronized. When the RF signal is switched off, the protons, which have absorbed photons, relax back to the lower‐energy spin state and realign with the static magnetic field. The most rapid form of relaxation involves dephasing of the proton spins (T2 relaxation) and subsequently realignment of the proton spins longitudinally within the static magnetic field (T1 relaxation). During this process, measurable amounts of RF signal are produced. This emission of electromagnetic radiation (RF signal) associated with spin relaxation of protons from high‐energy states is referred to as nuclear magnetic resonance (NMR). Because tissues differ in their chemistry and physical states, their hydrogen protons are also held together differently. This causes fundamental differences between the T1 and T2 relaxation rates between different tissues, and as a result variation in the intensity of emitted RF signal duration relaxation. It is because of these differences in relaxation rates between tissues that contrast between tissues is detectable, thus making MRI possible. The RF coils are therefore needed to both transmit and receive the NMR signal. The emitted RF radiation from the relaxing tissues is received by the RF coil (antennae) and this information is analyzed by a computer to create the final MR image. At the most basic level, the tissues with high hydrogen proton content such as water and fat are imaged, while regions of bone or air appear as a signal void or black.

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Figure 10.2.6  Fracture of the left bony orbit in an 18-month-old Labrador Retriever. A. Axial computed tomography slice image shows multiple fractures involving the left bony orbit. B, C. Reformatted three-dimensional images allowed a greater appreciation of the nature of the comminuted fractures involving the bony orbit. (Courtesy of Paul Mahoney, Willows Veterinary Centre & Referral Service, Solihull, UK.)

Arteries and veins are not imaged by routine MR sequences, as the blood present at the time of the stimulating RF pulse has moved away by the time the resultant RF signal associated with tissue relaxation is being generated. When performing medical MRI, the amount of rotation of the net tissue magnetization away from the longitudinal (z) axis (termed the flip angle) can be manipulated by changing the strength and duration of the RF pulse (Pooley, 2005). If the RF pulse rotates the net magnetization into the transverse plane, it is termed a 90° RF pulse, whereas if the RF pulse rotates the net magnetization in the –z direction, it is termed an 180° RF pulse. The strength and duration of the RF pulse can be manipulated to rotate the net magnetization to any flip angle, and these different flip angles are utilized when performing different MR sequences. For example, 90° and 180° RF pulses are used in the generation of the spin

echo (SE) or fast spin echo (FSE) sequences, including T1‐ and T2‐weighted images (T1WI and T2WI), while smaller flip angles are utilized when performing fast imaging techniques such as gradient recall echo (GRE; Pooley, 2005). Two important MR image acquisition parameters, which affect the contrast of different tissues during MRI scanning, are the echo time (TE) and the repetition time (TR; Pooley, 2005). The TE is the time between the RF pulse and the detection of the radiofrequency waves by the coil. The TR is the time lapse between each RF pulse sequence. TE and TR are adjusted when acquiring different MR sequences. For example, an image is considered a T1WI when the TR and TE are short, while a long TR and a long TE produce a T2WI (Pooley, 2005). The strength of a magnetic field is expressed by the SI unit Tesla (T). Modern medical MRI scanners may be “high field”

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C Figure 10.2.7  Dacryocystitis in a 3-year-old entire male Labrador Retriever. A. The transverse computed tomography image of a dacryocystorhinographic study through the midnasal region shows an area of dilation of the right nasolacrimal duct. B. The extent of this dilation can be appreciated on the reformatted sagittal image through the right nasolacrimal duct. C. The color-enhanced threedimensional reconstruction has had the lateral surface of the right maxillary bone removed over the nasolacrimal duct. (Courtesy of Paul Mahoney, Willows Veterinary Centre & Referral Service, Solihull, UK.)

(1.5 and 3.0 T) or “low field” (< 0.5 T). Clinically stronger magnets provide improved image quality and therefore diagnostic accuracy for many applications (Lee et  al., 2009). Despite these advantages, there are proponents of the expanding low‐field MR scanners because of cost savings and open format (Hayashi et al., 2004). Interpretation of Specific Magnetic Resonance Pulse Sequences T1-weighted image MRI

The two most common MRI sequences are T1WI and T2WI, and these are typically acquired as part of the standard MR examination of the orbit and brain (Fig. 10.2.8A, B). Normal

anatomy is best demonstrated on T1WI (Morgan et al., 1994). On T1WI fat has a hyperintense signal (“bright on T1”). As a result, a T1WI of the orbit is associated with bright signal intensity of the orbital fat. Structures of intermediate signal intensity include the extraocular muscles, optic nerve, and iris (Morgan et al., 1994; Penninck et al., 2001). The lens has a low signal intensity (black), while the vitreous has a signal intensity between the lens and the extraocular muscles (Morgan et al., 1994; Penninck et al., 2001). Very few pathologic lesions are hyperintense on precontrast T1WI. From an ophthalmic perspective, the most important lesions include subacute hemorrhage, highly proteinaceous fluid (e.g., sinus mucoceles), and melanin (e.g., melanoma; Caruso et al., 2001).

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C Figure 10.2.8  The appearance of the normal canine globe and orbit on dorsal (A) T1-weighted and (B) T2-weighted magnetic resonance imaging (MRI). A. The dorsal T1 image shows hyperintense retrobulbar fat, lens capsule, iris, and ciliary body. The aqueous humor and vitreous humor have a slightly lower signal when compared with muscle, and the normal lens has low signal characteristics. B. The dorsal T2 image shows the characteristic bright signal intensity of the vitreous and aqueous humor. The signal intensity of retrobulbar fat also appears hyperintense on fast spin echo T2, while the extraocular muscles, optic nerve, and brain have intermediate signal intensity. C. A dorsal reconstruction three-dimensional (3D) gradient recall echo (Fast Imaging Employing Steady State Acquisition [FIESTA], General Electric, Milwaukee, WI, USA) image of the normal MRI anatomy of the canine globe. The lens, iris, ciliary body, anterior chamber, posterior chamber, and vitreous are clearly seen. The 3D FIESTA sequence provides high signal-to-noise images, with good anatomic detail and short acquisition times. (A and C courtesy of Paul Mahoney, Willows Veterinary Centre & Referral Service, Solihull, UK.)

T2-Weighted Image MRI

T2WI MRI is typically better than T1WI for demonstrating intracranial or orbital pathology. On T2WI the cerebrospinal fluid (CSF) and the vitreous are hyperintense (“bright on

T2”). Orbital fat will also appear hyperintense on FSE T2WI (Conneely et al., 2008). The extraocular muscles, optic nerve, and brain have an intermediate signal intensity (Morgan et al., 1994; Penninck et al., 2001). In contrast to T1WI, most

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pathology is hyperintense on T2WI. These include demyelinating lesions (e.g., optic neuropathies), ischemia (e.g., stroke), inflammatory disease, toxic or metabolic disorders, and neoplasms (Lee et al., 2009). T2WI are also useful in differentiating a fluid‐filled versus a soft tissue lesion, as the latter will have lower signal intensity (Penninck et al., 2001). Gradient Recall Echo Imaging

GRE (or T2*, “T2 star”) sequences highlight the presence of blood products. GRE MR sequences can demonstrate hemorrhage, which is essential in human patients with underlying arteriovenous or cavernous malformations, intra‐ or extraaxial intracranial hemorrhage, or traumatic brain injury (Lee et al., 2004, 2009). Even trace amounts of hemorrhage may be detected because of the profound signal loss caused by the paramagnetic effects of deoxyhemoglobin and methemoglobin (Lee et al., 2009). By using GRE, along with T1WI and T2WI, the approximate age of a hematoma may be determined (Jutler et al., 2006). In veterinary patients brain hemorrhages can also be detected earlier on GRE MR sequences than on spin echo sequences (i.e., T1WI and T2WI), with the hematoma appearing as a black signal void within a few hours of the onset of bleeding (Tidwell, 2007). The gradient echo signal voids in a dog with multiple cerebral hemorrhagic infarcts are illustrated in Fig. 10.2.9. Rapid 3D GRE sequences have been designed for faster acquisition of data that can give improved image quality comparable to 2D imaging (Dutton, 2010b). The appearance of the globe and orbit on a 3D GRE sequence is illustrated in Fig. 10.2.8C.

Figure 10.2.9  Multiple cerebral hemorrhagic infarcts in a 10-year-old cross-bred dog. The dog presented with an 8-month history of seizures. Neurologic examination was normal apart from a reduced menace response on the right side. Transverse gradient recall echo magnetic resonance imaging revealed multiple areas of gradient echo signal voids, including the left thalamus (arrow), consistent with hemorrhagic lesions.

Fat Suppression

To improve visualization of pathologies, it is possible to suppress the high signal intensity of fat on T1WI (i.e., “fat suppression” or “fat saturation”; Lee et  al., 2009). Fat suppression may be achieved by using imaging techniques including spectral fat suppression or short tau inversion recovery (STIR; D’Anjou et  al., 2011; Dutton, 2010b). Spectral fat suppression techniques are useful in evaluating T1WI images of the orbit, where the normally hyperintense fat signal cannot be distinguished from the high signal of the contrast enhancement associated with an optic neuritis or an optic nerve sheath meningioma (Lee et  al., 2009; Penninck et al., 2001). The suppression of the orbital fat signal on a T1‐weighted postcontrast MRI in a dog with optic neuritis is illustrated in Fig. 10.2.10. Fat suppression techniques can also confirm the content of fat‐containing lesions, such as orbital dermoid cysts and lipomas (Lee et al., 2009). Alternatively, fat suppression may be achieved by STIR sequences. On these images, lesions are typically hyperintense and contrast well with the suppressed fat signal (Penninck et al., 2001; Tidwell, 2007). STIR images have relatively poor detail, but are good to screen tissues for pathol-

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Figure 10.2.10  Optic neuritis in an 11-year-old Golden Retriever. Sagittal oblique T1-weighted postcontrast magnetic resonance imaging with fat suppression. The sagittal oblique image allows visualization of the optic nerve throughout its length. There is marked thickening and contrast enhancement of the optic nerve (large arrows). Suppression of the orbital fat signal (small arrows) facilitates identification of the optic nerve contrast enhancement.

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ogy and therefore identify the regions requiring more detailed investigation (Fig. 10.2.11).

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Fluid Attenuation Inversion Recovery

Fluid attenuation inversion recovery (FLAIR) is a sequence that suppresses the normally high signal intensity of CSF on T2WI, and therefore improves visualization of subtle adjacent pathologic hyperintensity of the brain or the optic chiasm (Arakia et  al., 1999; Barkhof & Scheltens, 2002; Kawamoto et al., 1997; Penninck et al., 2001). FLAIR images are more sensitive in detecting many pathologic processes of intracranial tissues surrounded by CSF, including neoplasia and inflammation, when compared to T2WI (Fig. 10.2.12). The FLAIR technique may be useful to distinguish cystic lesions (low signal) from tissues with high fluid content (high signal; Tidwell, 2007). Contrast MRI

Many pathologic processes in the brain are associated with increased tissue fluid content and/or increased tissue vascularity. MR scanning with intravenous paramagnetic agent contrast agents such as gadolinium‐diethylenetriamine pentaacetic acid (Gd‐DTPA) may be used to enhance the appearance of these changes (Lee, 1991). Contrast‐enhanced MRI improves visualization of blood vessels, breakdown of the blood–brain barrier, tumors, or inflammation (Dutton, 2010b). The accumulation of contrast medium appears as increased signal intensity on T1WI MR (Fig. 10.2.13; Tidwell & Jones, 1999). Generally the use of contrast enhancement is recommended for most cases of orbital or neuro‐ophthalmic disease, but it may not be necessary for acute hemorrhage or in trauma cases (Lee et al., 2009). In the series of orbital diseases reported by Dennis (2000), contrast enhancement was helpful in delineating mass lesions, demonstrating intracranial extension, outlining abscesses, and showing muscle changes associated with inflammatory disease. Serious side effects associated with gadolinium‐based contrast agents are uncommon in humans and veterinary patients. Anaphylactic/anaphylactoid reactions following intravenous gadolinium‐based contrast agents have been reported in humans (Abujudeh et al., 2010; Shellock et al., 2006) and dogs (Girard & Leece, 2010). Nephrogenic systemic fibrosis has been reported following gadolinium in human patients with kidney failure (Cowper, 2008; Marckmann et  al., 2006), but not in the veterinary literature. MRI in Ocular, Orbital and Neuro-Ophthalmic Disease: Normal Anatomy and Pathologic Findings

On MR images tissues vary in signal intensity from very dark, dark, intermediate, bright, to very bright, and therefore provide excellent soft tissue contrast. The signal intensity from diseased tissues is described as hyperintense, isoin-

Figure 10.2.11  Extraocular muscle myositis in a 7-year-old Border Terrier. Dorsal short tau inversion recovery (STIR) magnetic resonance imaging (MRI). The extraocular muscles are thickened and have an increased signal on this sequence. There are no changes to the optic nerves; however, there are focal areas of increased signal within the left and right medial pterygoid muscles, which likely represented inflammatory change. Although the detail is not as good as other MRI sequences, the regions of fluid accumulation within tissues and therefore the location of pathology are clearly illustrated. (Courtesy of Paul Mahoney, Willows Veterinary Centre & Referral Service, Solihull, UK.)

tense, or hypointense, usually relative to the signal from tissue such as fat, muscle, or gray matter. When interpreting MRI studies used for investigation of ocular, orbital, and neuro‐ophthalmic diseases, knowledge of the normal appearance of these tissues is necessary. MRI of the normal eye and orbit of the dog and cat (Morgan et al., 1994) and horse (Morgan et al., 1993), the canine optic nerve (Boroffka et  al., 2008), the canine brain (Leigh et  al., 2008), and the cranial nerves of the dog (Couturier et  al., 2005) and cat (Gomes et al., 2009) have been described. In humans, the MRI findings of many ocular, orbital, and neuro‐ophthalmic conditions associated with congenital, traumatic, vascular, inflammatory, degenerative, and neoplastic diseases have been comprehensively described (Aviv & Miszkiel, 2005; Dutton, 2010b; Goh et  al., 2008; Jäger, 2005; LeBedis & Sakai, 2008; Müller‐Forell, 2004). The MRI findings reported in veterinary patients with ocular, orbital, and neuro‐ophthalmic disease include uveal melanoma in the dog (Kato et al., 2005; Miwa et al., 2005), orbital neoplasia in the dog (Armour et  al., 2011; Dennis, 2000) and cat (Armour et  al., 2011; Dennis, 2000; Morgan et  al., 1996), orbital inflammation in the dog and cat (Armour et al., 2011; Dennis, 2000; Kneissl et  al., 2007), orbital varix in the dog

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Figure 10.2.12  Optic neuritis in a 6-year-old Jack Russell Terrier. A. Transverse T2-weighted magnetic resonance imaging (MRI): enlargement of the optic chiasm (×) and an apparent hyperintensity of white matter (large arrow). It is difficult to determine the extent of the central nervous system white matter pathology due to the hyperintense signal of the cerebrospinal fluid (CSF). B. Transverse T2-weighted fluid attenuation inversion recovery (FLAIR) MRI in which the CSF signal is suppressed (small arrows show the effect of CSF signal suppression in the lateral ventricles). This allows the hyperintense white matter lesions (large arrow) to be appreciated.

A

B

Figure 10.2.13  Optic neuritis and granulomatous meningoencephalitis in a 3-year-old Cavalier King Charles Spaniel. A. Transverse T1-weighted magnetic resonance imaging (MRI) at the level of the optic chiasm (arrows). B. Transverse T1-weighted postcontrast MRI demonstrating enlargement and enhancement of the optic chiasm. Although subtle changes are present in the precontrast image (A), these could easily be overlooked, while the postcontrast appearance unequivocally demonstrates pathology in this region.

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(Holloway, 2015), optic neuritis in the dog (Armour et  al., 2011; Kitagawa et  al., 2009; Seruca et  al., 2010) and cat (Armour et al., 2011), optic atrophy associated with sphenopalatine disease in the horse (Barnett et  al., 2008), optic nerve meningioma in the dog (Morgan et  al., 1996; Regan et  al., 2011; Seruca et  al., 2011) and horse (Naylor et  al., 2010), sphenoid bone osteomyelitis in the dog and cat (Busse et al., 2009), sphenoid bone neoplasia in a dog (Beltran et al., 2010), and cases of CNS pathology affecting the central visual pathways in the dog (Cherubini et al., 2006; Cullen et al., 2002; Kitagawa et  al., 2009; Kraft et  al., 1997; Rossmeisl et al., 2007; Sturges et al., 2008; Thomas et al., 1996) and cat (Troxel et al., 2004; Seruca et al., 2011). In humans, MRI has been used to investigate many ocular conditions, including anophthalmos and microphthalmos, globe rupture, intraocular foreign body, retinal and choroidal detachment, uveitis and posterior scleritis, and primary and metastatic neoplasia (Chung et al., 2007; DePotter et al., 1998; Dutton, 2010b; LeBedis & Sakai, 2008). In veterinary ophthalmology, the imaging of most ocular abnormalities is performed using B‐mode ultrasound. One scenario in which MRI may be used in veterinary patients is in the assessment of ocular melanoma. The MRI appearance of human choroidal melanoma is a relatively hyperintense T1WI and relatively hypointense T2WI (Gomori et  al., 1986; Lee et  al., 2009; Mafee et  al., 1987) mass lesion due to the paramagnetic properties of the melanin (Damadian et  al., 1973; Lambrecht et al., 1988). This characteristic is helpful in evaluating choroidal melanomas or intracranial melanoma

A

metastases (Caruso et al., 2001). Only isolated case reports of MRI of uveal melanomas have been published in the dog, with Kato et  al. (2005) describing hyperintense T1WI/ hypointense T2WI in an anterior uveal melanoma in a dog, while a case of a choroidal melanoma in a dog lacked these characteristic MRI findings (Miwa et  al., 2005). The paramagnetic effect of melanin in a cat with a ciliary body melanoma is illustrated in Fig. 10.2.14. The MRI findings in cases of orbital neoplasia are largely provided by Dennis (2000), who reviewed the MRI findings of 25 small animal patients with signs of orbital disease, and Armour et al. (2011), who reviewed the distribution of orbital and intracranial disease in 79 canine and 13 feline patients referred for MRI studies by a veterinary ophthalmologist. In both series the most common type of orbital pathology was neoplasia: Armour et  al. (2011) 53/92 (57.6%) and Dennis (2000) 16/25 (64%). In the study by Armour et  al. (2011), carcinomas and sarcomas were the most prevalent tumor types, and both behaved in a locally invasive manner, frequently demonstrating heterogenous MR signal enhancement with extensive associated facial bone lysis, aggressive sinonasal infiltration, and intracranial extension (Fig. 10.2.15). In contrast, lymphoma tends to be less aggressive, with fewer cases extending beyond the bony orbit and with an MR signal intensity varying from heterogenous to homogenous (Armour et al., 2011). In the review by Dennis (2000), tumors appeared as discrete masses of medium signal intensity on T1WI MR and variable but mainly high signal intensity on T2WI MR. All

B

Figure 10.2.14  Ciliary body melanoma affecting the left eye of a 3-year-old Birman cat. A. Dorsal T2-weighted magnetic resonance imaging (MRI) showing a hypointense mass lesion in the ciliary body of the left globe (arrow). B. Transverse T1-weighted MRI showing a slightly hyperintense mass lesion corresponding to the mass lesion identified in (A). These changes are consistent with the paramagnetic effect of melanin.

Figure 10.2.15  Orbital carcinoma in a 4-year-old Irish Water Spaniel. Dorsal T2-weighted magnetic resonance imaging. The large irregular mass of low signal intensity is filling the left orbit, has eroded through the left medial bony orbital wall (frontal bone), and extended into the nasal cavity (small arrow). Extension though the orbital apex into the cranial vault has led to compression and distortion of the left frontal lobe of the brain (large arrow).

showed mild diffuse contrast enhancement after intravenous gadolinium administration. The extent of tumors was more clearly defined on MRI than with radiology or ultrasound, and osteolysis involving the bony orbit and extension of the disease beyond the orbit were considered reliable indicators of malignancy (Dennis, 2000). In addition, and in contrast to radiographs, the MRI allowed distinction between fluid accumulation and solid tissue in the frontal sinus, as the fluid appeared hypointense on T1WI and hyperintense on T2WI (Dennis, 2000). The MRI appearance of orbital cellulitis is characterized by diffuse connective tissue swelling without loss of the normal architecture (Dennis, 2000), allowing differentiation from orbital neoplasia (Armour et  al., 2011). Orbital abscesses demonstrate markedly enhancing walls around fluid‐filled cavities on T1‐weighted postcontrast images (Dennis, 2000). Although hydrated wooden foreign bodies may not be directly detectable on MRI (Woolfson & Wesley, 1990), the associated inflammatory reactions may be identified (Dennis, 2000). Larger wooden foreign bodies may be hypointense on MRI (Hartley et al., 2007). The MRI appearance of orbital inflammation with intracranial extension has been described in dogs (Kneissl et al., 2007); the condition was best identified by abnormal MR signal increase within the orbital fissure on transverse T2WI and dorsal STIR images, or on transverse or dorsal postcontrast T1WI.

MRI is the modality of choice when assessing the optic nerves and chiasm, providing the best morphologic assessment of these structures (Penninck et  al., 2001). Oblique dorsal and oblique sagittal planes allow visualization of both the globe and the retrobulbar tissues in the same section, and with serial sections the entire optic nerve is consistently imaged (Morgan et al., 1994). As already discussed, the use of imaging sequences that suppress the normally hyperintense fat signal from the orbit may improve the visualization of the contrast enhancement associated with optic nerve pathologies (Lee et al., 2009; Penninck et al., 2001). In humans, MRI is very useful in evaluating optic nerve meningioma (Aviv & Miszkiel, 2005; Dutton, 2010b; Goh et al., 2008; Jäger, 2005; LeBedis & Sakai, 2008; Müller‐Forell, 2004). Although MRI is not as reliable as CT in detecting intratumoral calcification, it provides better definition of the posterior (caudal) extent of the tumor (Morgan et  al., 1996). Most human orbital meningiomas are isointense to the optic nerve on T1WI and T2WI, although they may be hypointense on T1WI and hyperintense on T2WI (Aviv & Miszkiel, 2005). Fat‐saturated, contrast‐enhanced T1WI demonstrate the lesion best in humans (Aviv & Miszkiel, 2005). In the dog, optic nerve meningiomas have been described as isointense on T1WI and hyperintense or isointense on T2WI, and with marked homogenous contrast enhancement (Grahn et  al., 1993; Seruca et  al., 2011). Armour et  al. (2011) described a dural tail sign in five of nine cases of presumed orbital and intracranial meningioma; the dural tail sign is a linear contrast‐enhancing region of the dura mater strongly supportive of meningioma, although false positives are reported (Graham et al., 1998). The MRI findings in a horse with optic nerve meningioma, including strong contrast enhancement, association with the optic nerve, and its tapering caudal margin, are illustrated in Fig. 10.2.16. Optic neuritis in humans is characterized by an enlarged optic nerve that is contrast enhancing and hyperintense on T2WI in acute disease, whereas chronic optic neuritis classically is associated with an atrophic nonenhancing optic nerve that is hyperintense on T2WI (LeBedis & Sakai, 2008). Although the hyperintense optic nerve on T2WI is not specific and may occur with several pathologies including edema, demyelination with axonal loss, as well as chronic gliosis, the contrast enhancement reflects disruption of the blood–brain barrier and is characteristic of acute inflammation (Gass & Moseley, 2000; Jäger, 2005). The MRI findings of presumed optic neuritis in the dog included unilateral optic nerve hyperintensity (3/13, 23.0%), bilateral optic nerve hyperintensity (1/13, 7.7%), and optic chiasmal hyperintensity (3/13, 23.0%); all of the hyperintensities were noted on T2WI or FLAIR sequences (Armour et  al., 2011; Armour personal communication, 2012). The majority demonstrated optic nerve enhancement and/or multifocal patchy intracranial contrast enhancement (7/13, 53.8%), reflecting a more

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Figure 10.2.16  Optic nerve meningioma in a 16-year-old Thoroughbred gelding. A. Dorsal T1-weighted magnetic resonance imaging (MRI). There is a well-defined orbital mass, which is intimately associated with the optic nerve (arrow). The mass has a signal intensity similar to that of the brain parenchyma. Rostral displacement of the globe is apparent. B. Dorsal T1-weighted MRI. This image slice is slightly ventral to image (A) and shows the tumor tapering caudally along the margin of the optic nerve (arrow). C. Dorsal T2-weighted MRI. The mass has a signal intensity similar to that of the brain parenchyma. D. Dorsal T1-weighted MRI postcontrast with fat suppression. The mass shows strong, uniform, and homogenous contrast enhancement. The discrete nature of the mass, strong contrast enhancement, association with the optic nerve, and its caudal tapering margin were suggestive of a meningioma arising from the optic nerve sheath. This was subsequently confirmed on histopathology. MRI accurately defined the posterior extent of the tumor, identifying that complete surgical excision would not be feasible, and that adjunctive radiotherapy would need to be used as part of the treatment plan.

generalized concurrent CNS inflammatory disease (Armour et al., 2011). In the two cases of clinically apparent optic neuritis described by Seruca et  al. (2011), one demonstrated hyperintensity of the optic nerve on T2WI and STIR sequences and moderate contrast enhancement on T1WI of

both optic nerves. Granulomatous meningoencephalomyelitis (GME) is the most commonly reported cause of optic neuritis in the dog (Cherubini et  al., 2006; Nell, 2008) and as such MRI studies of the brain may be indicated in cases of clinically apparent optic neuritis to assess for CNS pathology

10.2: Ophthalmic Examination and Diagnostics

Tear Film Imaging Evaluation of the tear film, and its implications for ocular surface health, has long been an area of research in ophthalmology. In the medical field a number of tear film parameters are measured or assessed, but these have yet to become mainstream in veterinary ophthalmology (Foulks & Pfugfelder, 2014).

A

Tear Ferning Collection of a nonstimulated tear sample by micropipette, microcapillary tube, or via a Schirmer tear test strip can be undertaken and a small sample of tear fluid applied to a slide. This typically will dry on the slide in less than 10 min (although this is temperature and humidity dependent). The characteristic crystallization pattern (referred to as the “tear fern”) of the dried tear sample viewed by light microscopy has correlation to the tear film composition (in particular osmolarity and mucin content). The tear fern is graded (Rolando type I–IV or Masmali grade 0–4 scales) and is typically dense and full in a normal healthy sample, but fragmented or absent with large spaces in a keratoconjunctivitis sicca (KCS) sample. Clinical Applications

Tear ferning has been described in horses, and was found to be easy to perform, inexpensive, and without patient risk (Silva et al., 2016). Silva et al. also used a “STEPanizer” software program to more objectively assess the crystallization pattern of microphotographs, in addition to standard Rolando grading. Silva et  al. (2016) recommended further work correlating tear ferning results with other tear film parameters (e.g., tear osmolarity) for standardization of this modality. Tear ferning has been described in healthy dogs and sampling methods (micropipette, microcapillary tubes, and

B

Figure 10.2.17  Optic neuritis affecting the right side in an 8-year-old Labrador Retriever dog. A. Dorsal T2-weighted magnetic resonance imaging (MRI). The right optic nerve is enlarged and moderately hyperintense (arrow). B. Transverse T2-weighted MRI. The enlargement of the right optic nerve is evident (large arrow) and also the attenuation of the cerebrospinal fluid signal, which is clearly visible on the contralateral side (small arrow).

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consistent with GME or neoplasia (Armour et  al., 2011; Seruca et  al., 2011). The MRI findings typical in cases of acute optic neuritis include optic nerve enlargement, contrast enhancement, and loss of CSF signal, which are illustrated in Fig. 10.2.10 and Fig. 10.2.17. MRI findings in traumatic chiasmal lesions have been reported in humans (Arkin et al., 1996; Dilly & Imes, 2001; Gurses et al., 2006; Mark et al., 1992; Segal & Gans, 2009), but to the authors’ knowledge not in the veterinary literature. In humans, high‐resolution (1.5 T magnet or greater) MRI with gadolinium contrast enhancement is considered the best imaging modality for lesions involving the optic chiasm (Foroozan, 2003), but in clinical practice CT remains the imaging modality of choice following acute head trauma with posttraumatic blindness, due to its increased sensitivity at detecting treatable optic canal fractures (Mark et  al., 1992).

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Schirmer tear test strips) compared (Oria et al., 2017). Oria et al. (2017) also used both the Rolando and Masmali grading schemes and found the test to be simple and low cost, recommending its adoption in routine clinical practice (Fig. 10.2.18 and Fig. 10.2.19). Williams and Hewitt (2017) described tear ferning patterns in healthy normal dogs and in dogs with KCS, using a microcapillary tube collection and grading according to the Rolando scale. The KCS patients had “abnormal” tear ferning patterns (Rolando types III and IV); however, some normal, healthy dogs also had abnormal grades. The authors commented on variability and familiarity with sampling technique having an effect on the tear ferning result (e.g., stimulated vs. nonstimulated tears, presence of mucoid discharge and avoidance of sampling this).

Noninvasive Tear Film Break-Up Time

Clinical Applications

The Tearscope has been used to demonstrate the longer TFBUT in rabbits compared with humans (Wei et al., 2013) and to draw conclusions about the relative stability of the tear film in rabbits versus humans. Oculus Keratograph 5M

The Oculus® Keratograph 5M (Oculus, Wetzlar, Germany) uses an infrared light source (wavelength 880 nm) to project a ring pattern onto the tear film, and changes in the regularity of the reflected image (captured by video camera) indicate the onset of tear film break‐up. This disruption of the reflected image is detected by the instrument software and reported as the time to first point of TFBUT, as well as the average time of all break‐up points measured (Markoulli et al., 2018). As yet publications on the noninvasive TFBUT using the Oculus Keratograph 5M in veterinary patients are lacking.

Keeler Tearscope-Plus

The Keeler Tearscope‐Plus™ (Keeler, Windsor, UK) is a handheld noninvasive instrument used to assess tear film break‐up time (TFBUT) without the need for instillation of fluorescein. As fluorescein potentially destabilizes the tear film, and there is variation in the fluorescein volume applied (especially with fluorescein‐impregnated strips), this was felt to limit the practical usefulness of the TFBUT in the clinical setting. The Tearscope provides a colored interference pattern of the tear film from reflected white light. The instrument still has some subjectivity, as the observer is responsible for timing and judging the period until the first appearance of tear film disruption occurs (Markoulli et al., 2018). This is further compounded in veterinary ophthalmology as a forced blink is used at the start of the measurement, unlike in humans with a self‐controlled blink, which may have unintended implications for tear film stability and the TFBUT measurement (Wei et al., 2013).

A

Tear Film Optical Coherence Tomography Tear film optical coherence tomography (OCT) imaging has been applied to contact lens assessments, tear meniscus assessment in KCS, and nasolacrimal obstruction (functionally or physically), as well as on the effect of artificial tear film agents and blinking on tear film dynamics in humans (Chen et  al., 2010; Ibrahim et  al., 2010; Koh et  al., 2010; Palakuru et  al., 2007, 2008). See “Optical Coherence Tomography” later in this chapter.

Corneal Imaging Pachymetry Ex vivo measurements of corneal thickness are subject to inaccuracy due to postmortem/postsurgical swelling of the

B

C

Figure 10.2.18  Tear ferning patterns in healthy dogs according to the Rolando grading scale. A. Type I representation, dendritic fern growth is uniform, and there are no spaces between branches. B. Small spaces begin to appear between the stems. C. Incomplete crystallization process, single and small formations, and branches are rare or nonexistent. (Reproduced with permission from Oria A.P., Raposo A.C.S, Araujo N.L.L.C., et al (2017) Tear ferning test in healthy dogs. Veterinary Ophthalmology, 1, 1–8.)

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Figure 10.2.19  Tear ferning patterns of healthy dogs according to Masmali’s grading criteria. A. Representation of grade 0, with full crystallization without gaps between the ferns and branches. B. Representation of grade 1, decreased density of the branches, and appearance of small spaces between them. C. There are small branches, sometimes thick and large, with clear gaps between the ferns, representing grade 2. D. Characteristics of grade 3, in which spaces and gaps are increased, and coarse crystals are formed. (Reproduced with permission from Oria A.P., Raposo A.C.S, Araujo N.L.L.C., et al. (2017) Tear ferning test in healthy dogs. Veterinary Ophthalmology, 1, 1–8.)

tissue, especially if immersed in storage medium or fixative, and are therefore of limited value in the clinical setting. Various technologies are available to provide accurate measurement of in vivo corneal thickness, including ultrasound pachymetry (e.g., AccuPach® or Pach‐Pen®, Accutome, Malvern, PA, USA), in vivo confocal microscopy (IVCM; e.g.,

Confoscan4™, Nidek, Albignasego, Italy; Heidelberg Retina Tomograph  –  Rostock Corneal Module [HRT II RCM®], Heidelberg Engineering, Heidelberg, Germany), optical biometry with a Scheimpflug camera (e.g., Pentacam®, Oculus; Sirius®, Schwind, Kleinostheim, Germany; or Galilei®, Ziemer Ophthalmic Systems, Port, Switzerland),

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OCT (e.g., Visante®, Carl Zeiss Meditec, Jena, Germany), and optical coherence pachymetry (e.g., Orbscan®, Bausch + Lomb, Rochester, NY, USA). Optical pachymetry measures corneal thickness using an oblique light source across the cornea (often attached to a slit‐lamp biomicroscope and Scheimpflug camera) and calculating the distance between the observed epithelial and endothelial reflections based on the angle of incidence and magnification (Scheimpflug principle). Use of optical pachymetry requires clear corneal reflections and is therefore limited in cases of corneal edema, fibrosis, or infiltrates. There is interobserver variability with manual systems, and both the radius of curvature of the cornea and the refractive index of the cornea are added variables to the measurement. Development of automated optical coherence pachymetry systems (e.g., Orbscan) reduced interobserver variability, thereby increasing reproducibility and reliability. Orbscan uses a large number of slit‐beam images across the cornea, providing a topographic image of corneal thickness. OCT and in vivo confocal microscopy can also be used to gain corneal thickness measurements (see “Optical Coherence Tomography” and “In Vivo Confocal Microscopy of the Cornea”), although their technology was not originally developed for this facility. Ultrasound pachymetry uses ultrasound energy reflected from interfaces of differing refractive indices to measure corneal thickness, and is therefore equivalent to an ultrasound A‐scan. Probes can vary from 20 to 65 MHz and measure from the anterior tear film to the posterior surface of the endothelium. The distance between reflections is then calculated based on the speed of ultrasound through the cornea (1550–1639 m/s depending on species). Conversion factors are useful when calculating measurements in nonhuman species. For example, the feline cornea has an ultrasound velocity of 1590 m/s, and therefore human pachymeters will overestimate feline corneal thickness based on the human corneal ultrasound velocity of 1640 m/s. This technology can be used in the face of concurrent corneal opacity (edema, scarring, etc.). Ultrasound pachymetry has high intraobserver reproducibility, with lower interobserver variability than optical pachymetry (Salz et al., 1983). Careful placement of the probe both centrally and perpendicular to the corneal surface is important, and user errors are sources of variability. Modern machines offer alignment detection and have smaller probe tips, which allow their use in a wider range of species (see Fig. 10.2.20 and Fig. 10.2.21). Ultrasound pachymetry is the preferred method (gold standard) of pachymetry in human patients, with readings independent of patient fixation, improved reproducibility, accuracy, and portability. Reported sources of error with both optical and ultrasound pachymetry include dehydration of the cornea (causing decreased corneal thickness readings), hydration of the cornea (e.g., after periods of eyelid closure and reduced tear

Light source

Slit Aperture

Static and rotating glass blocks Reflections from epithelium and endothelium

Figure 10.2.20  Schematic illustration of optical pachymeter. (Illustration by Roser Tetas Pont.)

Figure 10.2.21  Pachymetry being performed on a normal rabbit cornea. (Courtesy of Dr. Ellison Bentley.)

evaporation), patient positioning (e.g., recumbency increases corneal thickness measurements in humans), marking of the cornea, and taking repeated measurements. Clinical Applications

Pachymetry is used in human patients prior to laser‐ assisted in situ keratomileusis (LASIK) procedures to ensure sufficient preoperative corneal thickness to avoid corneal ectasia complications postoperatively. Pachymetry has also been used to investigate the effects of corneal cross‐linking with riboflavin and ultraviolet‐A irradiation as a treatment for keratoconus, both ex vivo and in vivo, in animal models (Dong & Zhou, 2011; Kampik et al., 2010). Corneal transplant rejection has been objectively assessed using ultrasound pachymetry, with an increased thickness of the donor graft associated with rejection (more

traditionally assessed subjectively by increasing corneal opacity; Flynn et al., 2010). Corneal thickness is important in the early detection of glaucoma, for interpretation of tonometry results, and for prediction of development of glaucomatous visual deficits (Brandt et  al., 2001; Gordon et  al., 2002; Herndon et  al., 2004; Kourkoutas et  al., 2009). Central corneal thickness (CCT) has a bearing on the accuracy of indentation and applanation tonometers, as changes in the elasticity (in turn related to thickness, rigidity, and astigmatism) of the cornea affects these results. Increased corneal thickness will result in elevated indentation or applanation tonometry readings, while thinner corneas will produce reduced intraocular pressure readings. Linear scale correction factors of 1–3.6 mmHg per 50 μm of increased CCT, as well as a mathematic formula (Orssengo and Pye algorithm) incorporating factors of anterior corneal curvature, corneal thickness, and elasticity (Poisson’s ratio), have been proposed to adjust intraocular pressure (IOP) readings for CCT (Shih et al., 2004). Aside from the accuracy of IOP readings, CCT is a predictor of glaucoma damage, and hence pachymetry has been used extensively in the investigation and management of human glaucoma patients. A large study in humans (Ocular Hypertension Treatment Study, OHTS) demonstrated that CCT is also a risk factor for initial glaucoma damage (visual field loss) among people with ocular hypertension (Gordon et  al., 2002). It has been postulated that this may not be entirely due to the link with tonometry reading accuracy (and therefore initiation of early treatment), but CCT may be linked to corneoscleral shell (and lamina cribrosa) composition, and associated with optic disc response to IOP‐induced stress. This hypothesis has been questioned by a study on enucleated eyes comparing central corneal thickness with optic nerve head parameters, which found no association between measurements (Jonas & Holbach, 2005). A similar study on enucleated globes from Chinese patients with and without glaucoma also revealed no association between lamina cribrosa thickness and CCT, casting further doubt on the hypothesis (Ren et al., 2010). In vivo CCT measurements in guinea pigs (Cavia porcellus) using ultrasound pachymetry has been reported as part of a study describing the normal guinea pig cornea (Cafaro et al., 2009). CCT values (227.9 ± 14.1 μm) were not significantly different from peripheral corneal measurements, or between albino and pigmented animals, or males and females. Similarly, ultrasound pachymetry results have been reported for five western lowland gorillas (Gorilla gorilla gorilla; mean CCT 489 ± 52 μm) as part of a study reporting normal ocular findings in the species anesthetized for ­nonocular reasons (Liang et al., 2005). Ultrasound pachymetry has also been used to measure CCT in normal koi fish (Cyprinus carpio; mean 325.9 μm), with increased CCT in females compared to males. Increasing CCT was also

demonstrated with increasing age, body length, vertical corneal diameter, and horizontal corneal diameter in Koi fish (Lynch et al., 2007). The postnatal changes in CCT of domestic chickens (Gallus gallus domesticus) from hatching to day 450 have also been documented using ultrasound pachymetry (Montiani‐Ferriera et al., 2004). This study demonstrated an initial decrease in CCT from hatching until day 12 post hatch (postulated to be due to endothelial cell maturation and reduction of corneal hydration), followed by a gradual increase to maximal CCT at day 70. There was no effect of gender on CCT in the chicks. Central corneal thickness has also been measured by ultrasound pachymetry in captive black‐footed penguins (Spheniscus dermersus), and no correlation found with CCT and IOP (unlike in humans, dogs, and chickens), or with CCT and age or bodyweight (Gonzalez‐Alonso‐Alegre et al., 2015). Postnatal development of CCT in dogs has also been studied from eyelid opening to 42 weeks of age (Montiani‐ Ferriera et al., 2003). This showed a similar initial decrease in CCT up to 6 weeks of age, followed by an increase in CCT, which became a more gradual increase at 30 weeks of age. Breed‐specific differences in CCT were identified in this study, with Labrador Retrievers having significantly thicker corneas than Briard × Beagle dogs. An earlier study using ultrasound pachymetry reported canine CCT measurements of 520–597 μm, thicker peripheral versus central corneal readings and male versus female readings, as well as increasing thickness with increasing bodyweight (Gilger et al., 1991). Feline corneas have been assessed by both optical pachymetry (755 ± 33 μm; Carrington & Woodward, 1986) and ultrasound pachymetry (CCT 578 ± 64 μm; Gilger et  al., 1993), and 546 ± 48 μm (Schoster et  al., 1995). Feline CCT measured by ultrasound pachymetry was reported to increase with age (up to 100 months or 8 years), but no gender influence was apparent. Variations in corneal thickness topographically were not apparent in one study (Gilger et  al., 1991), while another study reported the thickest corneal readings laterally and subperiaxially, and the thinnest measurements dorsomedially in cats (Schoster et al., 1995). Corneal thickness has been investigated in horses, and within different breeds of horse. Mean CCT in horses is 770–893 μm and is unaffected by gender (Andrew et  al., 2001; Plummer et  al., 2003; Ramsey et  al., 1999; van der Woerdt et al., 1995). The peripheral cornea is significantly thicker than the central cornea in the horse (831–924 μm), and there was no apparent effect of age, xylazine sedation, or auriculopalpebral nerve block on readings (van der Woerdt et  al., 1995). Measurements of CCT in Miniature Horses revealed similar values to those recorded in full‐ sized horses (Plummer et al., 2003). No correlation between endothelial cell density and CCT was found in enucleated eyes from normal horses (after euthanasia), but an

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a­ ssociation at critical endothelial cell densities was not ruled out (Andrew et al., 2001). Ultrasound pachymetry has been used to demonstrate that American Quarter Horses affected with hereditary equine regional dermal asthenia (HERDA) have statistically thinner corneas than unaffected Quarter Horses (Badial et al., 2015; Mochal et al., 2010). HERDA is an autosomal recessive generalized connective tissue disorder of horses, resulting in abnormal elasticity and excessive fragility of the skin, analogous to Ehlers–Danlos syndrome in humans. Alterations of collagen microarchitecture have been demonstrated within the cornea as well as in dermal tissues in HERDA‐affected horses. Affected horses also have an increased risk of corneal ulceration. Ehlers–Danlos‐affected patients demonstrate corneal thinning, increasing the risk of keratoconus, keratoglobus, corneal plana, corneal rupture, and ocular fragility (Hyams et al., 1969; Segev et al., 2006). Ultrasound pachymetry has also determined the mean CCT for alpacas as 595 μm and for llamas 608 μm, with no gender or age effect on CCT in either species (Andrew et al., 2002; Fig. 10.2.22). Spectral domain OCT pachymetry has been used to measure mean CCT in normal sheep (741 μm), goats (617 μm), and alpacas (635 μm), and was able to determine the thickness of specific corneal layers in vivo (epithelium, stroma, Descemet’s membrane; Lo Pinto et al., 2017b). Ultrasound pachymetry has also demonstrated a transiently increased CCT in canine phacoemulsification patients postoperatively (from a mean of 611 μm preoperatively to a peak of 741 μm on day one postoperatively), returning to baseline values by one month postsurgery. The same study also showed that the mean diabetic canine CCT was greater over all time points than nondiabetic canine CCT (Lynch & Brinkis, 2006). Specular microscopy was not

Figure 10.2.22  Pachymetry being performed on a normal llama cornea. (Courtesy of Dr. Stacy Andrew.)

undertaken to assess corneal endothelial morphology or density in this study, but speculation remains that an increase in postoperative corneal thickness is due to loss of endothelial function (as demonstrated in human diabetic patients; Ziadi et al., 2002). Similarly, increases in corneal thickness in human patients following cataract surgery are reported, with reduction to presurgical values three months postoperatively, despite a permanent reduction in endothelial cell density (Ventura et  al., 2001). In humans, endothelial density correlates poorly with CCT until a critical minimum endothelial density is reached (Ventura et al., 2001). Ultrasound pachymetry has been used (in conjunction with spectral domain OCT and IVCM) to assess the effect of superficial keratectomy and conjunctival advancement hood flap in the treatment of canine spontaneous bullous keratopathy (Horikawa et al., 2016). This study demonstrated significant reductions in mean central corneal thickness associated with this surgical treatment, and owners reported increased corneal clarity and vision in their dogs postoperatively. The effect of intracameral preservative‐free lidocaine on corneal thickness, as well as on endothelial cell density and morphology, has been investigated in dogs, and no significant difference from pretreatment values was detected, suggesting a lack of adverse ocular effects (Gerding et al., 2004). Ultrasound pachymetry has also been used to assess the best preservation fluid for enucleated porcine eyes for use in wet labs, which was demonstrated to be tap water (compared to 14 other preservation methods) for up to 48 hours (Nibourg et al., 2014).

Specular Microscopy Specular microscopy is an imaging modality that allows morphologic analysis of the corneal endothelium, although the technology can be applied to image the corneal epithelium and stroma, as well as the lens. The first specular microscope for ex vivo endothelial cell photography (500× magnification) was developed by Maurice in 1968 (Maurice, 1968), although descriptions of the use of the specular reflex to examine the corneal endothelium were first published in 1920 (Volt, 1920). Just as light microscopy reveals an image from light transmitted through a tissue, specular microscopy provides an image from light reflected from a tissue. The specular reflex occurs at the interface of two refractive indices, and light is reflected back to an observer. The refractive index of the endothelium is greater than for aqueous humor, and therefore 0.022% of the projected light will be reflected (i.e., the majority of the incident light is transmitted or absorbed; McCarey et al., 2008). Light scattered within the corneal stroma (by collagen lamellae and keratocytes) will reduce the contrast of the endothelial image. Increased light scatter associated with a corneal opacity or edema further reduces the specular reflex, and therefore the image quality.

The area of endothelium that can be inspected with this system is dependent on two factors: the curvature of the cornea and the corneal thickness. The surface area of the specular reflex is confined by the radius of the curvature of the reflecting surface (cornea). Light reflected from a cylinder (as opposed to a flat surface) is condensed 90° to the axis of the curved surface. In addition, the epithelial surface is highly reflective due to the large refractive index difference between air and the tear film–cornea interface. The proximity of this anterior reflection to the endothelial specular reflex restricts the viewable area of the endothelium to a relatively small area. Original specular microscopes were contact microscopes, where the objective lens was placed directly against the corneal epithelium, therefore requiring topical anesthetic (and a compliant patient). Contact with the cornea applanates the surface, flattening the curvature and enlarging the specular reflex. Noncontact specular microscopes were later developed, utilizing automatic focusing technology, which generally have a smaller field of view but allow for greater patient comfort (Fig.  10.2.23). Specular microscopes may utilize a stationary slit beam, a moving slit beam, or spot illumination to obtain images, with modern machines using multiple slit beams that scan a wider area of cornea to increase the field of view. The width of the slit/spot beam will affect the size of the field of endothelial cells seen; however, increasing the beam width can be at the cost of increased light scatter across anterior corneal tissue (and therefore reduced image quality). This may be overcome by using multiple or scanning beams of finer width to create a composite image of the endothelium (Laing et al., 1979). There are four zones of specular reflection, the first at the corneal surface between the interface lens, coupling fluid, and corneal epithelium. The second is light reflected from the corneal stroma, and the third is from the endothelium.

Comea

Epithelial specular reflex Endothelial specular reflex

The last zone is at the level of the aqueous where there is very little reflection and it therefore appears dark. Images obtained thus have a dark boundary representing the intraocular surface of the cornea and the light boundary at the limit of the endothelium (Fig. 10.2.24 and Fig. 10.2.25). Techniques for determining endothelial cell density include the comparison method, the frame method, the corner method, and the center method. The comparison method uses a subjective visual comparison of the patient’s endothelial cell pattern to a known set of hexagonal patterns for set cell densities. The frame method uses a count of the number of cells within a frame; cells that extend over two frames along a border are counted as full cells over two adjacent borders, but are not counted on the corresponding adjacent two borders. The corner method identifies cell borders and defines the cell areas on a digital tablet. This is reliant on the subjective decision of defining a cell borders as well as the quality of the specular microscope image. The estimated error for this method is 5% (McCarey et al., 2008). The center method is the most commonly adopted technique, whereby the approximate center of each cell is marked with a dot and computer analysis calculates the cell area based on the radius to the center of adjacent cells. The technique is reliant on the diligence and expertise of the technician performing the analysis; the error range for  the center method is reported as 0.5%–5% (McCarey et al., 2008). Image quality has a bearing on error rates, with excellent‐ quality images, unsurprisingly, having fewer interobserver differences reported (Lass et  al., 2005). It is recommended that prospective studies utilizing specular microscopy should use the same microscope manufacturer, settings, and technician for capturing images (or similarly trained staff if multicenter, with periodic review of standards) and the same technician analyzing the images. Multicenter clinical trials

Light source

Specular reflection viewed on film plane FIGURE

Figure 10.2.23  Simplified illustration of a specular microscope. Light illuminates a section of the cornea and is reflected from the epithelium and endothelium of the cornea (only one layer will be in focus at a time) and viewed in a different plane (angle) from the incident light. As the surface that the light is reflected on is not flat (corneal curvature), the illuminated area of cornea (field of view) is flattened dorsoventrally (perpendicular to the axis of the curvature). (Illustration by Roser Tetas Pont.)

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Figure 10.2.24  A. Noncontact specular microscopy being undertaken on an anesthetized Beagle cross-bred dog. B. Specular microscopy image of the central corneal endothelium of a normal 9-month-old cross-bred dog. (Courtesy of Dr. Matt Chandler.)

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Figure 10.2.25  Specular microscopy (Topcon SP. 2000P, Topcon Medical Systems, Oakland, NJ) from a normal male 4-year-old rhesus monkey (A) and a normal 17-year-old Thoroughbred gelding (B). Note the brighter and darker borders of the image corresponding to the stromal and aqueous sides of the endothelium respectively. Avg, average cell size; CD, endothelial cell density; CV, coefficient of variation; Max, maximum cell size; Min, minimum cell size; N, number of cells; SD, standard deviation; T, thickness. (Courtesy of Dr. Stacy Andrew.)

have an estimated cell density variability of ± 10% (McCarey et al., 2008). As a general rule, three images from the central cornea and three images from the paracentral cornea, each with a minimum of 150 cells per image, are recommended in endothelial assessment of human patients. The contact specular microscopes are reported as being capable of capturing 700–3000 cells per image (although 3000 cells per image is considered exceptional) and noncontact specular microscopes capable of 120–170 cells per image (McCarey et al., 2008). Specular microscopy is used clinically to assess corneal endothelial cell density, rate of polymegathism (or coeffi-

cient of variation in cell size, i.e., an objective measure of cellular morphology variation), and pleomorphism (variation in cell shape, i.e., an subjective assessment of cell morphology differences). These assessments are often used sequentially in longitudinal studies on the effect of disease processes (e.g., Fuch’s endothelial dystrophy), surgical interventions (e.g., cataract surgeries, including intracapsular, extracapsular, and phacoemulsification techniques), surgical devices (e.g., phakic or anterior chamber intraocular lenses utilized in human ophthalmology), topical and intraocular drugs, and contact lens wear over repeated examinations (Acar et al., 2011; Alanko & Airaksinen, 1983;

Cremona et al., 2009; Esgin & Erda, 2000; Esquenazi et al., 2011; Inaba et al., 1985; Zhao et al., 2008). In a normal human endothelium, more than 60% of the cells are hexagonal, and this is the most efficient cell shape to maintain intercellular tight junctions and a continuous monolayer (Dougherty, 1998). Endothelial cell density and pattern vary with phylogeny, with birds and mammals having a mainly hexagonal pattern (goose 79%, dog 78%, rat 58–76%, rabbit 71% hexagonal) and higher densities, and amphibians, reptiles, and fish having lower densities with jigsaw‐like to polygonal patterns (Yee et al., 1987). The coefficient of variation (CV) in a normal human corneal endothelium is 0.22–0.31 (McCarey et  al., 2008). Increased polymegathism is usually the first evidence of endothelial disease, with readings of 0.32–0.40 considered elevated and above 0.40 viewed as abnormal (McCarey et  al., 2008). Although the endothelium may be adequately functional in these corneas, susceptibility to trauma (e.g., intraocular surgery, glaucoma, contact lens wear) may be increased. Polymegathism is reported with extended contact lens wear, particularly with lenses that have poorer oxygen permeability. This endothelial change is slow to recover, even when contact lens wear is discontinued (Liesagang, 2002; McCarey et al., 2008). Clinical Applications

Aging is associated with a gradual reduction in endothelial cell counts (young adults have densities of 3000–4000 cells/ mm2, reducing to 2400–2700 cells/mm2 for octogenarians). This has also been demonstrated in cats in a recent study, in association with increased polymorphism and polymegathism with greater age (Franzen et al., 2010). An older study suggested that the endothelial cell density reduction with age in cats was not statistically significant, but reported increasing polymegathism with age (Tailoi & Curmi, 1988). A similar reduction in endothelial cell density with age is reported in the dog (Bahn et al., 1986; Gwin et al., 1982) and horse (Andrew et  al., 2001). An endothelial cell density decrease, with endothelial cell polymegathism and polymorphism increases, has also been demonstrated in chinchillas (Chinchilla lanigera) associated with age (Bercht et  al., 2015). Diabetes in humans, and in canine models, is associated with endothelial polymorphism and polymegathism (Lee et  al., 2006; Matsuda et  al., 1990; Neuenschwander et  al., 1995; Yee et  al., 1985). In galactose‐fed dogs receiving the oral aldose reductase inhibitor sorbinil concomitantly, endothelial morphologic changes were prevented (Datiles et al., 1990). Reduced endothelial changes were also reported in experimentally induced diabetic rats receiving a topical aldose reductase inhibitor compared to nontreated diabetic rats (Matsuda et al., 1987). Surgical trauma is associated with reduced cell densities, and this reduction continues postoperatively at an

accelerated rate compared to age‐matched controls for the following 10 years (Bourne et al., 1994b). Routine phacoemulsification in humans is associated with a 5%–11% loss of endothelial cells (Bourne et  al., 2004; Oxford Cataract Treatment and Evaluation Team [OCTET], 1986). Interestingly, using the phacoemulsification needle in a “bevel down” position resulted in twice the endothelial cell loss (13.6% vs. 5.9%) compared to the conventional “bevel up” position (Faramarzi et  al., 2011). Risk factors for a clinically significant endotheliopathy (postoperative corneal edema) in humans include previous ocular surgery or inflammation, diabetes, glaucoma, preexisting polymegethism or pleomorphism, presence of corneal guttata, and Fuch’s endothelial dystrophy (Fig.  10.2.26; American Academy of Ophthalmology, 1997; Giasson et al., 2007). Specular microscopy has been utilized to evaluate the effect on endothelial cell density and polymorphism of increasing cataract maturity in dogs (Renzo et  al., 2014). This study showed no correlation in endothelial cell density or polymorphism (decreased “hexagonality”) between eyes with mature cataract (nondiabetic), hypermature cataract (nondiabetic), or an age‐matched control group with no cataract. Endothelial cell loss and damage during cataract surgery (by both phacoemulsification and extracapsular lens extraction surgery) have also been demonstrated in dogs with specular microscopy, and phacoemulsification time was not correlated with degree of cell loss (unlike in humans; Gwin et al., 1983). Bottle height (i.e., irrigation rate) during phacoemulsification surgery was negatively correlated with postoperative endothelial cell density in a rabbit model (Suzuki et  al., 2009). Specular microscopy has demonstrated that phacoemulsification causes endothelial cell damage and loss by the generation of free radicals (Murano, 2008), and the addition of an antioxidant to phacoemulsification solutions has been shown to be beneficial in some animal and in vitro models (Nemet et al., 2007; Rubowitz et al., 2003). An experimental study in dogs using differing intraocular irrigating solutions (saline, balanced salt solution, and balanced salt solution with added glutathione), however, failed to demonstrate any endothelial morphologic changes between groups using specular microscopy or transmission electron microscopy (Nasisse et  al., 1986). Specular microscopy has also been used to assess the corneal endothelial effect of different artificial intraocular lenses (IOLs) following phacoemulsification, in particular the increased endothelial cell loss associated with anterior chamber IOLs (20% loss vs. 12% loss with posterior chamber IOLs; Werblin, 1993). The use of topical Rho‐Kinase (ROCK) inhibitor eye drops in primates with experimentally induced endothelial cell dysfunction has been demonstrated to aid endothelial healing and cell density, although results were less encouraging in a human clinical trial of eight patients, with clinical improvement only apparent in those with central corneal

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Figure 10.2.26  A. Llama endothelial cells imaged by specular microscopy. B. Close-up view of the same endothelial cells. Polymegathism and pleomorphism are present with guttata. (Courtesy of Dr. Stacy Andrew.)

edema (Okumura et  al., 2013). In contrast to the potential endothelial benefits shown in this study, the same group demonstrated transient (< 24 hr) morphologic changes in the corneal endothelium of human patients and rabbits using specular microscopy and slit‐lamp biomicroscopy, associated with the topical use of another ROCK inhibitor (Ripasudil, licensed for the treatment of glaucoma; Okumura et al., 2015). Corneal endothelial cell recovery following experimental endothelial chemical injury in rabbits, and in three human patients with unilateral ocular chemical injuries, has been studied using specular microscopy, ultrasound pachymetry, and slit‐lamp biomicroscopy, and it was suggested that endothelial cell migration occurred from the peripheral cornea, which may act as a resource for corneal endothelial recovery (Choi et al., 2015). The effect of intraocular drugs on the corneal endothelium can also be assessed using specular microcopy. Studies in the rabbit model have used specular microscopy to assess the endothelial effect of intracameral moxifloxacin, levofloxacin, cefazolin, vancomycin, lidocaine, carbachol, epinephrine, bevacizumab, ethylenediaminetetraacetic acid (EDTA), and viscoelastic agents, among others (Hazra et  al., 2012; Kim et  al., 2008; Lindquist & Robinson, 1996; Liou et  al., 2002, 2004; Park et  al., 2008; Roberts & Pfeiffer, 1989). Specular microscopy has been used in cats to assess the effect of intracameral air versus fluorocarbons (SF6; Landry et al., 2011) and viscoelastic materials (Ohguro et al., 1991), as well as endothelial cell healing from experimental injuries (Bourne et  al., 1994a; Brogdon et  al., 1989; Huang et  al., 1989). Both specular microscopy and ultrasound pachymetry have been used to assess the effects of intracameral lido-

caine on the canine corneal endothelium, demonstrating no toxic effects of 0.1 ml of 1% or 2% preservative‐free lidocaine (Gerding et al., 2004). The endothelial effects of numerous topical drugs, preservatives, and antiseptics have been assessed by specular microscopy and pachymetry in animal models to assess their safety for clinical use (Burstein, 1980; Chang, 2004; Jiang et al., 2009; Matsuda et al., 1989; McGee et al., 2005).

In Vivo Confocal Microscopy of the Cornea The technique of confocal microscopy was first developed by Minsky in 1957 (Winston, 2016), where both the illumination (condenser) and the observation (objective) systems have common focal points (“confocal”). Reflected light is separated from incident light by a beam splitter (mirror) and the detector aperture obscures light that is not coming from the focal point (i.e., scatter), resulting in sharper images with increased resolution compared to conventional microscopy techniques. The high resolution was at the cost of field of view, and this was overcome by synchronized scanning of the tissue, and reconstruction of an image at both high magnification and resolution, with a reasonable field of view (200 × 300 μm). The microscope provides images of optical sections of structures with lateral resolutions of 1–2 μm and axial (depth of field) resolutions of 5–10 μm without the need to physically section or process the tissue (Jalbert et al., 2003). Cross‐sectional images of the tissue can be obtained using oblique views. Resolution at the cellular level has been demonstrated and compared encouragingly with histologic assessment of the same tissue (Masters, 1992, 2009; Petroll et al., 1994). Perhaps

of the optical section, and variation of the slit width controls the amount of illumination reaching the specimen. SSCMs are commercially available (e.g., Confoscan 4™, Nidek Technologies, Aichi, Japan; Confoscan P4™, Tomey, Phoenix, AZ, USA; Leica TCS™, Leica Microsystems, Wetzlar, Germany). LSCMs use a high‐intensity laser light source focused through a pinhole diaphragm, and oscillating mirrors to scan the tissue point by point. Sequential scans allow the development of 2D images. By altering the focal plane, deeper optical sections can be achieved, and with successive series and computer assistance, 3D constructs of the tissue imaged can be produced. The Heidelberg retina tomograph (HRT) is a commercially available LSCM with a 670 μm diode laser, originally developed to evaluate the topography of the retina and optic nerve head. Development of the modification of a detachable objective “Rostock cornea module” by Stave et  al. (2002; HRT II RCM) allowed visualization of the cornea at the cellular level (Fig. 10.2.28). A sterile single‐use contact element

the most important aspect of confocal microscopy is the application to in vivo situations. This allows disease progression of structures to be imaged sequentially, and cellular observations when biopsy and histology are not feasible or desirable. Three microscope types have been described: tandem scanning confocal microscopes (TSCM), slit scanning confocal microscopes (SSCM), and laser scanning confocal microscopes (LSCM, also known as confocal scanning laser ophthalmoscopes or CLSO). TSCMs use rotating Nipkow discs, which consist of a metal plate with microscopic holes arranged in an arithmetic spiral, providing multiple single spots of illumination (Fig.  10.2.27). Rapid disc rotation allows scanning of the whole specimen. TSCMs are no longer in production and were replaced by SSCMs. SSCMs use rapid scanning thin optical slits, and are therefore only truly confocal in one axis only, but they do offer increased light output and reduced scanning time (as all points in the axis of the slit are scanned simultaneously) compared to TSCMs. Adjustments of the slit width will vary the thickness

Laser source

Rotating mirrors

Pin-hole apertures

Objective lenses

Detector

Specimen

A

B Figure 10.2.27  A. Schematic illustration of the confocal microscopy principle where a small pinhole aperture eliminates any scattered reflected light, resulting in sharper images. B. Schematic illustration of a tandem-scanning confocal microscope using a Nipkow disc to provide multiple spots of illumination. (Illustrations by Roser Tetas Pont.)

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Figure 10.2.28  A, B. Illustration of a confocal microscope at differing focal depths within a tissue. C. Use of the confocal corneal module probe at an oblique angle allows a cross-sectional focal plane. (Illustrations by Roser Tetas Pont.)

(TomoCap™, Heidelberg) made from polymethylmethacrylate (PMMA) is coupled optically to the lens with the aid of a gel, and the cap is then coupled to the cornea via the tear film or a protective gel to the eye (Fig. 10.2.29). This modification can also achieve imaging of anterior chamber structures and the lens in vivo, provided the cornea is clear. This was further modified by Kafarnik et al. (2007) for use in veterinary patients and has subsequently yielded normal in vivo structural data for a number of veterinary species (Ledbetter & Scarlett, 2009). Clinical Applications

Corneal confocal microscopy has been utilized in human patients to diagnose and monitor the progression of a number of human keratitides, including Acanthomoeba spp. keratitis, fungal keratitis, and keratoconus, postrefractive surgery patients, and conditions associated with contact lens wear (Efron & Hollingsworth, 2008; Guthoff et  al., 2009; Kobayashi et al., 2008; Niederer et al., 2010; Patel & McGhee, 2009). A recent study of IVCM in cases of suspected Acanthamoeba keratitis has suggested that care should be taken interpreting images with “bright spots” as Acanthamoeba structures, as these were also present in keratitis cases associated with bacterial and fungal keratitides (less specificity than previously assumed; Fust et al., 2017). Much attention has been focused on corneal innervation and its implications for KCS, diabetes mellitus–associated peripheral neuropathy, LASIK, and laser‐assisted subepithelial keratomileusis (LASEK; Cai et al., 2014; Choi et al., 2015; Patel & McGhee, 2009), and more recently the corneal effects

of collagen‐cross‐linking treatments and autologous cultured limbal stem cell grafts (Hovakimyan et  al., 2016; Pedrotti et al., 2015). IVCM has also been used to perform endothelial cell counts, although specular microscopy remains the gold standard technique in donor bank systems (van Schaick et al., 2005). IVCM has been used to diagnose a microsporidial keratoconjunctivitis in a human patient following Descemet’s stripping automated endothelial keratoplasty that mimicked graft rejection, and prevented further inappropriate mismanagement with topical steroids over topical fluconazole (Devi et al., 2017). IVCM has been used to study the effect on corneal permeability of novel vehicles (micelles, nanoparticles, and niosomes) for commonly used topical drugs. For example, IVCM was used in a study investigating the beneficial penetration effects of hyaluronic acid–coated niosomes on tacrolimus in a rabbit model. with implications for prevention of rejection of corneal allografts in human patients (Zeng et al., 2016). This study may also have potentially promising benefits for veterinary patients suffering with immune‐mediated keratitis. Similarly, IVCM has been used to assess coulomb‐controlled idontophoresis delivery of riboflavin compounds for corneal cross‐linking treatment, in both epithelium‐debrided and epithelium‐intact corneas (Arboleda et al., 2014). IVCM has been used to assess the feasibility of using tissue‐engineered living corneal stroma, along with slit‐lamp biomicroscopy, immunofluorescence, and transmission electron microscopy, in a feline model (Boulze Pankert et al., 2014). It has also been utilized to study the effects of stem

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Figure 10.2.29  A. Image of Heidelberg in vivo confocal microscope with attached Rostock Corneal Module (HRT II RCM). B. RCM with TomoCap about to be applied to the cornea of a Boxer dog under general anesthesia.

cell treatment and gene therapy on inherited ocular diseases (Rocca et al., 2015; Serratrice et al., 2014). Although expensive, the microscope is already becoming available to human patients in clinical settings, and this is likely to be mirrored in veterinary ophthalmology in the future. Following on from studies of normal cat, dog, bird, and equine corneal IVCM (Kafarnik et  al., 2007; Ledbetter & Scarlett, 2009), studies of the normal corneal innervation of differing dog and cat breeds (brachycephalic vs. mesocephalic) have also been undertaken (Kafarnik et  al., 2008). Figure  10.2.30 shows IVCM from adult canine and feline corneas, illustrating the variable focal depths achievable with the HRT II‐RCM. IVCM has been utilized to examine corneal innervation in diabetic and nondiabetic canine patients with reference to tear parameters, corneal sensation, and keratitis in a clinical study (Kafarnik, unpublished data). IVCM of type 2 diabetic human patients has demonstrated a progressive loss of corneal nerve density (Lagali et al., 2017), and some authors have hypothesized that testing of corneal sensitivity may be an alternative method for the early identification of diabetic polyneuropathy (Yorek et al., 2016). Endothelial dystrophy in Boston Terriers (as a model for Fuch’s endothelial dystrophy in human patients) has been studied with IVCM, and demonstrated reduced endothelial cell counts and increased polymegathism and polymorphism in affected patients (Thomasy at al., 2016). IVCM has been used to create a baseline of data in the normal healthy laboratory Beagle as a reference for IVCM use in the development of ophthalmic drugs and devices tested on this species and breed (Strom et al., 2016a, 2016b). The use of IVCM in clinical cases of equine keratomycosis has been described and demonstrated to be more sensitive than fungal culture at identifying the presence of fungi (Ledbetter et al., 2011). Figure 10.2.31 is the confocal microscopy image of an ex vivo keratectomy sample from a horse

with Aspergillus spp. keratomycosis. Similarly, IVCM has been used in clinical cases of alpaca keratomycosis to demonstrate fungal elements (Ledbetter et  al., 2013), and to image microscopic corneal foreign bodies in five horses (Ledbetter et al., 2014). A recent study also described canine mycotic keratitis, both in vivo in clinical patients and ex vivo in experimentally infected corneal samples, and was able to monitor therapeutic response (Ledbetter et al., 2016). Comparison of IVCM with histologic findings has been attempted but can be problematic, as the field of view with IVCM is small, identification of the identical area imaged on histology can be extremely difficult, and, as yet, no large‐ scale 2D mapping procedures of the cornea exist. While IVCM has also been described for conjunctival tissue, sclera, limbus, eyelid, lacrimal gland, and tear film, the greatest application has been to corneal imaging. IVCM has been used for corneal pachymetry, and measurement of defined layer thicknesses of the cornea (e.g. epithelium, stroma) as well as keratocyte counts in vivo in rabbits (Petroll et al., 2013), and following superficial keratectomy and conjunctival advancement hood grafts in dogs with spontaneous bullous keratopathy (Horikawa et  al., 2016). Ex vivo confocal microscopy has been successfully used to reconstruct the 3D retinal circulation of the porcine retina as a model for the human retina (Fouquet et  al., 2017). The authors postulated a serial arrangement of retinal blood flow from superficial vascular plexus to intermediate vascular plexus and finally the deep vascular plexus, as opposed to a parallel arrangement with each layer relying on its own arteriolar supply and venous drainage. As IVCM reveals optical sections of a tissue, the opacity of the structure in question, or structures between the microscope and the area of interest, will obscure the image. This limits its application to those disorders where the opacity is

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Figure 10.2.30  Confocal microscopy images from normal canine and feline corneas using HRT II RCM. The bar represents 50 μm. A. Canine superficial corneal epithelial cells (1 μm depth of focus). B. Canine polyhedral intermediate epithelial cells (15 μm depth of focus). C. Canine subbasal nerve plexus (47 μm depth of focus). D. Feline keratocytes and corneal nerves in the anterior stroma (89 μm depth of focus). E. Canine keratocytes in the midstromal cornea (257 μm depth of focus). F. Canine corneal endothelial cells (541 μm depth of focus). G. Feline corneal nerve trunk in the midstromal cornea, with the fine black lines demonstrating compression lines (174 μm depth of focus). H. Cross-image through the anterior stroma and epithelium showing a stromal nerve and small nerve fibers entering the epithelium.

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Figure 10.2.30  (Continued )

not dense enough to obliterate light reflected through it if assessment beyond the surface reflection of the opacity is desired.

Corneal Optical Coherence Tomography Corneal imaging OCT applications include pre‐ and postrefractive surgery (including pachymetry), keratoconus, pre‐ and postpenetrating keratoplasties and lamellar keratectomies, assessment of pterygium, assessment of kerato-

cyte numbers and morphology, endothelial dystrophies, pre‐ and postautomated Descemet’s membrane stripping procedures, among other corneal diseases (Yadav et  al., 2011). The corneal topography can also be illustrated in 3D using corneal OCT and has applications to the diagnosis and treatment of astigmatism (Maeda, 2010). See “Optical Coherence Tomography” later in this chapter. Ultra‐high‐resolution OCT has been used to image rabbit corneal epithelial cells in vitro with an impressive spatial resolution of 1.3 μm (Reiser et al., 2005). OCT of 8–10‐week‐

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Figure 10.2.31  Fungal hyphae (Cylindrocarpon spp.) in the excised corneal button after deep lamellar keratoplasty in a Thoroughbred horse (30 μm depth of focus, using HRT II RCM. The bar represents 50 μm.

old rabbit globes was undertaken within 6 hours of harvesting. This study demonstrated that rabbit epithelial depth was significantly thicker at the center of the cornea than at the limbus. The authors postulated that this could be a protective function against the increased exposure of the central cornea to ambient radiation. Both time‐domain and spectral‐domain OCT have been used for pachymetry in Beagle dogs and compared against traditional ultrasound pachymetry (Strom et al., 2016a). This study demonstrated that time‐domain OCT and ultrasound pachymetry gave significantly thicker values for CCT compared with spectral‐domain OCT. This mirrored a similar previous study comparing spectral‐domain OCT with ultrasound pachymetry in normal anesthetized dogs (3 client‐ owned dogs and 12 adult Beagle dogs), which reported an increased CCT measurement with spectral‐domain OCT pachymetry compared to ultrasound pachymetry (Alario & Pirie, 2014). This may be due to inherent errors associated with ultrasound velocity preset as 1636 m/s, while the canine cornea has been reported to have an ultrasound velocity of 1590 m/s. Strom et  al. (2016b) also reported increasing canine CCT with increasing age and bodyweight, and thicker corneas in intact male dogs compared to female dogs. This contrasts with the Alario and Pirie (2014) study, which found no difference in CCT with gender or age. Spectral‐domain OCT (Optovue®, Optovue, Freemont, CA, USA) has been compared with ultrasound pachymetry (Pentacam) for measurement of feline CCT. While there was a statistically significant difference in measurement with the

two instruments (OCT giving lower CCT results), the authors felt this was not clinically significant (approx. 4%) given the magnitude of normal diurnal variation in CCT (approx. 8%) in this species (Cleymaet et  al., 2016). In this study they found that CCT did not vary with gender, which contrasts with the earlier study by Alario and Pirie (2013b) that demonstrated higher CCT values in spayed female cats compared to castrated males. Spectral‐domain OCT has an advantage over ultrasound pachymetry in allowing measurement of specific layers of the cornea (not just CCT), and this has been utilized in a number of studies across different species (Alario & Pirie, 2013a, 2013b; Gornik et al., 2016; Lo Pinto et  al., 2017a, 2017b; Pinto et  al., 2014; Strom et  al., 2016a, 2017b; Wang & Wu, 2013). The Optovue iVue® spectral‐domain OCT has been used in a clinical study of canine and feline cases with selected corneal diseases, and found to be reliable and accurate in most of the studied cases (Famose, 2013). Assessment of feline corneal sequestra was possible, but in some dense cases was limited by acoustic shadow posterior to the lesion, so that an accurate depth of the lesion could not be ascertained. The noncontact methodology of OCT (compared with ultrasound biomicroscopy) was felt to be an advantage; however, all patients required sedation to obtain usable images due to the fine focus required at high resolutions.

Anterior Segment and Retinal Imaging Retinal In Vivo Confocal Microscopy and Confocal Scanning Laser Ophthalmoscopy Confocal scanning laser ophthalmoscopy (cSLO) is synonymous with LSCM, but has been improved with the addition of adaptive optics (AO). This reduces optical aberrations, as well as lessening the impact of eye saccades on image quality. Irregularities in the corneal and lens surfaces, and astigmatism, are capable of generating aberrations that are difficult to correct. AO was developed by Dreher and colleagues in 1989, allowing corrections for astigmatism and defocus. It was further improved with the development of a Shack Hartmann wavefront sensor for the eye by Laing et al. in 1979. This wavefront sensor could accurately and rapidly measure the eye’s optical aberrations. In 1996, Williams and colleagues built the first AO microscope capable of correcting higher‐order aberrations (Roorda, 2010). Further modification of an LSCM system to incorporate fluorescein angiography aspects (fluorescein adaptive optics or FAO‐SLO) has allowed detailed imaging of the retinal vasculature within the nerve fiber layer, and results have precisely correlated with histologic comparisons (Scoles et al., 2009).

10.2: Ophthalmic Examination and Diagnostics

As IVCM utilizes optical sections of a tissue, it stands to reason that the opacity of the structure in question, or structures between the microscope and the area of interest (e.g., optic nerve head), limits the reflected light and thus the image formed. cSLO is utilized clinically in assessment of optic nerve head parameters (such as disc volume and rim and cup ratios) and glaucomatous cupping in people (Cankaya & Simsek, 2011). Assessment of optic and retinal vascular abnormalities associated with glaucoma is also currently the focus of extensive research using this technology. cSLO in combination with OCT has been used for investigation of many macular diseases in humans (Lima et al., 2011). AO‐cSLO is capable of imaging individual rod and cone photoreceptors, retinal pigment epithelial (RPE) cells, and white blood cells (Godara et al., 2010; Hofer et al., 2011). cSLO has been reported in normal Beagle dogs, cynomolgus monkeys, and Göttingen minipigs (Fig. 10.2.32). It was combined with fluorescein angiography in the same study (Rosolen et  al., 2001). cSLO has been used to demonstrate spontaneous occurring fundus findings in Sprague Dawley rats, including a diffuse hyperfluorescent region at the posterior pole in all the studied rats (ultimately considered a normal finding; Joshi et al., 2016). The study authors suggested that a baseline using in vivo screening should be taken prior to investigations for toxicologic/interventional studies.

Scanning Laser Polarimetry The retinal nerve fiber layer (RNFL) has birefringent properties due to retinal ganglion cell axon microtubules and neurofilaments being highly ordered and paralleled. Polarized light is composed of two orthogonal components; these components travel at different velocities when they pass through a birefringent tissue, which creates a relative phase shift. The phase shift is termed “retardation,” and the amount of phase shift or retardation is proportional to the thickness of the RNFL (Fig. 10.2.33). This modality has been shown to correlate well with histopathologic measurements of RNFL (Weinreb et al., 1990). The cornea and lens, with their ordered parallel arrangements of structures (collagen fibrils or lens fibers, respectively), also have birefringent properties. Measurement and compensation for anterior segment birefringence increases the accuracy of RNFL thickness measurements (Zhou & Weinreb, 2002). The first commercially released scanning laser polarimeter was the GDx Nerve Fiber Analyzer™ (Laser Diagnostic Technologies, San Diego, CA, USA). This was subsequently upgraded to include an anterior segment birefringent compensation with the GDx VCC (variable cornea and lens compensator). The GDx technology was bought by Carl Zeiss

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Figure 10.2.32  cSLO in a dog: (A) optic disc, (B) tapetal fundus, (C) nontapetal fundus, (D) retinal artery, and (E) retinal vein. (Reproduced with permission from Rosolen, S.G., Saint-Macary, G., Gautier, V., & LeGargasson, J.-F. (2001) Ocular fundus images with confocal scanning laser ophthalmoscopy in the dog, monkey and minipig. Veterinary Ophthalmology, 4, 41–45.)

Polarized light (orthogonal)

Microtubules (giving bifringent properties to retinal nerve fiber layer) Phase retardation

Figure 10.2.33  Schematic illustration of phase retardation of polarized light through birefringent tissue. (Illustration by Roser Tetas Pont.)

Meditec International (Jena, Germany), and is currently marketed as the GDx PRO™. Changes in RNFL thickness precede visual field loss and optic nerve head changes, and therefore monitoring of RNFL thickness can assist in the early detection of glaucoma patients (Quigley et al., 1992; Sommer et al., 1991). Scanning laser polarimetry and assessment of RNFL thickness are also used for long‐term monitoring of glaucoma patients and response to therapy (Da Pozzo et  al., 2009; Greenfield & Weinreb, 2008). Measurement of RNFL is also utilized in the assessment of optic neuritis associated with multiple sclerosis (Kolappan et al., 2009).

Optical Coherence Tomography OCT was originally developed to image the retina and optic nerve head with micron‐scale resolution (Huang et  al.,

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1991). This first description demonstrated the remarkable comparison of histology with ex vivo OCT of the human retina and optic nerve. In vivo use was described in 1994 with imaging of the anterior segment of the human eye (Izatt et  al., 1994). The ability to measure retinal layer and optic nerve head thickness allows in vivo assessment of the progression of a number of ophthalmic and neurologic diseases. OCT is capable of providing highly sensitive monitoring of the progression of many ophthalmic conditions, including macular diseases, glaucoma, optic neuropathies, and other neurologic diseases such as multiple sclerosis. Quantification of the retinal nerve fiber layer thickness also provides an indirect measure of axonal and neuronal loss in the inner retina. OCT uses interferometric technology. Light in an OCT system can be considered as broken into two arms: a sample arm (light reflected from the tissue of interest) and a reference arm (light reflected from a mirror of known optical distance from the light source). When these two arms combine an interference pattern occurs, which is dependent on the light wavelength and optical distance from the reflected tissue (or mirror for the reference beam), such that only light in each arm that has traveled less than a coherence length will interfere and contribute to the image. As only coherent (nonscattered) light is detected, high resolution of the imaged tissue is achieved. The use of a longer wavelength of light (near infrared, ~800 nm) allows deeper penetration of translucent or opaque tissues (millimeters) compared to confocal microscopy (5–10 μm; Fulimoto & Huang, 2010; Sainter et  al., 2004). Later OCT systems utilize light of longer wavelengths (~1300 nm), allowing reduced optical scattering and improved image penetration depth (21 mm). The images are illustrated using a false color scale, where different magnitudes of backscattered light are displayed as different colors on a rainbow scale. The RNFL is seen as a highly backscattering layer (red) that decreases in thickness further from the optic disc. The RPE and choroid are seen as a single thin highly backscattering layer posterior to the retina. Nuclear layers are weakly backscattering and appear blue‐black in color‐scale OCT images. The position and intensity of the reflection from the tissue can be mapped along a line of set depth through the retina (A‐scan). The image contains information about the spatial arrangement of structures within the tissue, and serial axial scans (i.e., at different depths) can be combined to give a cross‐sectional image (B‐scan). Further combination of images can allow a 3D image to be obtained by the latest generation of OCT machines (spectral‐domain OCT; Fig. 10.2.34, Fig. 10.2.35, and Fig. 10.2.36). En face images (C‐scan) can also be obtained by some machines, providing information on the topography of the tissue, and are particularly useful when imaging the optic nerve head and cup. These scans achieve images of retinal layers parallel to the

surface of the retina at differing depths. Irrespective of scan type, the patient is asked to fixate on a point during each scan, and digital processing of the captured signal is required to correct for small eye movements, as well as improving the signal‐to‐noise ratio. In veterinary patients, OCT is typically performed under general anesthesia to reduce eye movement. Measurement of the time of light delay reflected from the retina, compared to the time of light delay from the reference mirror of known optical distances, provides quantitative data on the position of retinal structures, and is known as time‐domain OCT. Current time‐domain OCT technologies can achieve axial resolution of approximately 10–15 μm (Townsend et al., 2009). Swanson et al. (1993) published the first retinal images obtained by time‐domain OCT in 1993, although the same group first described the technology in 1991 (Huang et  al., 1991). Time‐domain OCT is limited in speed of image capture, as data is collected pixel by pixel along an A‐scan, and acquisition is approximately 400 A‐scans/s. Eye movement artifacts limit the number of scans that can be undertaken at a time. More recently, spectral‐ domain (also known as Fourier‐domain) OCT has been developed that has higher spatial resolution (3–6 μm) and is considerably faster at acquiring scans than time‐domain OCT (Fercher et  al., 1995). Spectral‐domain OCT uses a broad bandwidth of light frequency with a stationary reference mirror, with the reflected images collected simultaneously by a spectrometer. Each frequency of light represents a different tissue depth and can be therefore mapped to differing retinal locations (Townsend et al., 2009). As each A‐scan is captured almost instantaneously, spectral‐domain acquisition can reach 24,000 and 55,000 A‐scans/s. Spectral‐domain images and measurements cannot be directly compared to time‐domain OCT results, and it is likely that spectral‐ domain OCT will be widely adopted in the future due to the impressive and rapid images obtained. A new generation of OCT known as “swept‐source” is available within the research community, but is not yet available clinically. Swept‐source OCT (SS‐OCT) has similarities to spectral‐domain OCT (the location of the reflection is encoded by frequency of the light), but instead of detecting a single broadband reflection, SS‐OCT covers the range of frequencies one at a time. This allows the scan acquisition rate to be greater than 200,000 A‐scans/s, thereby almost eliminating motion artifacts (Townsend et al., 2009). Ultra‐high‐resolution OCT retinal imaging was first demonstrated in 2001, and could achieve axial resolutions of approximately 3 μm, in comparison to commercially available OCT instruments with axial resolution of approximately 10 μm (Drexler et al., 2001). These images compare favorably with histologic studies and allow the identification of individual retinal layers, including the photoreceptor layer (Gloesmann et al., 2003; Srinivasan et al., 2008). Even the junction between the inner and outer segments of

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Figure 10.2.34  Optical coherence tomography two-dimensional (2D) and three-dimensional (3D) reconstruction images of a normal adult Beagle fundus. A. Cross-section and 3D reconstruction at peripapillary region. B. Fundus image and 2D cross-sectional image at the level of the optic nerve head, location illustrated by the central green line on the fundus photograph. C. Cross-section and 3D reconstruction image at the optic nerve head. D. Cross-section and 3D reconstruction image medial to the optic disc. E. Cross-section and 3D reconstruction image at the limit of the optic cup of the optic disc. (Courtesy of Matthew Annear and Simon Petersen-Jones, Michigan State University.)

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C Figure 10.2.35  Optical coherence tomography with three-dimensional (3D) reconstruction images of a normal feline (Domestic Shorthair kitten) fundus. A. Cross-section and 3D reconstruction image at the optic disc of a 12-week-old kitten. B. Cross-section and 3D reconstruction image at the optic disc of a 15-week-old kitten. C. Cross-section and 3D reconstruction image of the peripheral retina in a 15-week-old kitten. (Courtesy of Laurence Ocelli and Simon Petersen-Jones, Michigan State University.)

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B Figure 10.2.36  Optical coherence tomography (OCT) two-dimensional (2D) and three-dimensional (3D) reconstruction images of a feline fundus with multifocal retinal dysplasia (12-week-old Domestic Shorthair kitten). A. Fundus photograph and 2D cross-section OCT at level of retinal dysplastic lesions. B. Cross-section and 3D reconstruction at site of retinal dysplastic lesions. (Courtesy of Laurence Ocelli and Simon Petersen-Jones, Michigan State University.)

photoreceptors can be identified with ultra‐high‐resolution OCT, due to the increased backscatter from the refractive change between the inner segments and the tightly stacked membranous discs of the outer segments. Corneal modules have been developed that allow imaging of the anterior segment (e.g., Visante OCT 3.0™, Carl Zeiss Meditec; Cornea‐Anterior Module RTVue™, Optovue) from the tear film to the iris and anterior lens (see “Clinical Applications” following). The combination of cSLO with OCT has allowed high‐ resolution en face images of individual retinal layers to be achieved (Podoleanu, 2006). Polarization‐sensitive OCT combines the benefits of scanning laser polarimetry with OCT for imaging of the RNFL (Townsend et al., 2009).

Clinical Applications OCT is used extensively for the monitoring of retinal and optic nerve head diseases within clinical settings. Descriptions of the macula, optic nerve head, and RNFL are the most common in the literature, and longitudinal assessment of qualitative and quantitative information for each area can be obtained. Early studies established OCT as means of monitoring macular diseases such as macular edema, macular holes, age‐related macular degeneration (AMD), and choroidal neovascularization. OCT imaging can also be used to provide quantitative measurements using image‐processing algorithms to automatically extract values for retinal and retinal nerve fiber thicknesses. OCT is also used extensively in differentiating (and subsequent

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­ onitoring of) glaucomatous from nonglaucomatous optic m nerve head cupping in humans (Gupta et al., 2011; Schuman et al., 1995). The RNFL has high reflectance due to the arrangement of nerve fibers perpendicular to the angle of the OCT light beam, and due to its anterior location in the retina. Thinning of the RNFL is encountered in many diseases, including glaucoma and following acute optic neuritis, multiple sclerosis, and other neuropathies, and can be used as a highly sensitive method of assessing structural loss. OCT is able to distinguish subtle changes in tissue thicknesses prior to lesions being funduscopically obvious. Correlation with functional deficits has also been demonstrated at thresholds of retinal nerve fiber thickness (75 μm; Wollstein et  al., 2012). Polarization‐sensitive OCT is a technology used in glaucoma imaging research. The high axial resolution of OCT combined with measurement of tissue birefringence of scanning laser polarimetry could allow greater contrast between the RNFL and other retinal layers, and therefore more precise measurements of this layer. The retinal surface is used as a reference so that corneal compensation of birefringence is adjusted for, increasing the accuracy of measurements. Polarization‐sensitive OCT has also been used to study the RPE) with reference to age‐related macular degeneration) as well as the cornea (Gabriele et al., 2011). Descriptions of whole‐eye OCT imaging have been published in rodent eyes using stepped focal planes (i.e., increasing depths through the eye at which OCT is focused) in research settings (Zhou et al., 2008). Anterior segment OCT has been used extensively in humans both clinically and experimentally. OCT also has the advantage of being a noncontact imaging modality and therefore provides increased patient comfort. Anterior segment biometry with OCT can assist in the selection of appropriate IOLs, as well as providing information on anterior chamber depth, width, and crystalline lens vault. Assessment of the iridocorneal angle (ICA) with OCT has also been achieved, resulting in detailed assessment of the angle opening distance, angle recess area, trabeculo‐iris area and meshwork, the ICA in degrees, Schlemm’s canal, and Schwalbe’s line. The ICA has been quantitatively measured using time‐domain OCT (Visante Anterior Segment OCT) undertaken in several healthy mammalian species and normal baseline data reported (Almazan et  al., 2013). It is also able to provide images of anterior segment tumors (anterior to iris; posterior to iris ultrasound biomicroscopy is superior), iris cysts, nevi or melanoma, and iridoschisis (Konstantopoulos et al., 2007; Ramos & Huang, 2009). OCT of the canine retina was described by Panzan et al. in 2004, and comparisons of retinal thickness with dogs affected with progressive retinal atrophy (PRA) caused by the rcd1 mutation were made. Normal dogs have a thicker retina in the tapetal fundus compared to nontapetal fundus,

and rcd1‐affected dogs had reduced retinal thickness at the area centralis and dorsal retina. The nerve fiber layer thickness was similar in both rcd1‐affected and normal dogs (Panzan et  al., 2004). Figure  10.2.37 illustrates the fundus photographs and OCT images of a normal Papillon dog and a PRA‐affected Papillon dog. Progression of RPGRIP‐1 early‐onset PRA in the Miniature long‐haired Dachshund has been investigated with serial OCT examinations of the retina 3 mm dorsal to the optic disc. Progressive thinning of the outer nuclear layer was documented over a 2‐year period in affected dogs. Comparisons with histopathology and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) immunohistochemistry of retinas from affected dogs revealed that this thinning was due to photoreceptor apoptosis (Lhériteau et al., 2009). The multifocal retinopathy of Cotton de Tulear dogs was reported by Grahn and Wolfer (1997). Investigations included clinical ophthalmologic examination, electroretinographic studies, fluorescein angiography, indocyanine green angiography, ultrasonography, and OCT (Grahn et al., 2008). OCT revealed large retinal detachments in early life, with elevation of the inner limiting membrane of the retina several millimeters into the vitreous. The serous content of the bullae diminished after several years, leaving focal areas of hyper‐reflectivity visible on ophthalmoscopy. The effect of experimentally induced acute IOP elevation has been studied in dogs using OCT and demonstrated significant thinning (by approx 30 μm) of the ventral retina at days 15 and 30 compared to pre‐IOP elevation thicknesses. The dorsal retinal thickness was not significantly different from baseline values (Grozdanic et al., 2007). OCT has also been used to assess the effect of subretinal injections of recombinant adeno‐associated virus 2/2 (rAAV2/2), carrying the RPE65 gene (as a gene therapy of RPE65‐deficient retinal dystrophy in Briard dogs), on retinal thickness and morphology. The localized retinal detachment caused by the injection was reported to resolve by 24–48 hrs in all dogs, with most retaining normal retinal morphology on OCT images. Retinal thinning was seen in some areas by OCT and these areas corresponded to fluorescent antibody‐evident hyperfluorescent areas (Le Meur et al., 2007). Time‐domain OCT has been used to image the posterior segment of cats and was found to be useful for longitudinal studies and quantifying retinal thickness (Gekeler et  al., 2007). The resolution of this system was documented as 10–20 μm, which has been superseded by higher resolutions achievable by later generations of OCT (e.g., spectral‐domain and swept‐source OCT). A subsequent review article by McLellan and Rasmussen (2012) highlighted some of the constraints, limitations, and practical considerations for the use of OCT (both time‐domain and spectral‐domain) in posterior segment imaging of animal species.

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B Figure 10.2.37  A. Fundus photograph and optical coherence tomography (OCT) image of normal adult Papillon dog. B. Fundus photograph and OCT image of a young adult Papillon dog with progressive retinal atrophy. Note the marked outer nuclear layer thinning. (Courtesy of Simon Petersen-Jones, Michigan State University.)

OCT has been used extensively in chickens as animal models for human disease, but OCT in other avian species to investigate visual acuity and foveal characteristics, retinal structure, and pathologies has also been described (Potier et  al., 2016; Rauscher et  al., 2013; Ruggeri et  al., 2010). Reptile species have also been examined using OCT, but these studies have been limited to the spectacle, cornea, and/ or anterior segment (Cazalot et al., 2015; Da Silva et al., 2014; Gornik et al., 2016; Rival et al., 2015; Tusler et al., 2015).

Laser Doppler Flowmetry Another technology capable of measuring retinal blood flow utilizing Doppler principles is laser Doppler flowmetry (LDF), and this has been used experimentally to determine blood flow through superficial microcirculations in many tissues, including neural, muscle, skin, bone, respiratory, and intestine. LDF has also been used to investigate the pathophysiology of equine laminitis, as well as endoscopically to investigate inhalational injuries in a sheep

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model for smoke inhalation in humans (Adair et al., 2000; Loick et al., 1991). LDF uses a lower‐power laser, often helium‐neon (633 nm), although laser sources used in LDF can range from 540 to 780 nm. The light source must be monochromatic (single wavelength) so that the Doppler frequency shift in backscatter causes a broadening of the frequency of the original monochromatic light source, which is subsequently quantified. Ocular applications have been in experimental studies of animal models for human diseases and treatments. These research areas include glaucoma, AMD, diabetic retinopathy, retinopathy of prematurity, and other ocular diseases. Improved blood flow of the optic nerve head has been demonstrated with prostaglandin analogs in animal models (e.g., rabbits, cats, and nonhuman primates) using LDF technology (Ishii et al., 2001; Izumi et al., 2008a; Kurashima et al., 2010). Topical dorzolamide has been reported to have no effect on choroidal blood flow in rabbits measured by LDF, but it reduced aqueous production (demonstrated by laser fluorophotometry; Reitsamer et al., 2009). A study in cats using LDF demonstrated that acute hyperoxia induced vasoconstriction, and reduced blood velocity and flow, which subsequently returned to baseline within 10 minutes after hyperoxia ended. The same study also revealed that this effect could be ablated by intravitreal injection of BQ‐123 (specific vascular endothelin type A receptor antagonist) 60 min prior to hyperoxia. The authors suggested the results indicated that nitrous oxide contributes to retinal blood flow recovery after hyperoxia, probably through the action of endothelial nitric oxide synthase via the endothelin type B receptor in the vascular endothelium of the retinal arterioles. However, in the same study, intravitreal injections of BQ‐123 did not have a substantial effect on retinal circulatory parameters before the induction of hyperoxia, suggesting that endothelin‐1 did not play an important role in regulating retinal circulation under basal condition (normoxia; Izumi et al., 2008b). LDF has been used to demonstrate increased retinal blood flow in response to acute hyperglycemia in cats. Sogawa et al. (2010) concluded that acute hyperglycemia increased the retinal circulation, probably via increased serum osmolality, and might cause endothelial dysfunction in the retinal microcirculation in healthy cats. This effect had also been reported using fluorescein angiography in an earlier study, in which the effect of an increased circulatory volume was mimicked using equisomolar mannitol and revealed that retinal autoregulation was maintained by vasoconstriction. Vessel diameter, however, remained unchanged in the presence of hyperglycemia, resulting in a significantly increased retinal blood flow (Atherton et al., 1980).

Color Doppler Optical Coherence Tomography Doppler OCT is based on the principle that moving particles (such as red blood cells) inside a blood vessel cause a Doppler

frequency shift to the scattered light. The frequency shift is dependent on the refractive index of the medium, the incident light wavelength, the angle between the incident light and the flow direction, and the velocity of the flow. The phase difference between sequential axial scans at each pixel is determined to calculate the Doppler shift. The time difference between sequential scans limits the maximum detectable flow velocity (e.g., for RTVue OCT with a line rate of 27,230 Hz the maximum detectable flow velocity is 4.21 mm/s; Wang & Huang, 2010). If the flow velocity and vessel dimensions can be measured, the volume of flow over time can be calculated. Background movement of the retina due to eye movements can be measured from the OCT image and subtracted from the blood flow velocity measurement.

Optical Coherence Tomography Angiography Fluorescein angiography (FA) currently remains the gold standard for retinal and choroidal angiographic studies (De Oliveria et  al., 2017; Naigel et  al., 2015; Novais et  al., 2016) and is described in greater detail later in the chapter. However, it is time consuming and invasive, with the risk of adverse events ranging from nausea to anaphylaxis. Optical coherence tomography angiography (OCTA) works by repeatedly scanning the same chorioretinal area and measuring the differences in signals from sequential scans (amplitude or phase variance). Static tissue generally demonstrates little change, whereas moving structures (blood cell flow) will generate variations from one image to another. Using algorithms, 2D and 3D images of angiography can be produced. OCTA is able to investigate deeper posterior segment vasculature within the eye (e.g., choroidal) that FA may struggle to delineate (due to obscured vessels by overlying hyperfluorescence). The limitations of OCTA include a small field of view (excluding some peripheral areas), sensitivity to eye motion artifacts, and the lack of information on vessel leakage or pooling that FA provides. Optical microangiography (OMAG) combines both amplitude and phase variations in OCT signals to provide blood flow information within the scanned tissue volume. OMAG has an axial resolution of 8 μm (An et al., 2010; Dithmar & Holz, 2008) and, with the addition of a motion tracking system through an auxiliary line scan ophthalmoscope, has provided high‐resolution wide‐field OMAG (Zhang et  al., 2016).

Laser Fluorophotometry and Laser Flare Cell Meters Laser fluorophotometry provides a means of assessing aqueous production and outflow, and is used extensively in research to indirectly assess the blood–aqueous barrier

(BAB). An increase in aqueous concentration of a plasma protein, indicating BAB breakdown, can be identified by paracentesis, but this procedure itself will induce BAB breakdown. Laser fluorophotometry is a means of quantifying BAB breakdown by the passage of a tracer substance (injected intravenously) across the barrier. The ratio of the aqueous to plasma level of the tracer indicates the permeability of the BAB to this tracer. Sodium fluorescein is a small molecule and therefore readily passes through an intact BAB. This can limit its use for the identification of BAB breakdown, but allows the dilution of fluorescein in the anterior chamber to be measured, and thereby an indirect measurement of aqueous production and outflow (Shah et al., 1993). Fluorescein‐labeled albumin, which as a large molecule does not readily cross an intact BAB, is a useful tool for identifying BAB breakdown (Mitchell et al., 1986). Laser flare‐cell photometry can objectively, and noninvasively, monitor intraocular inflammation by quantifying aqueous flare and cells (Guex‐Crosier et  al., 1995; Ladas et  al., 2005). To quantitatively measure protein (flare), the machine records the amount of scattered light (usually a helium‐neon (He‐Ne) beam) detected by a photomultiplier in a set volume of aqueous. For cell counts two optical scanners are used in synchrony across a fixed area of aqueous. When a large particle (cell) is scanned, a sharp peak (of reflected light) is detected and the number of peaks is reflected in a cell count.

Fluorescein Angiography FA provides a means of examining the vascular components of the fundus. Some chemicals can be excited by light radiation, absorbing the radiant energy and causing free electrons within the chemical to reach higher levels of energy. The electrons are unstable in this state and ultimately release (emit) the absorbed energy. As the emitted radiation is of a lower energy than the absorbed radiation, the emitted radiation is always of a longer wavelength than the absorbed radiation wavelength. The first report of FA use to image retinal circulation was described by Novotny and Alvis in 1961, although Chao and Flocks (1958) had used experimental intravascular trypan blue to outline the retinal circulation before this report. FA has also been described in the anterior segment, and is capable of illustrating iris vasculature, iritis in nonpigmented animal models of disease, as well as iridal tumors and vascular anomalies in human patients (Cavallerano, 1996; Dithmar & Holz, 2008). Sodium fluorescein is water soluble and a weak acid with an absorption spectrum of 465–490 nm and an emission spectrum of 520–530 nm. Absorption and emission spectra are altered by pH and reach a maximum at pH 7.5–8.5

(Doughty, 2010). After intravenous injection, 70–80% of the sodium fluorescein is protein bound, largely by albumin. Unbound fluorescein is able to pass through blood vessel walls, except in the regions of blood–ocular and blood–brain barriers. Therefore, skin and mucosal surfaces (most noticeably the conjunctiva) take on a yellow appearance, which dissipates over a few minutes. Fluorescein is largely excreted by the kidneys, usually within 24 hrs in the absence of renal impairment, and resulting in discoloration of the patient’s urine (Dithmar & Holz, 2008). Sodium fluorescein is injected intravenously and the retina is illuminated with blue light (490 nm) using a barrier filter, which excites the fluorescein as it travels through the choroidal and retinal vasculature. Black and white fundus photography is undertaken using a red‐free filter (525 nm) to increase the contrast of images and record the fluorescence of tissues. Contrast enhancement by the retina itself occurs due to the presence of the yellow pigment xanthophyll in the outer nuclear and plexiform layers, which absorbs the blue excitation light wavelengths (Davies & Morland, 2004). Baseline photographs are taken prior to fluorescein injection to identify (and thereby exclude in interpretations) autofluorescence of retinal structures. Photography is usually undertaken using black‐and‐white film to enhance the contrast of images; however, high‐speed color film has also been used, and more recently digital images and movie clips have been recorded. Photographs are taken before and repeatedly after fluorescein injections to chart the stages of retinal circulation from the choroid to retinal vessels, and recirculation when present. Autofluorescence is recorded when natural products within the eye (fluorophores) are excited by light of a particular wavelength. These products may occur naturally in the eye or may accumulate as a byproduct of a disease process (e.g., drusen, lipofuscin). Ceroid lipofuscinosis autofluorescence in dogs and sheep (animal models for human neuronal ceroid‐lipofuscinosis disease) has been objectively quantified using a digital radiometer and FA, and compared to age‐matched controls (Armstrong et al., 1988). Lipofuscin accumulates in RPE as part of the normal recycling mechanism of photoreceptor outer segments. With aging, or other disease processes, this may be increased, causing increased autofluorescence. For example, a study investigating the effects of a diet deficient in xanthine, lutein, and omega‐3 fatty acids in rhesus macaques (from birth) demonstrated a greater retinal autofluorescence in deficient animals, equivalent to a 12–20 year accumulation of lipofuscin in animals fed a standard diet (McGill et  al., 2016). Similarly, loss of RPE cells leads to a reduction in normal autofluorescence. As lipofuscin accumulation may precede RPE cell death, increased autofluorescence may be predictive of future atrophy in AMD (Holz et al., 2007). The high level of protein binding of sodium fluorescein intravascularly is postulated to be partly responsible for the

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low toxicity observed to intravenous fluorescein injections. Emesis is reported in approximately 5% of small animals, and is the most commonly reported side effect. Side effects of FA in humans are reported as nausea in approximately 3% of patients, vomiting in approximately 1%, and skin reactions (flushing, itching, and urticaria) in 0.5% (Shahid & Salmon, 2010). Previous FA adverse events were associated with almost a 49% risk of a second adverse event on repeated FA in human patients (Kwiterovich et al., 1991). Rarely fatal anaphylaxis has been reported in humans, as well as cutaneous photosensitization (Danis & Stephens, 1997; Hitosugi et  al., 2004). Prophylaxis with antihistamines has been reported to reduce side effects (nausea and dizziness) in human patients, although this was not correlated with a reduction in plasma histamine (Ellis et al., 1980). In a prospective study (Kalogeromitros et  al., 2011), allergic skin testing or history of previous FA was not correlated with adverse reactions, leading the authors to conclude that adverse reactions were mediated by nonimmunologic means. Despite this, the authors recommended sodium fluorescein intradermal skin testing for predicting anaphylaxis in patients with risk factors in their medical history. This protocol is supported by another study of fluorescein anaphylactic reactions and the predictive value of intradermal skin tests (Matsuura et al., 1996). Investigation of a human patient suffering an adverse fluorescein reaction demonstrated positive skin tests and a dramatic increase in serum tryptase (a neutral protease from human mast cells) compared to nonreactive controls. The authors of this report postulated an immunoglobulin E‐mediated mechanism for this adverse reaction (Lopez‐Saez et al., 1998). Another prospective study described increased risk of adverse reactions following FA associated with allergic history, diabetes, or systemic hypertension (Lira et  al., 2007). In contrast, systemic hypertension was reported to be associated with a decreased risk of adverse reaction in another study (Musa et al., 2006). Anecdotal reports of reduced FA adverse events after prewarming of sodium fluorescein prior to injection were not supported by a prospective study (Lee et al., 2001). The sodium fluorescein solution is administered as a bolus injection via the jugular, cephalic, saphenous, ear, tail, or wing veins, depending on the species being investigated. A high‐concentration small bolus is recommended to achieve a sharp and bright dye‐front in the choroidal vasculature. Administration via an arterial vessel close to the eye (e.g., internal carotid artery) has also been recommended by some authors to avoid dilution of the bolus (Hayreh, 1974). Dosages of sodium fluorescein have been established for most species, which provide maximal fluorescence with minimal risk of adverse event. FA is usually performed under deep sedation or anesthesia in veterinary species, to avoid eye movements disrupting photographic sequences. General anesthesia is sometimes avoided due to the downward deviation of the globe, making

fundus photography more problematic. As both anesthesia and sedation have effects on the circulatory system, they might be expected to affect FA phase times. A comparative study examining different anesthetic protocols and FA in the dog has been reported, but failed to demonstrate any significant effect on FA phase times (Martin et al., 2001). Other dyes have also been described for fundus angiography and include indocyanine green (ICG) angiography (peak absorption 790–805 nm, peak emission 825–835 nm), pyranine (peak absorption 455 nm, peak emission 520 nm), and rhodamine (peak absorption 555 nm, peak emission 585 nm). ICG is a tricarboxycyanine dye with absorption and emission spectra within the infrared spectrum. Infrared radiation can better penetrate tissues containing pigment (such as RPE), areas of exudation, or hemorrhages. Not surprisingly, therefore, ICG angiography has been found to be more sensitive than FA in delineating abnormalities deep in the neurosensory retina (Okada et  al., 1998; see later Fig.  10.2.41 and Fig. 10.2.42). Intravascular ICG is 98% plasma‐protein bound and is therefore almost completely confined to the intravascular space. ICG has a lower intensity of fluorescence and therefore larger doses are usually required to provide comparable angiography. It is metabolized in the liver. ICG is available as a solution with 5% iodine as a stabilizer, and is therefore contraindicated in cases of hyperthyroidism. A noniodine‐containing agent incorporating infracyanine green is available to use in such circumstances. Both agents are also utilized intravitreally for staining of the inner‐limiting membrane during vitreoretinal surgeries (e.g., epiretinal membrane peeling; Stansecu‐Segall & Jackson, 2009). Leukocyte staining with tracking of movement (and calculation of velocity) through the fundus has been undertaken experimentally in rodents and nonhuman primates using acridine orange (Nishiwaki et  al., 1995; Ogura, 1999). Acridine orange is both carcinogenic and phototoxic to cellular lysosomes and is therefore not utilized in human or veterinary patients. Other leukocyte stains include fluorescein isothiocyanate, sodium fluorescein, ICG, and carboxyfluorescein diacetate (Fallacier et al., 1995; Khoobehi et al., 2003). Fluorescence is witnessed in the fundus 5–50 seconds after intravenous injection, depending on species and cardiovascular factors. Following intravenous injection, fluorescein enters into the choriocapillaris and leaks into the choroidal interstitium via numerous large vascular fenestrae. Thereafter the fluorescein is observed in the retinal arterioles, followed by retinal capillaries, then retinal venules, and finally a recirculation may be seen. Fluorescein is normally retained within retinal vessels by the lack of endothelial fenestrations, and entry into the retina from the choroid is prevented by the tight junctions between RPE cells (retinal blood barrier). The presence of pigment within the RPE obscures the choroidal phase if present, and. similarly, the presence of a tapetum reduces the quality of FA images,

thereby limiting the ability of FA to investigate abnormalities within the tapetal fundus. Descriptions of the FA phases are largely derived from the human literature. These were first described as (1) choroidal flush; (2) early arteriolar phase; (3) late arteriolar phase; (4) capillary phase; (5) early venous phase; and (6) late venous phase. This has subsequently been simplified to (1) preretinal or choroidal phase; (2) retinal arterial phase; (3) retinal arteriovenous phase (lasting up to the first appearance of fluorescein in the retinal veins, and subdivided into early, intermediate, and late arteriovenous phases by some authors); (4) retinal venous phase; and (5) late phase (during which the fluorescein fades away and may include a recirculation phase; Dithmar & Holz, 2008; Hayreh, 1974). Abnormalities in FA are broadly categorized into hypofluorescence and hyperfluorescence, and also by location and size of the abnormality. When interpreting pathologic fluorescence, the origin of the fluorescence (or lack of) and the temporal angiographic phase should be considered, as during the course of an angiogram hypofluorescence and hyperfluorescence can alternate in the same location(s). For example, chorioretinitis is typically associated with an initial hypofluorescence associated with retinal edema, followed by hyperfluorescence due to increased local vascular permeability. Hypofluorescence can be associated with blocking of fluorescence, for example by the presence of vitreal or intraretinal hemorrhages, or a subretinal (choroidal or RPE) process, where retinal vessel fluorescence would be normal overlying choroidal hypofluorescence. Alternatively, hypofluorescence may occur due to vascular filling defects, such as retinal occlusions or decreased tissue perfusion. Hyperfluorescence can occur due to a window defect or increased accumulation of fluorescein dye. A window defect occurs where normal fluorescence is no longer blocked by normal tissue that is absent or reduced, for example RPE coloboma or a retinal hole. Fluorescein may accumulate due to leakage from vessels with increased permeability, pooling in anatomic space (e.g., under a serous RPE detachment where fluorescein from the choriocapillaris may collect) or by staining of a tissue with fluorescein. Staining can occur in normal tissues (e.g., the sclera, which might be visible through a coloboma) or in pathologic conditions (e.g., fibrotic scarring of the choroidal vascular tissues). Hyperfluorescence may also been seen in abnormal vasculature, in that those vessels, if patent, will also fill with fluorescein, such as is encountered with choroidal neovascularization.

Clinical Applications FA is used to assess changes in posterior segment circulation, including choroidal or retinal neovascularization, aneurysms, increased vascular permeability, ischemia, or vessel occlusions. FA is useful in the investigation of neovas-

cularization associated with retinal disorders such as age‐ related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. FA allows both new vessel and increased vascular permeability imaging through various stages of diseases, as well as responses to treatments over time. FA has also been used to assess the effect of treatments of nonvascular diseases on posterior segment circulation (e.g., diode laser retinopexy for partial retinal detachment), as well as an objective means of assessing animal models of retinal/choroidal vascular diseases. Hill and Young first described FA in the normal cat in 1973, and this work was followed by research on experimental laser‐induced choroidal ischemia in cats illustrated by FA by the same authors (Hill & Young, 1973a, 1973b; Hill et al., 1973). Further FA work (combined with India ink histology) described the regional retinal circulation of the cat for the first time (Hill, 1977; Hill & Houseman, 1980; Hill & Young, 1976). FA has been used to investigate the role of vascular disease in inherited retinal degenerative diseases in cats, and demonstrated no change in FA phase times or appearances in the studies (Bellhorn et  al., 1974; Narfstrom, 1985; Rah et  al., 2005). The treatment of inherited retinal degeneration with retinal allograft transplantation has also been studied in the cat, with the aid of FA (Seller et al., 2009). Feline models for human retinal degeneration, retinal arteriolar branch occlusions, and serous retinal detachments have also been examined by FA (Hayashi et  al., 1997; Lai et  al., 1997; Levinger et  al., 1987; Marmor & Yao, 1994). Experimental exudative retinal detachments in cats have been investigated using rose Bengal‐induced (phototoxic) vascular occlusion, as a model for choroidal ischemia in humans (Wilson et al., 1991). FA in these cats demonstrated focal retinal and choroidal occlusions, followed by a progressive serous retinal detachment, which slowly resolved over 14–21 days. The safety of a subretinal microphotodiode array as a possible treatment for retinal degenerative disease has been investigated with both FA and OCT in a feline model (Volker et al., 2004). Metastasis of angioinvasive pulmonary carcinoma to the ocular posterior segment in cats has been investigated by FA and histopathology, and revealed invasion and growth of neoplastic cells within the chorioretinal vasculature, resulting in secondary ischemic necrosis of the retina and choroid (Cassotis et al., 1999). Alario et  al. (2013a) described anterior segment fluorescein angiography (ASFA) in normal cats using sodium fluorescein and a modified digital single‐lens reflex (dSLR) camera (Canon 7D™). Their protocol included premedication with maropitant and diphenhydramine, and no adverse events were reported. The authors postulated that the feline iris contains greater proportions of pheomelanin relative to eumelanin (unlike the canine iris), with a corresponding lower absorption coefficient (435–530 nm wavelength

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required to excite fluorescein) and therefore enhanced image quality (Fig. 10.2.38 and Fig. 10.2.39). Pirie and Alario (2015) reported the use of fluorescein and ICG for the anterior segment angiography of normal cats. The authors felt that ICG angiography was superior to FA; however, both were of diagnostic quality. Gelatt and others first described FA in the normal Beagle, as well as in Beagles with chorioretinitis, in 1976 (Gelatt et al., 1976). The optimum fluorescein dose was devised, and FA was recorded using high‐speed color film in a portable fundus camera. Filling defects have been reported in a normal dog associated with occlusion of the carotid artery by a technician holding the head for fundus photography (Martin et al., 2001). Alario et al. (2013b) also described ASFA in normal dogs using sodium fluorescein and a modified dSLR camera. The authors premedicated with maropitant and diphenhydramine and noted no adverse events (Gelatt et al., 1976 reported emesis in 15% of dogs), matching their findings in cats. They also recommended general anesthesia for optimal image quality, and that heavily pigmented irides precluded assessment of iridal vessels (see Fig.  10.2.40). Alario and Pirie (2015) reported fluorescein gonioangiography in normal dogs using sodium fluorescein (20 mg/kg of 10% sodium fluorescein) and a Lovac–Barkan goniolens, under general anesthesia and employing stay sutures in the perilimbal conjunctiva to aid globe positioning. They used the same maropitant and diphenhydramine premedication and reported no adverse events. Diffuse hyperfluorescence of the underlying sclera was evident within the drainage angle, but no angiographic phases (arterial, venous, capillary) were identified within the pectinate ligament (Alario & Pirie, 2015). The FA abnormalities associated with PRA in poodles have been described with two main FA appearances: a diffuse choriocapillary atrophy (hypofluorescence), or a patchy choroidal atrophy associated with major retinal vessels. Interestingly, carrier dogs also showed FA abnormalities, with patchy hyperfluorescence associated with depigmentation, arteriolar narrowing, and irregularities, and indistinct capillary beds compared to normal Poodles (Koskinen et al., 1985). FA has also been undertaken in Tibetan Terriers with PRA, but failed to identify vascular abnormalities earlier than were visible on ophthalmoscopy (Millichamp et  al., 1988). Gene therapy of RPE‐65–deficient Briard dogs with rAAV2/2, ‐2/1, or ‐2/5–mediated delivery of the RPE65 gene has also been investigated using FA. Focal zones of hyperfluorescence, corresponding to the areas of subretinal injection (and focal retinal detachment), were considered secondary to the trauma of injection. Interestingly, however, this abnormality was not seen in normal Briard dogs receiving the vehicle alone by subretinal injection, or in normal Beagle dogs receiving either the AAV2/4.hrpe65 or the AAV2/2.hrpe65 vector alone, perhaps suggesting a trauma

vulnerability in affected Briard dogs (Le Meur et  al., 2005, 2007). The inherited (autosomal recessive) nonprogressive multifocal retinopathy (canine multifocal retinopathy, CMR) of Great Pyrenees has been documented using FA, revealing areas of choroidal hypoperfusion, followed by fluorescein pooling into sub‐RPE defects, with no leakage of fluorescein into the overlying serous retinal detachments (suggesting that tight junctions between RPE cells remain intact). Light microscopy and electron microscopy confirmed the presence of multifocal serous retinal detachments at a young age, with focal retinal degeneration as noted on ophthalmoscopy. The retinal detachments were accompanied by hypertrophy, hyperplasia, increased pigmentation, and vacuolation of the retinal pigment epithelium (Grahn & Cullen, 2001; Grahn et al., 1999). These findings led the authors to postulate that the multifocal serous retinal detachments were secondary to focal secretion and absorption defects in the RPE cells, with similarities to central serous retinopathy in humans. A similar clinical presentation is seen in young Coton de Tulear dogs with nonprogressive multifocal serous retinal detachments as an inherited (autosomal recessive) condition. FA of affected dogs also showed no fluorescein leakage into the retinal detachments, confirming the lack of BRB breakdown (Grahn et al., 2008; Fig. 10.2.41 and Fig. 10.2.42). In contrast to Great Pyrenees with multifocal retinopathy, however, there was no pooling of fluorescein into sub‐RPE defects. Multifocal retinopathy encountered in Dachshunds with CLN2 neuronal ceroid lipofuscinosis has been investigated using both OCT and FA (Whiting et al., 2015). The retinopathy was demonstrated to be multifocal serous retinal detachments with no fluorescein pooling on FA, resembling the findings in CMR described by Grahn and colleagues. Genetic investigations ruled out a causative mutation in BEST1 (like CMR), but a mutation in TPP1. FA investigation of inherited multifocal chorioretinal lesions in Borzoi dogs revealed intact blood–ocular barriers (no fluorescein leakage), focal RPE hypertrophy, and focal absence of the choroiocapillaris (hypofluorescence) corresponding to chronic, focal lesions (Storey et al., 2005). Initial hyperfluorescence in acute lesions within the tapetal fundus were interpreted as window defects, and later hypofluorescence of the same region as RPE hypertrophy. FA examination of Bernese Mountain dogs with a suspected inherited retinopathy revealed hypofluorescence in a horizontal region lateral and dorsal to the optic disc (interpreted as an ischemic lesion) and fluorescein epithelial leakage from peripheral capillaries (Chadieu & Molon‐Noblot, 2004). Retinal degeneration associated with vitamin E deficiency has been described in hunting dogs fed on a scrap meat diet (Davidson et al., 1998). FA descriptions were also reported in

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F Figure 10.2.38  Standard (A), red-free (B), and anterior segment fluorescein angiography (ASFA; C–F) images obtained from a blue-eyed 2-year-old male neutered Siamese cat. For ASFA images, phases include (C) arterial phase (7 s), (D) capillary phase (10 s), (E) venous phase (16 s), and (F) late time period (10 min). Color and black-and-white* ASFA images are represented. A complete major arterial circle (MAC) is readily apparent in C and D. Additionally, slightly tortuous radial iris arterioles, some of which originate from radial ciliary arteries, are noted. Presence of a rudimentary minor arterial circle is noted in E. In F, leakage of fluorescein within the iris stroma is apparent, producing a negative contrast image (MAC is now black). *Black-and-white images were generated from color images obtained using Adobe Photoshop CS4 black-and-white tool function.

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E Figure 10.2.39  Standard (A), red-free (B), and anterior segment fluorescein angiography (ASFA; C–E) images obtained from a blue-eyed 3-year-old MN Domestic Shorthair cat. Images are magnified by a factor of 4 (400%) to demonstrate the finer vascular detail around the major arterial circle (MAC). Phases include (C) early arterial phase (6 s), (D) arterial phase (9 s), and (E) late venous phase (29 s). Color and black-and-white* ASFA images are represented. A complete MAC is apparent in C, demonstrating filling of both radial ciliary arteries, and iris arterioles in C and D. Several radial iris arterioles are noted to originate from radial ciliary arteries. Venous dilation is demonstrated in E. *Black-and-white images were generated from color images obtained using Adobe Photoshop CS4 black-and-white tool function.

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F Figure 10.2.40  Standard (A), red-free (B), and anterior segment fluorescein angiography (ASFA; C–F) images obtained using propofol from a heterochromic 1-year-old spayed female Australian Shepherd dog. For ASFA images, phases include (C) arterial phase (11 s), (D) capillary phase (15 s), (E) venous phase (20 s), and (F) late stage (10 min). Color and black-and-white* ASFA images are represented. Sectoral hypopigmentation located within the ventromedial iris is apparent in A and B. Fluorescence and the presence of iris vasculature are apparent only within this hypopigmented region (C–F). Fluorescein leakage within the iris stroma is apparent in F, creating a negative contrast image. Additionally, aqueous humor leakage creating a vertical line is noted. *Black-and-white images were generated from color images obtained using Adobe Photoshop CS4 black-and-white tool function.

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Figure 10.2.41  A. Fundus photograph from 6-month-old Coton de Tulear dog affected with multifocal retinopathy. B. Arterial phase of fluorescein angiogram. C. Venous phase. D. Recirculation phase. White star denotes the same fundus location in each image. Note the lack of fluorescein leakage or pooling (suggesting no blood–retinal barrier breakdown). (Reproduced with permission from Grahn, B.H., Sandmeyer, L.L., & Breaux, C. (2008) Retinopathy of Coton de Tulear dogs: Clinical manifestations, electroretinographic, ultrasonographic, fluorescein and indocyanine green angiographic, and optical coherence tomographic findings. Veterinary Ophthalmology, 11(4), 242–249.)

this study and documented early‐phase multifocal coalescing areas of hypofluorescence, predominantly in the tapetal fundus, corresponding to areas of ophthalmoscopically visible pigment clumps. These areas were hyperfluorescent later in the course of the angiograms, suggesting disruption of the BRB. Retinal vascular attenuation, narrowing, and constriction could also be visualized in areas of ophthalmoscopically visible retinal degeneration. FA has documented increased retinal vascular permeability in cases of experimental infection with Ricketsii ricketsii in dogs. While 50% of the experimentally infected cases showed increased vascular permeability on day 6 postinfection, this reduced to 6% of cases by day 17 (Drost et al., 1997). FA studies of transpupillary diode laser retinopexy in normal Beagle dogs showed disruption of the BRB at the level of

the RPE. Fluorescein leakage into the subsensory retinal space was also seen in most lesions at 24 hrs, was minimal at 3 days, and had resolved by 1 week (Pizzirani et  al., 2003; Fig. 10.2.43). Investigation of a canine model for diabetic retinopathy using galactose‐fed dogs (over 66 months) has been undertaken using fundus photography, FA, and histopathology (Takahashi et  al., 1992). This study demonstrated broad areas of nonperfusion, cystoid bodies (soft exudates), retinal microvascular changes, occluded retinal arterioles, preretinal and intravitreal hemorrhages, and optic nerve head neovascularization associated with the galactose diet. A further study to assess the potential of an antiangiogenic drug, ­combretastatin a‐4, in long‐term galactose‐fed dogs has also been investigated with FA. Sub Tenon’s, intravitreal, and

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Figure 10.2.42  A. Fundus image from a 2-year-old Coton de Tulear dog affected with multifocal retinopathy. B. Early phase of indocyanine green (ICG) angiography. C. Midphase. D. Late phase. White star denotes the same fundus location in each image. Note no ICG leakage or pooling (suggesting no blood–retinal barrier breakdown) and increased visibility of choroidal vasculature compared with fluorescein images. (Reproduced with permission from Grahn, B.H., Sandmeyer, L.L., & Breaux, C. (2008) Retinopathy of Coton de Tulear dogs: Clinical manifestations, electroretinographic, ultrasonographic, fluorescein and indocyanine green angiographic, and optical coherence tomographic findings. Veterinary Ophthalmology, 11(4), 242–249.)

i­ ntravenous administration of the drug failed to cause regression of retinal neovascularization established in the canine model for diabetic retinopathy (Kador et al., 2007). A canine model for retinopathy of prematurity has been reported by exposing neonatal puppies to 95%–100% oxygen for 4 days followed by 22–45 days of room air before FA, euthanasia, and histopathology. FA abnormalities included dilated and tortuous retinal vessels, pigmentary changes, incomplete vascularization of the peripheral retina, vitreal hemorrhages, and persistence of massive intravitreal neovascularization (McLeod et al., 1998). Retinal vein occlusion (RVO) is a relatively common cause of vision loss in humans with atherosclerotic or hypertensive vascular disease, and a canine model for this disease has

been studied by FA. The potential treatment of RVO by laser‐ induced venous anastomosis of choroidal and retinal vessels has also been studied by FA and histopathology, in the same canine model (McAllister et al., 1992). Smaller‐caliber anastomoses could also be created in the absence of RVO, but over a longer period (6–8 weeks instead of 3–6 weeks) compared to those created in dogs with previously induced partial RVOs. The same iatrogenic anastomosis procedure was repeated in rats to determine whether chorioretinal venous anastomoses could be induced in an animal with a Bruch’s membrane that is well developed, as it is in humans (unlike in the dog) and was successful (Vijayasekaran et al., 1994). Assessment of the biocompatibility of an epiretinal prosthesis prototype in mixed‐breed normal dogs has been

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Figure 10.2.43  A. Fluorescein angiogram of the right eye of a Beagle 24 hours after transpupillary diode laser retinopexy. Late venous phase. Multiple lesions demonstrate fluorescein leakage (hyperfluorescence) in both the tapetal and nontapetal regions of the fundus. B. The same dog and eye after 7 days. Late venous phase. No fluorescein pooling is seen. A blocking effect (hypofluorescent center; retinal pigment epithelial [RPE] hypertrophy, and pigmentation) is seen surrounded by a window defect (hyperfluorescent ring) in some of the most severe postdiode retinopexy lesions (black arrows). White arrows correspond to areas of blocking defect (RPE hypertrophy and repigmentation) surrounded by window defect (nonpigmented RPE). White arrowheads correspond to milder areas of milder retinopexy lesions with no blocking or window defects. (Reproduced with permission from Pizzirani, S., Davidson, M.G., & Gilger B.C. (2003) Transpupillary diode laser retinopexy in dogs: Ophthalmoscopic, fluorescein angiographic and histopathologic study. Veterinary Ophthalmology, 6(3), 227–235.)

undertaken with a view to developing a multielectrode array prosthesis capable of providing ambulatory vision in humans with photoreceptor loss. FA, as well as electroretinography and histopathology, demonstrated good tolerance of the implant in dogs (Majji et al., 1999). A similar procedure was used to assess the safety and feasibility of an epiretinal electrode array made from polydimethylsiloxane, including FA, OCT, electrophysiologic studies, and histopathology. FA demonstrated good retinal perfusion under the array (Guven et al., 2006). Confocal scanning ophthalmoscopy has been combined with FA to give sharper and more numerous angiographic images in the normal dog, cynomolgus monkey, and minipig (Rosolen et al., 2001). The authors felt that the increased rate of image capture (25 frames per second compared to the 8 frames per second of traditional FA capturing techniques) gave enhanced information on the retinal microcirculation and dynamics. Images were obtainable using a single piece of equipment and even in the face of moderate lens nucleus opacities. FA of the normal horse was first described by Walde in 1977. FA in normal horses under standing sedation and palpebral nerve blockade was later reported with two main phases, a choriopapillary phase and a retinal vascular phase (Molleda et al., 2008; Fig. 10.2.44). The retinal vascular phase

was further subdivided into three phases: a filling phase, a maximal fluorescent phase, and a fading phase. The choriopapillary phase started at 46.95 ± 9.48 s and was followed at 47.79 ± 10.38 s by the retinal vascular phase. Retinal arterioles and venules could not be distinguished on FA, as both vessel types filled with fluorescein simultaneously. The maximal fluorescent point was 59.79 ± 10.39 s and the retinal vascular fade was complete at 74.76 ± 9.81 s. This study also demonstrated sparse and shorter retinal vessels ventral to the optic disc, rather than an absolute deficiency of vascularization. FA has been described in the investigation of bilateral chorioretinal colobomas in a donkey (Martin‐Suarez et  al., 2009). The donkey presented with typical colobomas of both irides and optic discs (extending into adjacent peripapillary retina and choroid). FA abnormalities of hypofluorescence in the region of the colobomas and leakage of fluorescein from choroidal vessels at the border of the colobomas were described. The authors postulated that the hypofluorescent areas were due to absence of normal choroidal vessels, and the leakage of fluorescein may have occurred from abnormal choroidal neovascularization. An FA study of the normal sheep and goat has been published (Galan et al., 2006) and images were obtained without sedation or anesthesia of the animals. Sodium fluorescein

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A

B

C

D

Figure 10.2.44  Normal equine fluorescein angiography images. A. Choroidal phase (patchy fluorescein filling). B. Retinal vascular phase. C. Maximal fluorescence (retinal arterial and venous phase). D. Fading phase (fluorescence of optic disc rim from diffusion of fluorescein into optic nerve sheath). (Reproduced with permission from Molleda, J.M., Cervantes, I., Galan, A., et al. (2008) Fluorangiographic study of the ocular fundus in normal horses. Veterinary Ophthalmology, 11(1), 2–7.)

was administered via the jugular vein and serial fundus photographs obtained. The phases of FA could be identified and mean angiographic times obtained for both species (Fig. 10.2.45). FA of the anterior segment of normal goats, sheep, and alpacas has subsequently been undertaken using both sodium fluorescein and ICG and a dSLR camera adaptor under general anesthesia, with no reported adverse events (Lo Pinto et al., 2017a). Sodium FA of iris vasculature was not possible in all tested alpacas due to the heavy iridal pigmentation, or in the more heavily pigmented irides of sheep and goats. Sodium fluorescein extravasation that has also been reported in cats and dogs (Alario et  al., 2013a, 2013b) was encountered in sheep and alpacas, but not in goats. ICGA was able to provide diagnostic angiography images regardless of degree of iridal pigmentation in all three farm animal species (Lo Pinto, 2017a). FA has been used extensively in laboratory small mammals for the research of animal models of ocular posterior

segment disease in humans, but that is beyond the scope of this chapter. Elegant FA studies have illustrated the role of the pecten in the ocular perfusion of birds. Lack of retinal blood vessels would normally limit the thickness of the retina to the theoretical oxygen diffusion maximum of approximately 140 μm; however, this is not the case in birds, whose retinal thickness may reach 300 μm (Pettigrew et  al., 1990). FA studies have demonstrated that the pleated or cone‐like vascular structure of the pecten in birds acts as a primary source of nutrients to the inner retina. Saccadic oscillations, peculiar to birds, are responsible for the pecten “agitating” nutrients toward the central retina (Pettigrew et al., 1990). FA was also undertaken to characterize the nutrition of the avascular retina of Megachiroptera (fruit bats), specifically Pteropus poliocephalus (Brudenall et  al., 2007; Fig.  10.2.46). In the same study, vascular resin casts illustrated vascular loops emanating from the margins of the

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B

C Figure 10.2.45  Fluorescein angiography images of a sheep. A. Arterial phase. Stars of Winslow are visible with choroidal fluorescence (black arrow); optic disc shows no fluorescence at this stage. B. Arteriovenous phase. Tapetal fundus has more homogenous fluorescence, with light fluorescence seen in nontapetal fundus. Optic disc is now fluorescent. Laminar flow is seen in dorsal vein. C. Venous phase with all veins fluorescent. Nontapetal fundus fluorescence is decreasing. Bergmeister’s papilla is fluorescent (arrow). (Reproduced with permission from Galan, A., Martion Suarez, E.M., Granados, M.M., et al. (2006) Comparative fluorescein angiography of the normal sheep and goat ocular fundi. Veterinary Ophthalmology, 9(1), 7–15.)

optic disc, forming a truncated cone. Each vascular loop was shown to extend approximately 450 μm into the vitreous cavity. Following intravenous sodium fluorescein injection via a wing vein, the vascular loops showed the presence of fluorescein, and reached a maximum intensity by 20 s. Fluorescein was then seen to diffuse into the peripapillary vitreous from the vascular loops. Between 25 s and 30 s postinjection, the intensity of diffusing fluorescence at the optic disc obscured the vascular loops.

Future Directions An imaging system that combined the benefits of cSLO (including fluorescence data) and OCT has been described and was able to longitudinally image individual retinal gan-

glion cells, microglia, and Muller glia in a mouse model (Zhang et  al., 2015). This combination system was able to harness the advantages of both imaging modalities, while minimizing the impact of the limitations for each individual modality. Two‐photon nonlinear microscopy (or multiphoton microscopy) is a fluorescence technique that allows in vivo and ex vivo imaging of the eye. A nonlinear microscope excites fluorescence at a focal point of an infrared laser at an intensity high enough to allow a dye molecule to absorb two infrared photons simultaneously. Scanning this focal point (using an adaptive optics scanning light microscope) in three dimensions allows construction of a 3D image, while reducing background interference and reducing photo‐induced damage to the tissue. In vivo two‐photon fluorescence imaging of the retina has the potential to provide images of

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Figure 10.2.46  Fundoscopic view of Pteropus poliocephalus (A) 11 s and (B) 32 s after intravenous fluorescein injection, showing filling of vessels at the optic disc (central circular region) and subtending choroidal papillae. The intensity of fluorescein increases within the optic disc vessels by 32 s, and diffusion of fluorescein into the vitreous obscures the detail of individual vessel loops. Scale bar equals 800 μm. (Reproduced with permission from Brudenall, D.K., Schwab, I.R., Lloyd, W., III., et al. (2007) Optimized architecture for nutrition in the vascular retina of Megachiroptera. Anatomy, Histology and Embryology, 36(5), 382–388.)

c­ ellular structures, information on retinal function in health and disease, and also on the response to therapeutic interventions (Jayabalan et al., 2017; Sharma et al., 2017). Intraoperative OCT systems are being developed, and were first described in use in anterior segment surgery

(Geerling et al., 2005) and subsequently in macular surgery (Dayani et al., 2009). It has been speculated that this may be further advanced to provide a virtual OCT image over the surgical site for the benefit of the surgeon (Gabriele et al., 2011).

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10.3 Ophthalmic Examination and Diagnostics Part 3: Diagnostic Ophthalmic Ultrasound Ellison Bentley1, Stefano Pizzirani2, and Kenneth R. Waller, III1 1 2

Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA Department of Clinical Science, Tufts Cummings School of Veterinary Medicine, North, Grafton, MA, USA

The inability to directly observe intraocular and periocular structures due to diseases causing media opacities or changes in anterior architecture, as well as the inability to directly examine orbital tissues, has triggered the search for easily performed, noninvasive, real‐time, high‐detail diagnostic modalities to detect morphologic changes when standard routine ophthalmoscopy methods are unsuccessful. Due to the eye’s accessibility and fluid compartmental structure, it is ideal for multiple imaging technologies (Silverman, 2009). In 1956, Mundt and Hughes (Mundt & Hughes, 1956) used an amplitude scan (A‐scan) on an intraocular tumor, demonstrating the possible use of ultrasound in ophthalmology. Soon thereafter, a body of research developed on the sound velocities of various tissues and compartments of the eye, and in the 1960s ultrasound began to be used to measure distances in the eye. Later, Ossoinig (1979) developed the standardized A‐scan, which is used to differentiate tissues, particularly tumors. Brightness scan (B‐scan) instruments, developed in the 1970s, were originally used through closed eyelids, but later evolved to transcorneal and transscleral use. In the 1990s high‐frequency ultrasound developed, which greatly improved the resolution and ability to examine anterior segment structures (Pavlin et al., 1991). Recent developments include the digitization of ultrasound allowing for three‐dimensional imaging, higher‐frequency imaging, artifact‐reducing technology, improvement of Doppler imaging, and the use of contrast‐enhanced ultrasound (CEUS). Clinical ophthalmologists can easily use several different types of ultrasound during daily practice, without the need for sedation or general anesthesia, to examine ocular structures. Investigation of orbital tissues may be more challenging due to the bones surrounding the orbital space. Ocular and orbital ultrasonography, however, offer advantageous information in real time and with limited invasiveness, and may complement cross‐sectional modalities such as computed tomography

(CT) or magnetic resonance ­imaging  (MRI). A full understanding of its indications, including basic physics and principles, proper examination techniques, and limitations, will allow the clinician to gather a vast and useful amount of information.

Principles of Ultrasound Ultrasound uses acoustic waves whose frequency is above the human hearing range (> 20 KHz or > 20,000 oscillations/second). In ophthalmic ultrasound, frequencies are measured in megahertz (MHz = 1,000,000 hertz) and transducers are typically between 8 MHz and 65 MHz (with higher frequencies in development). Higher frequencies are associated with shorter wavelengths, a property that makes ultrasound waves easily reflected off small surfaces. Therefore, higher frequencies can recognize smaller differences, increasing the resolution, which is an essential parameter when examining the delicate structures of the eye. Higher resolution comes with the price of lower tissue penetration, as shorter, more frequent wavelengths cannot penetrate tissue as deeply as longer wavelengths. Most standard B‐mode transducers for globe imaging are 10–15 MHz and can penetrate about 60–40 mm. High‐resolution transducers are generally around 20–40 MHz and penetrate about 30 mm or less. Ultrasound biomicroscopy (UBM) is usually considered to be 50 MHz or higher, limiting tissue penetration to about 10 mm (Byrne & Green, 2002; Szabo & Lewin, 2013). Penetration is not a synonym for focal depth or resolution, nor a discrete fixed, given number, since it depends on tissue density, relative attenuation and backscatter, and transducer acoustic output. Penetration within the eye is favored by the presence of fluids and hydrated tissues with low attenuation values. Average sound velocity in the eye has been suggested to be between 1547.5 and 1555 m/sec (Hoffer, 1994; Oksala &

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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Lehtinen, 1958). However, some debate exists about the acoustic wave velocity in various ocular tissues and different species. One study (Schiffer et al., 1982) found a mean velocity of 1710 m/s using two canine lenses. Later, Gorig et  al. (2006) used 40 canine lenses and established a mean sound wave velocity of 1707 m/s. This study also established a mean sound wave velocity in the vitreous of 1535 m/s. The equine lens is reported to be 1529 m/s, and the equine vitreous 1527 m/s (Meister et al., 2014). In humans, the velocity through the crystalline lens is reported as 1641 m/s, and 1532 m/s in the vitreous. Although it may seem that a difference of a few m/s when measuring millimeters is inconsequential using the human values for intraocular lens (IOL) calculation, using biometry measurements from a dog would result in a mean calculated IOL power of 43 diopters (D) rather than 41.8 (Gorig et al., 2006). An A‐scan is a one‐dimensional display where echoes are depicted as spikes arising from the baseline. A thin, parallel sound beam passing through a small point in the eye forms an A‐scan. The greater the difference between interfaces, the higher the spike will be, hence the name amplitude scan, or time amplitude display. A B‐scan is essentially an oscillating A‐scan that passes through a cross‐section of tissue, with the echoes in a B‐scan represented as dots rather than spikes. The configuration of the dots and the brightness of the dots create the image. The greater the difference between interfaces (acoustic impedance) or the stronger the echo, the brighter the dot will be, hence the name brightness scan, or brightness intensity‐modulated display. Sound waves behave essentially like light rays and so many of the same principles of refraction and reflection apply. Just like light rays, the longitudinal sound wave can be reflected back toward its source when it strikes a tissue interface. This reflected wave is called an echo. Similar to the refractive index, acoustic impedance between two media influences the production of an echo. Sharp hyperechoic lines can be observed at the transition between ocular structures with very different densities or impedances, like corneal layers, or aqueous–lens and lens–vitreous interfaces. The greater the  difference in acoustic impedance between two media, the stronger the reflected sound wave will be. For example, the difference between the anterior lens surface and the aqueous is much greater than the difference between hypopyon and the lens, so the corresponding echo would be shorter (less distinguishable) in an eye with hypopyon. Other factors that affect the formation of the echo are absorption and refraction, the angle of sound incidence, and the size, shape, and texture of the acoustic interfaces (Byrne & Green, 2002). The angle at which the sound beam strikes an interface influences the strength, formation, and quality of the echo. The angle of incidence is equal to the angle of reflection, so when a beam strikes an interface perpendicularly, the echo is reflected directly back toward the direction of origination

(i.e., the transducer). Sound waves striking in an oblique fashion result in reflected sound waves diverted away from the direction of origin, leading to a weaker echo. When doing a clinical exam, brighter structures are often perpendicular to the sound beam. This property can be used to assess perpendicularity to the structures being examined. The size, shape, and texture of an interface also determine the character of the echo. A smooth surface is a specular reflector of sound, so if the sound wave strikes perpendicularly, it will reflect nearly all the wave back to its source. An ocular example of this is the lens capsule, whose sharp brightness is enhanced by the acoustic impedance between the fluids surrounding it. An irregular surface (for example the iris) will result in scattering reflector of sound, which means that the returning echo will be weaker, even if the original sound wave was perpendicular. Ultrasound energy is absorbed by the tissues it passes through. Absorption is related to frequency, sound velocity, and the thickness and density of the tissue through which it passes. Higher frequencies are absorbed to a greater degree, hence the decreased penetration. Greater tissue thickness and/or density also result in greater absorption of the sound waves, and can sometimes result in artifacts. Examples of absorption artifact are the “posterior shadowing” that occurs behind coarse calcified tissue or the “comet tail” reverberation distal to a metallic foreign body. Reflection, refraction, absorption, and scattering of the sound influence the attenuation of the beam through the tissue. Different tissue densities will also impact attenuation and limit image quality in the distal structures. The reader is referred to other textbooks for more details of ultrasound physics (Zagzebski, 1996).

Instrumentation and Processing Essential components of an ultrasonographic system are the transducer, the console, and the display screen. An ultrasound transducer functions as both a transmitter and a receiver. Ultrasound exploits the piezoelectric effect of some crystals (usually thin ceramic layers) that produce waves when resonating from electrical impulses, or may alternatively transform received echoes into an electrical signal. The piezoelectric crystal is electrically stimulated, causing a mechanical vibration. The vibration leads to the release of a longitudinal sound wave that passes through the tissue. After each vibration (pulse), a pause of several microseconds occurs so that the transducer can receive returning echoes. The returning echo causes the piezoelectric crystal to vibrate, which then produces an electrical signal that is transmitted to the machine and an image is made on the display screen. This pulse–echo process is repeated a thousand or more times per second to produce a “real‐time” display.

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increase. For example, increasing the gain allows the display of weaker signals like vitreous opacities, then as gain is decreased, weak vitreal opacities will go away, but stronger echoes (retina, sclera, masses) will remain (Fig.  10.3.1). Lowering gain effectively narrows the sound beam, because the strongest echoes are in the central axis of the returning sound wave. Since weaker echoes from deeper tissue are not amplified enough to be displayed, lowering gain also effectively decreases the depth of penetration. Many instruments have manual or automatic time gain compensation (TGC), which allows for selective gain adjustment by depth. This enables greater latitude in adjusting the amplification of distant, weaker tissues compared to closer, stronger echoes, which helps equalize echoes from similar tissues located at varying distances from the transducer.

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Frequency and pulse length both relate directly to spatial resolution (axial and lateral). Axial and lateral resolution partially (other factors contribute to the final image) indicate the quality of the image that can be obtained and define the sensitivity of the transducer. Axial resolution indicates how close two reflectors can be in the direction of the sound wave and still be distinguishable. A higher axial resolution means the ability to distinguish more accurately two different tissues or layers that are closer together. Lateral resolution refers to the ability to distinguish two different reflectors positioned next to each other in a line perpendicular to the direction of the sound wave. Lateral resolution is inferior to axial resolution. The relationship between axial and lateral resolution is influenced by several parameters; however, lateral resolution of transducers of different frequencies can be 2.4–4 times less than the axial resolution (Foster et al., 2000). The resolution depends on several factors including the type of transducer, the frequency, the focal length, and the beam aperture. The latter two factors can be indicated by the ratio of the focal length to the transducer diameter (f‐number); a lower number indicates a higher resolution. Usually, transducers that have an f‐number of 1.2–2.2 are used for ocular UBM (Pavlin & Foster, 1995). While axial resolution usually does not change greatly with distance, lateral resolution is generally affected more, decreasing with increasing distance to become much less reliable in the far field, especially when transducers with diverging beams are used. See Table 10.3.1. Gain is another important factor in ultrasound display. It is essentially turning up the volume or amplifying the brightness of the displayed signal. Gain is measured in decibels (dB), which are relative units of ultrasound intensity. Adjusting the gain does not alter the amount of energy produced by the transducer; rather, it only changes the displayed intensity or brightness of the returning echo displayed on the screen. Increasing gain increases sensitivity to weaker echoes and allows for the display of weaker signals. Overadjustment of gain can cause saturation in more echogenic structures, which can decrease resolution and lesion conspicuity. As the gain is lowered, the sensitivity to weak echoes decreases, and both lateral and axial resolution

10.3: Ophthalmic Examination and Diagnostics

Ultrasound Modalities A-Scan A‐scans are one‐dimensional displays in which returning echoes are reflected as vertical spikes from a baseline. Spacing between the spikes depends on the time it takes for the sound beam to reach the interface and for the echo to return to the transducer. The time between spikes can be converted to distance by knowing the sound velocity of the medium through which the echoes are traveling, which is expressed through the formula: Distance

velocity time

The height of the spikes indicates the strength, or amplitude, of the echoes. There are different types of A‐scans in ophthalmology. One type is biometry, in which an A‐scan is for axial eye length measurements. Biometric A‐scans typically use linear amplification, a focused transducer, and a frequency between 10 and 15 MHz (Fig. 10.3.2). A vector A‐scan is used simultaneously with B‐scan echograms and has similar characteristics to the B‐scan, usually logarithmic amplification, a

Table 10.3.1  Calculated wavelengths and axial resolutions based on averaged sound velocity in the eye for most commonly used frequencies in ocular ultrasonography, with two and three cycle pulse lengths. Frequency

Wavelength

Axial Resolution

10 MHz

155 μm

155–232 μm

15 MHz

104 μm

104–155 μm

20 MHz

78 μm

78–117 μm

35 MHz

44 μm

44–67 μm

50 MHz

31 μm

31–47 μm

Source: Derived from Ng & Swanevelder (2011).

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A

B

Figure 10.3.1  A. B-mode ultrasound image using a 10 MHz transducer with gain of 90 dB in a dog. Note multiple unorganized echogenic foci randomly distributed through the vitreous cavity, and a small linear object adjacent to the retina, choroid, sclera complex (arrow). B. Same image as in A, with gain set at 48 dB instead of 90 dB. Note that the linear opacity has almost disappeared, more consistent with a posterior vitreous detachment rather than retinal detachment.

focused transducer, and a frequency of 10 MHz (Fig. 10.3.2). Vector A‐scans can be used for more precise measurement of lesions and may be as accurate as a linear A‐scan (Berges et al., 1998). The standardized A‐scan was developed by Ossoinig (1979) to enhance tissue differentiation. Standardized A‐scans use S‐shaped amplification, a nonfocused 8 MHz transducer, and a parallel sound beam. Each transducer/instrument combination is externally standardized using a tissue model, which determines the decibel setting. This decibel setting is referred to as tissue sensitivity and is unique to each transducer. Images are then compared to known patterns to make a diagnosis. Standardized A‐scans have been used extensively in physician‐based ophthalmology, and experienced users can make very definitive diagnoses of tumor and exudate type based on recognition of these patterns. Since its axial positioning is critical and the aiming beam necessary for positioning requires patient cooperation, its use is more challenging in veterinary medicine, hence there are limited reports. Therefore, use of A‐scan sonography in veterinary clinical patients is mostly relegated to biometric studies. Biometry is sometimes used for determining changes in ocular distances during disease, such as increased axial length in buphthalmic globes in glaucoma. Biometry can also be used to attempt to elucidate underlying pathophysiologies of diseases, such as documenting shallow anterior chambers due to anterior shifting of the lens–iris diaphragm in cats with aqueous humor misdirection syndrome (Czederpiltz et al., 2005). Ekesten and Torrang (1995) found that lens thickness increased with age in Samoyeds, leading to a shallower anterior chamber. The main use of biometric A‐scans is to determine the optical characteristics of the globe to calculate IOL strengths and the source of refractive errors. Schiffer et al. (1982) first

described anterior chamber, lens thickness, vitreal chamber, and overall axial length measurements in 32 dogs in 1982. Cottrill et al. (1989) described A‐scan characteristics of mesocephalic and dolichocephalic dogs and found that dolichocephalic dogs had longer axial globe lengths. Murphy et  al. (1992) investigated a population of myopic German Shepherd dogs used as guide dogs for the blind and found no difference in axial length in myopic versus nonmyopic eyes, although later a vitreous based myopia was demonstrated in Labrador Retrievers (Mutti et  al., 1999). Gilger et al. (1998b) used biometry, combined with keratometry, to predict an IOL strength of 53–55 D in cats. Follow‐ up studies of IOL implantation in research cats demonstrated that a 52–53 D IOL is required to achieve emmetropia in cats (Gilger et al., 1998a). Several studies (McMullen & Gilger, 2006; McMullen et al., 2010) used biometry and keratometry to predict an IOL strength in horses (although the large equine eye may result in positioning differences that make it difficult to achieve emmetropia postoperatively in the equine eye). A‐scan exams can be easily performed in awake, sedated, or anesthetized animals. The transducer can be placed directly on the cornea or used with a scleral shell and water bath (immersion technique). The transducer should always be placed axially and a reliable scan is one in which the heights of the spikes from baseline are equal. Each spike should start at a perpendicular and at a nonsloping angle from baseline (Fig. 10.3.2A, B).

B-Scan The B‐scan emits an oscillating sound beam that “slices” through a tissue, producing a two‐dimensional acoustic section. B‐scans are essentially a combination of multiple

10.3: Ophthalmic Examination and Diagnostics

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3

DIRECT 4

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1

5

AVGAXL (1) = 18.43 MM STDDEV = 0.00 MM

A

AXL = 18.43 MM ACD = 2.97 MM LENS = 7.18 MM

B

C Figure 10.3.2  A. A-scan transducer on a dog’s eye. B. A-scan ultrasound image of a normal dog. The first peak on the left (1) is the transducer/cornea complex, the second peak (2) is the anterior lens capsule, the third peak (3) is the posterior lens capsule, and the last peak is the retina, choroid, and sclera (4), while 5 is the orbital tissues. C. B-mode ultrasound image using a 10 MHz transducer with a vector A-scan. The red line corresponds to the vector A-scan at the bottom of the image.

A‐ scans. Each echo is represented by a dot and the brightness of the dot represents the strength or amplitude of the returning echo (Fig. 10.3.2C). Transducers have a marker to indicate the direction of the slice, which corresponds to an icon in the upper portion of the displayed image on ophthalmic machines. The slice display width of most B‐scans

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approximates 180 degrees. B‐scan transducers used on ophthalmic‐specific machines typically have a frequency of 10 MHz. Lower‐MHz transducers are necessary for orbital imaging, as the penetration of a 10 MHz transducer and the presence of orbital bone do not allow for the consistent ability to characterize orbital lesions well.

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Artifacts in Ultrasonography Artifacts are images that appear on the display, but do not represent real anatomic or pathologic structures. Acoustic shadows or enhanced signals must be recognized and distinguished from true echoes to avoid false interpretations (d’Anjou & Penninck, 2015; Penninck & d’Anjou, 2015). External multiple signals result from reverberations between the transducer tip and a highly reflective acoustic interface (Feldman et  al., 2009). Examples of objects that produce external multiple signals are the surface of the crystalline lens, an artificial intraocular lens, an air bubble, the sclera, or bone (such as the orbital bone). The multiple reverberations are the result of the reflection of a sound wave of significant magnitude back to the transducer. When this true echo is strong enough, a portion of it will be reflected off the transducer surface and will go back to the original interface. The second wave will then produce a reverberation echo that appears distal to the true echo in the ultrasound image because it takes longer to return to the transducer (Fig.  10.3.3). Additional reverberation echoes may be produced by additional round trips of the sound wave. The true echo and the reverberation echoes are equidistant, and the reverberation echoes usually decrease in strength with increasing distance from the true echo. The most common occurrence of this reverberation artifact in ocular ultrasonography is from the lens capsule (Leo & Carmody, 2011), typically the posterior lens capsule in dogs. Internal multiple signals occur by reverberations within certain types of foreign bodies or small calcifications. They are associated with the sound beam striking a spherical foreign body, such as a BB pellet, shotgun pellet, or a small bubble of air or gas. Flat foreign bodies with closely spaced,

parallel surfaces, such as slivers of glass, can also cause internal multiple signals. Internal multiple signals appear as a chain of closely spaced signals emanating from the foreign body echo, or a “comet tail,” a hyperechoic artifact. This is generated by some of the energy from the sound wave being trapped between two reflective interfaces (Feldman et  al., 2009). The trapped energy bounces back and forth, with portions escaping and returning to the transducer. This results in a chain of echoes of decreasing amplitude extending from the foreign body. A comet tail artifact can be useful in identifying the type of foreign body. Strong sound attenuation in a focal area (like coarse calcifications or microcalcification aggregates) causes “posterior shadowing.” A geometric, well‐defined absence of echoes posterior to an extremely dense (hyperechoic) interface such as bone, calcium, or a large foreign body is due to complete acoustic shadowing. Partial acoustic shadowing leads to reduction of the echoes posterior to a lesion, which occurs in the case of large dense tumors, for example. Shadowing may make evaluation of structures behind the source of shadowing difficult, but can aid in diagnosis. Acoustic shadowing can also occur due to refraction at the edges of a smooth curved interface rather than solely by sound attenuation (Fig. 10.3.4). This occurs at the edge of the globe or from a cystic lesion (Sofferman, 2012).

Baum’s Bumps Baum’s bumps appear as elevation of the peripheral fundus and are B‐scan artifacts. These artifacts are thought to be created by refraction of the sound beam as it sweeps through the peripheral aspect of the lens in an axial transducer position. Repositioning the transducer peripheral to the limbus to avoid the lens should eliminate these artifacts.

Routine Globe Evaluation with B-Scans

Figure 10.3.3  B-mode high-resolution ultrasound using a 40 MHz transducer of an intraocular lens luxated into the anterior chamber of a dog (red arrow). Note external multiple signals (white arrows).

Most commonly in veterinary ophthalmology, a 10–20 MHz transducer on an ophthalmic‐specific system is used to evaluate the intraocular structures, with most practitioners concentrating on the posterior segment. The transducer is usually positioned directly on the globe after application of topical anesthetic. A coupling medium, such as methylcellulose or a thick artificial tear (not ointment), is applied to the transducer face prior to application. Examination through closed lids can be more difficult due to Bell’s phenomenon (rotation of the globe with the eyes closed) and attenuation caused by the lids. On the screen, the initial line that appears on the echogram represents the transducer face (often displayed on the left on ophthalmic‐specific machines). The transducer marker will correspond to one

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Figure 10.3.4  B-mode ultrasound image using a 10 MHz transducer of a dog with a cataract (note the heterogenous lens). This image demonstrates shadowing or edge artifact due to refraction of sound waves from the curved surface of the globe. This weakens the returning echoes and causes the globe wall to drop out (arrow) and a shadow.

side of the image (usually the top on ophthalmic‐specific machines). The operator should know where the marker corresponds to on different systems in order to orient the transducer correctly, and the same approach should be used in order for standardization of the exam. Since the best resolution is in the central portion of the transducer face, lesions should be centered within the ultrasound image whenever possible. A 10 MHz transducer is useful for evaluation of the globe and of the orbit; deep orbital spaces may benefit from lower frequencies, while high‐resolution ultrasound (HRUS) is needed to provide adequate imaging of the cornea and anterior chamber, and is discussed later in the chapter. Ultrasonographic evaluation is a dynamic test, and multiple, repeated wide scans, changing the position and orientation of the beam, provide better real‐time assessment that cannot be fully rendered by a still image. To examine the entire globe, and particularly the orbit, with a more complete ultrasound unit, linear transducers offer more appropriate resolution; however, they are more difficult to use on the curved shape of the globe. Sectorial, convex or semi‐convex transducers have smaller contact surfaces; however, lateral resolution fades in the far field. Enlisting the aid of an experienced radiologist can greatly increase the quality of the exam. Operators should also be

able to select different transducers according to the anatomic sector to be evaluated. Each transducer and frequency has advantages and limitations. Full knowledge of the technical properties of the machine(s) being used will result in a better assessment. Ultrasound imaging provides the location, density ­characteristics, and morphology of normal and abnormal tissues, without directly providing the exact composition of the tissue. Although several different ocular conditions manifest with specific ultrasonographic characteristics, specificity and sensitivity may vary, and not all the alterations can be etiologically or pathologically diagnosed with ultrasonography (Gallhoefer et al., 2013).

Transducer Positioning For standardization purposes, a well‐codified sectioning approach should be used, and then personalized, customized sections can be tailored to adapt to the specific case. Standardized examinations and labeling increase the likelihood of accurate evaluation of serial ultrasounds (Sandinha et al., 2017). The transducer landmark, regardless of the frequency or the kind of exam, should be routinely kept dorsal (12 o’clock) or medial (3 o’clock on the right eye or OD, and

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9 o’clock on the left eye or OS) for standardization and orientation of the obtained digital image. Note that labeled clock sections correspond to opposite positions in the two eyes, while the orientation of the image on the screen will be similar. Because the globe is a sphere, terminology used in section orientation is slightly different from that used in other body sections. Axial sections include the central cornea and the central lens or optic nerve, and are obtained with the trans-

ducer on the cornea. The section can be vertical, horizontal, or oblique, and images can be labeled using clock hours according to the position of the transducer marker. Any section that includes the central area of the lens and is paraxial on the cornea is labeled meridional, and can be vertical, horizontal, or oblique (Fig. 10.3.5). Paraxial, parallel sections can also be used and should be labeled latitudinal with the associated orientation (vertical, horizontal, or oblique). Transverse sections are those using the transducer

A

1

2

4

2

3

1

2

3

B

4

2

5

C

5

Figure 10.3.5  A. 10 MHz sectoral transducer used directly on the cornea of a dog. B. Position 1 can be labeled 10 meridional (for the transducer marker at 10 o’clock on the globe face), position 2 is 12 axial, and position 3 is 2 meridional. C. Position 4 can be labeled 10 latitudinal, position 2 is again 12 axial, and position 5 is 2 latitudinal. For both orientations, a complete scan can be performed by orienting the transducer perpendicular to the original scan plane, and again labeling by the clock hour of the transducer marker and the orientation. Oblique scans can also be obtained as needed. (Images from Pizzirani, S., Penninck, D., & Spaulding, K. (2015) Eye and orbit. In: Atlas of Small Animal Ultrasonography (eds. D. Penninck & M.-A. d’Anjou), pp. 19–54. Ames, IA: Wiley Blackwell).

­ erpendicular to the visual axis. Transverse sections can be p dorsal, ventral, medial, and lateral as standard exams are performed, and then oblique and differently oriented ­sections can be used customized to the specific case. Moving the transducer posteriorly can produce equatorial or para‐­ equatorial transverse sections (Fig. 10.3.6). Lower‐frequency transducers should be used for complete orbital evaluation, as their penetration depth is more appropriate for the distances involved. Transcorneal transducer positions can be used, and orbital sections are labeled longitudinal (vertical, horizontal, or clock hours) when the plane of section is along the orbital axis, and transverse (dorsal or

lateral, with medial and ventral difficult to perform) when the section is perpendicular to the orbital axis. Longitudinal latitudinal sections are variants and complementary sections. Alternative approaches include a window through the temporal fossa, which is performed by placing the transducer dorsocaudal to the orbital ligament. This is also a useful window when intraocular imaging is needed in a case with severe corneal damage, when information about intraocular anatomy may be crucial. Mesocephalic and dolichocephalic dogs are best suited to this approach (Stuhr & Scagliotti,  1996). An additional approach involves transducer placement inferior to the zygomatic arch caudoventral to the globe, which will allow imaging of the zygomatic gland and ventral orbital space (Pizzirani et al., 2015).

Normal Ultrasonographic Anatomy

A

B Figure 10.3.6  Perilimbal and limbal approach. Radial (A) or transverse (B) sections are obtained by placing the transducer on the limbus in dogs with anatomy that allows sufficient limbal exposure. These are labeled by the clock hour of the transducer marker and position (perilimbal radial versus transverse), and can be rotated around the globe as needed. (Images from Pizzirani, S., Penninck, D., & Spaulding, K. (2015) Eye and orbit. In: Atlas of Small Animal Ultrasonography (eds. D. Penninck & M.-A. d’Anjou), pp. 19–54. Ames, IA: Wiley Blackwell).

When using higher frequencies, the cornea is seen as two parallel echogenic lines divided by a nearly homogenous anechoic space, while the sclera is highly reflective. The well‐organized lamellae of the corneal stroma reflect less than the irregular scleral collagen bundles. The gradual transition between the two tissues at the limbus can be easily recognized and provides a useful landmark. The anterior chamber is anechoic, while the iris is echogenic and less well defined than the anterior lens capsule reflector, which is seen as a well‐defined hyperechoic line. The normal lens is anechoic; however, the lens capsules are seen as very sharp hyperechoic lines (Thijssen et al., 1985). With age, there is a decrease in water content in the nucleus, and the interfaces between the nucleus and peripheral cortex can be seen as a poorly delineated linear hypoechoic reflection within the lens. The anterior segment is best imaged with HRUS, as discussed later in this chapter, and/or using a standoff with a lower‐frequency transducer. Without a standoff, because of the focal length of the transducer, the most prominent echoes are the posterior lens capsule, which is seen as a curvilinear hyperechoic interface (see Fig.  10.3.2C). The normal vitreous is anechoic, and the posterior eye wall hyperechoic, thicker, and less well defined than the lens capsule. The sonographic posterior wall of the globe is represented ultrasonographically by the retina, choroid, and sclera. In the normal eye, these three layers are sonographically indistinguishable and are referred to as the RCS complex (De La Hoz Polo et al., 2016). The RCS complex is observed as a concave echogenic structure that is interrupted by the optic disc or papilla (a small hyperechoic line). The retrobulbar space contains the orbital cone, including the extraocular muscles, arteries and veins, and optic nerve. The optic nerve and the extraocular muscles may be identified as hypoechoic tubular structures surrounded by hyperechoic fat.

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Ocular and Orbital Abnormalities The standard 10–15 MHz transducers are not useful for examining the anterior segment. See the section on high‐resolution ultrasound for a description of anterior segment abnormalities.

Lens Cataracts are echogenic. An incipient cataract will have only a small echogenic area corresponding to the area of opacity. Cortical and nuclear opacities may be differentiated. Compared with age‐matched eyes, lens thickness will increase with some types of cataracts, such as the osmotic cataracts seen in diabetes (Fig.  10.3.7). Lens thickness will decrease as the lens becomes hypermature and begins to resorb. In these cases, the convexity of the anterior capsule decreases and flattening and wrinkling can be seen, depending on the stage of the cataract. Ultrasound evaluation of equatorial lens is useful to assess possible capsular tears and cortical herniation. Luxated lenses are easily identifiable in an abnormal position. Phacodonesis can be seen with subluxations and the iris may appear more posteriorly positioned. Congenital defects such as persistent hyaloid arteries/ persistent hyperplastic primary vitreous (PHPV) and associated lenticonus can be identified with ultrasound. These lesions are important in planning cataract surgery and often

Figure 10.3.7  B-mode ultrasound image using a 20 MHz sectoral transducer of a dog with a diabetic cataract. Note the increased thickness of the lens (arrows), and multifocal heterogenous echogenicity within the lens consistent with cortical and nuclear cataractous changes.

cannot be seen through a cataractous lens in the course of normal ocular examination. In these cases, evaluation using a color Doppler (power) mode can be used before surgery to ascertain if vascular patency is present (Fig. 10.3.8).

Vitreous Posterior vitreal detachments are often identified on cataract screening evaluations; however, their significance in veterinary medicine has not been yet determined. They can appear very similar to retinal detachments, but tend to be thinner and less reflective; they usually disappear as gain is decreased. The more echogenic detached retina will continue to be visible, while posterior vitreal detachments (and most vitreal opacities) will rapidly disappear. Evidence of vascular flow can also be helpful to differentiate vitreal membranes from retinal tissue. More difficult is the differentiation of retinal versus nonretinal tissue when thick fibrovascular membranes are present (Fig.  10.3.9). Floaters can often be seen in the vitreous from a variety of causes (Fig.  10.3.10). Typically, vitreal degeneration appears as hyperechoic dots or/and linear strands that are freely floating in the vitreous (Labruyere et al., 2008). Asteroid hyalosis appears as multiple small hyperreflective echoes in the vitreous, and some reverberation artifact is possible in the most advanced cases. In synchysis scintillans, the crystals are freely floating because of associated vitreal syneresis, assume different positions depending on ocular movements, and sink due to gravity when the globe is steady. Differentiation of vitreal hemorrhage, exudates, and tumors can be difficult (Gallhoefer et al., 2013) since they are all similarly hyperechoic. Vitreal hemorrhage varies in appearance depending on the location, amount, and duration. With severe vitreal hemorrhage, the entire posterior segment may appear hyperechoic, while with focal, confined hemorrhages, opacities of varying size can occur. Hemorrhage tends to settle ventrally, and fresh hemorrhage will move with eye movement. If pseudomembranes or fibrovascular membranes occur (making hemorrhage appear to be a retinal detachment), they must be followed carefully to determine their endpoint. Pseudomembranes from hemorrhage or inflammatory exudate will end in the vitreous, while retinal detachments will still be attached at the optic nerve at least, if not the ora ciliaris retinae. In some cases, differentiation between retinal detachments and fibrovascular membranes is still difficult (see Fig.  10.3.9). Hemorrhages and exudates are more likely to disappear as gain is decreased than tumors, but differentiation with this method becomes more difficult in chronic cases. While fresh hemorrhage is usually less echogenic, older, organized hemorrhage can be more echogenic and therefore may not disappear with decreased gain (Fig. 10.3.11). Careful monitoring over time with consistent transducer positioning and gain settings can help to distinguish hemorrhage or exudate from

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Figure 10.3.8  Persistent hyaloid vasculature in a dog. A. Clinical photo demonstrating cataract and intralenticular hemorrhage. B. Two-dimensional B-mode ultrasound vertical axial image, demonstrating a heterogenous and irregular lens, with a thin linear echogenic strand extending from posterior lens capsule to optic nerve, consistent with persistent primary vitreous/hyaloid vessel. C. Power Doppler confirms vascularization of the lens. D. Continuous wave Doppler demonstrates blood flow within the vessel.

tumors. Special techniques such as Doppler and contrast‐ enhanced ultrasound may be useful as well, and are discussed later in this chapter (Bertolotto et  al., 2014; Lacelli et al., 2009; Sconfienza et al., 2010). Other lesions that can be identified in the vitreous are foreign bodies. These are typically highly reflective and may or may not cause shadowing or multiple echoes, depending on their composition.

Retina Retinal detachments are probably the most common indication for ophthalmic ultrasound. The classic appearance of a retinal detachment is the “gull”‐wing appearance, which occurs when the retina remains attached at the ora ciliaris retinae and the optic nerve. However, a detached retina can

have many different ultrasonographic appearances, depending on whether it is acute or chronic, partial or complete, exudative or disinsertional (rhegmatogenous or tractional). Following a membrane located on an ultrasound examination to the optic nerve will generally confirm a retinal detachment. Again, when the gain is decreased, the reflective retina will remain on the image while the less echogenic vitreal opacities will often disappear. Contrast‐enhanced ultrasound or Doppler (power) mode can also be used to recognize retinal vasculature. Subretinal exudate is generally associated with hemorrhage or infection, and will appear echogenic and often homogenous posterior to the retina (Fig.  10.3.12). In many cases veterinary ophthalmologists examine patients with chronic retinal detachments, when retinal gliosis may cause a highly reflective membrane that will appear thickened and hyperechoic.

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A Figure 10.3.10  B-mode ultrasound image using a 10 MHz transducer in the 12 axial position of asteroid hyalosis in a dog. Note the multifocal echogenic punctate to coalescing foci in the vitreous cavity.

B Figure 10.3.9  B-mode ultrasound using a 10 MHz transducer. Two different meridional sections of the right eye of a Golden Retriever, presented for severe corneal edema, intraocular hemorrhage, and chronic glaucoma. Eye was enucleated and found to be affected with canine ocular gliovascular syndrome. Note hyperechoic fibrogliovascular membranes subtending the vitreal cavity in different directions (arrow heads). The hypoechoic homogenous material within the membrane frame represents hemorrhagic material (asterisks). L, lens.

Choroid Chorioretinitis typically appears as a thickening of the RCS complex (Fig. 10.3.12B). Although the resolution may be not ideal for this diagnosis, usually an increased‐thickness hypoechoic zone is seen between the more echogenic retinal and scleral layers.

Sclera Scleral ruptures can be identified in trauma with careful examination to identify a loss of continuity. Often a hemorrhagic track will lead to the area of scleral rupture. Posterior

scleritis has a typical ultrasonographic appearance (McCluskey et al., 1999) of diffuse thickening of the posterior sclera, often associated with diffuse retinal and choroidal thickening (Fig.  10.3.13). Elongation of the globe can also be possible, and the vitreal cavity can be deformed to almost a triangular shape with a posterior vertex. Episcleral inflammation causes distention of sub‐Tenon’s space, producing a hypoechoic space outside the globe. When this occurs around the optic nerve, it is referred to as the “T‐sign” (Byrne & Green, 2002).

Orbit Orbital disease can cause ultrasonographic deformities of the posterior aspect of the globe; blunting of the posterior aspect of the globe; diffuse increased or decreased echogenicity of the retrobulbar space, prohibiting delineation of the optic nerve; and discrete hypo/hyperechoic, sometimes cavitated masses in the retrobulbar space (Mason et al., 2001). Tumors have variable echogenicity, can cause deformities of the posterior aspect of the globe, and appear as discrete or infiltrative masses depending on their nature (Fig. 10.3.14). Inflammatory retrobulbar processes can be diffusely heterogenous to distinct hypoechoic or heterogenous masses. Diffuse, hypoechoic, ill‐defined, nondeforming lesions are most consistent with cellulitis. Although some retrobulbar masses can mimic an abscess, the latter is more likely when fluid contained in an ill‐defined thick hyperechoic wall is identified. Clinical signs and history are helpful, while aspirates and biopsies have higher diagnostic yield. Orbital cysts have thinner walls and usually less echoic content. These lesions can be differentiated by ­ultrasound‐ guided aspirates. Orbital foreign bodies are challenging to

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B Figure 10.3.11  B-mode ultrasound images of a dog. A. Note vitreal hemorrhage (red arrow) and retinal detachment (white arrows) with gain at 90 dB. Arrowheads denote reverberation artifact due to interaction of the sound wave with a highly reflective surface, in this case the corneal/gel interface. B. Same image as A, with gain of 57 dB. Note that the hemorrhage has faded from the image, while the retina remains.

image; however, orbital ultrasonography can be very helpful, depending on the composition, size, and location of the material. Shadowing and reverberations are possible. Tubular materials like porcupine quills can be identified, although with smaller plant materials both sensitivity and specificity are not reliable (Welihozkiy et  al., 2011). The optic nerve may become diffusely enlarged due to inflammation; diffuse or focal enlargements can also be caused by neoplasia. Extraocular muscles will increase in volume and become hypoechoic due to myositis. Other cross‐sectional imaging techniques such as CT and MRI can provide a better evaluation of the complex structures of the orbit, particularly given that the bone surrounding the orbital cone limits sonographic assessment (Boroffka et  al., 2007;

Penninck et  al., 2001), and are often used in conjunction with ultrasound.

High-Resolution Ultrasound/ Ultrasound Biomicroscopy Visualization of the relationship between living tissues in vivo at a microscopic level is a goal of many imaging modalities. Higher‐frequency ultrasound transducers have been developed with frequencies ranging from 20 MHz (HRUS) to 60 MHz (UBM), which allow imaging at axial resolutions comparable to low‐power microscopic views (20–80 μm; Coleman et  al., 2006). Conventional 10 MHz transducers

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C Figure 10.3.12  B-mode ultrasound images using a 10 MHz transducer. A. Image of a dog with blastomycosis. Note retinal detachment (white arrows) and subretinal exudate (yellow arrows). B. Sonogram of a dog with blastomycosis. Again, note extensive retinal detachment (white arrows) and less defined subretinal exudate. Also note thickened choroid (yellow arrows) and optic nerve (black arrow). C. Partial retinal detachment in a dog without subretinal exudate (arrow).

Figure 10.3.13  B-mode ultrasound image using a 10 MHz transducer of a dog with scleritis. Note the thickened retina, choroid, sclera complex (arrows) and the hyperechoic space external to the globe (arrowheads), suggestive of scleritis.

have axial and lateral resolutions of about 200 and 500 μm, respectively (Pavlin & Foster, 1998). With improved image detail afforded by the higher‐frequency transducers, tissue

penetration is limited to 5–15 mm. For ophthalmic applications, however, the critically important but optically occult structures of the anterior segment of the eye are within this range (Bentley et al., 2003). Clinical ophthalmic applications of HRUS in physician‐ based ophthalmology include evaluation of anterior segment tumors and cysts, scleral disease, intraocular lens assessment, trauma, and differentiation of the various forms of glaucoma. Several in vivo studies using UBM in dogs have been published (Aubin et  al., 2003; Crumley et  al., 2009; Gibson et al., 1998; Rose et al., 2008). Although these studies showed the promise of UBM, originally UBM required heavy sedation or general anesthesia in small animal patients, because obtaining an image involved using a water‐filled cup for the exposed oscillating transducer, which made patient positioning critical. These limitations have gradually been decreasing as higher and higher‐resolution handheld transducers with covers have been developed (Bentley et al., 2003, 2005). Imaging with currently available handheld high‐resolution transducers (20–50 MHz) does not typically require anesthesia or sedation, and can be performed with the animal sitting in almost any position. The investigation

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Figure 10.3.14  A. B-mode ultrasound image of a retrobulbar abscess in a dog using a high-frequency linear transducer. Note the heterogenously hypoechoic cavitary mass posterior to the globe (G; mass margins delineated by crosses). Retrobulbar fat is abnormally hyperechoic. B. Canine patient affected with adenocarcinoma of the third eyelid. Longitudinal vertical section of the orbit, B-scan, linear 15 MHz transducer. The globe is anechoic (G) while the posterior wall is hyperechoic (arrow). Ventrally to the globe there is a large (25 mm × 20 mm) hyperechoic, slightly heterogenous lobulated mass associated with the rostral and medial aspect of the orbit (asterisks). The mass is encapsulated (arrowheads) and does not appear to invade the adjacent bone, globe, or retrobulbar tissues. (Courtesy of Federica Maggio.)

of medioventral sectors is, however, difficult due to the size of the transducer, the presence of a third eyelid, and the proximity of the nasal bones. Brachycephalic breeds are obviously easier to examine.

perpendicular to the visual axis (Fig.  10.3.15). Images are generally labeled with the clock hour and transducer position. Structures and distances can be measured using the internal calipers on the ultrasound machine.

Technique

Cornea/Sclera

Most animals can be examined with manual restraint while sitting or in sternal recumbency following administration of topical anesthetic agents. Some animals may require light sedation and/or need to be examined in lateral recumbency. The transducer can be easily positioned to examine the superior and temporal quadrants of the eye, but light to deep sedation may be required in some cases to accurately examine the ventral and nasal quadrants. The eyelids are manually held open and the transducer is placed directly over the cornea or sclera. To examine the peripheral cornea and sclera, iridocorneal drainage angle, iris, ciliary body, and lens, scans are obtained with the transducer held perpendicular to the globe and the scan plane perpendicular to the direction of the limbus (radial paraxial limbal transducer position). To examine multiple ciliary processes circumferentially and the iris tangentially, the transducer is held perpendicular to the globe with the scan plane parallel to the limbus (transverse transducer position) and

The cornea is seen as two parallel reflective lines with a hypoechoic to anechoic space between them, in contrast to the highly reflective sclera. The limbal anatomy should be identifiable in normal eyes. Corneal thickness may be assessed with a high‐resolution transducer, although an ultrasound pachymeter is likely more accurate and easier to use (Al‐ Farhan & Al‐Otaibi, 2012; Fante et  al., 2013; Jeong et  al., 2017). Both tumors and sequestra are hyperechoic. HRUS can be used to assess lesion depth, although our experience suggests that it is more accurate for tumor depth than sequestrum depth due to shadowing in thick sequestra. In less dense sequestra, the most superficial portion of the sequestrum corresponds with the hyperechoic signal on the ultrasound image, while the less stained deep tissue may appear normal on ultrasound (Bentley et al., 2003). The faint pigment seen clinically probably does not cause enough alteration of the corneal stroma to reflect more than normal tissue, which correlates with the minimal changes seen ­histopathologically on

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Limbus Descemet’s

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Ciliary cleft

Iris Lens Ciliary process

B

A

Figure 10.3.15  A. B-mode ultrasound of a normal dog with a 40 MHz transducer in the radial position with section perpendicular to the limbus. Note the labeled normal structures. B. B-mode ultrasound of a normal dog with the transducer in the transverse position. Note the slender hyperechoic structures corresponding to the ciliary processes (CP) and the thin, linear hyperechoic space adjacent to the ciliary body (asterisks), which corresponds with the ciliary cleft.

coma (Czederpiltz et al., 2005). Using the contralateral normal eye as a control can be useful to determine changes in anterior chamber depth. When used for this purpose, positioning of the transducer is critical. The operator should look for symmetry of the iridal leaflets and be careful not to exert pressure on the axial cornea. Using abundant surface gel is usually helpful.

Uvea

Figure 10.3.16  A B-mode ultrasound using a 40 MHz transducer to evaluate corneal sequestrum in a cat. Note the internal calipers on the machine used to measure normal less echoic cornea (yellow double arrows, 0.39 mm), underlying the more hyperechoic sequestrum (red arrows).

such lesions. Nevertheless, useful information regarding depth can be obtained preoperatively with a high‐resolution transducer (Fig. 10.3.16). HRUS can also be useful for determining the extent of intraocular extension of superficial tumors, like epibulbar limbal melanocytomas, evaluation of episcleral nodules, granulomatous episcleritis, and possible staphylomas. HRUS of the cornea can be used to confirm the cystic cavity in epidermal inclusion cysts.

Anterior Chamber The anterior chamber can be evaluated for the presence of exudate, hyphema, fibrin, and other abnormal pathologic variations. Most anterior chamber exudates are echogenic and often move with eye movement. Congenital abnormalities, such as Peters’ anomaly, can be identified as posterior keratoconus, endothelial plaques, and strands of iridal tissue spanning from iris to cornea (Fig. 10.3.17). Changes in anterior chamber depth can also be evaluated via HRUS, which can be useful in cases of lens luxation or some types of glau-

The iris should appear as a moderately hyperechoic leaflet with somewhat ill‐defined margins. Its shape and thickness vary depending on pupil size. The ciliary body appears as a triangular leaflet when the transducer is positioned correctly. However, a full ciliary process is not imaged in every position. Full assessment of multiple ciliary processes is best achieved through the transverse paralimbal position (Fig. 10.3.15B). Differentiation between iris cysts and iris masses, as well as evaluation of tumor extent, is facilitated by a high‐resolution transducer (Bentley et  al., 2003; Taylor et  al., 2015). Cysts can appear as thin‐walled, fluid‐filled structures, or anterior displacement of the iris due to the cysts can be noted. Difficult cases are those in which the cysts are peripheral and posterior to the iris, causing an apparent mass lesion. Careful assessment of the posterior aspect of the iris for anterior bowing on ultrasound is usually diagnostic, even if cysts cannot be easily imaged due to their thin walls (Fig. 10.3.18). One study found that 14 of 15 feline eyes submitted for tumors that were not found on histopathology had cysts (Fragola et al., 2017). Only one of these eyes had prior ultrasound, performed with a 10 MHz transducer, suggesting that HRUS is underutilized for assessment of these conditions. Cysts located peripherally in the medial and ventral sectors can also be challenging to visualize. Identification of cystic cavities in corpora nigra in horses is helpful in cases where they may not be obvious clinically, and ultrasound can provide useful information for treatment or longitudinal monitoring (Fig.  10.3.19). Tumors are easily recognized as

B

Figure 10.3.17  Axial and paraxial views with a 35 MHz sectorial transducer of the anterior chamber (AC) in a 6-month-old Dachshund with corneal opacities and Peters’ anomaly. A. The different thickness of the cornea (C) is highlighted with the two arrowheads that point to a Descemet’s membrane (hyperechoic discrete lines) on different levels due to embryologic neurocrest tissue attached to the endothelial aspect of the cornea. The asterisk corresponds to an area of absent Descemet’s with a strand of tissue extending into the anterior chamber (AC). B. Descemet’s membrane cannot be clearly visualized, likely due to a minor posterior keratoconus. A strand of neurocrest tissue is spanning from the iris to the cornea (arrow). L, lens.

A

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D

Figure 10.3.18  High-resolution ultrasound with 35 MHz transducer of the anterior chamber in three canine patients presenting with similar findings of focal anterior iris bulging. Ultrasonography allows characterization of the different lesions. A. Dog with iris bombe caused by posterior synechia (arrow). The asterisk marks the posterior chamber behind the iris. B. Dog with iris neoplasia. The mass is composed by solid homogeneously and moderately hyperechoic tissue (*; histopathology revealed iris melanocytoma). C and D. Golden Retriever with multiple iridociliary cysts causing dilation of the posterior chamber and bowing forward of the iris. The arrows indicate the thin hyperechoic capsule of the cysts.

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echoic with age due to deposition of collagen at the base of the ciliary processes. The assessment of the ciliary cleft is complementary to gonioscopy. Evaluation of the ciliary cleft can be useful in evaluating glaucoma patients or potential glaucoma patients, as the ciliary cleft can be assessed as being open or closed (Fig. 10.3.20). A narrow or closed ciliary cleft in animals predisposed to glaucoma has been shown to increase the risk of glaucoma development (Dubin et al., 2017). Evaluation of the iridocorneal drainage angle and ciliary cleft is also a tool to investigate the mechanism by which various antiglaucoma drugs lower intraocular pressure in domestic animals (Gomes et al., 2011; Kawata & Hasegawa, 2013; Kawata et al., 2010; Kwak et al., 2017; Tsai et al., 2012).

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Figure 10.3.19  Ultrasound biomicroscopy scan of the anterior chamber in a horse using a 35 MHz sectorial transducer. Vertical axial section through the pupil. The corpora nigra (CN) is usually hyperechoic. In this case four small cysts (asterisk, anechoic voids) are present. Standard B-scan transducers will not detect the cystic cavities. AC, anterior chamber; C, cornea; DI, dorsal iris; L, lens; VI, ventral iris.

hyperechoic masses, and judging the extent of the tumor is helpful to determine appropriate treatment options. HRUS is better for identifying peripheral iridal and ciliary body extension of the neoplastic process when compared to conventional B‐scans (Conway et al., 2005). HRUS can also be used to locate the ciliary processes for more accurate transscleral cyclophotocoagulation.

Lens The high‐resolution transducer can be useful to evaluate the lens for peripheral lens capsule ruptures, which cannot be easily seen with slit‐lamp biomicroscopy. UBM transducers with frequencies of 35 and 50 MHz do not penetrate beyond the anterior cortex and can be used to evaluate changes in the anterior and equatorial lens only. Because of the much higher resolution and the impedances between the aqueous and the anterior lens capsule and the anterior lens capsule and the anterior cortex, two defined hyperechoic lines in the anterior lens are normally detected with UBM transducers.

Iridocorneal Angle and Uveal Drainage System The iridocorneal angle and the ciliary cleft can be easily identified with both paraxial radial and transverse positions of the transducer. The ciliary cleft appears as a hypoechoic space between the ciliary body and the sclera, and often has a teardrop or rectangular shape. Measurement of the aperture is difficult due to the indistinct boundaries and lack of objective landmarks. The ciliary body base becomes more

Contrast-Enhanced Ultrasonography/ Doppler One study in veterinary medicine has correlated histopathologic diagnoses with ultrasonographic diagnoses, and found overall acceptable correlation for most categories (neoplasia, hemorrhage, retinal detachment, subretinal exudate; Gallhoefer et al., 2013). Some findings, such as retinal tears, were not often detected via ultrasonography, and the ability to diagnosis other categories, such as subretinal exudate, varied by location. This study found that it can be difficult to differentiate hemorrhage from neoplasia, and that clinicians should be cautious when trying to determine ultrasonographic diagnoses in eyes with extensive solid, nonfloating hemorrhages. Additionally, several cases were identified with vitreous membranes that looked remarkably similar to retinal detachments on ultrasonography. Therefore, other methods to differentiate blood from intraocular masses and definitively determine retinal detachments could be a useful addition to clinical ultrasound. In 1968, investigators reported visualizing cardiac shunts with ultrasound using air bubbles via injection, and CEUS began (Gramiak & Shah, 1968). Free air bubbles were too large to pass in the pulmonary circulation, which limited their use. Over time, specific contrast ultrasound agents were developed for intravenous use, typically in a bolus. These agents are essentially high molecular weight/low solubility gas microbubbles (perfluorocarbons or sulfur hexafluoride) stabilized by a lipid polymer or albumin shell (Haers & Saunders, 2009: Seiler et al., 2013). These bubbles can pass through the pulmonary circulation given their small size (1–10 μm) and have a longer half‐life than normal air bubbles. Ultrasound contrast agents are strictly intravascular, making them ideal for differentiating vascular versus avascular structures, such as intraocular tumors versus hemorrhage or retinal detachment in the face of hemorrhage or vitreal membranes. Unfortunately, B‐mode, grayscale imaging results in poor detectability of ultrasound contrast agents in tissue. The

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Figure 10.3.20  A. B-mode ultrasound image using a 40 MHz transducer of the normal eye of a dog affected with glaucoma in the contralateral eye. Note the open ciliary cleft in the radial 12 o’clock position. B. B-mode ultrasound image using a 40 MHz transducer in the eye of a dog affected with secondary glaucoma. Note the ciliary cleft cannot be imaged. C. Subgross view of the same eye imaged in B. Note the correlating absence of identifiable ciliary cleft. (Courtesy of the Comparative Ocular Pathology Laboratory of Wisconsin.)

microbubbles of ultrasound contrast agents are very small and behave as scattering reflectors, and the microbubbles expand and contract when insonified, which means they produce echoes that are at multiples of the fundamental (transducer) frequency (i.e., harmonics; Haers & Saunders, 2009; Silverman et al., 2005). At the fundamental frequency, contrast agents are echogenic only at high doses and are severely attenuating, which means that signal strength is lost deep to enhanced structures. Fundamental imaging generally utilizes a high acoustic output, which is destructive to the circulating microbubbles, limiting their longevity. In order to better image the contrast agents, contrast harmonic imaging is used. Contrast harmonic imaging utilizes the nonlinear oscillation of the contrast agents, which occurs due to the expansion and contraction of the contrast agent microbubbles as sound passes through them, which then generates harmonic frequencies. Harmonic imaging is a technique in which the beam is sent at one frequency (fundamental or transducer frequency) while the machine receives a different returned frequency.

An initial small study in veterinary patients noted an anaphylactic reaction to Optison™ (perflutren protein type A; GE Healthcare, Princeton, NJ, USA) in two dogs (Yamaya et al., 2004). A later study (Seiler et al., 2013) evaluated the safety of ultrasound contrast agents in 488 dogs and cats that received an ultrasound contrast agent compared to 262 patients that had ultrasonography alone. Only dogs were noted to have adverse effects, and those were vomiting and syncope, occurring in 0.2% of dogs (Seiler et al., 2013). In an experimental setting, visualization of the normal rabbit choroid was possible, and iatrogenic avascular lesions could also be demonstrated (Hirokawa et  al., 2002). High‐ frequency ultrasound was used to assess experimentally induced choroidal melanomas in mice and rabbits, and findings correlated well with histology (Kang et al., 2013). Early studies in physician‐based ophthalmology demonstrated the utility of CEUS in evaluation of tumors, mostly choroidal melanomas. Prior to treatment, choroidal melanomas were well perfused on contrast harmonic imaging, while Doppler failed to highlight some of the same tumors

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(Schlottmann et  al., 2005). Contrast ultrasound also highlighted changes in vascularization of choroidal melanomas after treatment, demonstrating its possible use as a monitoring tool (Forte et  al., 2005). While multiple publications investigate the use of CEUS in various abdominal organs in veterinary patients, only Labruyere et  al. (2011) have published on the use of this technique in veterinary ophthalmol-

ogy. This study also compared color Doppler ultrasonography with CEUS and found that in most eyes the color assessment was unsuccessful due to eye movement artifacts. CEUS, however, enabled visualization of blood flow in detached retinas in all cases and did not falsely show blood flow in vitreous membranes. The chapter authors have used CEUS to differentiate hemorrhage from vascularized tumors (Fig. 10.3.21).

A

C

B Figure 10.3.21  A. Photograph of a dog with iridociliary cysts, hyphema, and mass effect. B. Contrast-enhanced ultrasound of the same eye with a high-frequency linear transducer. The left panel is the fundamental frequency and the image on the right is the contrast harmonic mode. Note the irregular echogenic mass enhances (arrows), consistent with vascularized tissue rather than hyphema. C. Subgross photograph of the same eye, cut in the superior–inferior plane. The mass was diagnosed as a pigmented iridociliary adenoma. (Courtesy of the Comparative Ocular Pathology Laboratory of Wisconsin.)

Blood vessels’ presence and flow can be detected using the Doppler effect, which is based on an apparent shift in sound frequency when reflected off a moving target (e.g., red blood cells in vessels). Motion away from the transducer results in a lower frequency than the original, and motion toward the transducer results in a higher frequency, which is then displayed as a color map or graph. When applied to the eye, movements of the globe can create artifacts; however, with patience and repetition, consistent findings can be detected, and the modality offers advantages in some cases (Labruyere et  al., 2011). Doppler modality in ultrasonography can be used with two different techniques, color Doppler (CD) or power Doppler (PD). While CD does not detect flows that are perpendicular to the beam, PD is not influenced by the angle of the beam relative to the flow. PD is more sensitive than CD and it provides useful information in the eye due to its ability to detect the smaller blood vessels of the eye independently of the direction of the flow or the position of the

beam. The chapter authors found it useful in recognizing dubious retinal detachments or to detect blood flow in persistent hyaloid vessels (see Fig.  10.3.8). The CD technique has less sensitivity, and considering the caliper of ocular blood vessel, this may represent a disadvantage, along with the artifacts created by eye movement if performed in an awake or lightly sedated dog.

Three-Dimensional Ultrasound Three‐dimensional (3D) ultrasonography is best known through its use for prenatal imaging in humans. In this technique, sequential two‐dimensional (2D) scans are combined with computerized reconstruction software. However, 2D images in three planes can also be obtained (Fig.  10.3.22). This allows the surfaces of structures and lesions to be rendered and the volume of lesions to be calculated. The use of

Figure 10.3.22  B-mode ultrasound multiplanar image using a three-dimensional transducer to allow simultaneous evaluation of X, Y, and Z planes of a retrobulbar abscess in a dog, with the planes centered around the small dot in the middle of the abscess.

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3D ultrasonography in ophthalmology has remained relatively limited and is mostly reported for the use of posterior segment and optic nerve tumors, including extraocular extension (Garcia et al., 2005; Sconfienza et al., 2010). At the

moment, the need for specialized equipment limits its use in veterinary medicine, although the utility of 3D imaging and printing diagnosis and surgical planning is obvious (Dorbandt et al., 2017).

References Al‐Farhan, H. & Al‐Otaibi, W. (2012) Comparison of central corneal thickness measurement using ultrasound pachymetry, ultrasound biomicroscopy and the Artemis‐2 VHF scanner in normal eyes. Clinical Ophthalmology, 6, 1037–1043. Aubin, M., Powell, C., Gionfriddo, J.R., et al. (2003) Ultrasound biomicroscopy of the feline anterior segment. Veterinary Ophthalmology, 6(1), 15–17. Bentley, E., Miller, P., & Diehl, K. (2003) Use of high resolution ultrasound as diagnostic tool in veterinary ophthalmology. Journal of the American Veterinary Medical Association, 223(11), 1617–1622. Bentley, E., Miller, P.E., & Diehl, K.A. (2005) Evaluation of intra‐ and interobserver reliability and image reproducibility to assess usefulness of high‐resolution ultrasonography for measurement of anterior segment structures of canine eyes. American Journal of Veterinary Research, 66(10), 1775–1779. Berges, O., Puech, M., Assouline, M., et al. (1998) B‐mode‐ guided vector‐A‐mode versus A‐mode biometry to determine axial length and intraocular lens power. Journal of Cataract and Refractive Surgery, 24(4), 529–535. Bertolotto, M., Serafini, G., Sconfienza, L.M., et al. (2014) The use of CEUS in the diagnosis of retinal/choroidal detachment and associated intraocular masses: Preliminary investigation in patients with equivocal findings at conventional ultrasound. Ultrachallenging Medicine, 35(2), 173–180. Boroffka, S.A.,Verbruggen, A.M., Grinwis, G.C., et al. (2007) Assessment of ultrasonography and computed tomography for the evaluation of unilateral orbital disease in dogs. Journal of the American Veterinary Medical Association, 230(5), 671–680. Byrne, S.F. & Green, R.L. (2002) Ultrasound of the Eye and Orbit. St Louis, MO: Mosby. Coleman, D.J., Silverman, R.H., Rondeau, M.J., et al. (2006) Explaining the current role of high frequency ultrasound in ophthalmic diagnosis (ophthalmic ultrasound). Expert Review of Ophthalmology, 1(1), 63–76. Conway, R.M., Chew, T., Golchet, P., et al. (2005) Ultrasound biomicroscopy: Role in diagnosis and management in 130 consecutive patients evaluated for anterior segment tumours. British Journal of Ophthalmology, 89(8), 950–955. Cottrill, N.B., Banks, W.J., & Pechman, R.D. (1989) Ultrasonographic and biometric evaluation of the eye and orbit of dogs. American Journal of Veterinary Research, 50(6), 898–903. Crumley, W., Gionfriddo, J.R., & Radecki, S.V. (2009) Relationship of the iridocorneal angle, as measured using ultrasound biomicroscopy, with post‐operative increases in

intraocular pressure post‐phacoemulsification in dogs. Veterinary Ophthalmology, 12(1), 22–27. Czederpiltz, J.M., La Croix, N.C., van der Woerdt, A., et al. (2005) Putative aqueous humor misdirection syndrome as a cause of glaucoma in cats: 32 cases (1997–2003). Journal of the American Veterinary Medical Association, 227(9), 1434–1441. d’Anjou, M.‐A. & Penninck, D. (2015) Practical physical concepts and artifacts. In: Atlas of Small Animal Ultrasonography (eds. D. Penninck & M.‐A. d’Anjou), pp. 1–18. Ames, IA: Wiley Blackwell. De La Hoz Polo, M., Torramilans Lluís, A., Pozuelo, O., et al. (2016) Ocular ultrasonography focused on the posterior eye segment: What radiologists should know. Insights Imaging, 7(3), 351–364. Dorbandt, D.M., Joslyn, S.K., & Hamor, R.E. (2017) Three‐ dimensional printing of orbital and peri‐orbital masses in three dogs and its potential applications in veterinary ophthalmology. Veterinary Ophthalmology, 20(1), 58–64. Dubin, A.J., Bentley, E.K., Buhr, A., et al. (2017) Evaluation of potential risk factors for development of primary angle‐ closure glaucoma in Bouviers des Flandres. Journal of the American Veterinary Medical Association, 250(1), 60–67. Ekesten, B. & Torrang, I. (1995) Age‐related changes in ocular distances in normal eyes of Samoyeds. American Journal of Veterinary Research, 56(1), 127–133. Fante, R., Shtein, R., Titus, M., & Woodward, M. (2013) Anterior segment optical coherence tomography versus ultrasound pachymetry to measure corneal thickness in endothelial keratoplasty donor corneas. Cornea, 32(5), 70–82. Feldman, M.K., Katyal, S., & Blackwood, M.S. (2009) US artifacts. RadioGraphics, 29(4), 1179–1189. Forte, R., Cennamo, G., Staibano, S., et al. (2005) Echographic examination with new generation contrast agent of choroidal malignant melanomas. Acta Ophthalmologica Scandanivica, 83(3), 347–354. Foster, F.S., Pavlin, C.J., Harasiewicz, K.A., et al. (2000) Advances in ultrasound biomicroscopy. Ultrasound in Medicine and Biology, 26(1), 1–27. Fragola, J.A., Dubielzig, R.R., Bentley, E., et al. (2017) Iridociliary cysts masquerading as neoplasia in cats: A morphologic review of 14 cases. Veterinary Ophthalmology, 21, 125–131. Gallhoefer, N.S., Bentley, E., Ruetten, M., et al. (2013) Comparison of ultrasonography and histologic examination for identification of ocular diseases of animals: 113 cases (2000–2010). Journal of the American Veterinary Medical Association, 243(3), 376–388.

Garcia, J., Garcia, P., Muldoon, T., et al. (2005) Surface rendering of 3D ultrasound images in ophthalmology. Ophthalmic Surgery Lasers Imaging, 37, 347–351. Gibson, T.E., Roberts, S.M., Severin, G.A., et al. (1998) Comparison of gonioscopy and ultrasound biomicroscopy for evaluating the iridocorneal angle in dogs. Journal of the American Veterinary Medical Association, 213(5), 635–638. Gilger, B.C., Davidson, M.G., & Colitz, C.M. (1998a) Experimental implantation of posterior chamber prototype intraocular lenses for the feline eye. American Journal of Veterinary Research, 59(10), 1339–1343. Gilger, B.C., Davidson, M.G., & Howard, P.B. (1998b) Keratometry, ultrasonic biometry, and prediction of intraocular lens power in the feline eye. American Journal of Veterinary Research, 59(2), 131–134. Gomes, F.E., Bentley, E., Lin, T.L., et al. (2011) Effects of unilateral topical administration of 0.5% tropicamide on anterior segment morphology and intraocular pressure in normal cats and cats with primary congenital glaucoma. Veterinary Ophthalmology, 14(Suppl. 1), 75–83. Gorig, C., Varghese, T., Stiles, T., et al. (2006) Evaluation of acoustic wave propagation velocities in the ocular lens and vitreous tissues of pigs, dogs, and rabbits. American Journal of Veterinary Research, 67(2), 288–295. Gramiak, R. & Shah, P. (1968). Echocardiography of the aortic root. Investigative Radiology, 3, 356–366. Haers, H. & Saunders, J.H. (2009). Review of clinical characteristics and applications of contrast‐enhanced ultrasonography in dogs. Journal of the American Veterinary Medical Association, 234(4), 460–470. Hirokawa, T., Nishikage, T., Moroe, T., et al. (2002) Visualization of uveal perfusion by contrast‐enhanced hamonic ultrasonography at a low mechanical index: A pilot animal study. Journal of Ultrasound Medicine, 21(3), 299–307. Hoffer, K.J. (1994) Ultrasound velocities for axial eye length measurement. Journal of Cataract Refractive Surgery, 20(5), 554–562. Jeong, S., Kang, S., Park, S., et al. (2017) Comparison of corneal thickness measurements using ultrasound pachymetry, ultrasound biomicroscopy, and digital caliper in frozen canine corneas. Veterinary Ophthalmology, 21(4), 339–346. doi:10.1111/vop.12509. Kang, S.J., Zhang, Q., Patel, S.R., et al. (2013) In vivo high‐ frequency contrast‐enhanced ultrasonography of choroidal melanoma in rabbits: Imaging features and histopathologic correlations. British Journal of Ophthalmology, 97(7), 929–933. Kawata, M. & Hasegawa, T. (2013) Evaluation of the distance between Schwalbe’s line and the anterior lens capsule as a parameter for the correction of ultrasound biomicroscopic values of the canine iridocorneal angle. Veterinary Ophthalmology, 16(3), 169–174. Kawata, M., Tsukizawa, H., Nakayama, M., et al. (2010) Rectification of width and area of the ciliary cleft in dogs. Journal of Veterinary Medical Science, 72(5), 533–537. Kwak, J., Kang, S., Lee, E.R., et al. (2017) Effect of preservative‐ free tafluprost on intraocular pressure, pupil diameter, and

anterior segment structures in normal canine eyes. Veterinary Ophthalmology, 20(1), 34–39. Labruyere, J.J., Hartley, C., & Holloway, A. (2011) Contrast‐ enhanced ultrasonography in the differentiation of retinal detachment and vitreous membrane in dogs and cats. Journal of Small Animal Practice, 52(10), 522–530. Labruyere, J.J., Hartley, C., Rogers, K., et al. (2008) Ultrasonographic evaluation of vitreous degeneration in normal dogs. Veterinary Radiology & Ultrasound, 49(2), 165–171. Lacelli, F., Sconfienza, L.M., Bertolotto, M., et al. (2009) Ultrasonographic evaluation of the globe with contrast enhanced ultrasound (CEUS) and 3D imaging in comparison with conventional high‐resolution ultrasound (HRUS). ECR 2009. EPOS, European Society of Radiology. doi: 10.1594/ecr2009/C‐719. Leo, M. & Carmody, K. (2011) Sonography assessment of acute ocular pathology. Ultrasound Clinics, 6, 227–234. Mason, D.R., Lamb, C.R., & McLellan, G.J. (2001) Ultrasonographic findings in 50 dogs with retrobulbar disease. Journal of the American Animal Hospital Association, 37(6), 557–562. McCluskey, P.J., Watson, P.G., Lightman, S., et al. (1999) Posterior scleritis. Ophthalmology, 106(12), 2380–2386. McMullen, R.J., Davidson, M.G., Campbell, N.B., et al. (2010) Evaluation of 30‐ and 25‐diopter intraocular lens implants in equine eyes after surgical extraction of the lens. American Journal of Veterinary Research, 71(7), 809–816. McMullen, R.J., Jr. & Gilger, B.C. (2006) Keratometry, biometry and prediction of intraocular lens power in the equine eye. Veterinary Ophthalmology, 9(5), 357–360. Meister, U., Ohnesorge, B., Korner, D., et al. (2014) Evaluation of ultrasound velocity in enucleated equine aqueous humor, lens and vitreous body. BMC Veterinary Research, 10, 250. Mundt, G.H. & Hughes, W.F. (1956) Ultrasonics in ocular diagnosis. American Journal of Ophthalmology, 41, 488–498. Murphy, C.J., Zadnik, K., & Mannis, M.J. (1992) Myopia and refractive error in dogs. Investigative Ophthalmology & Visual Science, 33(8), 2459–2463. Mutti, D.O., Zadnik, K., & Murphy, C.J. (1999) Naturally occurring vitreous chamber‐based myopia in the Labrador Retriever. Investigative Ophthalmology & Visual Science, 40(7), 1577–1584. Ng, A. & Swanevelder, J. (2011). Resolution in ultrasound imaging. Continuing Education in Anaesthesia Critical Care & Pain, 11(5), 186–192. Oksala, A. & Lehtinen, A. (1958) Measurement of the velocity of sound in some parts of the eye. Acta Ophthalmologica, 36(4), 633–639. Ossoinig, K.C. (1979) Standardized echography: Basic principles, clinical applications and results. International Ophthalmology Clinics, 19(14), 127–210. Pavlin, C.J. & Foster, F.S. (1995) Ultrasound Biomicroscopy of the Eye. New York: Springer. Pavlin, C.J. & Foster, F.S. (1998) Ultrasound biomicroscopy: High‐frequency ultrasound imaging of the eye at microscopic resolution. Radiology Clinics of North America, 36(6), 1047–1058.

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Pavlin, C.J., Harasiewicz, K., Sherar, M.D., et al. (1991) Clinical use of ultrasound biomicroscopy. Ophthalmology, 98(3), 287–295. Penninck, D. & d’Anjou, M.‐A. (2015) Atlas of Small Animal Ultrasonography. Ames, Iowa: Wiley Blackwell. Penninck, D., Daniel, G.B., Brawer, R., et al. (2001) Cross‐ sectional imaging techniques in veterinary ophthalmology. Clinical Techniques Small Animal Practice, 16(1), 22–39. Pizzirani, S., Penninck, D., & Spaulding, K. (2015) Eye and orbit. In: Atlas of Small Animal Ultrasonography (eds. D. Penninck & M.‐A. d’Anjou), pp. 19–54. Ames, IA: Wiley Blackwell. Rose, M.D., Mattoon, J.S., Gemensky‐Metzler, A.J., et al. (2008) Ultrasound biomicroscopy of the iridocorneal angle of the eye before and after phacoemulsification and intraocular lens implantation in dogs. American Journal of Veterinary Research, 69(2), 279–288. Sandinha, M.T., Kotagiri, A.K., Owen, R.I., et al. (2017) Accuracy of B‐scan ultrasonography in acute fundus obscuring vitreous hemorrhage using a standardized scanning protocol and a dedicated ophthalmic ultrasonographer. Clinical Ophthalmology, 11, 1365–1370. Schiffer, S.P., Rantanen, N.W., Leary, G.A., et al. (1982) Biometric study of the canine eye, using A‐mode ultrasonography. American Journal of Veterinary Research, 43(5), 826–830. Schlottmann, K., Fuchs‐Koelwel, B., Demller‐Hackenberg, M., et al. (2005) High‐frequency contrast harmonic imaging of ophthalmic tumor perfusion. American Journal of Radiology, 184, 574–578. Sconfienza, L.M., Lacelli, F., Ardemagni, A., et al. (2010) High‐resolution, three‐dimensional, and contrast‐enhanced ultrasonographic findings in diseases of the eye. Journal of Ultrasound, 13(4), 143–149. Seiler, G.S., Brown, J.C., Reetz, J.A., et al. (2013) Safety of contrast‐enhanced ultrasonography in dogs and cats: 488 cases (2002–2011). Journal of the American Veterinary Medical Association, 242(9), 1255–1259.

Silverman, R.H. (2009) High‐resolution ultrasound imaging of the eye: A review. Clinical and Experimental Ophthalmology, 37(1): 54–67. Silverman, R. H., Coleman, D.J., Ketterling, J., et al. (2005) High‐frequency harmonic imaging of the eye. Proceedings of the SPIE International Society of Optical Engineering, 5750, 16–25. Sofferman, R.A. (2012) Physics and principles of ultrasound. In: Ultrasound of the Thyroid and Parathyroid Glands (eds. R.A. Sofferman & A.T. Ahuja), pp. 9–19. New York: Springer. Stuhr, C.M. & Scagliotti, R. (1996). Retrobulbar ultrasound in the mesaticephalic and dolichocephalic dog using a temporal approach. Veterinary & Comparative Ophthalmology, 6(2), 91–99. Szabo, T.L. & Lewin, P.A. (2013) Ultrasound transducer selection in clinical imaging practice. Journal of Ultrasound Medicine, 32(4), 573–582. Taylor, L.N., Townsend, W.M., Heng, H.G., et al. (2015) Comparison of ultrasound biomicroscopy and standard ocular ultrasonography for detection of canine uveal cysts. American Journal of Veterinary Research, 76(6), 540–546. Thijssen, J.M., Mol, H.J., & Timmer, M.R. (1985) Acoustic parameters of ocular tissues. Ultrasound in Medicine and Biology, 11(1), 157–161. Tsai, S., Bentley, E., Miller, P.E., et al. (2012) Gender differences in iridocorneal angle morphology: A potential explanation for the female predisposition to primary angle closure glaucoma in dogs. Veterinary Ophthalmology, 15(Suppl. 1), 60–63. Welihozkiy, A., Pirie, C.G., & Pizzirani, S. (2011) Scleral and suprachoroidal foreign body in a dog: A case report. Veterinary Ophthalmology, 14(5), 345–351. Yamaya, Y., Niizeki, K., Kim, J., et al. (2004) Anaphylactoid response to Optison(R) and its effects on pulmonary function in two dogs. Journal of Veterinary Medical Science, 66(11), 1429–1432. Zagzebski, J.A. (1996) Essentials of Ultrasound Physics. St Louis, MO: Mosby.

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10.4 Ophthalmic Examination and Diagnostics Part 4: Clinical Electrodiagnostic Evaluation of the Visual System Gil Ben-Shlomo Departments of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA

When light enters the eye and stimulates the retinal photoreceptors, it triggers alteration of electrical potentials, which propagate through all layers of the neuroretina and the visual pathways to the visual cortex. Different electrodiagnostic techniques can be utilized for the recording of this electrical activity. These techniques provide objective, noninvasive means to evaluate the visual system’s function. They are particularly useful in veterinary ophthalmology due to the lack of verbal communication between the examiner and the examinee, which makes the evaluation of the visual system challenging. However, it is important to note that electrodiagnostic testing is not a measure of vision. For example, an animal with normal retinal function may still be blind due to cataract or postretinal lesion. Conversely, an animal with altered electrical activity of the visual system may retain some degree of visual function (e.g., early stage of progressive retinal atrophy). Hence, the results of electrodiagnostic tests should be interpreted in light of medical history, complete physical examination findings, and behavioral tests of vision such as maze testing and the ability to maneuver through an obstacle course. Different electrodiagnostic techniques can be used to assess different parts of the visual system, and these will be discussed in this chapter. However, since full field electroretinography (ERG) is the only routine visual electrodiagnostic test performed in clinical veterinary ophthalmology, it will be the focus of this chapter. Changes associated with specific pathologies of the visual system are beyond the scope of this chapter and are discussed in the respective chapters. Understanding the retinal physiology is crucial to the understanding of the ERG and is reviewed in detail in Chapter 4.

The Full Field Electroretinogram (fERG) The full field electroretinogram (also known as flash ERG or fERG) was the first electrodiagnostic test of the visual system, originally reported in 1865 (Holmgren, 1865). In

performing the fERG, a light stimulus (i.e., a flash of light) is projected on the tested eye, illuminating the retina. The change in illumination generates electrical responses by the retina that can be recorded and analyzed. Retinal photoreceptors and bipolar cells are the main generators of the fERG, and the recorded trace is the sum of all retinal electrical activity. Since the introduction of the first commercial ERG machine in the second half of the 20th century, its popularity and use have increased dramatically in veterinary ophthalmology, and today it is considered essential equipment for veterinary ophthalmologists. The fERG is most commonly used for screening patients prior to cataract surgery, and as a diagnostic test in patients with visual impairment or blindness, to differentiate retinal from postretinal blindness.

Equipment and Technical Considerations Initially, recording systems that were designed and built by individual researchers were used to record ERG for research purposes only. With the advancement of electronic amplification and recording equipment in the mid-20th century, clinical application was possible in humans, and later in veterinary patients (Karpe, 1946; Parry et al., 1953). Since then, further technologic advances and cooperation between system designers and clinicians/researchers have led to a rapid improvement in the quality of commercial electrodiagnostic systems. Today, high-quality commercial ERG machines are readily available and negate the need for profound technical skills, and knowledge in physics and electronics, in order to perform the test. Moreover, handheld ERG devices have become available in recent years. These handheld devices are highly mobile and easy to use, which is an advantage for the veterinary ophthalmologist, facilitating ERG evaluation in various locations (e.g., in the clinic, barn, zoo, etc.) and easy adjustment to the patient’s head position, especially when the ERG is performed on conscious patients (Fig. 10.4.1).

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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Stimulation

Figure 10.4.1  A handheld ERG machine with a mini-Ganzfeld stimulator is held in front of the patient’s eye, and can be adjusted easily and quickly to the head position as needed. (Reproduced with permission from Ben-Shlomo, G., Plummer, C., Barrie, K., & Brooks, D. (2012) Characterization of the normal dark adaptation curve of the horse. Veterinary Ophthalmology, 15, 42–45.)

Stimulator

Modern commercial ERG machines include a full-field (Ganzfeld or mini-Ganzfeld) stimulator. The Ganzfeld‐type stimulator (vs. a strobe flash) is a dome, or a half‐sphere bowl, with an integrated photo‐stimulator, allowing homogenous luminance over the entire retina, and is the preferred type of stimulator for ERG testing (Fig.  10.4.2; Mcculloch et  al., 2015). Furthermore, the Ganzfeld/mini‐Ganzfeld stimulator can also provide background illumination when light adaptation is needed. Rather than placing the whole head of the examined animal inside a dome, handheld mini‐Ganzfeld stimulators are placed over the tested eye, which is more practical in clinical veterinary ophthalmology, especially when the tested animal is conscious or is large (e.g., a horse; Fig. 10.4.1 and Fig. 10.4.2). Some stimulators include an integrated infrared camera that allows monitoring of the eye and corneal electrode positions while the eye is covered by the stimulator (Fig. 10.4.2C). Contact lens electrodes with an integrated light stimulator have also been used successfully for fERG in dogs (Kim et al., 2008; Maehara et al., 2005; Yu et al., 2007). These devices need to meet all requirements for a Ganzfeld‐type stimulator, including appropriate calibration and verification of uniform retinal illumination, in order to achieve reliable and reproducible readings.

While different light sources can be used for ERG stimulation (e.g., xenon flash lamp), light‐emitting diodes (LED) are superior to others since they are inexpensive, small, and can be controlled by simple electronic means to give either continuous light output or brief flashes, over a wide range of intensities. Additionally, their light output changes very little over extended use (Hogg, 2006). Over the last decade, major advances have been made in LED technology, leading to the widespread use of LED as the light source in many modern machines. Calibration of the stimulator on a regular basis, according to the manufacturer’s instructions, is recommended to ensure reliable and consistent results (Mcculloch et  al., 2015). Due to the LED properties, these stimulators require calibration less frequently than other light sources. The recommended flash duration should not exceed 5 msec, which is shorter than the integration time of any photoreceptor. Stimulus intensity is measured by its time‐ integrated luminance, and the most common units used for ERG are candela‐seconds per meter squared (cd·s/m2). Specific light intensities for fERG will be discussed later in this chapter. Chromatic stimuli (i.e., blue and red lights) may be used to facilitate enhanced separation of rod and cone ERGs. Blue stimuli over a red background will favor the rod system, while red stimuli over a blue background will favor the cone system. The red or blue backgrounds will suppress the response from the cone or rod photoreceptors, respectively. While chromatic ERG may be used for advanced protocols, only white flashes (and background) are used for routine clinical ERG (Ekesten et al., 2013; Mcculloch et al., 2015). An in‐depth review of the principles of chromatic ERG is available (Estevez and Spekreijse, 1982). Amplification and Signal Filtering

The electrical potentials generated by the retina and visual system are too small to be recorded and accurately analyzed. Therefore, a system of pre‐amplifiers and amplifiers is needed to increase the voltage of the signal (usually 1000× for the fERG). The ERG system has a set of three inputs (i.e., positive, negative, and ground), which are connected to a differential amplifier. The differential amplifier amplifies only the difference in signals between the recording and reference electrodes, as discussed in the following section on electrodes. The recording electrode is connected to the positive input, the reference electrode to the negative one, and the common (or ground electrode) to the ground input; hence, the positive potential occurs at the recording electrode. Inadvertent connection of the recording electrode to the negative input and the reference electrode to the positive one will result in inverted trace (see the later section on interpretation of the results and Fig. 10.4.11). A set of positive and negative inputs (i.e., recording and reference electrodes) are referred to as a channel. One channel allows ERG recording from one eye. Some recording systems are equipped with two

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A

B

C

Figure 10.4.2  Ganzfeld (A) and mini-Ganzfeld (B) stimulators. These stimulators provide a flash of light that illuminates the retina homogenously. The mini-Ganzfeld in (B) is part of a handheld ERG system. An infrared camera integrated into the mini-Ganzfeld stimulator of a handheld ERG device allows monitoring of the eye and electrode position during the testing (C). The green circle on the screen aids the examiner in positioning the stimulator centrally and ensures even stimulation of the retina.

channels for simultaneous recording of both eyes. However, when mini-Ganzfeld stimulators are used, positioning two stimulators over both eyes (one stimulator over each eye) may be challenging in a conscious animal. The amplifier also filters the signal, and should be set to record frequencies between 0.3 Hz and 300 Hz, which is the range of signals generated from the various structures of the visual system. Frequencies below or above these frequencies will be rejected (band‐pass filter). Modern machines are preset for these settings. Changing the frequencies of the high‐ or low‐pass filters will affect the amplitude and implicit time of the ERGs (Mcculloch et al., 2015) and, as such, should be avoided. Comparisons between ERG recordings should be done, ideally, after recording with the same band‐pass filter. Nonetheless, the ERG machine should allow the change of the low (high‐pass) and high (low‐pass) filters in order to record oscillatory potentials (OPs), which are high‐frequency wavelets originating from the inner retina. In addition, the OPs can be extracted from a recorded trace post hoc using the ERG machine’s software or mathematic software. In order to separate the OPs from the ERG, the low filter must be set to 75–100 Hz; this will eliminate the slow components of the ERG (i.e., the a‐ and b‐waves) that mask the OPs (for more information, see “Analysis of the fERG” below). “Notch filters” can be applied to reject 50 Hz or 60 Hz “noise” and thus improve the appearance of the recorded trace. However,

such filtering affects the waveform, and should be avoided. Alternatively, periodic interfering signals (such as the electrical system’s 50 Hz or 60 Hz) can be removed by software after the recording, if warranted. This may be referred to as “smoothing” of the trace. Electrodes

The principle of electroretinography testing is the amplification of the difference between two inputs coming from electrodes around the eye and rejection of noise or common signals. For example, a heartbeat that is generated from a location relatively distant from the eye, creating equal signals on the two electrodes at the eye (i.e., common signal), will not be recorded. Therefore, two electrodes are needed in order to record ERG from a single eye: a signal‐receiving (or recording) electrode and a reference electrode. Historically, the recording electrode may be referred to as the “active” electrode. However, this is a misnomer, as this electrode passively records the electrical changes generated by the retina. A third, grounding electrode is needed to ground the patient and reduce power line frequency (mains) interference (60 Hz in the Americas and parts of Asia, and 50 Hz in large parts of the rest of the world). Electrodes that contact the cornea, the bulbar conjunctiva, or skin of the eyelid (upper or lower) may be used as recording electrodes (Mcculloch et al., 2015; Steiss et  al., 1992; Fig.  10.4.3). The reference electrode is

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placed adjacent to the eye, usually posterior to the lateral canthus, and the grounding electrode is placed elsewhere on the body (see below). Corneal contact lens electrodes (e.g., the ERG‐JetTM, Fabrinal, La Chaux‐de‐Fonds, Switzerland) are most commonly used as the recording electrode in veterinary (and human) patients. They provide the most stable recording and higher amplitudes compared to other types of electrodes such as conjunctival or eyelid electrodes, and are recommended for clinical fERG recordings (Mcculloch et al., 2015; Steiss et  al., 1992). However, other electrodes that contact the cornea, such as silver‐impregnated microfiber (introduced by Dawson, Trick, and Litzkow and now referred to as the DTL electrode) and gold‐coated foil strips, are also effective (Komaromy et al., 2003; Pereira et al., 2013; Strom and Ekesten, 2016). In small animals such as dogs and cats, the contact lens electrode covers most or all of the cornea, and has the added value of protecting the cornea from desiccation, especially when the test is being performed on sedated or anesthetized patients, or when an eyelid speculum is being used. Conversely, as its diameter is much smaller than the equine cornea, it does not protect the cornea from drying. Hence, the corneal surface of the horse (or other species with large corneas) should be moistened regularly, especially when a longer ERG protocol is being used, and particularly when the patient is sedated or anesthetized, and/or when blinking is blocked pharmacologically or by means of an eyelid speculum. It is worth noting that a contact lens electrode does not have to cover the whole cornea in order to be

A

B

C

effective, and the commonly used ERG‐jet electrode designed for human patients is effective and routinely used by this author and others for ERG recording in small and large animal patients alike (Ben‐Shlomo and Grudzien, 2015; Ben‐ Shlomo et al., 2012; Church and Norman, 2012; Hepworth et al., 2014). In exotic animals with very small eyes, such as some types of birds, bats, or rodents, modified DTL or gold‐ loop electrodes can be used as the recording electrode (Fig. 10.4.3). Needle electrodes (either platinum or stainless steel) are most commonly used in veterinary patients as the reference and grounding electrodes. However, a recent study showed that non‐needle electrodes are effective as reference and grounding electrodes for ERG recording in dogs, and produce ERG traces similar in quality, amplitude, and implicit time to those obtained by needle electrodes (Ben‐Shlomo and Grudzien, 2015), while decreasing patient discomfort and biohazard risk (Fig. 10.4.3). After each use, reusable electrodes must be cleaned and sterilized appropriately to prevent transmission of infectious pathogens. Reusable electrodes should be carefully inspected for any damage prior to each recording, since damaged electrodes can negatively affect the quality of the recording and increase the level of noise. Electrodes placement

The majority of artifacts affecting ERG recordings are almost always the result of defective electrodes or improper placement technique (Gehlbach and Purple, 1993; Hogg, 2006;

D

E

F

Figure 10.4.3  A. The ERG-Jet contact lens electrode is the most common recording electrode used by veterinary ophthalmologists. B. The DTL electrode has been used successfully in small and large animals. C. A gold-loop electrode of varying sizes (e.g., 2–3 mm in diameter) may be used for ERG recording in exotic animals with small eyes. D. A modified DTL electrode can also be used for smaller eyes. E. Platinum or stainless-steel needle electrodes are most commonly used as the reference and ground electrodes. F. A noninvasive, gold-cup electrode can also be used as reference and ground electrodes.

Wong and Graham, 1995). Ensuring the integrity of the electrodes, especially when reusable ones are used, and mastering the technique (i.e., consistent electrode placement and acceptable electrode impedance) are of paramount importance for a good‐quality and diagnostic recording. Most modern ERG systems include an integral impedance meter, allowing for the measurement of electrode impedance, which should be under 5 kΩ when connected to the patient. Higher impedance may suggest that the electrodes are defective, or that they are poorly connected to the patient. This will result in a poor‐quality recording. Hence, checking the electrodes’ impedance after connecting them to the patient and prior to the beginning of the ERG recording is recommended. Appropriate electrode impedance and placement will result in waveforms that are comparable to those of the International Society for Clinical Electrophysiology of Vision (ISCEV; Mcculloch et  al., 2015), discussed later in this chapter. The Recording Electrode

Corneal contact lens electrodes are recommended due to their reproducible and reliable recordings (Mcculloch et al., 2015), and are most commonly used in veterinary patients. Specifically, the ERG‐Jet contact lens electrode is popular among veterinary ophthalmologists as it is lightweight, well tolerated, easy to place, and relatively inexpensive. In general, contact lens electrodes provide higher amplitudes compared to conjunctival or eyelid electrodes (Steiss et al., 1992). Topical anesthesia is required when a contact lens (or other corneal) electrode is used, and ionic conductive solution (e.g., artificial tears containing sodium chloride) should be applied to the cornea to protect it from drying during ERG recordings. When using a contact lens electrode, viscous eye drops such as 2.5% hypromellose (e.g., Gonak™, Akorn, Lake Forest, IL, USA; Goniovisc™, Hub Pharmaceuticals, Plymouth, MI, USA) will ensure good adhesion of the contact lens to the cornea, in addition to improving the conductivity of the signal. The recording electrode should be connected to the positive input of the recording system. The Reference Electrode

Either subdermal needle (platinum or stainless steel) or non‐needle electrodes can be used as the reference electrode. Appropriate skin preparation with skin preparation gel (e.g., NuPren®, Weaver and Company, Aurora, CO, USA) and application of conductive paste (e.g., Ten20®, Weaver and Company) are of great importance in order to achieve appropriate conductivity and to maintain impedance of 5 kΩ or less when non‐needle electrodes are being used. A gold cup electrode is effective as a non‐needle electrode. The cup should be filled with a conductive paste mounted over the edge of the cup. Then, the patient’s hair should be parted as much as possible (there is no need to shave the hair), and the electrode applied firmly to the skin in order to achieve good

contact and adhesion of the electrode (Fig.  10.4.3F and Fig.  10.4.4; Ben‐Shlomo and Grudzien, 2015). Needle electrodes should be introduced fully into the subdermal space (and not intradermal or left half out). Reusing needle electrodes over a long period of time or on a high number of patients will result in blunt needles and increased discomfort with placement. Placing reference electrodes over muscle masses should be avoided in order to minimize electromyogram interference. A common location for the reference electrode is posterior to the lateral canthus, over the zygomatic arch, which lacks muscle mass. Based on the clinical experience of this author, the closer the reference electrode is to the lateral canthus and eyelids, the greater is the chance for the ERG to be affected by the eyelids’ muscle activity when the patient is conscious and blinking. Moreover, a study by Mentzer et  al. (2005) evaluated the effect of reference electrode position on the ERG and showed that positioning the reference electrode 3–5 cm posterior to the lateral canthus resulted in significantly higher amplitudes in response to most light intensities, versus placing it only 1 cm posterior to the canthus. In horses and other large animals, the reference electrode should also be placed approximately 3 cm posterior to the lateral canthus (Ben‐ Shlomo et al., 2012; Komaromy et al., 2003). The Burian‐Allen electrode (Hansen Ophthalmic Development Laboratory, Coralville, IA, USA) incorporates both the reference and recording electrodes into one contact lens device (“bipolar electrode”). It consists of a corneal contact lens electrode that is held against the cornea with a spring, and an integral plastic eyelid speculum that prevents blinking. A reference electrode is assembled within the surface of the eyelid speculum and touches the conjunctiva. While the Burian‐Allen electrode is commonly used in human patients, it is considered uncomfortable and poorly tolerated by pediatric patients, who often require sedation when this electrode is being used (Coupland, 2006). As such, it may not be tolerated well by conscious veterinary patients. In addition, it has been shown to produce significantly lower ERG amplitudes in dogs when compared to the recordings obtained by the ERG‐Jet electrode and a reference electrode that was placed posterior to the lateral canthus (Mentzer et  al., 2005). The reference electrode should be connected to the negative input of the ERG machine. The Grounding (Common) Electrode

Either subdermal needle or non‐needle electrodes can be used as grounding electrodes (Ben‐Shlomo and Grudzien, 2015). They should be placed on to an indifferent point on the body; common placement sites include the neck, forehead, base of the ear, or at the midline on the top of the skull. In horses and other large animals, the grounding electrode may be placed on the middle of the neck (Ben‐Shlomo et al., 2012). The grounding electrode should be connected to the common/ground input of the ERG machine.

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Figure 10.4.4  A. The ERG-Jet contact lens electrode is placed on the cornea of a conscious dog, and non-needle, gold-cup electrodes are used as the reference and ground (not seen in the picture) electrodes. The gold-cup electrodes are connected to the patient by means of a special, thick, conductive gel that also keeps the electrode from falling. The hair of the patient is parted as much as possible, and the electrode is applied to the skin. The electrodes are secured to the collar of the patient with medical tape to minimize their movement when the head moves. B. The small plastic rods on the surface of the contact lens electrode prevent the eyelids from blinking over the contact lens and blocking the light stimulus. The traces in Fig. 10.4.5A and Fig. 10.4.7B were recorded from this conscious patient with these electrodes, in one session.

Signal Averaging and Electrical Noise Reduction

Signal averaging can be used in order to decrease the effect of random background noise on the ERG. The ERG recording is triggered by the light stimulus and it is synchronized with it. Conversely, background noise and electromyogram are random with respect to the ERG stimulus. Consequently, as the repeated traces are being recorded and averaged, the noise is canceled out, resulting in a significant increase in the signal‐to‐noise ratio. Signal averaging is particularly useful to reduce noise generated by the patient’s muscle activity, as it is truly random in relation to the light stimulus. However, most electrical noise is the result of a bad technique, such as poor maintenance or poor placement of the electrodes; prolonged averaging should not be used to compensate for bad technique. In addition, an electrical signal from the surrounding electrical system (i.e., 50 Hz or 60 Hz) may contaminate the ERG trace. It may be phase‐locked (i.e., synchronized) with the light stimulus and, as a result, the averaging may not be effective (Odom, 2006). The smaller the ERG amplitude, the more significant the effect of background electrical noise is (i.e., decreased signal–noise ratio). Consequently, when low‐intensity flashes are used, more averaging may be needed, as low‐intensity stimulus generates weaker responses with lower amplitudes. Conversely, less averaging may be needed when high‐inten-

sity flashes are used. In addition, the brighter the flashes are, the longer the interval between stimuli should be in order to allow recovery of the retinal photoreceptors between flashes (e.g., a frequency of 0.1 Hz). Low‐intensity stimuli may be given in shorter intervals (e.g., 0.5 Hz). As a general rule, averaging should be minimized as much as possible. The modern environment is saturated with electrical devices that produce electromagnetic contamination of the recorded signal. While modern ERG machines are designed to circumvent this problem, at least partially, recording systems should be kept away from high‐powered electrical devices and electric motors in particular (e.g., refrigerators, air conditioners, elevators). Unplugging electrical equipment that is not needed for ERG recording may help reduce the electrical noise. Nevertheless, noise from electrical equipment can be transmitted through the power line for a significant distance. While there are solutions for this problem, such as the use of a Faraday cage (see the later section on light and dark adaptation and Fig. 10.4.6), an electrically shielded room, or a dedicated power supply to the ERG room (to ensure a clean power supply), these solutions are expensive. Alternatively, the use of battery‐operated ERG devices that are not connected to the main power line during the recording may help decrease (or eliminate) main line interference (Fig. 10.4.1 and Fig. 10.4.2B–C).

Protocols for fERG Recording

Many fERG protocols have been published by different researchers and laboratories. These protocols evolved over the years based on the progress of our understanding of retinal physiology as well as advances in technology and computing. In 1989, the ISCEV published the first standard for clinical fERG in human patients (ISCEV, 1989), which allowed recording of reproducible and comparable fERG throughout the world. The ISCEV standard triggered the publication of guidelines for fERG recording in dogs, which were first published in 2002 (Narfstrom et al., 2002). These protocols are updated periodically. The technique and protocols for ERG recording discussed later in this chapter are based on the latest updates of the ISCEV protocol and the guidelines for clinical ERG in dogs (see Recording the fERG section below) (Ekesten et al., 2013; Mcculloch et al., 2015; Robson et al., 2018). These recommendations should serve as the basis for clinical ERG in other species when specific recommendations are lacking. Following these recommendations allows for a more reliable comparison of results between different hospitals and laboratories, as well as results of scientific and clinical publications. Patient Preparation Mydriasis

Complete mydriasis is needed to achieve uniform stimulation of the whole retina, which is crucial for reliable and reproducible results. Pupil size should be evaluated before and at the end of the fERG recording. Patient Restraint

When human patients undergo ERG testing, they are instructed to look at a fixation point incorporated into the stimulus source. Fixated gaze reduces movement‐related artifacts, keeps the pupil fully exposed to the light stimulus, and prevents movement of the contact lens electrode. Clearly, this is not achievable with veterinary patients. However, the use of signal averaging, as discussed above, is very helpful in decreasing movement‐related artifacts. Short fERG protocols can be performed successfully on conscious dogs with minimal manual restraint for quick evaluation of retinal function, such as when the cornea or lens is opaque (e.g., mature cataract) or in order to differentiate retinal from postretinal blindness (e.g., sudden acquired retinal degeneration syndrome vs. optic neuritis or a central lesion; Norman et al., 2008). The short protocols are well tolerated by most canine patients. Furthermore, a recent study has shown that while sedation and anesthesia resulted in significant attenuation and delay of the ERG responses in dogs, there was no significant effect on the quality of the recorded signal compared to fully conscious dogs (Freeman et  al., 2013). In the last two decades, technologic advancements have led to the development of handheld ERG devices, such as the Multispecies ERG (RetVetCorp, Columbia, MO, USA)

and the RETevet™ (LKC Technologies, Gaithersburg, MD, USA). These devices have significantly improved our ability to perform ERG on nonanesthetized animals, large and small, as it is easy to adjust their position to the animal’s head position and minor movements. The RETevet machine is also equipped with an infrared camera that is built in to the mini‐Ganzfeld and allows monitoring of the globe, eyelids, and contact lens electrode positions during the recording (Figure 10.4.2C). Longer protocols or testing of anxious or aggressive animals may require chemical restraint. The published guidelines for clinical electrophysiology in the dog recommend the use of anesthesia for the recommended protocol, which is intended to test for inherited photoreceptor disorders, and include photopic and scotopic fERG (Ekesten et al., 2013). While under anesthesia, the eyelids (including the third eyelid) should be maintained open by means of an eyelid speculum, and subconjunctival stay sutures at the limbus may be used to stabilize the globe and ensure full exposure of the pupil to the light stimulus. However, long protocols (even longer than the recommended one) were performed successfully on sedated (Maehara et al., 2005) or conscious dogs (Kim et al., 2008; Yu et al., 2007), utilizing a contact lens electrode with a built‐in light source. This author routinely and successfully performs extended protocols in conscious canine patients, utilizing handheld, mini‐Ganzfeld–equipped ERG systems, as demonstrated by the traces shown in Fig. 10.4.5A and Fig. 10.4.7B which were all recorded in a conscious dog in one session. Various sedation and anesthetic protocols have been utilized for fERG recordings in dogs and cats, and their effect on the fERG evaluated (Baro et  al., 1990; Freeman et  al., 2013; Jeong et  al., 2009; Kommonen, 1988; Kommonen et al., 1988; Lin et al., 2009; Maehara et al., 2005; Narfstrom et  al., 1985; Norman et  al., 2008; Rosolen et  al., 2002; Tanskanen et al., 1996). In general, both sedation and anesthesia decrease the fERG amplitudes and prolong the implicit time. In the clinical setting, it is crucial to compare fERG results of patients to normal values obtained using the same sedation or anesthesia protocols. Otherwise, drug‐ related attenuation of the fERG may be falsely attributed to retinal disease. If sedated or anesthetized, patients should be maintained well oxygenated, as hypoxemia results in attenuation of the fERG (Howard and Sawyer, 1975; Kang Derwent and Linsenmeier, 2000; Niemeyer et al., 1982). Hypercapnia, or decreased levels of carbon dioxide in the blood (secondary to hyperventilation), can also alter the fERG recording (Murray and Borda, 1984; Varela Lopez et al., 2010). Equine fERG can be performed safely and effectively under standing sedation. An intravenous (IV) dose of 0.015 mg/kg detomidine is effective for short or long fERG protocols (Ben‐Shlomo et  al., 2012; Church and Norman, 2012; Hepworth et  al., 2014; Komaromy et  al., 2003; Sandmeyer et al., 2007). Therefore, general anesthesia is not required for a routine clinical ERG in the horse. In addition, sedation is safer and cheaper than general anesthesia,

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increasing the likelihood of approval of this testing modality by equine owners. In order to maximize the effect of sedation, this author starts the dark adaptation process when the horse is in the stocks and unsedated; approximately halfway through the dark adaptation time (i.e., 10 minutes), the sedation is administered intravenously under dim red light, followed by placement of the electrodes. Under these conditions, only an experienced clinician should administer the sedation, and extreme caution should be taken to avoid injection of the sedative drugs into the carotid artery, which can be lethal. Alternatively, an indwelling intravenous catheter may be placed prior to dark adaptation. The equine’s orbicularis oculi muscle, which is responsible for blinking, is very strong. Therefore, eyelid akinesia by auriculopalpebral nerve block is strongly recommended. This will allow the examiner to keep the eyelids open, reduce blinking artifacts, and avoid displacement of the contact lens electrode. The cornea should be kept moist by periodic application of ionic eyewash solution to prevent desiccation of the cornea, especially since to date there is no contact lens electrode that covers the whole corneal surface of the horse eye. In both small and large (nonanesthetized) animals, this author avoids the use of an eyelid speculum, as it seems to cause more patient discomfort and resistance when it is used. Manual opening of the eyelids just prior to administration of the light stimuli works very effectively in the clinic. Light and Dark Adaptation

Both rods and cones contribute to the fERG and each responds in a characteristic way to different types of light stimulation. Therefore, manipulation of the intensity, duration, and frequency of the light stimulus, as well as the ambient light conditions, facilitates separation of rod and cone recordings. Under bright light conditions (photopic), rod

photoreceptors are saturated and rhodopsin is bleached (Gouras, 1965). Hence, light adaptation will allow recording of the cone response, with minimal to no contribution from rods. At least 10 minutes of light adaptation using white background light of 30 cd/m2 is recommended in human and canine patients in order to minimize rod input and achieve stable and reproducible light‐adapted ERGs (Ekesten et al., 2013; Mcculloch et al., 2015). Conversely, dark adaption allows rod photoreceptors to regenerate their photopigment and restore activity. The fERG amplitude gradually increases during the dark adaptation period until it reaches a plateau (Fig. 10.4.5). Appropriate dark adaptation time and recording under dark conditions (scotopic ERG) are crucial for reliable and reproducible recording of rod activity. Dark adaptation time may vary between species. The recommended dark adaptation time in the dog is 20 minutes (Ekesten et al., 2013; Yu et al., 2007), whereas in the horse a gradual increase of the fERG b‐wave amplitude was documented up to 25 minutes of dark adaptation and plateaued thereafter (Ben‐Shlomo et  al., 2012). However, in that study, the mean b‐wave amplitude after 20 minutes of dark adaptation was not statistically different from the mean b‐wave amplitude at 25 minutes of dark adaptation (Fig. 10.4.5B). Thus, in the horse, the dark adaptation period prior to scotopic ERG recording should be at least 20 minutes (Ben‐Shlomo et al., 2012). As a general rule, following dark adaptation, low‐intensity stimuli should be presented prior to stronger stimuli. Specific characteristics of the light stimulus for the recording of rod and cone ­activity is discussed below. Ideally, scotopic ERG should be recorded in a completely dark room. However, this is challenging when working with veterinary patients due to safety considerations for both  examiner and examinee. Practically, red light with a

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Figure 10.4.5  A. The b-wave amplitude of the fERG increases during dark adaptation. Representative traces recorded from a healthy dog under scotopic conditions, and in response to a light stimuli of 0.01 cd·s/m2, during a 20-minute dark adaptation period. B. The dark adaptation curve of the horse, showing the mean b-wave amplitudes (± SEM, the standard error of the mean) for the different time points of dark adaptation. (Panel B reproduced with permission from Ben-Shlomo, G., Plummer, C., Barrie, K., & Brooks, D. (2012) Characterization of the normal dark adaptation curve of the horse. Veterinary Ophthalmology, 15, 42–45.)

­wavelength of 625 nm or higher should be used, as this wavelength is above the spectrum of rod photoreceptors. The ambient red light should be kept dim, at the lowest intensity possible. When possible, the ambient dim red light should be turned off when not needed. Direct illumination of the eye with bright red light (e.g., while using a red flashlight in order to set or fix electrodes) should be avoided. Computer screens and monitoring devices (e.g., anesthesia monitor) should be covered with a red filter of 625 nm or higher (Fig. 10.4.6). It is worth noting that photoreceptors require a significant amount of time to fully recover after exposure to bright light (Pugh, 1975). Tuntivanich et al. (2005) have shown that following indirect ophthalmoscopy and fundus photography in dogs, the fERG amplitudes and implicit times were significantly affected, and at least 60 minutes of dark adaptation was needed for the recovery of the fERG following these procedures. This should be taken into account when fERG is recorded in the clinic, usually following a complete eye examination that includes the use of bright lights. It should also be taken into consideration for research study designs when ERG testing is planned. Recording the fERG Rod Response

The rod response is recorded under scotopic conditions and should be the first to be recorded following an appropriate period of dark adaptation, as it is the most sensitive to light adaptation. The light stimulus is a weak flash of 0.01 cd·s/m2, which is below the cone photoreceptors’ threshold, and it will  not trigger cone response. If needed, responses may be

averaged (ideally not more than four averagings), applying the stimuli with a minimum interval of 2 s (0.5 Hz). If a single response is recorded (i.e., without averaging), repeating the recording once to ensure reproducibility is recommended. Rod function may be evaluated during the dark adaptation period. In this case, similar flash intensity (0.01 cd·s/m2) can be used, starting immediately at the beginning of the dark adaptation period, and repeated every 4 minutes thereafter, up to 20 minutes. This protocol will demonstrate the changes in rod‐driven responses over the dark adaptation period (see Fig. 10.4.5A). Combined Rod–Cone Response

The combined rod–cone response is recorded under scotopic conditions, usually immediately after the recording of the rod response. The flash intensity used is 3 cd·s/m2 (“standard flash”), and an interval of at least 10 s (0.1 Hz) between stimuli should be applied when averaging is used (Mcculloch et  al., 2015). As few flashes as possible should be used to avoid light adaptation of the retina. The combined rod–cone response may be used as part of a longer protocol. However, it is probably most commonly used in the clinical setting as a standalone test for patient screening prior to cataract surgery, and to differentiate retinal from postretinal blindness when the fundus looks normal on fundoscopy (e.g., sudden acquired retinal degeneration syndrome vs. central blindness or retrobulbar optic neuritis). An additional high‐intensity flash of 10 cd·s/m2 may be used for the combined rod–cone response. The response to this high‐intensity stimulus will result in a greater amplitude compared to the standard flash,

Figure 10.4.6  An ERG recording system, including a Ganzfeld stimulator, is located inside a Faraday cage, which is connected to a true ground cable (on the left). The doors of the Faraday cage allow access to it from the outside. The operator’s station is located outside of the Faraday cage to decrease electrical noise. The monitor is covered with a 630 nm red filter. Other monitors (e.g., electrocardiogram monitors, pulse oximeter, etc.) should be covered similarly.

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and may provide more reliable responses in patients with opaque media (i.e., mature cataracts) or younger animals with immature retinas. The high‐intensity flash should be used after the lower‐intensity flash (3 cd·s/m2) has been used. Averaging is not recommended with this high‐intensity stimulus, as repeated stimuli may light‐adapt the retina. If averaging is used, the number of stimuli should be kept to a minimum and given in intervals of at least 20 s (0.05 Hz; Mcculloch et al., 2015). Cone Response Single Flash

Cone response should be evaluated under photopic conditions, as previously discussed, to ensure reproducible light‐ adapted ERG and to minimize rod contribution to the recording. Following at least 10 minutes of light adaptation, a 3 cd·s/m2 flash is delivered on the background of the adapting light. The intervals between stimuli should be at least 0.5 s (2 Hz). Flicker ERG  The flicker ERG evaluates the cone response

and is performed under photopic conditions, after at least 10 minutes of light adaptation. The intensity of the flicker stimulus is 3 cd·s/m2 given at a rate of 30 Hz. Choosing a frequency that is not an exact multiple of the power line frequency may help reduce related electric noise (a range of 28–33 Hz is acceptable). For example, in the USA, where the electrical system is 60 Hz, the flicker frequency can be set to 31 Hz. These flicker ERG settings are selective for the cone system, since rods have low temporal frequency and are unable to follow frequencies greater than approximately 15 Hz (Hecht & Shlaer, 1936). Analysis of the fERG Recording

Light stimulus, through phototransduction, triggers hyperpolarization of the photoreceptors, through in turn leads to propagation of radial currents from the outer to the inner retina (i.e., from the photoreceptors, to the bi‐polar cells, to the retinal ganglion cells [RGCs]), with the mediation of the horizontal and amacrine cells. These changes in the cells’ electrical activity can be recorded and analyzed (Fig. 10.4.7). While the recording is a gross summation of all retinal cells, different cell types generate different components of the fERG trace. An in‐depth review of retinal physiology, which is the basis for understanding the ERG, is beyond the scope of this chapter and is covered in Chapter 4. The Components of the fERG

The a‐ and b‐waves are the main components of the fERG, and are recorded and analyzed routinely in veterinary patients. The flicker ERG is also routinely performed. Clinical ERG is usually recorded over 250 msec post flash, plus at least a 20 msec baseline recording prior to the flash

stimulus (Mcculloch et al., 2015). Analyzing these components is useful for the clinical diagnosis of retinal diseases. The a-Wave

The a‐wave is the first, slow, negative component of the fERG, and it is mainly associated with the hyperpolarization of the rod and cone photoreceptors. Under scotopic conditions, the low‐intensity stimulus (0.01 cd·s/m2) is not strong enough to trigger a recordable a‐wave. A strong stimulus (e.g., 3 cd·s/m2) will trigger a rod‐driven a‐wave from a dark‐ adapted retina, with a lesser contribution from the cone system (Brown, 1968; Frishman, 2006). Under photopic conditions, when the rods are saturated, the a‐wave is cone driven. The a‐wave amplitude is measured from the pre‐ stimulus baseline to the first negative trough (see Fig. 10.4.7). The a‐wave implicit time (also known as “peak time”) is measured from the time of the flash to the peak of the wave. The a‐wave is truncated by the large, positive component of the fERG, the b‐wave. The b-Wave

The b‐wave is the largest component of the fERG, generated primarily from depolarizing (ON) bi‐polar cells, with a lesser contribution from Müller cells (the retinal glia cells; Karwoski & Xu, 1999; Robson & Frishman, 1995; Robson et al., 2004; Xu and Karwoski, 1994). Under scotopic conditions and a weak flash stimulus, the b‐wave is predominantly rod driven. When a strong stimulus is given to a dark‐adapted retina, cones also contribute to the b‐wave, and a combined rod–cone response is recorded. Under photopic conditions and saturation of the rods, the b‐wave will be cone driven. The b‐wave amplitude is measured from the a‐wave trough to the b‐wave peak; the b‐wave implicit time is measured from the time of the flash to the peak of the wave (see Fig. 10.4.7). The Flicker ERG

The flickering stimuli result in a “steady‐state” ERG. The amplitude of the flicker ERG is measured from a trough to the succeeding peak, and several (at least three) measurements may be averaged, avoiding the smallest and largest amplitudes. The implicit time is measured from the stimulus flash to the following peak. The response to the first stimulus of the flicker, which may resemble a flash ERG, should be avoided for both the amplitude and implicit time measurement (see Fig. 10.4.7). The flicker ERG can be also analyzed by Furrier analysis in the frequency domain. Oscillatory Potentials

OPs consist of a series of high‐frequency, low‐amplitude wavelets superimposed on the b‐waves, recorded in response to a strong stimulus. OPs can be recorded under photopic or scotopic conditions, with contribution from both rods and

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B Figure 10.4.7  A. Diagram of the six basic ERGs defined by the ISCEV Standard. These waveforms are exemplary only and are not intended to indicate minimum, maximum, or typical values. Bold arrowheads indicate the stimulus flash; solid arrows illustrate a-wave and b-wave amplitudes; dotted arrows exemplify how to measure time to peak (t, implicit time or peak time). (Reproduced with permission from Mcculloch, D.L., Marmor, M.F., Brigell, M.G., et al. (2015) ISCEV Standard for full-field clinical electroretinography (2015 update). Documenta Ophthalmologica, 130, 1–12.) B. Representative traces of basic ERG responses recorded from a healthy dog. See Fig. 10.4.8 for representative oscillatory potentials recorded from a healthy dog.

cones (Peachey et al., 1987). By convention, the OPs’ peak is marked with the letter “O” followed by a number indicating its order of occurrence; that is, the first OP is O1, the second is O2, and so on (Wachtmeister & Dowling, 1978). The number of OPs varies depending on species, adaptation state, and

stimulus characteristics (e.g., intensity, frequency). As such, there is no consensus on how to measure OPs. Observing the presence and waveform of OPs’ peaks and comparing them qualitatively to normal controls may be adequate for most clinical needs (Mcculloch et al., 2015).

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OPs originate from the inner retina, most likely the inner plexiform layer, but they do not all have the same origin (Heynen et  al., 1985; Wachtmeister, 1998). They have not received a lot of attention in the veterinary literature, but have been described in dogs (Sims, 1990; Sims & Brooks, 1990), cats (Doty & Kimura, 1963), and horses (Sandmeyer et al., 2007), among other species (Figs 10.4.7, 10.4.8).

four averaged flashes at 0.5 Hz), followed by two single flashes of high light intensity (3 and 10 cd·s/m2), evaluating the combined rod–cone response. These protocols last 40 s and 18 s, respectively. Such short protocols provide a crude interpretation of the overall retinal function and are not sufficient for a thorough investigation of retinal photoreceptor diseases.

Clinical Protocols

Interpretation of the Results

Along the years, different protocols have been used by different laboratories and hospitals for clinical evaluation of the fERG. In veterinary medicine, as mentioned above, guidelines for clinical ERG in dogs were published in order to facilitate reproducible and comparable results between different locations. This protocol is recommended for full evaluation of both rod and cone systems, and is useful for evaluation of photoreceptor disorders (Table 10.4.1; Ekesten et al., 2013). Other, including more extensive, protocols are usually performed for research purposes, but can be applied to clinical cases if warranted, and be tailored to investigate the particular retinal cell of interest (Acland, 1988). In the clinic, shorter protocols may be, and often are, used in order to evaluate gross retinal function and differentiate retinal from postretinal blindness (e.g., optic neuritis, cortical blindness), or for preoperative screening of cataract patients. These may include the application of a bright flash (3 cd·s/m2; four averaged flashes at 0.1 Hz) following 20 minutes of dark adaptation, which evaluates the combined rod–cone response. The QuickRetCheck protocol, designed by Narfström, evaluates retinal photoreceptor function under scotopic conditions over a very short period of time (Norman et al., 2008). In this protocol, following 20 minutes of dark adaptation, the rod system is evaluated by a weak light stimulus (0.01 cd·s/m2;

Like any other diagnostic test, it is extremely important to interpret the ERG results based on a complete history and a thorough eye examination. This is crucial for accurate interpretation of the results. For example, a normal ERG response may be recorded from a blind dog with postretinal blindness (e.g., optic neuritis) or with mature cataracts. The a‐ and b‐wave amplitudes and implicit times should be compared to normal references. Decrease in amplitude, increase of implicit time, or absence of any component of the waveform compared to normal controls indicates pathology of the generator cells of the respective component. Each laboratory or hospital should establish their own normal references, as these may vary based on chemical restraint protocol, electrode type and location, stimulator type, stimulus characteristics (i.e., intensity and duration), and so on. Age and breed also add to the variability of the results. In dogs, postnatal retinal development affects the ERG’s waveform and values. The b‐wave first appears approximately 2 weeks after birth, and there is a marked increase in its amplitude over the first 4 weeks of life. Further increase of the fERG amplitudes and decrease of the implicit times are observed until 8 weeks of life, when they are approximating values of the adult dog (Gum et  al., 1984; Kirk & Boyer, 1973). The flicker ERG also reaches adult values around 8 weeks of age (Acland & Aguirre, 1987). Additional changes to the fERG

Table 10.4.1  Stimulus and recording parameters for the recommended fERG protocol. Dark Adaptation Time (Min)

Condition

Flash Intensity

Stimulator Background Light

Interstimulus Time (Rate)*

0

Scotopic

0.01 cd·s/m2

Off

2 s ( 0.5 Hz)

Rod response

4

Scotopic

0.01 cd·s/m

2

Off

2 s ( 0.5 Hz)

Rod response

8

Scotopic

0.01 cd·s/m2

Off

2 s ( 0.5 Hz)

Rod response

12

Scotopic

0.01 cd·s/m

2

Off

2 s ( 0.5 Hz)

Rod response

16

Scotopic

0.01 cd·s/m2

Off

2 s ( 0.5 Hz)

Rod response

20

Scotopic

0.01 cd·s/m

2

Off

2 s ( 0.5 Hz)

Rod response

20

Scotopic

3 cd·s/m2

Off

10 s ( 0.1 Hz)

Combined rod–cone response

Photopic

3 cd·s/m2

30 cd/m2

0.5 s ( 2 Hz)

Cone response

Photopic

2

30 cd/m2

Test

Light adaptation time (min) 10 10

3 cd·s/m

30 Hz

Source: Ekesten et al. (2013). *  The recommended interstimulus time (and rate) is taken from the ISCEV protocol (Mcculloch et al., 2015).

Cone response

may occur over time, especially in older animals. Different breeds may also show different fERG values, as was well demonstrated by Sussadee et al. (2015). Hence, ideally, the fERG results of a patient should be compared to normal values that are age and breed matched, and are specific to each hospital or laboratory. However, comparing clinical fERG results to a breed and age matched controls may not be practical in all cases. The fERG of the cat also changes after birth, reflecting postnatal development of the retina. The b‐wave appears during the first 10 days after birth, and adult values of the fERG are reached approximately 3 months after birth (Jacobson et al., 1987). In the dog (as well as in other species), OPs cause notching in the peak of the b‐wave. This may challenge the clinician

as to where to place the marker in order to measure the b‐wave amplitude and implicit time, and hence may affect the results. In the dog, peaks O3 and O4 are usually located at the peak of the b‐wave (Fig. 10.4.8) and either of them may be the highest point on the b‐wave. For consistent measurements of the ERG parameters, each hospital or laboratory should establish a protocol for dealing with this issue; that is, always placing the b‐wave marker on O3 or O4, or averaging the values obtained by using O3 and O4 (Sims, 1990). The electroretinographist should also be familiar with common sources of noise and artifacts, which in turn may help address them, and interpret the traces accordingly. On an awake or sedated animal, it is not uncommon to see a large positive component on the recorded trace, which is

2

1 20 µV/Div.

2

20 µV/Div.

O.D.

O.D.

5 ms/Div.

B

1

2

5 ms/Div.

A

20 µV/Div.

1

O.D.

5 ms/Div.

C

Figure 10.4.8  A. A combined rod–cone response. The a- and b-waves are clearly present (1 and 2, respectively). O1 is noted on the ascending phase of the b-wave, and the oscillatory potentials (OPs) are notching the top of the b-wave, which is marked on top of O3 (2). In this case, O3 is also the highest point on the b-wave. The b-wave amplitude is measured from the a-wave trough (1) to the peak of the b-wave (2). B. In the same trace, the fast OPs were removed by post hoc filtering of frequencies faster than 70 Hz. Note that this also removed the high-frequency (low amplitude) noise observed on the trace after the peak of the b-wave. C. In the same trace, the slow components of the fERG (i.e., the a- and b-waves) were removed by post hoc filtering of frequencies slower than 70 Hz. This unmasked the OPs. The amplitude difference between markers 1 and 2 reflects the amplitude of O3.

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10.4: Ophthalmic Examination and Diagnostics

Section II: Foundations of Clinical Ophthalmology

coding for these ports between different machines may add to the confusion. Switching these two electrodes will change the polarity of the trace, as seen in Fig.  10.4.11. Since the b‐wave is defined as the first positive component of the fERG, the inverted a‐wave may be confused with the b‐wave, which will result in misinterpretation of the fERG trace. Apart of the waveform itself, paying attention to the implicit time should help identify the mistake, since the b‐wave is expected approximately 30 msec after the flash (vs. approximately 11 msec for the a‐wave).

the result of a postflash blink artifact (Fig.  10.4.9). This artifact should not be confused with the c‐wave of the fERG (see below), which is recorded over a much longer period of time. Taking into consideration the implicit time of the c‐wave will help with differentiating it from an artifact. When noise is present, calculating its frequency based on the trace or Furrier analysis may help in identifying its source. Figure  10.4.10 clearly demonstrates a 60 Hz noise that originates from the main power line. Checking the ground electrode for appropriate placement, or replacing it if defective, may eliminate this noise. Occasionally, the recording and reference electrodes may be switched accidently when they are connected to the inputs on the recording system. The lack of uniform color

Other Components of the fERG

In veterinary practice, clinical electroretinography is focused on recording and analyzing the a‐ and b‐waves, and to a

20 µV/Div.

2

O.D.

1

5 ms/Div.

Figure 10.4.9  An fERG trace with a large, positive blink artifact (red arrow) that follows the a- and b-waves (peaks marked as 1 and 2, respectively). This artifact should not be confused with the c-wave.

1

2

3

4

5

6

20 µV/Div.

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770

O.D.

5 ms/Div.

Figure 10.4.10  A large (~160 μV), regular sinusoidal wave, consistent with an electrical current, is masking the ERG wave form. There are 6 peaks (arrows) over a 100 msec period (marked by two blue vertical lines). Thus, this is a 60 Hz noise, which is the frequency of the electrical system in the USA. Checking the integrity of the electrode is a logical first step. Searching for major electrical equipment that may be the source of the noise is the second. Using a handheld, battery-operated ERG machine may help in eliminating a 60 Hz noise originating from the power line.

10.4: Ophthalmic Examination and Diagnostics

771

10 µV/Div.

SECTION II

1

O.D.

2 5 ms/Div.

Figure 10.4.11  Connecting the recording electrode to the reference electrode’s input on the pre-amplifier (and vice versa) results in an inverted trace. The a-wave (1) shows as the first positive wave, followed by the negative-looking b-wave (2). The implicit times of the two waves, approximately 12 msec for the first wave (1) and 30 msec for the second wave (2), should help identify the mistake. This emphasizes the need for the electroretinographist to be familiar with the recording system, as well as with the normal values of the different fERG components.

lesser degree the flicker ERG (and rarely the OPs). However, other components can be recorded by the fERG. To date, these components are mostly used for research, but they may also be used for the assessment of clinical cases. A brief description of additional selected components of the fERG is provided in this section. The c-Wave

The c‐wave is a late, positive potential, described in humans, dogs, cats, and other species (Dawson & Kommonen, 1995; Granit, 1933; Linsenmeier et al., 1983), and is considered to be a measure of interaction between the photoreceptors and retinal pigment epithelium (RPE; Linsenmeier et al., 1983). In humans as well as in the dog, the c‐wave is not always present and there is great variability between individuals. When present, the c‐wave peaks long seconds (species dependent) after the flash stimulus. The c‐wave is not recorded during routine clinical fERG testing, as the latter is recorded over a much shorter period of 200–300 msec. The i-Wave

The i‐wave is a low‐voltage, positive component of the fERG. It is recorded under photopic conditions, and follows the b‐wave (Lachapelle, 1987; Peachey et al., 1989). The origin of the i‐wave is believed to be the RGCs and/or the optic nerve (Rosolen et  al., 2003; Rousseau et  al., 1996); hence it may provide useful clinical information. However, the exact origin of the i‐wave is yet to be determined. Rosolen et al. (2004) recorded the i‐wave from the dog, cat, rabbit, mini‐pig, ­cynomolgus monkey, and guinea pig. The i‐wave in these species showed approximately 20 msec after the b‐wave, and was absent in rats and mice (Rosolen et al., 2004; Fig. 10.4.12).

The Photopic Negative Response

The photopic negative response (PhNR) is a negative wave that occurs after the b‐wave, and is measured from the baseline to the bottom of the negative trough following the b‐wave (Kondo et al., 2008). Takada et al. (2017) have shown that the canine PhNR can be recorded in response to a series of light intensities under photopic conditions. However, up to 100 waveforms are needed to be averaged to reduce variability and background noise. They also showed that the origin of this component in the dog is the inner retina and RGCs. As such, the PhNR allows the evaluation of inner retinal damage in the glaucomatous canine patient (Whiteman et al., 2002). The Scotopic Threshold Response

The scotopic threshold response (STR) is a small potential, recorded in response to very weak flashes (below the b‐wave threshold) under scotopic conditions (Sieving & Nino, 1988). It has been recorded in several mammals, including dogs and cats (Sieving et al., 1986; Yanase et al., 1996). Although it is a negative response, it is different than the a‐wave, and should not be confused with it. The STR is believed to reflect rod‐driven activity of amacrine and RGCs, and has been shown to be affected by canine retinal degenerative disease (Kommonen et al., 1997).

Other Electrodiagnostic Tests In human ophthalmology, electrodiagnostic testing of the visual system is performed by physicians or scientists who specialize in this field, as they require advanced training

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i a Human

Beagle dog

Cynomolgus monkey

NZW rabbit

Hartley guinea pig

European cat

Figure 10.4.12  Representative examples of photopic ERGs from selected species. A vertical arrow (at the beginning of each tracing) identifies flash onset, while the oblique arrow after the b-wave points to the i-wave. a, a-wave; b, b-wave; i, i-wave. The calibration symbol is depicted at the side of the tracings: horizontal: 50 msec; vertical: 50 μV for human, cynomolgus monkey, and guinea pig and 100 μV for other species. (Reproduced with permission from Rosolen, S.G., Rigaudiere, F., Legargasson, J.F., et al. (2004) Comparing the photopic ERG i-wave in different species. Veterinary Ophthalmology, 7, 189–192.)

and/or very expensive equipment. For these reasons, these tests are usually not available for, and are rarely performed in, veterinary patients. This section provides a brief overview of these tests.

Visual Evoked Potential Like the fERG is the summed electrical activity of the retinal cells, the flash visual evoked potential (VEP) is the summed electrical potentials in the visual cortex triggered by visual stimulation and recorded at the scalp. The VEP reflects the function of the entire visual pathway from the retina to the visual cortex. As such, it may provide diagnostic information regarding the function of the visual system, and is used routinely in human medicine, complementary to the fERG. A basic VEP can be recorded using a single channel and this is probably the most practical one for veterinary patients. Multiple channel recording (to assess chiasmal and retrochiasmal activity) requires advanced equipment that is not available to most veterinary ophthalmologists. VEP was recorded from many species, including dogs (Boyer & Kirk, 1973; Kimotsuki et  al., 2005; Sato et  al., 1982; Sims et  al., 1989; Strain et  al., 1990), cats (Creel et  al., 1973; Sims & Laratta, 1988), and horses (Strom & Ekesten, 2016), as well as other species. In dogs, different techniques, including variation in the state of dark adaptation, mydriasis, and electrode locations, have led to variable results of VEP recordings. However, Strain and his colleagues established a reproduc-

ible VEP protocol, which was employed successfully in both anesthetized and conscious dogs (Kimotsuki et  al., 2005, Kimotsuki et al., 2006; Strain et al., 1990). As the VEP amplitudes are much smaller than the fERG ones (up to approximately 15 μV), the VEP trace is more susceptible to noise (due to decreased signal‐to‐noise ratio). As a result, a higher number of averagings may be required. A narrower band‐pass filter (1–100 Hz) may further help to reduce the noise level. The electrodes were placed on the midline of the scalp; the recording, reference, and ground electrodes were placed over the midline of the nuchal crest (Oz), forehead (Fpz), and vertex, respectively (Kimotsuki et al., 2005; Strain et al., 1990). The flash VEP protocol by Strain et al. (1990) resulted in three positive (P1, P2, and P3) and two negative (N1 and N2) components by 150 msec after the flash. The peaks’ implicit times were approximately 15, 30, 55, 80, and 140 msec for P1, N1, P2, N2, and P3, respectively. Kimotsuki et al. (2005) have shown, utilizing a similar protocol, that P1 and N1 are referred to the retinal potentials, P2 is referred to the potentials from the retina to the brainstem, and N2 to those from the brainstem to the visual cortex. Like the fERG, the VEP is changing rapidly in the postnatal period. The VEP was first recorded 10 days after birth in the dog, and the implicit times of the VEP components progressively decreased from day 16 to day 28 (Boyer & Kirk, 1973). Age‐related differences were also noted in adult dogs (1–10 years of age), with the implicit times of P2, N2, and P3 being significantly delayed with aging. The amplitudes of

10.4: Ophthalmic Examination and Diagnostics

P3

P2

P1

N1

1–year–old

Pattern Electroretinogram The pattern electroretinogram (PERG) is an effective way to assess the inner retina, and mainly the ganglion cells, and as such it is an excellent tool to diagnose early glaucomatous damage (Ben‐Shlomo et  al., 2005; Forte et  al., 2010; North et al., 2010). The exact generator of the PERG may vary by species. The location of the electrodes for the PERG is similar to that for the fERG. However, unlike the fERG, there is no change in illumination of the retina during PERG testing. Instead, the PERG is recorded to an alternating high‐­contrast checkerboard (preferably) (Robson et al., 2018) or gratings; that is, the black and white components of the checkerboard alternate in a predetermined rate, while the overall luminance stays constant. The size of the checkerboard as well as the reversal rate can be changed, and the stimulus can be tailored to a specific subset of ganglion cells (Ben‐Shlomo et al., 2005; Forte et al., 2010). Like VEP, the amplitude of the PERG is much smaller than the fERG, making it more susceptible to noise contamination, and it requires a high number of averagings. The main components of the PERG are the first positive component and the second negative component, with approximate implicit times in human subjects of 50 msec and 95 msec, respectively, and as such they are named P50 and N95 (also known as P1 and N2; Fig. 10.4.14). The PERG has been used for research purposes to evaluate glaucoma damage in dogs (Grozdanic et  al., 2010; Hamor et al., 2000; Ofri et al., 1993) and cats (Schallek et al., 2012). However, similar to the pattern VEP, in addition to the equipment and expertise needed, fixation of gaze is crucial for appropriate recording of the PERG, and as such it cannot be performed reliably on conscious animals. Therefore, the fERG i‐wave is a more practical way to assess RGCs’ function in canine and feline patients (Rosolen et al., 2004).

N2

P50

9–year–old

A

15–year–old 20 μV

Amplitude [μV]

5

0 N35

0

50

100

150

200

250

300

(msec)

Figure 10.4.13  Typical waveforms of the flash visual evoked potential in young (1-year-old), middle-aged (9-year-old), and older (15-year-old) dogs. The latencies of P2 and N2 were delayed in older dogs, especially in the 15-year-old Beagle. (Reproduced with permission from Kimotsuki, T., Yasuda, M., Tamahara, S., et al. (2006) Age-associated changes of flash visual evoked potentials in dogs. Journal of Veterinary Medical Science, 68, 79–82.)

0

N95

100

200 Time [ms]

Figure 10.4.14  A pattern electroretinographic (PERG) trace. Note the low amplitude compared to the fERG. (Reproduced with permission from Bach M., Brigell M.G., Hawlina M., et al. (2012) ISCEV standard for clinical pattern electroretinography (PERG): 2012 update. Documenta Ophthalmologica, 126, 1–7.)

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P2–N2 and N2–P3 also showed a significant correlation with aging (Kimotsuki et  al., 2006; Fig.  10.4.13). As such, like with the fERG, the results of the VEP should be compared to age‐ and breed‐matched controls, using a similar technique. More recently, a method was established for flash VEP recording in the horse (Strom & Ekesten, 2016). The ground electrode was placed at the forehead and the reference electrode approximately 3 cm caudal to the lateral canthus. The most consistent and reproducible recordings were achieved when the recording electrode was placed in the midline, rostral to the nuchal crest, and 100 responses were averaged. Like in dogs, intraindividual variability was noted. Reproducible components were recorded in all horses and include N1, P2, N2, and P4, with a mean implicit time of 26, 55, 141, and 216 msec, respectively. Additional studies are needed to assess the clinical application of this diagnostic tool in the horse. A pattern reversal, or pattern onset‐offset stimuli, can also be used for VEP recording. However, these tests require visual fixation, which can only be achieved under anesthesia in veterinary patients. The pattern‐reversal VEP is most useful for evaluation of the optic nerve function (Robson et  al., 2018). The need for both general anesthesia and additional, expensive equipment as well as advanced training is making the pattern VEP less practical in clinical veterinary ophthalmology.

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774

A

B

Figure 10.4.15  Multifocal electroretinography (mfERG). Stimulus pattern consisting of 61 (A) and 103 (B) scaled hexagons and typical mfERG trace arrays with 61 elements (C) and 103 elements (D). (Reproduced with permission from Hood, D.C., Bach, M., Brigell, M., et al. (2012) ISCEV standard for clinical multifocal electroretinography (mfERG) (2011 edition). Documenta Ophthalmologica, 124, 1–13.)

Multifocal electroretinogram The multifocal ERG (mfERG) is a relatively new electroretinographic test, providing geographic mapping of retinal activity. The electrode placement is similar to that for the fERG, and the stimulus displays an array of hexagons (usually 61 or 103) in different sizes (Fig. 10.4.15), covering 20° to 30° (radius) of the retina, and scaled to produce a local response of approximately equal amplitude for each hexagon, in the normal human retina (Sutter & Tran, 1992). During the recording, each hexagon flickers in a pseudo‐random sequence of black and white presentation. This is in contrast to the PERG, where the black and white squares of the checkerboard are of equal size and number, and they always switch from black to white (and vice versa) at the same rate. Then, in the mfERG, through complex mathematic extraction and cross‐correlation between the stimulation sequence and the recorded ERG, the signal attributed to each hexagon is presented (Hood, 2000). The standard mfERG is cone driven, and recording the mfERG rod response, though doable, is challenging (Hood et al., 1998). The standard mfERG reflects electrical activity in the outer retina, mainly bipolar cells and to a lesser extent the cones. The inner retina (i.e., RGCs and amacrine cells) has a minor contribution to the mfERG (Hare & Ton, 2002; Hood et al., 2000). The standard mfERG shows an initial negative component (N1), a positive component (P1), and a second negative component (N2). In human subjects, N1 is

c­ omposed of the same components as the a‐wave of the fERG, and P1 is composed of the same components as the b‐wave and OPs (Hood et al., 1997). As with other tests in this section, given the requirement for advanced training and costly equipment, as well as fixation of gaze (and hence the need for general anesthesia in veterinary patients), and the lack of substantial medical benefit from this test to the ­veterinary patient, it is unlikely to become a common diagnostic tool in veterinary ophthalmology.

Electro-oculogram The electro‐oculogram (EOG) evaluates the RPE and it is recorded by two electrodes placed at the medial and lateral canthi of each eye, and assesses the standing potential of the pigment epithelium. The maximum value measured under light adaptation divided by the smallest dark‐adapted value represents the Arden light peak/dark trough ratio, which assesses the generalized function of the RPE/photoreceptor complex. With any severe rod dysfunction, the EOG will not provide diagnostic value (Heckenlively et al., 2006; Robson et al., 2018). In order to perform the test, the patient has to move the eyes horizontally, from side to side. Consequently, each time the eyes move from side to side, the different electrodes are being exposed to a different polarity of the eye, and the difference between the electrodes can be recorded. Since this test requires the patient’s cooperation, it is impractical in veterinary patients.

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Robson, A.G., Nilsson, J., Li, S., et al. (2018) ISCEV guide to visual electrodiagnostic procedures. Documenta Ophthalmologica, 136, 1–26. Robson, J.G. & Frishman, L.J. (1995) Response linearity and kinetics of the cat retina: The bipolar cell component of the dark‐adapted electroretinogram. Visual Neuroscience, 12, 837–850. Robson, J.G., Maeda, H., Saszik, S.M., et al. (2004) In vivo studies of signaling in rod pathways of the mouse using the electroretinogram. Vision Research, 44, 3253–3268. Rosolen, S.G., Rigaudiere, F., & Lachapelle, P. (2002) A practical method to obtain reproducible binocular electroretinograms in dogs. Documenta Ophthalmologica, 105, 93–103. Rosolen, S.G., Rigaudiere, F., & Le Gargasson, J.F. (2003) [A new model of induced ocular hyperpressure using the minipig]. Journal Français d’Ophthalmologie, 26, 259–267. Rosolen, S.G., Rigaudiere, F., Legargasson, J.F., et al. (2004) Comparing the photopic ERG i‐wave in different species. Veterinary Ophthalmology, 7, 189–192. Rousseau, S., Mckerral, M., & Lachapelle, P. (1996) The i‐wave: Bridging flash and pattern electroretinography. Electroencephalography and Clinical Neurophysiology, 46(Suppl.), 165–171. Sandmeyer, L.S., Breaux, C.B., Archer, S., et al. (2007) Clinical and electroretinographic characteristics of congenital stationary night blindness in the Appaloosa and the association with the leopard complex. Veterinary Ophthalmology, 10, 368–375. Sato, S., Sugimoto, S., & Chiba, S. (1982) A procedure for recording electroretinogram and visual evoked potential in conscious dogs. Journal of Pharmacology Methods, 8, 173–181. Schallek, J.B., Mclellan, G.J., Viswanathan, S., et al. (2012) Retinal intrinsic optical signals in a cat model of primary congenital glaucoma. Investigative Ophthalmology & Visual Science, 53, 1971–1981. Sieving, P.A., Frishman, L.J., & Steinberg, R.H. (1986) Scotopic threshold response of proximal retina in cat. Journal of Neurophysiology, 56, 1049–1061. Sieving, P.A. & Nino, C. (1988) Scotopic threshold response (STR) of the human electroretinogram. Investigative Ophthalmology & Visual Science, 29, 1608–1614. Sims, M.H. (1990) Partial masking of the canine electroretinogram by oscillatory potentials: The problem of frequency bandwidth. Journal of Veterinary Internal Medicine, 4, 40–42. Sims, M.H. & Brooks, D.E. (1990) Changes in oscillatory potentials in the canine electroretinogram during dark adaptation. American Journal of Veterinary Research, 51, 1580–1586. Sims, M.H. & Laratta, L.J. (1988) Visual‐evoked potentials in cats, using a light‐emitting diode stimulator. American Journal of Veterinary Research, 49, 1876–1881. Sims, M.H., Laratta, L.J., Bubb, W.J., et al. (1989) Waveform analysis and reproducibility of visual‐evoked potentials in dogs. American Journal of Veterinary Research, 50, 1823–1828.

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11 Ophthalmic Genetics and DNA Testing Simon M. Petersen-Jones Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA

The Canine Genome The first working draft of the canine genome was made available in 2004 (CanFam1.0), revised in 2005 (CanFam2.0) (Lindblad‐Toh et  al., 2005), and revised again in 2011 (CanFam3) (Fig. 11.1) (Hoeppner et al., 2014). The availability of a good quality sequence of the canine genome coupled with modern molecular techniques has greatly facilitated the study of genetic traits in this species. The canine genome has approximately 2.4 billion basepairs of DNA spread across 38 pairs of autosomal chromosomes and two sex chromosomes (the human genome is just over 3 billion basepairs). Across the genome ~20,700 protein coding genes were predicted, most being homologues of human genes. Because an organism has two copies of autosomal chromosomes which are present in all cell nuclei, except for gametes, each individual has two copies of each gene that is on the autosome (one maternally derived, the other paternally derived). The two genes or chromosomal DNA features (the maternally and paternally derived) are known as alleles. Thus, an individual will have two alleles of each stretch of DNA on an autosomal chromosome. The dog initially used to supply DNA for the canine genome project (National Human Genome Research Institute) was “Tasha,” a female Boxer. A Boxer was chosen because the breed was reported to have low genetic variability. The genome sequence of dogs from multiple breeds are now available revealing the normal genetic variability between breeds. Mapping of genetic traits can be performed using heritable variations in DNA sequence (polymorphisms) from across the genome. Prior to the sequencing of the genome, variations in genome sequence that were inherited in a Mendelian fashion had been identified and were used for mapping genetic traits. Microsatellites, which are stretches of repeated nucleotides, were identified and sets of microsatellites that

are positioned reasonably evenly across the canine genome were established for use in mapping (Sargan et  al., 2007). Studies using these sets of microsatellites in canine families allowed their relative positions across the genome to be established. Microsatellites are repeats of two (dinucleotide), three (trinucleotide), four (tetranucleotide), or more runs of nucleotides. The variability of these markers is in the number of repeats between different alleles. Variability in microsatellites arose because of mistakes that the cellular DNA replication machinery made in copying the repeated DNA units during meiosis, and these differences became fixed in the population. Sets of markers such as microsatellites that are located within or close to candidate genes for inherited retinal degenerations (IRDs) in dogs have been developed to be used to investigate any new IRD by testing for association between the marker locus and the IRD. An association would be suggested if the version of the marker was shared by all the dogs with the IRD under investigation (Winkler et  al., 2017). Microsatellites are useful for this approach because each one can have several different versions within a population. Another type of variable marker that has become very important for mapping is the single‐nucleotide polymorphism (SNP). SNPs are a variation of a single nucleotide at one particular locus. They therefore only have two variations (alleles) making them less powerful for mapping than microsatellites which may have multiple different alleles. However, the high density of SNPs across the genome makes them very valuable for mapping. SNPs, as well as additional microsatellites, were identified during the sequencing of the canine genome. Lists of SNPs are available online and have been used in construction of microarray mapping tools (see later section). The annotation of the genome also highlights repeat elements which include microsatellites, thus allowing the identification of additional microsatellites that if polymorphic (i.e., present as more than one version in the population) can be used for mapping purposes.

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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Figure 11.1  This is a screenshot of the UCSC Genome Browser showing the region of the canine Cngb1 gene.

Other Genomes The genomes of many other species (including cat, horse, and farm animals) have been sequenced above and are available through online sites such as: University of California Santa Cruz Genome browser (genome.ucsc.edu); Ensembl (ensembl.org); NCBI (ncbi.nlm.nih.gov/genome).

The Structure of Genes DNA is formed from four nucleotides; two purines, adenine (A) and guanine (G) and two pyrimidines, cytosine (C) and thymine (T). In double‐stranded DNA, adenine of one strand pairs with thymine on the other (complementary) strand and cytosine pairs with guanine. Genes are sections of DNA that code for protein production. The genes are made up of exons which have the genetic information that is transcribed into messenger RNA for subsequent translation into proteins. The coding DNA after translation into messenger RNA is read in triplets of nucleotides (codons). The first codon of the translated sequence, known as the start codon, consists of adenine, uracil (thymine in the DNA), and guanine

(AUG), which codes for methionine and is the starting amino acid of the protein. Subsequently from the start codon, each three‐nucleotide codon instructs the insertion of a particular amino acid or tells the cell to terminate the protein (a stop codon). Most amino acids are coded for by more than one triplet of nucleotides, for example, alanine is coded for by either GCA, GCC, GCG, or GCT. The exons (DNA of the gene that is converted into messenger RNA) are separated by noncoding stretches of DNA that are called introns. During formation of messenger RNA, the introns are removed or “spliced” out leaving a continuous stretch of coding RNA. The number of exons and intervening introns varies between genes. The roles of noncoding regions of DNA are becoming better understood and have been shown not to be the “junk” DNA they were once considered. Some noncoding portions of the DNA on the chromosomes are promoters for genes. Promoters control gene expression and respond to elements to increase or decrease levels of expression. They also control factors such as tissue specificity of expression. Noncoding functional RNAs originate from the noncoding DNA. These include ribosomal RNA, transfer RNA, and microRNAs. MicroRNAs are short RNA molecules that play an important role of regulation of mRNA

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translation and thus influence the production of proteins. Study of the role of genomic DNA that does not code for proteins is improving our understanding of the importance of these regions. Other noncoding elements include transposons and retrotransposons that are mobile genetic elements. These include both short interspersed nuclear elements (SINEs) and long interspersed nuclear elements (LINEs). SINEs are sometimes described as “jumping genes”; they are mobile elements that can propagate within the genome via a “copy and paste” mechanism. If the insertion of a SINE element occurs in a gene‐coding region, it may result in altered gene function. For example, the merle coat pattern is caused by a SINE insertion in the SILV gene which is important in normal melanocyte function (Clark et al., 2006). Progressive retinal atrophy (PRA) in the Tibetan Terrier and Tibetan Spaniel is caused by a SINE insertion in the FAM161A gene (Downs & Mellersh, 2014).

Alternative Splicing of Genes Alternative splicing allows for different gene products to be produced from the same gene. The exons used vary between the different gene products; for example, one exon may be included in some of the mRNAs and not in others. This may be dependent on factors such as which tissue the gene is being expressed in. Alternative splicing thus allows for multiple different proteins to be produced from a single gene and explains how complex organisms can be produced from what could be considered to be a low number of genes.

What DNA Changes Result in Hereditary Disease? Disease Caused by Changes in Coding Regions of DNA Gene mutations are changes in the genomic DNA sequence that affect coding regions of DNA. They can arise from external influences such as radiation or mutagenic chemicals or internal factors such as errors during meiosis or DNA replication. They can also result from insertions of retrotransposon mobile elements into genes as previously described. DNA mutations can be insertions or deletions of DNA (varying in size from one nucleotide to a large region of DNA) or be a change in a single nucleotide. DNA change within a coding region of a gene can alter the gene coding by changing the amino acid that is coded for (a missense mutation). They can change the coding from that for a particular amino acid to a stop codon (codes to terminate the protein production), known as a nonsense mutation or premature stop codon. Some DNA variations do not alter the amino acid that is being coded for (silent mutation) and are therefore not expected to alter the protein production in any significant way. Insertions or deletions can alter the reading frame thus changing the amino acids coded for and often leading to a premature stop codon. Frame deletions or insertions (removal or addition of codons without altering the “read” of the downstream codons) can occur and alter the coded protein that might alter its function or its folding to cause disease, or it might be tolerated.

Genetic Traits

Disease Caused by Changes in Noncoding Regions of DNA

There is a complex interaction between the genetics of an individual and the environment, both of which combine to result in the individual’s phenotype. The phenotype includes physical traits as well as pathological conditions. Some pathological conditions are straightforward inherited conditions, such that if the gene mutation causal for the condition is present, the individual will develop the condition. However, other factors such as interactions of other genes can alter the disease phenotype. For example, these factors might influence age of onset, rate of progression, or even whether the trait is expressed at all (thus contributing toward variable penetrance of some genetic traits). This is often described as “background genetic effects.” Some hereditary conditions are under the influence of several genes and are described as having polygenic inheritance. Other genetic variation confers susceptibility or resistance to disease, for example, resistance to infection or predisposition to cancer formation. Thus, a genetic predisposition for a condition may be present, but unless there is an environmental influence, the condition may not develop, or may be less severe.

Changes in DNA in noncoding regions can also result in disease. There are several possible mechanisms. These include DNA changes that involve regulatory regions such as gene promoters. The regulatory regions influence expression levels, and alterations in these regions might reduce gene expression. Some DNA changes in introns can alter the splicing of exons that occurs during messenger RNA production. An example of the latter is an alteration in an intron in CEP290 that results in autosomal recessive PRA in the Abyssinian and other cat breeds (Menotti‐Raymond et  al., 2007, 2009). The change in the intron creates a new site for the exon/intron donor site adding additional nucleotides to the exon in question. These additional nucleotides change the “read” of the coding introducing a premature stop codon that is predicted to shorten the protein (Fig. 11.2).

Nonsense- Mediated mRNA Decay Nonsense‐mediated mRNA decay is a mechanism by which the cell prevents the translation of abnormally shortened

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Figure 11.2  Details of the gene mutation in CEP290 that causes the RdAc form of PRA in the Abyssinian and other breeds of cat (Menotti-Raymond et al., 2007). The region at the end of exon 50 and beginning of intron 50 is shown. There is a change of a T to a G nucleotide nine positions into the intron. This creates a strong splice donor site that in the mutant version is used instead of the wild-type splice site. In the lower part of the figure, the resulting wild type and RdAc mRNA and protein translation can be seen. The altered splice site adds four nucleotides to exon 50 (marked in red) leading to a frameshift and coding for two altered amino acids (shown in red) followed by a stop codon.

transcripts. It allows the cell to regulate whether alternatively spliced transcripts are translated or not. It is thought that many of the possible alternatively spliced transcripts do not produce a protein product because they are degraded in the cell by this surveillance mechanism. If a DNA mutation results in the introduction of a premature stop codon, the resulting transcript might undergo nonsense‐mediated decay. This is more likely if the premature stop codon is positioned in the mRNA more than about 50 nucleotides upstream of the final exon. This mechanism means that the altered mRNA is not translated, preventing production of a shortened peptide that could have a deleterious effect on the cell. Abnormalities resulting from degradation of mRNA with a premature stop codon result from a lack of the gene product. A mutation that results in a loss of gene product often results in recessive conditions. The fact that the body can function normally with only one functional copy of the gene shows the flexibility that is present in many of the biochemical pathways in the body. The situation where a phenotype results from the lack of one functional copy of the gene in the presence of a normal copy of the gene is described as haploinsufficiency. A single functional copy of genes such as those controlling development may not be sufficient to create a normal phenotype. Haploinsufficiency is one mechanism for dominantly inherited disease.

Modes of Inheritance Autosomal Recessive Inheritance

Autosomal recessive conditions are ones where the mutation is on an autosome and the animal heterozygous for the mutation does not have an obvious phenotype. Animals homozygous for the mutation will develop the disease.

Mutations in genes coding for proteins in biochemical pathways where the presence of a reduced protein level (as in the heterozygous animal) does not result in a deleterious effect – known as being haplosufficient – cause recessively inherited conditions. The presence of carrier animals (heterozygotes) in the population makes eradication of such conditions difficult without having a DNA‐based genetic test. The condition can skip generations. Autosomal Dominant Inheritance

Conditions resulting from the presence of a mutation on an autosome that in the heterozygous state causes the condition are described as autosomal dominant. Dominant disease (if fully penetrant) does not skip generations. Another feature is that a cross between two affected animals can produce unaffected offspring (unlike autosomal recessive conditions where an affected to affected mating results in all offspring being affected). Dominant disease can result from mutations in structural genes, in developmental genes, and in circumstances where the mutated gene product is produced and has a deleterious effect. Examples of the latter would be when the mutated product is not trafficked appropriately within the cell and accumulates in an abnormal location, where it irreversibly binds a partner protein blocking a pathway, or when it is in some other way toxic to the cell. Such gene mutations are described as having a dominant negative effect. The mutation in the transcription factor CRX that was identified in Abyssinian cats with dominant early‐onset PRA is one example of a condition which results when the mutant protein binds to gene transcription sites but fails to activate them (Menotti‐Raymond et al., 2010; Occelli et al., 2016). Diseases that result when one copy of the gene is not produced and a single copy is not sufficient to create a

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­ ormal phenotype are described as resulting from haploinn sufficiency as described earlier.

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X- Linked Dominant and Recessive Inheritance

Mutations that involve genes on the X chromosome lead to X‐linked conditions. X‐linked recessive disease is manifest where all copies of the X chromosome have the mutation thus affecting males (XY, which are described as being hemizygous) and females (XX) that are homozygous for the condition. Such conditions would be much more common in males than in females. X‐linked dominant conditions would affect males (XY) and females (XX) heterozygous for the condition. Note that for avians, the males are homogametic (ZZ) whereas the females are heterogametic (ZW). Random X Chromosome Inactivation (Lyonization)

Random X chromosome inactivation (Lyonization) is a normal phenomenon whereby only one X chromosome is active in the cells of females. This is required so that the female does not have both copies of X chromosome genes active (i.e., twice as many as the male). The inactivated X chromosome is visible in the nucleus on microscopy as the Barr body. In mammals, the inactivation of one of the chromosomes is random (i.e. either X chromosome could be inactivated) and occurs during development at the blastocyst stage. Once one X chromosome is inactivated, all daughter cells from that cell will have the same X chromosome inactivated. This has the effect that there are groups of cells with the same X chromosome active. The coat color pattern of tortoiseshell cats is a commonly quoted example of random X chromosome inactivation. The gene that confers black or orange color (dependent on the version of the gene) lies on the X chromosome. The patches of one coat color indicate that the cells in that region of the skin all have the same X chromosome inactivated. An ophthalmologic example is female dogs that are carriers of X‐linked PRA. The retinas of these dogs have patches of cells with one X chromosome inactivated. In the regions where the normal copy of the gene is inactivated and the mutant copy is expressed, retinal degeneration develops (Beltran et al., 2004). Mitochondrial Inheritance

Mitochondrially inherited conditions are those that are caused by mutations of the mitochondrial DNA. Mitochondrial DNA is inherited in a maternal fashion; that is, it is passed from the dam to her offspring. An ophthalmic example of a maternally inherited condition is Leber hereditary optic neuropathy in humans.

Complex Traits Complex traits result from interaction of several genetic factors, often with additional environmental influences.

Predisposition to certain disorders may be complex, multifactorial, or polygenic. The form of PRA (cone rod dystrophy type 1) in Miniature Longhaired Dachshunds and other breeds associated with a mutation in RPGRIP1 has on further study been shown to be a complex condition with a second locus influencing expression of the phenotype and influences of additional loci being suspected (see below and Chapter  25 for more details). Conditions that result from conformational differences in dogs (entropion, ectropion, etc.) may be under the influence of several genes that control head conformation, eyelid length, etc.

Quantitative Trait Loci Quantitative trait loci (QTL) describe the several genetic loci that contribute to a particular characteristic. Studies to identify the QTL that influence body conformation, fecundity, etc. in production animals are important. The QTL that influence the development of complex disease traits are also important. Some studies have been undertaken to try to identify the QTLs that influence the rate of progression of the progressive rod cone degeneration (PRCD) form of PRA (Zangerl et al., 2009). In mice, a QTL was mapped that influences susceptibility to light‐induced retinopathy (Danciger et al., 2000). It was eventually identified as a polymorphism in the RPE65 gene. The investigation of QTLs is going to become an important step in our understanding and development of therapies for diseases in the future.

Pharmacogenetics Pharmacogenetics refers to the genetic variation that influences response to drugs. For example, genetic traits can influence drug metabolism in individuals. This can lead to certain individuals being at higher risk of drug side effects or drug reactions compared with other individuals. In the future, the study of pharmacogenetics might allow the tailoring of drug therapies to individuals to minimize side effects and allow for optimal outcomes. A gene mutation conferring sensitivity to neurotoxic side‐effects of drugs such as ivermectin has been identified in dogs (Mealey et al., 2002).

The Process of Identification of Disease-Causing Mutations Tools that allow identification of the DNA change underlying genetic disease and genetic traits have been developed, enabling these features to be investigated in many species. The investigation of genetic disease within a dog or cat breed should start with careful and precise phenotyping of the condition coupled with pedigree analysis to try to ascertain

11: Ophthalmic Genetics and DNA Testing

Genome-Wide Association Study (GWAS) The canine genome project led to the identification of large numbers of genetic variants across the canine genome. Variations at single nucleotides are known as SNPs. These are naturally occurring genetic variations that can be used for gene mapping. Microarrays that allow genotyping of individuals for large numbers of SNPs across the genome are available. Affymetrix and Illumina both manufacture microarrays for different species that can be used to genotype large numbers of SNPs. The Illumina canineHD whole genome genotyping BeadChip will genotype a dog at over 170,000 SNPs across the genome. At the time of writing, new high‐ density SNP arrays for dogs are being released detecting larger numbers of SNPs and insertion/deletions equally distributed across chromosomes. These are called Axiom arrays A and B and between them include approximately 1.1 million canine markers; Axiom array A having over 460,000 markers and B having over 670,000 markers. To investigate an hereditary trait, both diseased and control animals are genotyped using the SNP microarray. The animals used need to be carefully phenotyped to be as confident as possible that the diseased animals have the same hereditary condition. With conditions that show genetic heterogeneity, such as PRA, it can be difficult to be certain that the pool of diseased animals have the exact same condition (i.e., the same causal mutation). Computer programs are used to analyze the SNP genotyping data. For recessive disease, screening is performed to identify regions of homozygocity shared across the affected animals. If an association study is performed, the results at each SNP are analyzed to see if one version of a SNP is significantly correlated with the disease status.

DNA Sequencing Several techniques have been developed for sequencing DNA. Some methods are suitable to ascertain the DNA sequence of a short stretch of DNA accurately – such as copies of a DNA sequence generated by a polymerase chain reaction (PCR). These most commonly use “Sanger sequencing” being based on the dideoxy termination method developed by Sanger and Coulson. Next‐generation sequencing techniques are used for large sequencing projects up to whole genome sequencing. These techniques most commonly ascertain the DNA sequence of vast numbers of short strands of DNA prepared from the DNA to be sequenced. There is “massive parallel” sequencing of these short strands such that the average number of repeat sequencing reads of each section of DNA of the target sequence gives good coverage of the genome, for example a “depth of coverage” of 30× might be chosen meaning that there are an average of 30 reads for each region of the genome. These short strands of DNA are typically aligned by computer software to the reference sequence of the organism being sequenced. Some other next‐generation techniques are designed to sequence longer strands of DNA using different technologies. These long‐read techniques are better at identifying structural DNA rearrangements than the short fragment typical next‐generation sequencing. Further analysis of the result of sequencing includes the identification of where the sequences obtained differ from the reference genome or between samples. So, if a series of disease cases (for example animals with one specific genetic disease) were sequenced and compared with control samples (unaffected control animals) the software could identify where there were differences between the cases and controls and whether these DNA variations were in coding regions of genes, introns, or intergenic regions. If they were in coding regions it could also predict the effect on the protein that was being coded for. There are different methods of next generation sequencing that have specific advantages and disadvantages with regular advances being made in these technologies driving down the cost of sequencing. Using the next generation sequencing technologies, the whole, or part, of the genome of an animal can be sequenced. Examples of sequencing just part of the genome include exome sequencing and targeted sequencing. In exome sequencing the exons and flanking introns are sequenced. Since the coding portions of the genome (exons of the genes) only make up a small proportion of the entire genome (~1%), exome sequencing can have much lower costs because only a small fraction of the DNA is sequenced using this approach. This can be effective in identifying coding region changes and intron/exon splice site mutations but will not identify other noncoding disease‐causing variants. Targeted sequencing is used to sequence a specific portion of the genome.

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whether a simple Mendelian trait is present, whether the condition is heterogeneous, or is a complex genetic trait. The phenotyping and pedigree analysis might suggest potential candidate genes for the condition. Such candidate genes are based on those shown to cause analogous diseases in other breeds, or other species, or are based on the known function of particular genes. Some conditions have numerous potential candidate genes; for example, hereditary retinal dystrophies show great genetic heterogeneity, and there are several examples of breeds of dog in which several forms of PRA are segregating (Downs et al., 2014a). In other conditions, there are just a few candidate genes that might be responsible for the condition. Screening of candidate genes within families in which the disease is segregating can be by use of genetic markers (such as microsatellites and SNPs) that are very closely linked to the candidate gene under investigation. These can be used to show if the disease status is linked to any of the potential candidate genes. Sequencing of any linked candidate gene to identify any potential disease‐causing mutations is the next step.

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For example, if a genetic disease was mapped to a specific chromosomal region a targeted sequencing approach could be developed to sequence the DNA from just the mapped region. This approach is relatively expensive to set up, but once it is set up, it can be used cheaply on DNA from many individuals. Next generation sequencing can also be used to identify what genes are being expressed in a particular tissue. To do this, the RNA is isolated from the tissue in question and then sequenced (RNA‐Seq). The resulting information on the genes active in that tissue is known as the transcriptome. The constant improvements in these technologies and continued reduction in costs means the identification of disease‐causing mutations becomes easier, and the use of genomic information and transcriptomes can improve our understanding of disease processes and help introduce approaches such as personalized medicine.

Tests for Genetic Disease There are a rapidly increasing number of DNA‐based genetic tests available as more gene mutations underlying hereditary diseases are identified (for a list of ophthalmic conditions for which DNA tests are available please refer to the ECVO Hereditary Eye Diseases Manual [Chapter 10] on the ECVO web site: ECVO.org). It is important to appreciate and explain to clients the information that the tests actually provide. When designed to identify a specific gene mutation, the test will do only that. This means that a test for PRA will only identify if an animal is affected or is not affected by (or in the case of recessive PRA, is a carrier for) that specific type of PRA. Some breeds of dogs have multiple forms of PRA, each caused by a different genetic mutation. Each test will only identify one of those forms. To use the Golden Retriever as an example, it is known that at least three forms of PRA are segregating within the breed. Dogs could have the PRCD form of PRA (which is common across several breeds of dog) (Zangerl et al., 2006), or they could have PRA caused by a mutation in the SLC4A3 gene (Downs et  al., 2011), or the TTC8 gene (Downs et  al., 2014b). In the Papillon, about 70% of PRA was shown to be caused by a mutation in CNGB1 (Winkler et al., 2013), meaning that PRA in the breed can also result from one or more additional gene mutations. Thus, a Papillon could be clear of the CNGB1 form of PRA and yet still develop PRA (caused by a non‐CNGB1 form of PRA). DNA‐based tests are completely specific for the one form of hereditary disease they were designed to identify, and they should also be very accurate, if they are well designed. Obviously, there is still opportunity for human errors to be made, for example, if samples are mislabeled, which is probably more of a risk if multiple dogs are being sampled at the same time.

The interpretation of tests can be complicated in some situations such as with more complex conditions where there may be more than one locus involved. For example, the cone rod dystrophy type 1 (CORD1) form of PRA originally associated with an RPGRIP1 insertion mutation appears to require the presence of a variation in the MAP9 gene and probably an additional unknown locus for the phenotype to develop (Das et al., 2017; Miyadera et al., 2011). The RPGRIP1 insertion has been detected in several breeds of dog but does not appear to always be associated with retinal degeneration (Kuznetsova et  al., 2012; Miyadera et  al., 2009). In some breeds there is a high incidence of the RPGRIP insertion and yet a low incidence of PRA. For this reason the results of DNA tests for the RPGRIP1 insertion should be interpreted with care until further research is completed to resolve the remaining questions about RPGRIP1 insertion involvement in retinal disease. Further details are included in Chapter 25.

Sample Collection To carry out a genetic (DNA‐based) test, a DNA sample is required. This is commonly isolated from a blood sample or cheek swab. The instructions from the laboratory conducting the test should be followed. Care must be taken to ensure that the sample is not contaminated (e.g., with DNA from another animal or person) and is clearly labeled. When samples from multiple animals are being collected, particular care should be taken with identification of the animal, and the sample should be clearly and accurately labeled immediately after it is collected.

Mutation Detection Tests A mutation detection test is one that is designed to specifically identify the DNA alteration that has been shown to cause the genetic trait being tested for. Such a test is very accurate and extremely specific. Dog owners and breeders need to appreciate that for conditions with genetic heterogeneity, for example, PRA, a test for one specific form of PRA will identify the presence/absence of only that form of PRA as discussed earlier.

Linked-Marker Test When a genetic trait has been mapped and the mutation causing the defect has not yet been identified, it can still be possible to design a genetic test. When the disease‐causing mutation arose, it would have happened on a chromosome with specific versions of the variable DNA (polymorphisms) across that chromosome. The mutation would be passed down the generations such that all affected animals are descendants of the founder animal. The region of the chromosome surrounding the mutation would be shared by all

the affected animals (identity by descent). The shared region is thus “linked” to the disease mutation. If there is a closely linked DNA marker, the affected animals will share the same version of that marker. The version of that polymorphic marker present in the unaffected animals can be used to suggest that they do not have the disease allele. If an individual has the version of the marker that is not associated with the disease mutation, then it is likely that they are clear of the mutation. If an animal has the marker version associated with the disease, they may also have the disease allele; however, there is also a possibility that animals with the version of the marker associated with the mutation do not have the mutation. This is because when the mutation arose, some of the population had the same version of the marker as the founder animal, and descendants of those animals may exist in the current‐day population. Thus, the interpretation of linked‐marker tests can be problematic. If the marker is not very closely linked to the disease mutation, then a crossover between marker and mutation site can occur at meiosis, leading to further complications in interpretation. Before the causal mutation for the PRCD form of PRA was identified, a linked‐marker test was made available and enabled breeders to make informed breeding plans. Direct‐mutation detection tests are preferable whenever possible.

Multiplex Testing Genetic testing in dogs is moving towards panel screening which utilizes a custom genotyping array. Such arrays can include multiple different known disease‐causing mutations as well as test DNA variants underlying physical traits and be used to show degree of genetic diversity. Companies offer-

ing this service will test all submitted dog DNA samples on the genetic panel regardless of what diseases are known to segregate within the breed. Such an approach considerably reduces the costs of genetic testing and can reveal the presence of disease‐associated mutations in dog breeds not previously recognized as being affected (Donner et  al., 2016). There is a definite need for genetic counseling to enable dog owners and breeders to understand and interpret the mass of results provided from such panels.

Breeding from Carriers for Recessive Disease Breeding from carriers of recessive disease where the underlying gene mutation is known can be performed without risk of producing affected offspring, so long as carriers are mated with genetically clear animals. In some circumstances, use of carrier animals in breeding programs can be important. If a recessive disease is present in a breed at a high incidence, avoiding breeding from all affected and carrier animals can considerably limit the available gene pool for breeding. Use of only a small proportion of available animals for breeding could run the risk of bringing out other “background” hereditary diseases that are in the population at low levels. It may also run the risk of losing some desirable characteristics from the breed. If there is a particularly good specimen that happens to be a carrier for a recessive disease that can be tested for, it may be sensible to use the animal in breeding programs (avoiding mating with another carrier animal). Then by selective breeding over a few generations, the desirable characteristics can be separated from the disease genotype (i.e., separating the “good genes” from the “bad genes”).

References Beltran, W.A., Didia, P., Acland, G.M. & Aguirre, G.D. (2004) Retinal histopathology of X‐linked progressive retinal atrophy 2 (XLPRA2), a canine model of early onset X‐linked retinitis pigmentosa. Investigative Ophthalmology & Visual Science, 45, 3619. Clark, L.A., Wahl, J.M., Rees, C.A. & Murphy, K.E. (2006) Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog. Proceedings of the National Academy of Sciences of the United States of America, 103, 1376–1381. Danciger, M., Matthes, M.T., Yasamura, D., et al. (2000) A QTL on distal chromosome 3 that influences the severity of light‐induced damage to mouse photoreceptors. Mammalian Genome, 11, 422–427. Das, R.G., Marinho, F.P., Iwabe, S., et al. (2017) Variabilities in retinal function and structure in a canine model of cone‐rod dystrophy associated with RPGRIP1 support multigenic etiology. Scientific Reports, 7, 1–15.

Donner, J., Kaukonen, M., Anderson, H., et al. (2016) Genetic panel screening of nearly 100 mutations reveals new insights into the breed distribution of risk variants for canine hereditary disorders. PLoS One, 11, e0161005. Downs, L.M., Hitti, R., Pregnolato, S. & Mellersh, C.S. (2014a) Genetic screening for PRA‐associated mutations in multiple dog breeds shows that PRA is heterogeneous within and between breeds. Veterinary Ophthalmology, 17, 126–130. Downs, L.M. & Mellersh, C.S. (2014) An Intronic SINE insertion in FAM161A that causes exon‐skipping is associated with progressive retinal atrophy in Tibetan Spaniels and Tibetan Terriers. PLoS One, 9, e93990. Downs, L.M., Wallin‐Hakansson, B., Bergstrom, T. & Mellersh, C.S. (2014b) A novel mutation in TTC8 is associated with progressive retinal atrophy in the Golden Retriever. Canine Genetics and Epidemiology, 1, 4. Downs, L.M., Wallin‐Hakansson, B., Boursnell, M., et al. (2011) A frameshift mutation in Golden Retriever dogs with

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progressive retinal atrophy endorses SLC4A3 as a candidate gene for human retinal degenerations. PLoS ONE, 6, e21452. Hoeppner, M.P., Lundquist, A., Pirun, M., et al. (2014) An improved canine genome and a comprehensive catalogue of coding genes and non‐coding transcripts. PLoS One, 9, e91172. Kuznetsova, T., Iwabe, S., Boesze‐Battaglia, K., et al. (2012) Exclusion of RPGRIP1 ins44 from primary causal association with early‐onset cone‐rod dystrophy in dogs. Investigative Ophthalmology & Visual Science, 53, 5486–5501. Lindblad‐Toh, K., Wade, C.M., Mikkelsen, T.S., et al. (2005) Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature (London), 438, 803–819. Mealey, K.L., Bentjen, S.A. & Waiting, D.K. (2002) Frequency of the mutant MDR1 allele associated with ivermectin sensitivity in a sample population of collies from the northwestern United States. American Journal of Veterinary Research, 63, 479–481. Menotti‐Raymond, M., David, V.A., Pflueger, S., et al. (2009) Widespread retinal degenerative disease mutation (rdAc) discovered among a large number of popular cat breeds. Veterinary Journal, 186, 32–38. Menotti‐Raymond, M., David, V.A., Schaffer, A.A., et al. (2007) Mutation in CEP290 discovered for cat model of human retinal degeneration. Journal of Heredity, 98, 211–220. Menotti‐Raymond, M., Deckman, K.H., David, V., et al. (2010) Mutation discovered in a feline model of human congenital retinal blinding disease. Investigative Ophthalmology & Visual Science, 51, 2852–2859.

Miyadera, K., Kato, K., Aguirre‐Hernandez, J., et al. (2009) Phenotypic variation and genotype‐phenotype discordance in canine cone‐rod dystrophy with an RPGRIP1 mutation. Molecular Vision, 15, 2287–2305. Miyadera, K., Kato, K., Boursnell, M., et al. (2011) Genome‐ wide association study in RPGRIP1 (‐/‐) dogs identifies a modifier locus that determines the onset of retinal degeneration. Mammalian Genome, 23, 212–223. Occelli, L.M., Tran, N.M., Narfstrom, K., et al. (2016) Crx(Rdy) cat: a large animal model for CRX‐associated Leber congenital amaurosis. Investigative Ophthalmology & Visual Science, 57, 3780–3792. Sargan, D.R., Aguirre‐Hernandez, J., Galibert, F. & Ostrander, E.A. (2007) An extended microsatellite set for linkage mapping in the domestic dog. Journal of Heredity, 98, 221–231. Winkler, P.A., Davis, J.A., Petersen‐Jones, S.M., et al. (2017) A tool set to allow rapid screening of dog families with PRA for association with candidate genes. Veterinary Ophthalmology, 20, 372–376. Winkler, P.A., Ekenstedt, K.J., Occelli, L.M., et al. (2013) A large animal model for CNGB1 autosomal recessive retinitis pigmentosa. PLoS One, 8, e72229. Zangerl, B., Goldstein, O., Philp, A.R., et al. (2006) Identical mutation in a novel retinal gene causes progressive rod‐cone degeneration in dogs and retinitis pigmentosa in humans. Genomics, 88, 551–563. Zangerl, B., Lindauer, S.J., Gupta, A., et al. (2009) WGA studies to identify potential PRCD disease modifier candidate regions. ARVO Meeting Abstracts, 50, 4095.

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12 Fundamentals of Ophthalmic Microsurgery David A. Wilkie Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA

Introduction Although microsurgery has principles and rules to be used as guides, surgery is also a very individual and personal activity with strong beliefs and personal opinions possessed by most veterinary ophthalmic surgeons. The rules of micro­ surgery are meant as a foundation to guide the novice veteri­ nary ophthalmic surgeon and once understood, can occasionally be molded and adapted to suit the surgeon and the individual patient. However, the surgeon must always re‐visit the basic microsurgical rules and principles when a new technique or procedure is to be performed. This chapter is intended as a guide and starting point for microsurgery. Specific procedures will be discussed in subsequent chapters and on occasion, opinions and techniques may differ slightly. Remember, surgery is both a technique and an art, and as such, artists will have differences of opinion. Surgeons must have a goal and a plan to achieve the goal, but must also be adaptable and familiar with more than one technique so that obstacles encountered during the surgical procedure may be overcome. Not all surgeries proceed according to the plan. All eyes are different, and the surgeon who says “I always do it this way” is destined to encounter situations where their technique does not meet the patient’s needs. Regardless of our individual variations, we must all follow the basic rules: to use appropriate magnification and instrumentation, to be efficient and precise, to ensure mini­ mal tissue trauma, to minimize surgical time, to maintain the anterior chamber using small incisions and viscoelastic materials, to obtain excellent tissue wound apposition with the smallest and most appropriate suture materials, and finally, to achieve a successful, comfortable, cosmetic, and whenever possible, visual outcome. Microsurgery can be defined as the dissection or repair of delicate and minute structures using magnification and handheld microsurgical instruments (Chang et  al., 1986; Dorland, 2009). In veterinary ophthalmology, this would

include surgery of the cornea, conjunctiva, intraocular tis­ sues, and selected adnexal structures. The unique feature of ophthalmic microsurgery when compared with general sur­ gery is the use of the operating microscope. In addition, the instrumentation, position of the surgeon, and the methods of holding and manipulating the surgical instruments differ from traditional general surgery techniques. The use of mag­ nification enhances the surgeon’s appreciation of subtle tis­ sue differences and facilitates proper instrument and suture placement, minimizing tissue trauma and improving out­ comes. The use of magnification has facilitated surgical pro­ cedures that would be impossible to undertake without assisted vision (Jarrett, 2004). Surgical principles and techniques used in ophthalmic microsurgery differ considerably from those used in general surgery. Successful ophthalmic microsurgery requires that the surgeon understand not only the design and complexi­ ties of the operating microscope, but how tissues are affected by minute manipulations with microsurgical instruments. Furthermore, ophthalmic microsurgery requires a detailed understanding of how microsurgical techniques need to be adjusted to accommodate the unique features of ocular tis­ sues such as conjunctiva, cornea, lens, and retina. A diligent effort to master the principles of ophthalmic microsurgery is probably the single most important prerequisite to becoming an accomplished ophthalmic surgeon. The surgeon must at all times keep several ophthalmic microsurgical principles and rules in mind. The first princi­ ple is that time is trauma. With respect to ophthalmic ­tissues, the surgeon should be efficient and not waste time once the procedure has begun. Second, tissues should be handled as little and as efficiently as possible. The surgeon should not touch or grasp tissue unless they are ready to move the pro­ cedure forward, avoiding the mistakes of an inexperienced surgeon who often grasps, pushes, and pulls tissue as they contemplate the next maneuver. As with all surgeries, oph­ thalmic microsurgery procedures are composed of a series of

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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steps in sequence, each one designed to move the surgery forward toward the goal. The surgeon must be familiar with these steps, perform them economically, efficiently, and atraumatically, making no wasted movements and moving steadily forward toward the surgical goal.

History of Ophthalmic Microsurgery The use of magnification, provided by simple head loupes of limited optical power, to facilitate surgery first occurred in 1876 (Harms & Mackensen, 1967; Nasisse, 1997). Sub­ sequently, a monocular operating microscope was described for aural surgery in 1921 (Chacha, 1979), and the first oper­ ating microscopy for human ophthalmic surgery was described in 1950 (Perrit, 1950). This operating microscope was subsequently used to facilitate a superficial keratectomy (Perrit, 1952). The operating microscope was improved with the addition of coaxial illumination by the Carl Zeiss Company (Littmann, 1971), the invention of the X–Y mecha­ nism by Jose Barraquer, and a motorized zoom by Richard Troutman (1974). In veterinary ophthalmology in the 1960s, microsurgery was performed using head loupes. Operating microscopes were first used in the mid‐1970s (Gelatt, 2011a). Because of the high costs of operating microscopes, many veterinary ophthalmologists purchased and often still continue to pur­ chase used, refurbished operating microscopes. As more models and improvements became available, veterinary ophthalmologists in both specialty practices and academic institutions embraced microsurgery. The higher magnifica­ tions of the operating microscope permitted observations of the surgical fields never appreciated before, enhanced surgi­ cal success, and improved patient care. As microscopes became commonplace, instrumentation and sutures were refined allowing more precise, accurate, and atraumatic sur­ gery to be performed.

Magnification The goals of magnification are to provide an improved view of the tissues of concern, allow a comfortable working distance for the surgeon, facilitate adjustment of the interpupillary dis­ tance to suit the surgeon, and permit a wide field of view. The correct working distance should allow the surgeon to sit upright with their back straight and their arms at a 90‐degree angle at the elbow (Fig. 12.1). This will allow the surgeon to take advantage of armrests for stability, minimize neck and back fatigue, and thereby decrease hand tremors. The use of magnification is essential to ophthalmic surgery, and all oph­ thalmic procedures should be considered as requiring magni­ fication. The amount of magnification is adjusted to suit the

Figure 12.1  Surgeon seated at the operating microscope. The surgeon’s back is straight, he is leaning forward slightly and his arms are bent at a 90‐degree angle with his arms resting on armrests attached to the surgical chair and his hands on the vacuum pillow surrounding the patients head (insert).

procedure with the use of surgical loupes appropriate for many eyelid and adnexal procedures whereas a microscope would be preferred for all corneal and intraocular procedures. It is essential to train young surgeons to use magnification for all ophthalmic surgery at the start of their training program. It will greatly improve their tissue handling and appreciation for tissue trauma and wound apposition. In addition, it is easier to begin with magnification at the start of their ophthalmic sur­ gical career than to try and relearn its use later when presbyo­ pia arrives and it becomes impossible to perform even the simplest adnexal surgeries without magnification. Finally, surgeons should be trained to use appropriate types of magni­ fication, avoiding the ­inexpensive and frankly inappropriate simple loupes like the  Optivisor® (Donegan Optical Co., Lenexa, KA, USA). Although the operating microscope is the recommended standard for current veterinary ophthalmic microsurgery worldwide, their use is largely confined to the operating room.

Head Loupes Head loupes are a less expensive, portable alternative to the operating microscope (Jarrett, 2004; Spaeth, 1990a). Choosing the correct surgical loupes for the application involves several factors, including resolution, working dis­ tance, field of view, depth of field, magnification, weight of the loupes, and the surgeon’s interpupillary distance (Baker & Meals, 1997; Pieptu & Luchian, 2003). As a

e­ general rule, as magnification of the loupes increases, the depth of field and field of view decreases (Stanbury & Elfar, 2011). Also, the longer the working distance, the greater the field of view. The larger the field of view, the less the surgeon will need to turn their head or manipulate the tissues. It is also important to consider the weight and fit of loupes. Lightweight loupes are more comfortable for longer periods of use, and they are less likely to slide down the surgeon’s nose as they work. If loupes are to be used, they should be of high optical quality (Nasisse, 1997). Resolution determines the amount of fine details that can be distinguished. The type of glass used in the lenses and coatings applied to it can affect the resolution of the loupes. To test a set of loupes, look through them at a piece of graph paper. Notice color distortions or curvature of the lines. A high‐resolution loupe will have crisp, straight lines. The lines, seen through lower quality lenses, will be slightly blurred and curved. The working distance is the distance at which the loupes will focus (Baker & Meals, 1997). The working distance must be equal to the distance from the loupe lens to the top of your subject. Each loupe has a defined working distance, but the working distance each surgeon requires will depend upon their height, posture, and table height. The working distance is also affected by whether the surgeon will be seated or standing (Baker & Meals, 1997) (Fig.  12.2 and Fig. 12.3). It is best to determine your personal desired work­ ing distance, and then choose a set of loupes that meets the surgeon’s criteria. In general, the taller the surgeon, the longer the working distance required. This will also be

Figure 12.2  The primary surgeon is seated and is using a pair of Zeiss Galilean 2.3× loupes. His arms are resting on the chair’s armrests and his hands on the vacuum pillow.

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Figure 12.3  Equine corneal surgery with all surgeons standing. The primary surgeon is wearing a pair of Zeiss prismatic 4× loupes whereas the assistant surgeons are wearing Heine 2.5× Galilean loupes (Heine Optotechnik, Herrsching, Germany). The surgeon is stabilizing his hands on the patient’s head.

affected by the surgeon’s own vision corrective requirements and whether they are wearing their corrective eyewear when using the loupes. Most loupe manufacturers are able to include the surgeon’s visual prescription in the loupe should this be desired. The area that is in focus when viewed through the loupes is the field of view (Baker & Meals, 1997). The longer the working distance of a loupe, the greater its field of view will be. Likewise, the lower the magnification factor, the larger the field of view. This trade‐off must be considered carefully when choosing loupes. As a general rule, for every 30% increase in magnification, the width of field is decreased by approximately 2.5 cm (Baker & Meals, 1997). When using a Galilean loupe, the center of the image is clear, but the outer rim of the image is blurred, thereby decreasing the available field of view. With prism loupes, the image is sharp to the very edge of the field of view. Like the field of view, the depth of field is directly related to the working distance and magnification factor. The depth of field is the amount of depth that is in focus when viewing the subject through the loupe (Baker & Meals, 1997). Greater depth of field is preferred, because you can see deeper into the subject without repositioning. For greater depth of field, choose a loupe with a longer working distance or a lower magnification factor. In ophthalmic surgery, this is less important because the tissues of concern (eyelids, conjunc­ tiva, cornea) do not require much depth of field. Head loupes are available in magnifications from 2.0 to 8.0× and can be mounted on glasses or a headband system (Baker & Meals, 1997) (Fig.  12.4). The least expensive and poorest quality loupes are the simple loupes, an example of which is the Optivisor®. Simple loupes consist of one pair of

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Figure 12.4  Zeiss prismatic loupes mounted on a headband and Zeiss and Heine Galilean loupes mounted on an eyeglass frame.

positive meniscus lenses and are limited by spherical aberra­ tion and color fringing (Baker & Meals, 1997). These are of plastic construction, have a fixed interpupillary distance, and a very short working distance. The short working dis­ tance results in poor surgeon body and arm positions and strain on the surgeon’s neck and back. The optical quality of the Optivisor® is poor, and except for limited fieldwork or very short procedures, use of these should be avoided if pos­ sible. Although simple loupes might be of historical interest and are acceptable for a general veterinarian who uses mag­ nification rarely, they are not appropriate for the specialist with advanced training and surgical skills who wishes to be taken seriously as an ophthalmic microsurgeon. There are several manufacturers of compound or Galilean‐ type loupes which are capable of providing up to 2.5× magni­ fication (Stanbury & Elfar, 2011) (Fig. 12.5). Galilean loupes use multiple lenses to offer magnification and are generally lightweight and less expensive. These are usually mounted on glasses, have an adjustable ­interpupillary ­distance, and the working distance varies so that the surgeon may select a loupe with a comfortable working distance for themselves. For greater magnification, up to 8.0×, prismatic loupes (Keplerian) are available and provide the highest optical quality available (Baker & Meals, 1997) (Fig. 12.6). Designed by Johannes Kepler, Kepler‐type prismatic loupes use a series of lenses and prisms to magnify the subject. These are similar in principle to low‐power telescopes (Stanbury & Elfar, 2011). They offer greater magnification, sharp resolu­ tion, and a greater depth of field. They are also heavier, more expensive, and have a longer tube or barrel to the loupe itself (Stanbury & Elfar, 2011). If magnification of 6.0× or higher is required, a microscope would be preferred because the shallow depth of field and surgeon’s head movements makes working more difficult at this higher magnification. Head loupes are most often used for microsurgery when operating microscopes are not available such as in the field or a large animal barn setting and for orbital and eyelid surgeries

Figure 12.5  Galilean surgical loupes. The loupes on the left are Heine 2.5× mounted on a plastic glasses frame (Heine Optotechnik, Herrsching, Germany) whereas those on the right are Zeiss 2.3× on a wire frame.

Figure 12.6  Prismatic surgical loupes. The loupes on the left are Heine 3.5× mounted on a plastic glasses frame (Heine Optotechnik, Herrsching, Germany) whereas those on the right are Zeiss 4.0× on a headband.

(see Fig. 12.2 and Fig. 12.3). Head loupes generally require a separate lighting source, although some models are now avail­ able with small lamps mounted on top of the telescope (Fig.  12.7). In general, most veterinary ophthalmologists should have a personal set of loupes adjusted to their interpu­ pillary distance and that suit their working distance. If possi­ ble, a surgeon should have two sets of loupes: one, a lower magnification Galilean‐type, and the other, a higher magnifi­ cation prismatic loupe. This will allow the surgeon to choose the loupe and magnification that suit the procedure and tissue of concern.

Microscope The surgical microscope is capable of providing magnifica­ tion from 5× to 40× (Stanbury & Elfar, 2011). For ophthal­ mic microsurgery, magnification of 5–20× is generally sufficient. Although microscopes are vastly superior to the

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Figure 12.7  Zeiss 5.0× prismatic loupes with a light source and fiberoptic cable attached.

magnification provided by loupes, there is an increase in ini­ tial cost and maintenance, longer surgical setup time, less intraoperative positioning flexibility, and less portability (Stanbury & Elfar, 2011). There are several manufacturers of operating microscopes, but the most common and best qual­ ity are made by Zeiss, Leica, Wild, and Topcon. Modern operating microscopes have coaxial illumination, variable magnification, motorized zoom, focus, and X–Y axis adjust­ ments. Light is provided by a halogen‐tungsten lamp and fiberoptic coaxial illumination (Fig. 12.8). Foot controls are most often used to adjust the light, magnification, zoom, focus, and X–Y axis (Fig. 12.9). The microscope itself can be mounted on the table, a floor stand, or the ceiling. Modern operating microscopes can accommodate multiple surgeons and have the ability to add a still or video capture system for documentation and teaching. In addition, other delivery devices such as surgical lasers may be attached to the operat­ ing microscope providing flexibility to perform additional surgical procedures (Fig. 12.10). Keep in mind that as addi­ tional components are added to the operating microscope, the surgeon must be certain the microscope arm can support this added weight and the arms balance must be adjusted accordingly. There are also head‐mounted operating micro­ scopes that provide portability but have the issues of weight and associated neck strain, the need for the surgeon to hold their head completely still, and no assistant surgeon visibil­ ity (Fig. 12.11). The magnification of head‐mounted micro­ scopes is less (2.0–9.0×) than that provided by traditional operating microscopes. They are available with both foot control and video capability. The standard operating microscope used by most veteri­ nary ophthalmic surgeons is mounted on a floor stand with wheels to allow some degree of movement within the operat­

Figure 12.8  Headpiece of a Zeiss OPMI microscope® with a primary surgeon, assistant surgeon, and an HD video camera attached. The surgeon attaches sterile microscope handle covers to the silver microscope handles on the right and left side of the microscope column.

Figure 12.9  Foot control for a Zeiss operating microscope®. The surgeon controls zoom at the heel of the foot, focus at the ball of the foot and X–Y axis at the toe of the foot. The surgeon also controls an on/off switch for the microscope light.

ing room. Although these units are mobile, moving them out of the operating room and to another part of the hospital is discouraged and may result in damage and misalignment of the optics. Attached to the floor base are several articulating arms that support the optical heads and allow movement and positioning over the eye (Fig. 12.12). Each moving arm has a

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Figure 12.10  Headpiece of a Zeiss OPMI microscope® with an Iris Medical diode laser delivery device® attached to its base (large arrow). Note that a protective filter has also been installed in the microscope column to protect the surgeon and assistant surgeon (small arrow).

Figure 12.12  Zeiss OPMI microscope® with articulating arms mounted on a floor stand.

Figure 12.11  The Varioscope® (Leica Microsystems Inc., Buffalo Grove, IL, USA) M5 head mounted microscope from AcriVet is shown. This microscope has a capability of 2.0–9.0× zoom and has a video camera attached.

tension adjustment (pressure screw) that allows the surgeon to move the microscope into position and then lock it in posi­ tion or leave the tension less tight, allowing further position adjustments once the patient is positioned. The tension or pressure adjustment should be such that the microscope may be moved and repositioned manually during surgery, but tight enough to avoid drift and keep the microscope in the

position the surgeon places it. Gross focus should be done manually, moving the microscope head into position and reserving the motorized fine focus for use during surgery. The optical heads consist of several components. There will be a primary surgeon’s eyepieces and then if equipped, a beam splitter, permitting observation by one or more assis­ tant surgeons, and/or an image capture device. Generally, the assistant surgeon will be seated 90 degrees from the primary surgeon (see Fig. 12.8). Although the beam splitter does allow the assistant to see the same image as the surgeon, they are not permitted stereopsis in this position. Additionally, the beam splitter will allow a video and/or still camera to be attached, allowing viewing on a television screen and docu­ mentation of the procedure. If the operating microscope is to be used for laser procedures, a filter must be installed in the optical path to protect the surgeon and assistant surgeon (see Fig. 12.10). Most current operating microscopes have a con­ tinuous motorized zoom that is controlled by a foot pedal (see Fig. 12.9). Some older or less expensive models may have a fixed step magnification that requires manual changes. The objective lens and surgeon’s eyepieces may be changed to adjust the focal length and magnification. The focal lengths available range from 150 to 400 mm. Base objectives with shorter focal lengths increase the magnification, but reduce the microscope’s working distance (between the

patient’s eye and base of the microscope and objective lens). Most ophthalmic surgeons will choose a focal length of 175 mm which provides a comfortable working distance for most animals (Gelatt, 2011a; Nasisse, 1997). The surgeon’s oculars would most commonly have a magnification power of 10× or 12.5× (Gelatt, 2011a; Nasisse, 1997). The magnifi­ cation for the surgeon and other viewing systems provided by the operating microscope is determined by the focal length of the binocular tubes, the focal length of the objec­ tive, the optical power of the oculars, and magnification changer according to the following formula (Chacha, 1979; Hoerenz, 1980; Murray, 1986; Nasisse, 1997): Magnification Focal length of binocular tubes Focal length of the objective magnifying power of the eye pieces magnification power of magnification changer. Prior to beginning any surgery, both the patient and the microscope must be properly positioned and adjusted (Fig. 12.13). The microscope must be set so that the X–Y axis is centered, the magnification set to the lowest setting, and the focus zeroed or set to neutral to permit maximum up and down fine focus. For most microscopes, the X–Y may be zeroed by pushing a small button on the top of the X–Y motor­ ized box. The fine focus is zeroed using the foot pedal to align the focus dots usually located on the right side of the micro­ scope column to ensure full range of up and down fine focus control during surgery. The interpupillary distance is set for each surgeon, and the microscope, surgical table and surgical chair, and armrest heights are adjusted to ­accommodate the Figure 12.13  Prior to surgery, the microscope, surgical chairs, and all other required equipment are positioned and adjusted. In this photo, an Alcon phacoemulsification machine® (Alcon, Fort Worth, TX, USA) and Stryker video image system® (Stryker, Kalamazoo, MI, USA) are also positioned where the surgeon requires them.

primary surgeon. Once the eyepiece objectives are zeroed, the primary surgeon should ensure the assistant surgeon and video camera are all in focus when the primary surgeon is in focus. This should be checked and verified at the highest magnification that will be used during the procedure. The foot pedal is positioned where the surgeon can easily reach it and it can be on either the right or left side according to the surgeon’s preference. If multiple foot pedals are required, as in the cases of phacoemulsification, vitrectomy, endocyclo­ photocoagulation (ECP), or other laser procedures, it is com­ mon for the microscope foot pedal to be controlled using the nondominant foot. Many surgeons choose to remove their shoes to allow them to feel the foot pedal more accurately. The foot pedal will have a middle rocker bar or foot rest, allowing the foot to be rested on the pedal and tipped forward or backward and left and right to control the fine focus and zoom (see Fig. 12.9). The X–Y axis joystick sits at the front of the foot switch. The primary surgeon must be familiar with the microscope foot switch and where the controls are so that its adjustment becomes intuitive during the surgical proce­ dure. The surgeon must also use the features of the micro­ scope, increasing and decreasing magnification, and adjusting focus for various steps of the procedure to improve visualization and outcome. Failure to adjust the microscope during various steps of a surgery would be like purchasing an expensive manual sports car and driving only in first gear. Your money was not well spent and you are failing to get the maximum output from the equipment. Remember, as magni­ fication is increased, the field of view and depth of field will be decreased. The depth of field at 3.5× is 2.6 mm whereas at 20×, the depth of field is markedly reduced to 0.4 mm (Spaeth, 1990a; Troutman, 1974). The diameter of the operating field

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of view also changes with increasing magnification with a diameter of 50 mm at 3.5× reduced to only 10 mm at 20× (Spaeth, 1990a). When the patient is placed on the surgical table, the patient, head, and eye are positioned according to surgeon’s prefer­ ence. In general, the animal will be in lateral recumbency with the head flexed and the cornea parallel with the floor and looking up into the microscope. Some surgeons will pre­ fer to place the patient in dorsal recumbency with the head tilted to the side. Sandbags and vacuum pillows are used to ensure the patient and the head do not move during the pro­ cedure (Fig. 12.14). Once the patient is draped, sterile han­ dles (Fig. 12.15) or a sterile microscope drape (Fig 12.16) are

Figure 12.16  A sterile microscope drape is used to provide the surgeon access to the microscope handles during surgery. (Photograph courtesy of John Sapienza.)

Figure 12.14  A vacuum pillow designed to allow the surgeon to position the patient’s head and, by evacuating the air, custom fit the pillow to each patient and maintain stability and position during the surgery. The surgeon may also use the pillow to rest and stabilize their hands.

attached to the operating microscope and the microscope is manually adjusted up or down for gross focus. Do not use the foot switch or fine focus at this time. Once seated, if required, the surgeon makes final adjustments to the table and chair height, and gross focus on the microscope (Fig. 12.17). The microscope light is turned on, and most surgeons will then choose to turn off the operating room lights that illumi­ nate the patient, leaving on only the light that illuminates the instrument table. This will provide the best view of the surgical field and minimize reflection and glare associated with nonessential illumination. To minimize the possibility of retinal phototoxicity, the light intensity on the microscope should be set to the lowest level acceptable and turned on only when required.

Anesthesia

Figure 12.15  Sterile handles for the Zeiss OPMI microscope® to allow the surgeon to maneuver and manipulate the microscope during surgery.

At the time of, or immediately prior to anesthesia, depend­ ing on the procedure, many surgeons will choose to admin­ ister a systemic anti‐inflammatory and/or an intravenous antibiotic. Inflammation results from surgical trauma and is best prevented or minimized by preoperative anti‐inflamma­ tories and atraumatic surgery. Despite our best efforts, the ocular surgical field is a contaminated one, and so intrave­ nous antibiotics at the time of surgery are indicated when the surgery invades the intraocular tissues. If additional topical medications are required immediately prior to sur­ gery, solutions rather than ointments should be used. Although some ophthalmic surgical procedures can be performed with sedation and local nerve blocks, especially in large animals, microsurgery requires general anesthesia. Inhalation anesthesia with or without the use of nondepo­ larizing neuromuscular blocking agents is the standard of care for most ophthalmic microsurgical procedures. The use

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of neuromuscular blocking agents provides excellent globe exposure and will minimize globe compression as a result of extraocular muscle tension. Use of these agents is routine and standard of care for both small animal and equine cor­ neal and intraocular surgery. The most commonly used neu­ romuscular blocking agent, atracurium besylate (0.2 mg/kg dog and cat; 0.02–0.06 mg/kg horse), administered intrave­ nously, will provide approximately 20–25 minutes of paraly­ sis. If needed, a second injection (at a dose of 0.1 mg/kg dog and cat; 0.025 mg/kg horse) may be administered for a bilat­ eral procedure. Once atracurium is administered, the patient must be manually ventilated or preferably placed on a mechanical ventilator. Although some surgeons may choose to administer a lower dose of a neuromuscular blocking agent, achieving adequate globe position without respiratory paralysis, these animals must still be ventilated to avoid res­ piratory acidosis (Sullivan et al., 1996). The effects of atracu­ rium may also be reversed at the end of a short procedure by administration of edrophonium 0.5 mg/kg or neostigmine 0.02 mg/kg intravenously. An anticholinergic (glycopyrro­ late 0.02 mg/kg IV or atropine 0.04 mg/kg IV in small ani­ mals; glycopyrrolate 0.005 mg/kg IV in horses) should be administered concurrently with neostigmine.

Surgeon Positioning When performing ophthalmic microsurgery, the surgeon should be seated when possible. Prior to initiating surgery, the patient and the surgeon should be positioned to ensure access to the surgical field while providing the surgeon with a stable and comfortable environment. A surgical chair with adjustable armrests, preferably ones that can be

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Figure 12.17  Intraoperative photograph during phacoemulsification. The primary and assistant surgeons are seated, the surgeon’s arms and hands are stabilized, sterile microscope handles are attached to the microscope, the video is turned on, and the majority of the operating room lights have been turned off.

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Figure 12.18  Two hydraulic surgical chairs. The chair on the left with two armrests is used by the primary surgeon. The chair on the right is used by the assistant surgeon and the single arm rest is positioned in front of the surgeon. The armrests must be covered by sterile covers such as a mayo stand cover.

covered with a sterile drape or mayo stand cover, is essen­ tial (Fig.  12.18). The chair height should be able to be adjusted using a hydraulic foot pedal so that the surgeon can change this during surgery. A second chair, with adjust­ able height for the assistant surgeon, should also be used, but does not require armrests (see Fig.  12.18). When the surgeon is seated and the chair, armrests, surgical table, and microscope are adjusted properly, muscle strain on the surgeon’s back, neck, and arms is minimized, allowing sta­ ble and controlled hand and finger movements (Nasisse, 1997). The surgeon’s back is straight, they should lean

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Table 12.1  Microsurgical presurgical surgeon checklist. Adjust chair height Adjust chair armrest position

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Adjust table height Adjust microscope height Set microscope fine focus to neutral Center X–Y axis Adjust microscope tilt Adjust interpupillary distance Set microscope to highest magnification to be used Adjust focus of oculars Ensure video and assistant images are also in focus Return microscope to low magnification Place foot pedals to be comfortably accessible Source: Modified from Nasisse, M.P. (1997) Principles of microsurgery. The Veterinary Clinics of North America. Small Animal practice, 27, 987–1010.

slightly forward with their arms resting at a 90‐degree angle and their hands stabilized with the wrists straight, allowing precise finger movements to control the surgical instruments (Macsai, 2007) (see Fig.  12.1). The optics on the microscope can also be tilted to suit the surgeon. The chair height should also allow for comfortable placement of the surgeon’s legs and feet so that the foot pedals for the microscope and phacoemulsification, vitrectomy, or ECP units are accessible and able to be manipulated comforta­ bly. When not using the foot pedal, the surgeon’s feet are either flat on the floor or resting on the foot pedal. Once the surgery begins, the surgeon will typically lean forward slightly with the forearms resting to the level of the wrist on the armrest and the hands further supported on the vac­ uum cushion or patient (Fig. 12.17). The hands may be sup­ ported in this manner by resting the ball of the hand or extending the outside fifth finger for support. This will minimize hand tremor and allow for precisely controlled finger movements. For surgeons just beginning microsur­ gery, it helps to have a checklist of preparation steps to be performed prior to surgery (Table 12.1).

Patient Preparation and Globe Positioning Pre‐ and perioperative medications will vary depending on the procedure to be performed. Typically, topical antibiotics, anti‐inflammatories and mydriatics are administered start­ ing a few hours to days prior to most corneal and intraocular surgery. Systemic antibiotics and nonsteroidal anti‐inflam­ matory drugs are often administered in the immediate perio­ perative period for adnexal, corneal, and intraocular surgery.

Specific medication protocols are found in the subsequent chapters by area of surgical interest. Prior to surgery, depending on the procedure, the patient should be gently clipped to remove the adnexal hair. Avoid abrasions or excessive trauma to the periocular tissue that will result in patient irritation and rubbing after surgery. Avoid all surgical disinfectants containing alcohol or chlo­ rhexidine diacetate because they are extremely toxic to the cornea and conjunctiva (Fowler & Schuh, 1992). The perio­ cular tissues and globe can be rinsed and aseptically prepped using a repeated application of dilute 0.5% povidone iodine solution (1:20 dilution) followed by a gentle saline rinse (Gelatt, 2011a; Roberts et  al., 1986). This procedure is repeated for at least 2 minutes ensuring the cornea and con­ junctival cul‐de‐sac are gently irrigated. Once the patient has been positioned on the surgical table, a 10% povidone iodine swab may be used to paint the eyelids but must not come in contact with the cornea or conjunctiva. Use of oint­ ments on the surgical eye is avoided because they interfere with the surgeon’s view and are potentially irritating to the intraocular tissue. Protective ointments are advised, how­ ever, for the contralateral eye in cases of unilateral surgery. If a retrobulbar block is to be used, this is generally admin­ istered at the time of initial clipping and sterile preparation (Gelatt, 2011a). Again, depending on the procedure and surgeon prefer­ ence, the patient is most typically placed in lateral recum­ bency with the head at one end of the table where the surgeon will be seated. Some surgeons will prefer to place the patient in dorsal recumbency with the head tilted to the side. The head and neck are rotated so that the eye is looking up into the operating microscope and the cornea and eyelid are parallel to the floor. Sandbags and U‐shaped vacuum pil­ lows may be used to help stabilize the head position and ensure it remains stable throughout the procedure (see Fig.  12.14). If needed, ropes and tape can also be used to ensure patient position remains stable throughout the proce­ dure (Fig. 12.19). The anesthesiologist will typically need to be at the opposite end of the table from the surgeon. To avoid kinking of the airway, a right‐angle insert is placed at the end of the endotracheal tube and connected to the anesthetic tube or a guarded endotracheal tube is used. All monitoring equipment and access ports for the patient should be placed so that the anesthesiologist may access them without dis­ turbing the surgeon and surgical field. The anesthesiologist should avoid using the end of the surgical table during the surgery because contact with the table will result in signifi­ cant movement and disturbance of the surgical field under the operating microscope. For corneal and intraocular pro­ cedures, many surgeons will choose to use a nondepolariz­ ing neuromuscular blocker to facilitate globe position and minimize risks of movement. The anesthesiologist should therefore be prepared to manually or mechanically ventilate the patient and to monitor the PO2 and end tidal PCO2 to

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Figure 12.19  A patient has been positioned in lateral recumbency. The cornea and eyelids of the superior eye are positioned parallel to the floor, looking up into the microscope, and the vacuum pillow is secured.

ensure adequate ventilation. Most nondepolarizing agents will have an effect in 30–60 seconds after administration with a duration effect of 20–25 minutes so they should be administered accordingly. Horses are managed and positioned much the same as dogs (Gelatt & Wilkie, 2011). If the operation is for one eye only, the horse may be positioned in lateral recumbency and the head and eye rotated to permit the cornea to be as parallel as possible to the floor and looking up into the operating microscope’s objective lens (Fig. 12.20). To stabi­ lize and cushion the head and keep the ventral eye from laying on the operating table, the author uses a partially inflated inner tube (Fig. 12.21). For bilateral eye surgeries, the horse is positioned in dorsal recumbency and the head rotated to permit the operative eye to be as parallel to the operating microscope’s objective as possible. Globe posi­ tion can be more difficult to maintain in equine ophthal­ mic surgery as the eye position varies during the surgery with changes in the plane of anesthesia. Horses are gener­ ally maintained at a lighter plane of anesthesia compared with small animals and so changes in globe position throughout the surgery are common. As the horse’s extraocular muscles are so massive, globe movement and deformation may occur during intraocular procedures under general anesthesia if the horse is light. During cata­ ract surgery, the anterior chamber may collapse, the poste­ rior lens capsule may move anteriorly and even rupture, permitting vitreous presentation. Hence, administration of neuromuscular blocking agents followed by mechanical ventilation in horses undergoing corneal and intraocular surgeries is highly recommended. Alternately, if mechani­ cal ventilation is not possible, a retrobulbar nerve block

Figure 12.20  A horse being prepared for unilateral phacoemulsification. The horse is in lateral recumbency with the microscope, Oertli phacoemulsification machine® (Oertli, Berneck, Switzerland), and Stryker video setup® (Stryker, Kalamazoo, MI, USA) in position.

may be performed prior to the procedure to paralyze the extraocular muscles and stabilize the globe. Once positioned and prepped, the patient is sterilely draped using water repellant disposable paper drapes or disposable adhesive drapes according to surgeon prefer­ ence. For ocular surgeries using significant fluid, such as

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Figure 12.21  A partially inflated inner tube is used to cushion the horse’s head and prevent the down eye from laying on the operating table during surgery.

Figure 12.22  A disposable, sterile sticky drape with a fluid collection bag designed to collect excessive fluid during surgery. (Photograph courtesy of John Sapienza.)

phacoemulsification, sterile sticky drapes designed to col­ lect excessive fluid are available (Fig 12.22). Care is taken to avoid external pressure on the globe or adnexal structures by the drapes. Such pressure may result in collapse of the anterior chamber, extrusion of viscoelastic material, iris prolapse, or vitreous expansion during surgery. Care is also taken during surgery to make certain the drape position has not shifted, resulting in pressure on the globe. External forces to the globe may also be created by an eyelid specu­ lum that is improperly placed or is of the incorrect size.

To assist with hemostasis and decrease swelling, topical epinephrine (1 : 1000 to 1 : 10,000) may be applied to the cor­ nea and conjunctiva prior to initiating the surgery. This will vasoconstrict the conjunctival vessels, minimize bleeding, and decrease fibrin and swelling postoperatively. It can be used in virtually all ophthalmic procedures and will help to maintain a blood‐free surgical field. If needed, one or more stay sutures may be placed to facili­ tate globe position and manipulation. Stay sutures are placed adjacent to the limbus and should be placed to hold deep to the conjunctiva, involving the episcleral tissue. If a single stay suture is used, it should be placed just posterior to the ventronasal limbus to both rotate the globe upward and dis­ place the nictitans downward and out of the surgical field. Additional stay sutures are placed according to the proce­ dure to be performed and field of view required. Once placed, a serrefine or other small clamp is attached to the ends of the stay suture for manipulation. If additional expo­ sure is required, a lateral canthotomy may be performed to increase exposure and reduce eyelid tension on the globe. It is more common for novice surgeons to perform a lateral canthotomy with its use decreasing with increased experi­ ence. A lateral canthotomy is perhaps most commonly indi­ cated for terriers with small palpebral fissures requiring a large corneal incision to manage a lens luxation. During the entire surgical procedure, the cornea and ocular tissues must be kept moist. This is generally a task for the assistant sur­ geon. Balanced salt solution or sterile saline is typically used for this purpose and applied using a small irrigation bottle and an irrigating cannula every 20–30 seconds. Following surgery, the patient should have a calm recov­ ery. The patient may recover in lateral recumbency with the operated eye up or in sternal recumbency for bilateral proce­ dures. A cold compress may help decrease hemorrhage and swelling after eyelid and adnexal procedures. Some surgeons will choose to place a temporary, partial tarsorrhaphy suture for corneal and intraocular procedures as a means to decrease exposure and protect the surgical site. Elizabethan collars, exercise restriction, and systemic nonsteroidal anti‐ inflammatory drugs are common after most ophthalmic sur­ geries. In horses, a subpalpebral lavage delivery system may be placed at the end of the surgery to facilitate postoperative medication.

Instrumentation With the evolution of microsurgery, it became apparent that standard ophthalmic instruments were too large as viewed under the operating microscope, and needed to be reduced in size to function at higher magnifications, but still large enough to be easily held by surgeons. Using standard instru­ ments viewed through the operating microscope, incisions, tissue manipulations, and wound ­appositions were crude

12: Fundamentals of Ophthalmic Microsurgery

Table 12.2  Basic ophthalmic microsurgical pack. Eyelid speculum – Barraquer wire in several sizes Forceps – Brown‐Adson Colibri utility 0.3 mm and 0.5 mm Bishop‐Harmon fine teeth Castroviejo scleral fixation Tying forceps Scissors – Stevens tenotomy – blunt, curved Westcott tenotomy – blunt, curved Needle holders – Barraquer type medium and heavy curved nonlocking, rounded, and knurled handle Derf or Alabama‐Green Desmarres chalazion clamp Jaeger eyelid plate Calipers – Jameson, Castroviejo Carter sphere introducer Muscle hooks Irrigating cannulas – 21, 23, 27, 30 gauge Beaver and Bard Parker blade handles Mosquito hemostats Martinez corneal dissector Serrefine clamps Cyclodialysis spatula

Table 12.3  Basic corneal/intraocular ophthalmic microsurgical pack. Eyelid speculum – Barraquer wire in several sizes Forceps – Colibri utility 0.12 mm and 0.3 mm Bishop‐Harmon delicate teeth Castroviejo scleral fixation Utrata capsulorhexis Intraocular lens folding McPherson tying – straight and angled Scissors – Stevens tenotomy – blunt, curved Westcott tenotomy – blunt, curved Vannas – curved with a sharp tip Right and left corneal section scissors Intraocular Needle holders – Barraquer type delicate and fine curved, nonlocking, rounded, and knurled handle Lens dialer/manipulator Phaco chopper Calipers – Jameson, Castroviejo Lens loop Irrigating cannulas – 21, 23, 25, 30 gauge Beaver blade handles Martinez corneal dissector Serrefine clamps Cyclodialysis or iris spatula

orbital procedures and several major ophthalmic microsur­ gical packs designed for cornea, cataract, and other anterior segment procedures. A basic ophthalmic pack will typically contain an eyelid speculum (Barraquer wire in several sizes) (Fig. 12.23), forceps (Brown‐Adson, Colibri, Bishop‐Harmon, scleral fixation, tying), scissors (Stevens and Westcott ­tenotomy), needle holders (large and small curved, nonlock­ ing Barraquer type, and Derf or Alabama‐Green type), Desmarres chalazion clamp (Fig. 12.24), Jaeger eyelid plate (Fig.  12.25), calipers (Jameson, Castroveijo) (Fig.  12.26), Carter sphere introducer (Fig. 12.27), muscle hooks, irrigat­ ing cannulas, and Beaver and Bard Parker blade handles (Fig. 12.28). Additional instruments may include mosquito hemostats, Martinez corneal dissector (Fig. 12.29), serrefine clamps (Fig. 12.30), cyclodialysis spatula, and other specific instruments according to the surgeon’s preference. For a microsurgical corneal/intraocular pack, many of the same instruments will be included, but will have more delicate teeth and jaws. Additional instruments in a microsurgical pack may include intraocular scissors and forceps such as the Vannas scissor and Utrata forceps, lens loop, intraocular lens (IOL) forceps, IOL manipulators, phaco choppers, or other specific instruments according to surgeon preference.

SECTION II

and inexact, and tissue trauma was severe. The bright illu­ mination of the microsurgical operative field also requires the finish to be modified so the micro instruments do not reflect light back into the surgeon’s eyes. In general, micro­ surgery instruments were developed by reducing the ­traditional or standard ophthalmic instruments by about one‐third. The traditional or standard ophthalmic ­instruments were reduced from about 150 mm to about 100 mm to accommodate a working distance of 150–175 mm between the patient’s eye and the base objective lens of the operating microscope (Gelatt, 2011a, 2011b). The size of the jaws, blades, or forceps tips were reduced further to permit ­atraumatic handling of the tissues, needles, and suture materials. The instrumentation used in ophthalmic microsurgery begins with a basic ophthalmic microsurgical pack for eye­ lids, orbit, and other adnexal procedures (Table  12.2), but will then expand to include specialized microsurgical packs for cornea, cataract, or posterior segment work (Table 12.3). Phacoemulsification, irrigation/aspiration and vitrectomy, cryosurgery, laser, wet field cautery, and vitreoretinal instru­ ments will often have their own surgical packs. The particu­ lar style of a specific instrument is often a matter of surgeon preference. Most surgeons will have several basic or minor ophthalmic surgical packs that will be used for adnexal and

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800

Figure 12.23  Barraquer wire eyelid speculums in adult and pediatric sizes.

Figure 12.27  Carter sphere introducer. Figure 12.24  Demarres chalazion clamp.

Figure 12.25  Jaeger eyelid plate.

Figure 12.28  Beaver handle with #64 blade (top) and Bard‐ Parker handle (bottom) with #15 blade.

Figure 12.26  Jameson (top) and Castroviejo (bottom) calipers.

Figure 12.29  Martinez corneal dissector.

Figure 12.30  Serrifine clamp.

Figure 12.31  Autoclavable plastic microsurgical tray to store and protect microsurgical instruments.

In addition, a drape pack containing towel clamps, drapes, scissors, and a sterile bowl are used so that these instruments are not wrapped with the more delicate ophthalmic instru­ ments. If vitreoretinal procedures are performed, this may require an additional set of microsurgical instruments. In addition, specialized packs for phacoemulsification or other procedures requiring specialized instrumentation may be indicated. Finally, if microsurgical procedures are to be per­ formed on large animals, specifically horses, then additional equine microsurgical packs may be kept. All microsurgical instruments should be stored in a specialized tray with a lid to protect them from damage and prevent them from con­ tacting each other (Fig. 12.31). Instruments that are not used on a routine basis should be wrapped and sterilized individ­ ually to minimize wear and tear on the instrument associ­ ated with cleaning and autoclaving. Immediately prior to initiating surgery, all instruments that will be required for the procedure should be selected, removed from the micro­ surgical tray, and arranged on the surgical table in the order they will be used (Fig.  12.32). Once used, they should be returned to the surgical table in the same order so both the surgeon and assistant surgeon can find them quickly. When selecting microsurgical instruments, the surgeon has a variety of choices in styles and qualities of materials and manufacturing. The length of the instrument, size of the teeth and jaws, angle of the jaws, length of the jaws, sharp versus blunt tips, straight versus curved, flat versus

rounded handles, serrated, six‐sided, or knurled handle grips, locking versus nonlocking, with or without a tying platform, with or without a pin stop, dull versus polished finish, stainless steel versus titanium are just a few of the decisions to be made (Gelatt, 2011b; Troutman, 1974). Instruments that are to be rotated in the surgeon’s fingers should be rounded or six‐sided whereas those that are used without rotating should have flat handles (Fig. 12.33). To prevent slippage during manipulation, instrument han­ dles are serrated, knurled, or six‐sided (Troutman, 1974) (Fig. 12.33). Many ophthalmic microsurgical instruments are hinged using an X or box hinge design and spring han­ dles as seen with Wescott tenotomy scissors or Barraquer needle holders. With spring handles, as the instrument is closed, the springs straighten, a pin stop prevents overclos­ ing, and then the springs return to the curved position opening the jaws as finger pressure is released (Fig. 12.33). To work correctly, finger pressure must be placed over the pin stop (Eisner, 1990). A bar hinge design is used for most microsurgical forceps. It is important to understand that not all stainless steel is of the same quality nor are all manufacturers equal in the quality of their product (Grevan, 1997). It is advisable to pur­ chase higher quality stainless steel or titanium instruments for selected instruments such as the most delicate tissue and tying forceps, needle holders, and scissors. Titanium is stronger and more corrosion resistant than stainless steel and will retain its sharpness longer. Some of these decisions are dependent on surgeon preference and cost whereas oth­ ers are made based on the use of the instrument and the tar­ get tissue. As is true for most things, you generally get what you pay for, and inexpensive microsurgical instruments of inferior quality will often corrode, break, or fail to grasp tis­ sue, needles, or suture correctly and so in the long‐term, do not save monies. The delicate nature of microsurgical instruments requires a change in the methods for cleaning and storage. Immediately after surgery, instruments should be gently cleaned by hand using a soft toothbrush or microwipe and distilled water. Cleaning must remove all blood, tissue, saline, and viscoelastic materials from the instruments. Residual materials such as viscoelastics, if not removed, could be a factor in toxic anterior segment syndrome or fibrin in subsequent cases. If an ultrasonic cleaner is to be used, great care must be taken to separate the instruments and prevent contact with each other during the cleaning procedure to avoid damage to the delicate tips. Once clean, instruments are sprayed/coated with surgical instrument milk to lubricate and protect from rust and corrosion and then placed in a specialized microsurgical protective tray with a lid (Fig.  12.34). Do not rinse the instrument milk; rather, leave it on for the sterilization process. Only after this process is complete and the instruments are safely sealed in the tray should the instruments be handed over

801

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Section II: Foundations of Clinical Ophthalmology

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Figure 12.32  Instruments arranged on a surgical table in preparation for routine phacoemulsification and IOL insertion.

Figure 12.33  Barraquer fine needle holders with rounded and knurled handles to facilitate rotation in the surgeon’s fingers and a pin stop (arrow) to prevent overclosure.

for steam sterilization. Although young surgeons may feel this is a task best given to others, it is very appropriate to instill an appreciation for the care and maintenance of the instruments by having the surgeon perform this task as they are learning. If cannulas are to be reused, they must be copiously irrigated with distilled water followed by air. For other more specialized instruments such as the phacoe­ mulsification and vitrectomy handpieces or ECP probe, the manufacturers’ directions for care, cleaning, and mainte­ nance should be followed. In general, any instrument with a lumen for irrigation/aspiration will need to be rinsed and again distilled water followed by air to dry is appropriate. Tips may be cleaned with a soft toothbrush or a delicate instrument sponge or surgical spear. There are also special­ ized systems such as the QuickRinse® (Advanced Optisurgical Inc., Lake Forest, CA, USA) that are specifi­ cally designed to flush debris from phaco and irrigation

Figure 12.34  Microsurgical pack with instrument milk to lubricate and prevent corrosion.

and aspiration handpieces, cannulas, vitrectomy cutters, reusable tubing, and any other microsurgical instruments with a lumen, using automated pressure rinsing and air drying cycles. It is essential to note that instruments with a lumen that are rinsed must be steam autoclaved because gas sterilization will not penetrate any residual liquid in the lumen and thus will not adequately sterilize these instruments. Additional ophthalmic microsurgical instrumentation may include a cryosurgical unit for eyelid and lens luxation procedures, phacoemulsification machine with irrigation, aspiration, phacoemulsification, and vitrectomy abilities, wet‐field cautery, diode laser with indirect, transscleral,

12: Fundamentals of Ophthalmic Microsurgery

SECTION II

microscope, intraocular, and endocyclocoagulation attach­ ments, CO2 laser, fluid–gas exchange pumps for vitreoretinal surgery, viscous oil injection and aspiration, corneal donor and recipient trephine devices for corneal transplantation, and other additional instrumentation depending on the sur­ geon’s interest and capabilities.

Instrument Handling As ophthalmic microsurgery requires extremely delicate and precise tissue and instrument manipulations, only fin­ ger movements are required. As a result, the instruments are held in a pencil‐like grip and the hands and arms are supported by armrests, the surgical table, vacuum cushion, or the patient (see Fig. 12.17). The wrist and elbows are sta­ ble and locked when using the pencil‐like grip, and only finger movements are used. To be more specific, microsur­ gical instruments held in a pencil‐like grip are supported by resting against the first metacarpophalangeal joint of the first finger with the fingertips of the thumb and first finger used to control and rotate the instrument (Macsai, 2007) (Fig. 12.35). Hand stability is provided by resting the outside of the fifth finger on the vacuum pillow or patient’s periorbital tissues. The surgeon must resist the tendency to grasp the instruments tightly because this will decrease flexibility, fatigue the hand and forearm, traumatize tis­ sues, and damage instruments and needles. The palm grip, which is used to hold instruments in most other surgical procedures, does not allow for precise and delicate manip­ ulations (Fig.  12.36). The palm grip is designed to allow movement of wrists and elbows providing power, but not control. The palm grip, although appropriate for Stevens tenotomy scissors, is to be avoided in most delicate oph­ thalmic procedures.

Figure 12.35  Westcott tenotomy scissors held in a pencil grip.

803

Figure 12.36  The palm grip may be used for Stevens tenotomy scissors but is not indicated for most other microsurgery instruments.

Incision Blades Incisions for ophthalmic surgery should be precise, accurate, and atraumatic. Although historically, some surgeons chose to crush or clamp adnexal tissues in a hemostat prior to cut­ ting, this is unacceptable and results in excessive tissue trauma and scar formation. Although some may argue it provides hemostasis, it violates the rules of atraumatic sur­ gery and should be strictly avoided. Precise incisions may be performed using a blade or scis­ sors. In general, blades are used to initiate corneal and skin incisions and scissors may be used to complete the incision. For conjunctival incisions, scissors alone are most often used. To ensure a precise incision, the tissue must be stabi­ lized prior to initiating the incision. For eyelid incisions, sta­ bility may be provided by a Jaeger eyelid plate or a chalazion clamp (see Fig.  12.24 and Fig.  12.25). Bishop‐Harmon for­ ceps with fine teeth may be used to grasp eyelid skin. Eyelid incisions are most commonly performed using a No. 3 Bard‐ Parker handle and a No. 15 blade (see Fig. 12.28). For corneal incisions, the tissue is immobilized by grasp­ ing the perilimbal tissues using a Colibri forceps, and the incision is initiated using a #64 Beaver or similar type blade (see Fig. 12.28). The forceps should be positioned as close to the incision as possible and the blade moved away from or toward the forceps depending on surgeon prefer­ ence. If possible, the forceps should be positioned to ensure the entire incision may be completed without repo­ sitioning of the forceps because tissue trauma results from each grasp and release. When possible, incisions should be completed in one motion with respect to length and depth because repositioning of the blade will result in a jagged incision. The depth of the incision depends on the proce­ dure being performed. If the surgery requires entry into

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Section II: Foundations of Clinical Ophthalmology

the anterior chamber, the initial corneal incision should be >75% depth without penetrating the anterior chamber. This will make the entry wound easier and minimize the amount of tissue the corneal section scissors must incise. For phacoemulsification, a uniplanar or biplanar incision may be chosen according to the surgeon’s preference, most commonly a 2.8–3.2 mm biplanar incision created follow­ ing a deep 3.0–4.0 mm groove that will accommodate IOL insertion. Should it be required, enlargement of the wound using corneal section scissors can be performed. With deep corneal incisions, the surgeon may experience tissue chatter, which usually indicates a deep wound or a dull blade. If chatter is encountered, digital pressure should be slightly decreased. If this does not stop the chatter, the blade should be changed. Microsurgical blades for corneal procedures differ from traditional Bard‐Parker blades. Although the Bard‐Parker system may be used for orbit and adnexal surgery, it is not indicated for corneal and intraocular surgery. The Beaver microsurgical blade system is indicated for disposable cor­ neal knives. The most commonly used blades are the No. 64, No. 63, and No. 65 Beaver blades (Fig. 12.37). The No. 64 blade has a rounded tip, cuts on the tip and one edge, and is most commonly used to begin the corneal ­incision or for dissection of a keratectomy or corneo‐­ conjunctival transposition. The No. 65 or 63 blades have a sharp angled tip and may be used for the corneal entry. Alternatively, reuseable sapphire or diamond knives may be used for both corneal incisions and corneal entry inci­ sions (Fig. 12.38). Sapphire and diamond knives are most commonly used for phacoemulsification incisions to create a deep limbal groove followed by an entry incision with a precise width that corresponds to the phaco needle used. Although initially sapphire and diamond knives are more expensive, if cared for properly, these blades will last through many incisions and are much sharper and more precise than disposable blades.

Figure 12.37  A Beaver handle with a #64 blade is held. The #65 and #63 Beaver blades are also shown.

Figure 12.38  A 3.2 mm (top) and a round‐tipped (bottom) sapphire knives are shown.

Scissors Scissors may be used to complete an incision after an initial incision by a blade (cornea, skin) or may be used for the entire incision (conjunctiva, iris, lens capsule). Ophthalmic scissors vary in size, tip design, and handles. The tips of scis­ sors may be sharp, rounded or semirounded, and straight or curved (Grevan, 1997). Scissor handles may be ringed, hinged, or spring‐handled (Grevan, 1997) (Fig. 12.39). Ring‐ handled scissors are more traditional but should be used in a mini‐tripod grip with the index finger placed at the fulcrum for maximum control (see Fig. 12.36). Scissors are designed for specific purposes and a variety of scissors will be required. Common ophthalmic scissors include Stevens and Westcott tenotomy, right and left corneal section, and Vannas and intraocular scissors such as the Duet MicroSurgical Technology® (Microsurgical Technology, Redmond, WA, USA) system scissors (Fig. 12.39, Fig. 12.40, Fig. 12.41, and Fig. 12.42). Scissors are used both to cut and to dissect tissue. For dissection of conjunctival tissue to create a conjunctival graft, blunt‐tipped Stevens or Wescott tenotomy scissors are most common (see Fig. 12.39). More delicate scissors such as the Vannas are used to incise the anterior lens capsule or cut uveal tissue as seen with a uveal prolapse, iridectomy, or

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12: Fundamentals of Ophthalmic Microsurgery

Figure 12.39  Curved, blunt‐tipped, Stevens tenotomy scissors with ringed grips (top) and curved Westcott tenotomy spring‐ handled scissors (bottom).

Figure 12.40  Curved intraocular MicroSurgical Technology® (Redmond, WA, USA) scissors are shown. The insert shows use of the Microsurgical Technology forceps while performing a modified ab externo sulcus IOL fixation.

sphincterotomy (Fig.  12.41). Corneal section scissors are curved and designed to cut in either the right or left direction (Fig. 12.42 and Fig. 12.43). They should be used to complete a corneal incision after an initial deep groove has been made with a blade. Following an initial deep groove and entry into the anterior chamber, the lower blade of the corneal section scissors is inserted into the anterior chamber. Care is taken to avoid iris trauma. The scissor blades are aligned with the groove and the lower blade is elevated slightly to open the incision and allow the superior blade smooth entry into the groove. Corneal section scissors should not be closed completely during the cutting stroke, allowing them to remain in the incision and to be advanced without having to be repositioned in the eye. To facilitate this, many corneal section scissors come with a stop that is lifted to prevent complete closure as the scissors are advanced (Fig.  12.44). Once the end of the incision is reached, the stop is depressed, the scissors are closed completely, and may then be removed

Figure 12.41  Curved Westcott tenotomy scissors (top) and curved Vannas lens capsule scissors (bottom) both with pin stops to prevent overclosure.

Figure 12.42  Troutman‐Castroviejo corneal section scissors with a stop are shown in a pencil grip.

Figure 12.43  Right and left Troutman‐Castroviejo corneal section scissors.

atraumatically. If no stop is present, then the blades should be closed halfway, opened, and advanced to avoid the need to reintroduce the blade with each cut. Intraocular scissors are designed to be worked from outside the eye whereas the

Section II: Foundations of Clinical Ophthalmology

Figure 12.45  Storz® (Bausch and Lomb Storz, Manchester, MO, USA) intraocular scissors. The working movement of the scissors is outside the eye and is controlled using the thumb and index finger to control the action of the scissors inside the eye.

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806

Figure 12.44  Troutman‐Castroviejo corneal section scissors. In the upper image the thumb has elevated the stop, preventing complete closure of the blades. In the lower image, the thumb has lowered the stop, allowing complete closure of the blades.

s­ cissor action occurs inside the eye (see Fig. 11.40 and Fig. 11.45). These are most commonly indicated for two‐ handed capsulorhexis, a posterior capsulorhexis, sutured IOL, or vitreoretinal surgery.

Suture The function of the suture is to maintain apposition of the wound edges until the wound has attained sufficient strength to resist external forces (Macsai, 2007). The choices in suture material include absorbable versus nonabsorbable, braided versus monofilament, size of the suture, and size and type of needle. The surgeon must make the suture and needle selec­ tion based on tissue of interest, tensile strength of the tissue, the duration the suture will be required, suture pattern to be used, and whether the suture will be removed or remain (Nasisse, 1997). In general, monofilament sutures and non­ absorbable sutures will be less reactive than braided and absorbable materials. Nonabsorbable sutures, however, must

generally be removed at a later time. Although considered nonabsorbable, nylon loses its tensile strength beginning at 12–18 months, so for a more permanent suture as required for sulcus fixation of an IOL, polypropylene (Prolene®, Ethicon Inc., Somerville, NJ, USA) or sutures made from expanded polytetrafluoroethylene (Gore‐Tex®) would be the suture of choice. The suture selected should be of the small­ est size to achieve success, relying on delicate tissue handling, minimal tissue trauma, and excellent wound apposition to ensure primary intention healing with minimal reaction and scar. In general, most eyelid surgeries can be repaired in dogs, cats, and horses using 6‐0–7‐0 size suture whereas corneal surgery will work best with 8‐0–10‐0. Although historically, veterinary ophthalmic surgeons have relied on heavier gauge, absorbable suture material, this is not, in most instances, in the best interest of the outcome, and we must work instead to employ smaller, less reactive materials following the princi­ ples of microsurgery. Care must be taken to avoid suture trauma during suturing. The surgeon should avoid closure of instruments, such as forceps or needle holders, on suture material that will remain in the tissue. Closure of instru­ ments on the suture results in crimping and weakening of the suture that may result in breakage and wound dehiscence (Abidin et al., 1989). The most commonly used absorbable suture in veterinary ophthalmology is polyglactic acid (Vicryl®, Ethicon Inc., Somerville, NJ, USA) followed by polyglycolic acid (Polysorb®, Covidien, Mansfield, MA, USA) or polyester polydioxanone (PDS®, Ethicon Inc.). The first two are most commonly found as braided suture material and will elicit a tissue reaction, whereas PDS is a stiffer, longer lasting mono­ filament material. These are often used as buried sutures for orbital and adnexal procedures. If Vicryl or another absorb­ able suture is used in the cornea, to minimize irritation and tissue reaction, the smallest appropriate suture should be selected. In addition to this, there are two additional tech­ niques to minimize reaction and subsequent scar formation. The first is to remove the suture from the cornea once it is no longer required, for example, when blood vessels have crossed the incision or graft site. The second is to select Vicryl as a monofilament rather than a braided suture. This can be done at a suture size of 9‐0 or smaller. As a monofila­ ment, this suture will handle in a similar manner to nylon and will elicit virtually no tissue reaction as it dissolves. This

12: Fundamentals of Ophthalmic Microsurgery

diameter (Spaeth, 1990b). The volume of material in 7‐0 and 8‐0 sutures is 5× and 3× greater than in 9‐0, respectively (Spaeth, 1990b). The surgeon must realize this increase in suture volume will result in an increase in suture reaction and also an increase in knot size and associated irritation.

Suture Pattern The suture pattern will depend on the surgeon’s preference, tissue being apposed, suture material used, and health of the adjacent tissues. The objective of the suture is to appose and align the tissues to ensure wound healing. In the case of the cornea, a water‐tight seal is required and astigmatism is to be minimized. In general, for ophthalmic sutures, apposition is all that is required because tension is not usually a concern and minimal compression is needed. For more specific ­tissue‐related suture patterns, the reader is referred to spe­ cific chapters listed by tissue of interest. Corneal sutures may be placed using a simple interrupted or continuous pattern. Continuous patterns will include the various simple continuous, Ford‐interlocking, and double continuous patterns. Corneal sutures are placed to secure a conjunctival or corneo‐conjunctival graft, to close a corneal incision or laceration, or stabilize a corneal transplant. In general, simple interrupted sutures take longer to place, leave more knots behind, provide unidirectional tension vectors, and are more likely to leak or tear out. The com­ pressive or appositional effect of a simple interrupted suture is maximal only in the plane of the suture tract (Eisner, 1990; Nasisse, 1997). Lateral to the suture tract the compres­ sive effect diminishes, and the adjacent suture must be placed so that the compressive effects overlap to attain a water‐tight closure. The lateral extent of the compression effect may be increased by increasing the size of the suture loop within the cornea (Eisner, 1990; Macsai, 2007). The result is that the larger the suture loop, the fewer sutures that will be required (Fig. 12.46). When overtightened, sim­ ple interrupted sutures cause the posterior aspect of the wound to gape, resulting in leakage and the surgeon then

Table 12.4  Suture material size based as defined by the United States Pharmacopoeia (USP) code. USP designation

Collagen diameter (mm) B = Watertight closure

Leak

Leak

A < B = Wound leak

Figure 12.46  Zones of compression seen with simple interrupted sutures. Note how the different length of the suture bites alters the zones of compression. Failure to achieve overlap of the compression zones will result in wound leakage. (Source: Modified from Macsai, M.S. (2007) Ophthalmic Microsurgical Suturing Techniques. Berlin: Springer.)

attempting to compensate by placing additional and unnec­ essary sutures (Macsai, 2007). Simple continuous sutures take less time to place as com­ pared with interrupted, but may also result in lateral shift­ ing, and a break in the suture will allow significant wound dehiscence. Unlike interrupted sutures, the force vectors created by a continuous suture are not limited to the plane of the suture loop (Eisner, 1990). Simple continuous patterns may be varied to alter the vector effects. In general, a sym­ metric sawtoothed pattern will provide nearly even vector forces in all directions (Eisner, 1990; Nasisse, 1997). A dou­ ble continuous or counter suture pattern takes slightly longer to place and leaves more suture material, but has the advantages of even vector forces in all directions, a better water‐tight seal, less astigmatism, and better wound integ­ rity should a suture break occur. For accurate and stable clo­ sure of a corneal wound, a continuous double sawtooth pattern is best, followed by a symmetric sawtooth pattern (Fig. 12.47). The author prefers a double continuous pattern for corneo‐conjunctival transpositions and some conjuncti­ val grafts as well. If a simple continuous pattern is preferred, a Ford‐interlocking pattern will work well for closure of con­ junctival graft donor sites and may also be used for some conjunctival grafts themselves. Sutures are tied using instruments, preferably two tying forceps. For efficiency with larger suture materials, many surgeons will use the tying platform on the Colibri forceps and the needle holder to tie, but this should not be done on smaller sutures because it will damage the suture material. For suture 8‐0 and smaller, two tying forceps should be used. The McPherson tying forceps are most common and a straight and angle pair are best (Fig.  12.48). The surgeon must avoid over compression of these delicate forceps which will result in gaping of the tip and a failure to grasp the suture. A right‐handed surgeon holds the straight forceps in their left hand and the angled forceps in the right (Troutman, 1974). The left forceps wraps the suture around the right. The first knot is usually a double or triple throw with three single throws on top of this knot. Care is taken that the

A

B

C

D Figure 12.47  A. A simple sawtooth suture pattern. B. A symmetrical sawtooth suture pattern. C. A double sawtooth suture pattern. D. A symmetrical double sawtooth suture pattern. (Source: Modified from Eisner, G. (1990) Eye Surgery: An Introduction to Operative Technique. New York: Springer Verlag.)

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Figure 12.49  Large superior and inferior eyelid masses have been excised. Closure has been performed using 6‐0 polypropylene skin sutures. A figure‐eight suture pattern was used to align the eyelid margin followed by simple interrupted sutures. The ends of all sutures are left long and tucked under the subsequent suture to ensure they are directed away from the cornea. Swage

Needle point

Chord length

Figure 12.48  McPherson straight and angled tying forceps.

suture is pulled horizontally, 180 degrees across and at a right angle to the incision plane to ensure a square knot. The first knot is appositional and not too tight because it will tighten further when the second knot is tied. Knots are tied for apposition only and the suture ends are cut as close to the knot as possible for corneal sutures. If 9‐0 or smaller inter­ rupted sutures are used in the cornea, the knots may be bur­ ied in the suture tract. For adnexal skin sutures, the end of the suture must be left long enough to allow for removal of the suture but must not contact the cornea. In general, for adnexal sutures, the end of the suture directed toward the cornea is cut close to the knot whereas the end directed away from the cornea is left long to facilitate removal. With multi­ ple adnexal sutures, the subsequent sutures may be used to incorporate the preceding sutures to direct them away from the cornea (Fig. 12.49).

Surgical Needles and Needle Holders Needles for ophthalmic surgery are always swaged on because of the small size of the suture materials used and the need to be atraumatic. The most precise and least likely to deform is the laser‐drilled swaged needle (Macsai, 2007). Needles may be described by the curve of the needle, the wire diameter, length of the needle, chord length, radius, and by the shape of the needle in cross section or point geometry (Fig. 12.50). The curve of microsurgical ophthal­ mic needles can be straight, 1/8, 1/4, 3/8, and 1/2 circles. For corneal surgery, needles with a 3/8 to 1/2 curve and a short 5–6 mm length are most common. The 3/8 needle will result

Wire diameter Need

Needle radius

le b o dy

N e e d le e n gth l

Figure 12.50  Terms used to describe the anatomy of a surgical needle.

in a larger shallower bite whereas the 1/2 needle results in a short, deep bite (Macsai, 2007). The length of a needle must be sufficient to allow both passage and retrieval without damage to the needle point as it is being withdrawn. The point geometry is described as taper (round needle with a taper point), cutting (cuts on the inside curve), reverse‐­ cutting (cuts on the outside curve), tapercut (round needle ending in a triangular cutting tip), and side cutting or spat­ ula (flat top and bottom, cuts on the side) (Fig.  12.51). In general, cutting/reverse‐cutting needles are used for the eye­ lids and adnexa whereas spatula needles are used for corneal surgery. The advantage of the spatula tip is that the needle will split the tissue plane, remaining at the same depth and minimizing the risk of perforation and suture migration in thin and delicate tissues such as the cornea. For corneal clo­ sure in small animals, the author uses 9‐0 monofilament Vicryl (polyglactin 910) on a CS160‐8 spatula needle which has a 1/2 curve and a length of 5.5 mm. Microneedle holders vary by the size of the jaw (delicate, fine, medium, heavy), straight or curved jaw, smooth or ser­ rated jaw, locking or nonlocking, and the style of the handle

Section II: Foundations of Clinical Ophthalmology

Figure 12.51  Various types and shapes of surgical needles and their effects on tissue penetration and suture placement. The top row shows the needle in cross section, the middle row shows the needle head in three dimensions, and the bottom row shows the needle track in cross section within the tissue. (Source: Modified from Eisner, G. (1990) Eye Surgery: An Introduction to Operative Technique. New York, Springer Verlag.)

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Figure 12.52  The jaws of two Barraquer microneedle holders. The jaws at the top are medium and those on the bottom are delicate in size.

(see Fig.  12.33). It is essential that the size of the instru­ ments, specifically the jaw of the needle holder, used to grasp the needle correspond in size to match the needle selected (Fig.  12.52). If the jaws of the needle holder are too large, they will deform and flatten the needle when compressed, straightening the needle and weakening it, resulting in breaking of the needle and/or inaccurate depth of suture placement and dehiscence. In contrast, if a microneedle holder is used to grasp a large needle, the converse is true with the delicate needle holder jaws and hinge being dam­ aged and sprung such that they will no longer hold the microneedles they were designed for. Microsurgical needles should be grasped slightly anterior of the midpoint. Grasping behind the midpoint (toward the swaged on suture) will result in bending of the needle as it is advanced. Grasping too far forward of the midpoint may damage and dull the tip. When using a curved needle holder, the needle is grasped with the jaws curving upward. Although novice surgeons may prefer a locking needle holder, nonlocking needle

­ olders are best for most ophthalmic procedures to avoid the h jerking movement of the needle associated with release of the locking mechanism. Curved, nonlocking, round‐­handled Barraquer or Castroviejo type needle holders are typically preferred for ophthalmic needles. When passing a microsurgical needle, the tissue must be stabilized using appropriate forceps positioned adjacent to the point of needle insertion. If possible, when using toothed forceps to stabilize tissue, the forceps should be held so that the needle enters the tissue on the side of the forceps with the fewest teeth and with the force directed toward the side of the forceps with the greatest number of teeth (Macsai, 2007; Troutman, 1974). In order to permit a needle to be inserted and withdrawn, the needle length must be greater than the suture tract itself. This increased length may result in incongruity with the needle having a longer or shallower than intended bite if its radius of curvature is followed with­ out manipulation of the tissues (Eisner, 1990). To adjust for this, the needle encounters the cornea perpendicular (90 degrees) to the surface and is inserted into the tissue stroma (Macsai, 2007). As the needle enters the stroma, the needle holder is rotated in the surgeon’s fingers, allowing the needle to follow its natural curve while the forceps elevate and open or evert the wound slightly. The forceps are used to stabilize, provide counter pressure, and rotate the tissue as required to allow the needle to follow its path. With a two‐ step or beveled incision, the needle should exit the stroma at the junction of the deep initial corneal groove and the step cut initiated by the scissors. It should exit perpendicular to the cut surface. When closing a corneal incision/laceration, the needle is again placed perpendicular to the corneal stroma (parallel to the corneal surface) on the second side of the wound at the level of the step incision. When suturing a cornea without a two‐step incision, the needle is placed to a depth of 75%–90% of the corneal stroma. The needle holder is rotated as the needle enters the stroma. The forceps should maintain control, stabilizing and slightly rotating the tissue

until the needle has completed its path and exited perpen­ dicular to the surface. Only then are the forceps released. When suturing a vertical incision, the needle should exit the tissue at a distance equidistant to the point of entry with respect to the incision (Macsai, 2007). For an oblique inci­ sion, the suture should emerge equidistant to the deep layer of the incision (Macsai, 2007). To complete a pass, as the needle is advanced, it is grasped and regrasped closer to the swaged end and the rotation movement continued. The nee­ dle should be advanced and exit out of the tissue far enough that it can be grasped and removed without grasping and damaging the needle tip. Although it has been suggested that when withdrawing the needle the curve of the needle holder should be reversed, this is not required or essential. When placing a continuous suture pattern, it is both efficient and acceptable to advance the needle far enough to allow the needle holder to regrasp it anterior to the midpoint and in a position that is correctly oriented for the next needle pass. The surgeon must then follow a path of rotation with their fingers to remove the needle without bending it while the forceps stabilize and provide counter pressure. This will decrease surgical time, is more efficient, and will minimize both suture and needle trauma. The result should be needle and suture passes of equal tissue depth and equal length with respect to the wound margin (Macsai, 2007). To avoid suture trauma and be efficient, the needle should remain in the surgical field during suture tying. This will reduce manipulation of the suture and associated suture trauma and will also save time. For more details on suture selection and suture patterns, the reader is referred to the surgical sections in specific chap­ ters for the tissue of interest.

Forceps

Forceps are designed for specific purposes, and it is essential to use the correct forceps for each step of the procedure. The basic functions of forceps are to manipulate and stabilize ocular tissues, tying of sutures, removal of foreign bodies or distichia, performing a capsulorhexis, and IOL manipula­

tion (Grevan, 1997). Forceps may have teeth (variable in number and size) to grasp tissue, and in addition may have a tying platform behind the teeth to grasp and manipulate suture. The teeth may interdigitate in a 1 × 2 design (Gelatt, 2011a) as seen with the Colibri and Bishop‐Harmon forceps or may simply appose as seen with the Utrata capsulorhexis forceps (Fig.  12.53 and Fig.  12.54). Teeth may arise at a 90‐degree angle (dog‐toothed) as seen with the Colibri and Bishop‐Harmon forceps or emerge at a steeper angle as seen with scleral fixation forceps (mouse‐toothed) (Fig.  12.55). The size of the teeth is variable in the same design of forceps with smaller teeth designed for more delicate tissues. Use of forceps with large or inappropriate teeth will result in exces­ sive tissue trauma. Use of small and delicate forceps on thicker adnexal tissue may result in bending and damage to the teeth. Bishop‐Harmon straight tissue forceps are most commonly used for eyelid (fine teeth) and conjunctiva (deli­ cate teeth) manipulation. Although Brown‐Adson forceps may be used for manipulation for skin during enucleation or orbital surgery, they are too traumatic for eyelid reconstruc­ tion procedures. Colibri forceps are most commonly used for corneal and conjunctival surgery and have 0.12 mm (cornea) or 0.3 mm and 0.5 mm teeth (conjunctiva). Colibri forceps are angled and should be held so that the tips are directed downward so that only the teeth contact the tissue. Typically, they will also have a tying platform to manipulate sutures. The use of angled forceps such as the Colibri will provide better visualization of the surgical field under the operating microscope compared with straight forceps like the Bishop‐ Harmon or Castroviejo. There are tying forceps without teeth that are designed with smooth, rounded blade edges for suture manipulation (see Fig.  12.48). Although tying forceps, such as the McPherson, are designed for small and delicate suture mate­ rials, it must be understood that complete closure of even these forceps will damage and weaken sutures. If possible, only the suture ends that will be removed should be han­ dled, and the surgeon should attempt to avoid closure of instruments on sutures that will remain in the eye. Grasping of needles with delicate tying forceps will damage and spring

Figure 12.53  Colibri 0.12 mm utility forceps (top) and Bishop‐Harmon (delicate) forceps (bottom).

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Figure 12.54  Colibri 0.12 mm utility forceps (left) with 1 × 2 teeth that interdigitate and Utrata capsulorhexis forceps (right) with 1 × 1 angled teeth that appose.

just behind the swaged on end of the needle and the needle suspended in the tear film to be grasped by the needle holder (Troutman, 1974). Additional forceps may include those for IOL manipula­ tion and those that are designed for deeper intraocular work where the action mechanism is outside the eye as seen with the MicroSurgical Technology® or Storz® forceps (Bausch and Lomb Storz, Manchester, MO, USA) (see Fig. 12.40 and Fig. 12.45). It is essential to use the correct forceps for each step of the procedure. Use of forceps with large or inappropriate teeth will result in excessive tissue trauma. Use of small and deli­ cate forceps on adnexal tissue or to grasp suture needles may result in bending and damage to the teeth. The novice sur­ geon must also work to resist the temptation to overpower the forceps, squeezing the forceps too hard, damaging both the tissue and the instrument.

Hemostasis

Figure 12.55  Bishop‐Harmon fine, 1 × 2 straight teeth without a tying platform (top) and scleral fixation forceps with angled 1 × 2 teeth and a tying platform (bottom).

the jaws, resulting in a failure to subsequently grasp small suture materials. Instead, needles may be grasped ready to use in the needle holder as they emerge from the tissue. Alternately, the suture may be grasped in the tying forceps

Hemostasis may be achieved by use of instruments such as a chalazion clamp for eyelid surgery (see Fig. 12.24), vasocon­ strictive agents such as epinephrine, and wet‐field cautery. Epinephrine used at a 1 : 10,000 dilution will provide vaso­ constriction of conjunctival and eyelid vasculature when performing conjunctival or corneo‐conjunctival grafts and adnexal procedures. It may also be used intracamerally to vasoconstrict the anterior uveal vasculature, dilate the pupil, and minimize fibrin formation. Intracameral epinephrine is applied at the start of the intraocular procedure and may be reapplied if intraoperative bleeding is encountered. Wet‐ field cautery is preferred over the battery‐operated handheld

Figure 12.56  Cellulose surgical spears are absorbent without shedding fibers.

cautery units, but both have value. In general, the handheld battery units maybe used for minor adnexal bleeding whereas wet‐field cautery is indicated for the management of bleeding associated with the globe, both external and internal. If bleeding occurs, cellulose sponges must be used for intraocular procedures to avoid the shedding of fibers associated with cotton swabs because these fibers may enter the eye (Fig. 12.56).

Viscoelastics Viscoelastic substances are used in ophthalmic surgery to protect tissue and cells from mechanical trauma, create and preserve space for surgical manipulation, lubricate, separate tissues, prevent adhesions, tamponade hemorrhage, and to move or relocate tissue. They are, therefore, “tools for spacial tactics” (Eisner, 1990). The use of viscoelastic substances has been shown to minimize damage to and loss of corneal endothelial cells from all of these causes (Artola et al., 1993b, 1993a; Liesegang, 1990; Wilkie & Willis, 1999). Selection of a viscoelastic is dependent on the task required with no one viscoelastic fulfilling all needs, requiring the ophthalmic surgeon to be familiar with a variety of viscoelastic sub­ stances and their properties, and to select one most appropri­ ate for the task performed. Viscoelastic substances must be sterile, nontoxic, nonpyrogenic, noninflammatory, and non­ immunogenic. In addition, they are balanced with respect to their electrolytes, osmolality, pH, and colloid osmotic pres­ sure so that they are suitable for use in the anterior and pos­ terior chambers and vitreous cavity. Injection of viscoelastic materials is critical, placing the viscoelastic precisely at the desired site and taking into consideration the volume shift

that occurs with injection and the need to maintain path­ ways for these shifts to occur. Removal of viscoelastic mate­ rial can be done using automated irrigation‐aspiration, manual irrigation, or the viscoelastic material can be left in the anterior chamber if its effects are still required postop­ eratively, allowing removal by aqueous dilution and outflow. The decision to remove a viscoelastic material at the conclu­ sion of surgery is based on preoperative gonioscopy, the need for visco‐occupation in the postoperative period, manipula­ tion and trauma associated with removal, and ultimately, surgeon preference. Viscoelastics have properties of both fluids and solids and are described based on their rheologic properties of viscosity, pseudoplasticity, viscoelasticity, and surface tension (Liesegang, 1990; Wilkie & Willis, 1999). A variety of viscoelastic materials are available, containing hyaluronic acid, hydroxypropylmethylcellulose (HPMC), chondroitin sulfate, polyacrylamide, or some combination thereof. Viscoelastics have been discussed as being either cohesive (high viscosity/molecular weight) such as 1–2% sodium hyaluronate or dispersive (low viscosity/molecular weight) such as Viscoat® (3% sodium hyaluronate plus 4% chondroitin sulfate) (Wilkie & Willis, 1999). For a detailed, more complete discussion of viscoelastics and their indica­ tions and properties, the reader is referred to the Surgery of the Lens (Chapter 23) and additional references (Liesegang, 1990; Wilkie & Willis, 1999).

Conclusion Over the past decades, veterinary ophthalmic microsurgery has made significant advances with respect to small inci­ sion techniques, availability of high‐quality magnification, refinement in surgical instrumentation, widespread use of viscoelastic materials and better suture materials, and ­precision‐engineered needles. Phacoemulsification and foldable IOL implantation are now the accepted standard of care for cataracts and with this, the long‐term success rate for cataract surgery and vision restoration has improved greatly for all species. Sutured IOLs and ECP techniques have been described and refined, improving outcomes for those patients for whom surgical success was previously less than acceptable. Finally, veterinary ophthalmic surgery continues to expand into the realm of posterior segment ­vitreoretinal surgery. As ophthalmic surgeons, we must ensure we remain cur­ rent in our understanding of these new techniques and pro­ cedures in order to provide the best possible care for our patients and to ensure the next generation of veterinary oph­ thalmic surgeons are trained effectively. We must always strive to improve on our outcomes, refuse to accept poor sur­ gical results, and instead challenge ourselves to find better approaches to traditional techniques when outcomes are less than acceptable.

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As we seek to improve, we must all follow the basic rules: to use appropriate magnification and instrumentation, to be efficient and precise, to ensure minimal tissue trauma, to minimize surgical time, to maintain the anterior chamber using small incisions and viscoelastic materials, to obtain excellent tissue wound apposition with the smallest and most appropriate suture materials, and finally, to achieve a

successful, comfortable, cosmetic, and whenever possible, visual outcome. Finally, we must remember that microsurgery is both a technique and an art and as such we must constantly work to refine and improve ourselves as microsurgeons. We must also remain open to new ideas and respect the opinions of others who may have a different method to achieve success.

References Abidin, M.R., Towler, M.A., Thacker, J.G., et al. (1989) New atraumatic rounded‐edge surgical needle holder jaws. American Journal of Surgery, 157, 241–242. Artola, A., Alio, J.L., Bellot, J.L., et al. (1993a) Lipid peroxidation in the iris and its protection by means of viscoelastic substances. Ophthalmic Research, 25, 172–176. Artola, A., Alio, J.L., Bellot, J.L., et al. (1993b) Protective properties of viscoelastic substances against experimental free radical damage to the corneal endothelium. Cornea, 12, 109–114. Baker, J.M. & Meals, R.A. (1997) A practical guide to surgical loupes. Journal of Hand Surgery, 22, 967–974. Chacha, P.B. (1979) Operating microscopes, microsurgical instruments and microsutures. Annals of the Academy of Medicine, Singapore, 8, 371. Chang, T.S., Zhu, S.X. & Wang, Z.C. (1986) Principles, Techniques and Applications in Microsurgery. Singapore: World Scientific Publishing Co. Dorland, W.A.N. (2009) Dorland’s Pocket Medical Dictionary. Philadelphia: Saunders. Eisner, G. (1990) Eye Surgery: An Introduction to Operative Technique. New York: Springer‐Verlag. Fowler, J.D. & Schuh, J.C.L. (1992) Preoperative chemical preparation of the eye: a comparison of chorhexidine diacetate, chlorhexidine gluconate, and povidone‐iodine. Journal of the American Animal Hospital Association, 28, 451–457. Gelatt, K.N. (2011a) The operating room. In: Veterinary Ophthalmic Surgery (eds Gelatt, K.N. & Gelatt, J.P.). Oxford: Elsevier/ Saunders. Gelatt, K.N. (2011b) Ophthalmic surgical instrumentation. In: Veterinary Ophthalmic Surgery (eds Gelatt, K.N. & Gelatt, J.P.). Oxford: Elsevier/Saunders. Gelatt, K.N. & Wilkie, D.A. (2011) Surgical procedures of the lens and cataract. In: Veterinary Ophthalmic Surgery (eds Gelatt, K.N. & Gelatt, J.). Oxford: Elsevier/Saunders. Grevan, V.L. (1997) Ophthalmic instrumentation. Veterinary Clinics of North America. Small Animal Practice, 27, 963–986. Harms, H. & Mackensen, G. (1967) Ocular Surgery under the Microscope. Chicago, IL: Year Book Medical. Hoerenz, P. (1980) The operating microscope: IV. Documentation. Journal of Microsurgery, 2, 126–139.

Jarrett, P.M. (2004) Intraoperative magnification: who uses it? Microsurgery, 24, 420–422. Liesegang, T.J. (1990) Viscoelastic substances in ophthalmology. Survey of Ophthalmology, 34, 286–293. Littmann, H. (1971) Neue zusatzgea fur die microchirurgie des auges. Anales del Instituto Barraquer, 10, 209. Macsai, M.S. (2007) Ophthalmic Microsurgical Suturing Techniques. Berlin: Springer. Murray, J.W. (1986) The operating microscope. Plastic Surgical Nursing, 6, 65–69, 72. Nasisse, M.P. (1997) Principles of microsurgery. Veterinary Clinics of North America. Small Animal Practice, 27, 987–1010. Perrit, R.A. (1950) Recent advances in corneal surgery. American Academy of Ophthalmology and Otolaryngology course materials. Perrit, R.A. (1952) Superficial keratectomy. Journal of the International College of Surgeons, 17, 220. Pieptu, D. & Luchian, S. (2003) Loupes‐only microsurgery. Microsurgery, 23, 181–188. Roberts, S.M., Severin, G.A. & Lavach, J.D. (1986) Antibacterial activity of dilute povidone‐iodine solutions for ocular surface disinfection in dogs. American Journal of Veterinary Research, 47, 1207–1210. Spaeth, G.L. (1990a) Fundamental surgical procedures. In: Ophthalmic Surgery: Principles and Practices (ed. Spaeth, G.L.). Philadelphia, PA: W.B. Saunders. Spaeth, G.L. (1990b) Instrumentation, sutures, and standard ophthalmic procedures. In: Ophthalmic Surgery: Principles and Practices (ed. Spaeth, G.L.). Philadelphia, PA: W.B. Saunders. Stanbury, S.J. & Elfar, J. (2011) The use of surgical loupes in microsurgery. Journal of Hand Surgery, 36, 154–156. Sullivan, T.C., Hellyer, P.W., Lee, D.D., et al (1996) Low‐dose pancuronium neuromuscular blockade during intraocular surgery‐evaluation of efficacy in inducing extraocular muscle paralysis and effects on respiratory function. Transactions of the American College of Veterinary Ophthalmologists, Maui, HI. Troutman, R.C. (1974) Microsurgery of the Anterior Segment of the Eye. St Louis, MO: C.V. Mosby. Wilkie, D.A. & Willis, A.M. (1999) Viscoelastic materials in veterinary ophthalmology. Veterinary Ophthalmology, 2, 147–153.

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13 Digital Ophthalmic Photography Richard J. McMullen, Jr.1, Nicholas J. Millichamp2, and Christopher G. Pirie3 1

  Department of Clinical Sciences, Auburn University, JT Vaughan Large Animal Teaching Hospital, Auburn, AL, USA   Eye Care for Animals‐Houston, Houston, TX, USA 3   Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA 2

Photography is an essential part of veterinary ophthalmology, and the digitization of photography has been important in increasing both the quality and the availability of ophthalmic lesion images. Because digital cameras provide their user with instant feedback in terms of image composition, exposure, and definition, it takes relatively little time and effort to be able to capture clear, well‐focused, and effectively composed images. Although many readers are familiar with and may even possess vast archives of slides or printed photographs taken with film cameras, digital photography has superseded the era of film. The relatively low cost of quality digital photographic equipment allows for widespread use of this technique in every situation. We have made a conscious decision to concentrate solely on digital photography in this chapter. The focus will be on providing guidelines and insights from the contributing authors to minimize the trial‐and‐error tactics of digital photography often employed by novice photographers. Although there is a plethora of digital photography equipment available, the information provided in this chapter pertaining to camera operation and image capturing techniques uses the digital single lens reflex (dSLR) camera as its basis. For this edition we have also chosen to include a section on smartphone ophthalmic photography. The technologic advances that have been made over the past few years have resulted in smartphone cameras that are both powerful and versatile. Since our phones are never out of arm’s reach, they are often the first‐choice camera in both our private and professional lives. The chapter will cover general principles of digital photography, with the emphasis on utilizing different modes of operation (aperture priority, shutter priority, and manual). Photographic equipment, including cameras, lenses, and flash systems necessary to obtain high‐quality images, will

be evaluated, followed by a brief description of appropriate photographic technique. Discussion of specific techniques commonly used to accurately photograph ocular structures and commonly encountered artifacts will follow. Specific tips and appropriate settings for optimizing image capture will be given, which will allow accurate digital imaging of common lesions within specific ocular tissue. Finally, a summary of currently available hardware and software will be presented.

Photography Basics Photography is a discipline requiring both technical skill and an artistic perspective. However, to obtain high‐quality images consistently, the photographer must have a sound understanding of the equipment being used and the mechanics behind its operation. This section will focus on several key basic concepts of photography.

Exposure Exposure is a fundamental concept in photography. Understanding exposure and knowing the parameters that control it is vital to becoming a better and more consistent photographer. There are several ways of defining exposure (e.g., overexposed vs. underexposed); however, a correct exposure is simply a matter of obtaining an image that is the way you want it to be (Peterson, 2010). To obtain this correct exposure, the photographer must always be in complete control of his/her equipment such that the necessary adjustments can be easily made. Simply relying on automatic settings and/or the meter reading of the camera itself may render a good exposure; however, the photographer may not consider it to be correct.

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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Several parameters can affect the exposure within the final image, all of which are intricately related to one another. These include the scene light, shutter speed (e.g., exposure time), aperture (e.g., light intensity), and International Organization for Standardization (ISO) values (e.g., light sensitivity). All of these parameters will be discussed in more detail individually in the following sections. In the case of ophthalmic photography, however, scene light is generally not a significant consideration per se. Room lighting is usually not recommended as it creates several unwanted and often distracting specular reflections (Christopherson, 1982). Controlling light in the scene is often done by either a modeling light and/or a flash and will be discussed separately. Prior to discussing shutter speed, aperture, and ISO values individually, it is important to understand their relationship to one another. Furthermore, it is useful to think of them in terms of stops. A full stop is defined as either doubling or halving any value (e.g., shutter speed). Each of these three parameters can be considered in terms of stops, and an adjustment in one can be compensated for by a reciprocal adjustment in one of the two other parameters. This is the principle behind reciprocity, whereby doubling a full stop in one parameter is equivalent to halving a full stop in another (Shaw, 1987). Once a correct exposure has been obtained, the photographer has the capability to alternate any one of these parameters as needed. For example, an image obtained of a corneal lesion yields a correct exposure at 1/125 second (shutter speed), f/8 (aperture), and ISO 100. However, due to patient movement, the image is blurred. To compensate for motion, a faster shutter speed is necessary. A shutter speed of 1/250 second is chosen; however, to maintain correct exposure, the aperture should be stepped down one full stop, or the ISO setting decreased. This concept can be extended to incorporate moving in 1/2 or 1/3 stop increments as well. Thinking in terms of stops allows the photographer a great deal of creativity, while maintaining a correct exposure in the final image.

blur is dictated by several factors, which may include the focal length of the lens, the working distance, and the direction of object movement (toward/away vs. side to side; Shaw, 2000). The focal length of the lens can impact the slowest shutter speed capable of maintaining a sharp image, specifically when the camera is handheld. As a rule of thumb, the shutter speed should be faster than the focal length of the lens being utilized. For example, when using a 105 mm lens, the shutter speed should exceed (e.g., be faster than) 1/100 second. The working distance and direction of object movements can impact shutter speeds as well, both affecting the speed at which the object moves across the sensor. At a shorter working distance, smaller movements either by the photographer or the object have a greater effect. Similarly, the direction of object movement can greatly impact image quality. Movements parallel to the sensor (e.g., globe movement) are more detrimental than back‐and‐forth movements, as the former reflect movement across the sensor to a greater degree.

Aperture (Intensity) The aperture is the diameter of the lens opening, which regulates the intensity of light reaching the sensor at a point in time. This opening is formed by a series of overlapping blades within the lens (Fig. 13.1). It is defined by an f‐number, which represents a fraction of the lens focal length. As such, the aperture (e.g., size of the opening) is a relative value. For example, an aperture of f/4 on a 60 mm lens represents a lens opening of 60/4 = 15; however, f/4 on a 200 mm lens is 200/4 = 50. Despite this, all lenses set to the same aperture (e.g., f/4), regardless of focal length, will transmit the same intensity of light to the camera sensor (Adams & Baker, 2003). As with shutter speed, aperture is altered in stop increments, which may vary by full, 1/2, or 1/3 stop ­increments. A change of one full stop is equivalent to twice (or half) the amount of

Shutter Speed (Exposure Time) Most current cameras utilize a focal plane shutter. This consists of two overlapping curtains (slit or guillotine) located in front of the camera sensor (Adams & Baker, 2003). The shutter is responsible for controlling the amount of light that reaches the sensor by regulating the length of time it remains open. Shutter speeds may vary in increments (e.g., stops) ranging from thousandths of a second to minutes. Of note, however, is that most digital cameras today allow 1/2 to 1/3 stop increments to be performed as well, thereby providing the photographer with even greater flexibility. Alteration in the shutter speed allows the photographer the capability to halt motion and/or create blur, whichever is preferred. However, in the case of ophthalmic photography, the former is a priority. The shutter speed required to prevent motion

Figure 13.1  Image obtained from the rear lens of a Nikon 105 mm macro lens with aperture stopped down to f/8. Note the overlapping aperture blades regulating the diameter of the lens opening.

13: Digital Ophthalmic Photography

ISO (Sensitivity) ISO is a numeric value that defines the sensitivity of the camera to light (Peterson, 2010). This value can range from 25 to > 6400 and may be defined in terms of relative speed: < 200 (slow), 400–800 (fast), and > 800 (very fast). Previously, the ISO value was determined by the film employed within the camera; however, using a digital camera this is now simply a matter of pressing a button. Altering the ISO varies the sensor’s sensitivity to light, a process that occurs through amplification of the signals generated by the photosites within the sensor (Gulbins, 2008; Long, 2010c). Increasing the ISO setting translates into a greater light sensitivity. However, more important to our understanding of exposure, altering the ISO changes the amount of light required by the sensor. This latter point is inversely related to the ISO setting. For example, while increasing the ISO setting from 100 to 200 increases the sensor’s sensitivity to light, it decreases the amount of light required for an exposure. By altering the ISO setting, the photographer has an additional tool by which to control exposure. Increasing the ISO reduces the amount of light required, thereby allowing faster shutter speeds and/or smaller apertures to be employed. The former may be required to reduce patient movement/blur, while the latter may be employed to increase DOF. However, it is always preferential to utilize an ISO setting as low as possible (e.g., < 400) to maintain maximum image quality (Olsen, 1979). Amplification of the signal generated by the photo sites may introduce digital noise (e.g., luminance or color) and degrade the final image. Luminance noise generates an overall graininess within the final image, while color noise creates a mottled color effect, particularly within shadowed regions of the image (Busch, 2004a; Long, 2010d).

Exposure Modes Most digital cameras today offer a variety of exposure modes, each having their own advantages and disadvantages. Proper use of each requires a clear understanding of what is being controlled for by the camera and what possible limitations may exist. Common exposure modes include full auto, programmed auto, shutter priority, aperture priority, and manual exposure (Canon, 2009; Lowrie, 2007; Stansfield, 2010).

Fully Automatic

As the name would imply, while in this exposure mode the camera makes all decisions regarding exposure settings (e.g., shutter, aperture, ISO) and various other parameters (e.g., autofocus mode, white balance, color space). It allows the photographer to simply point and shoot. There is no flexibility or possible alteration of any major camera setting. While this mode often provides consistent results and requires very little in the way of understanding photographic principles, the final image may not be exposed correctly. Program Mode

This exposure mode is similar to fully automatic in that it determines the shutter speed and aperture based on the scene; however, alteration in other settings such as ISO, white balance, metering modes, and so on is possible. This mode offers greater flexibility while still controlling some settings that dictate exposure. Shutter Priority

This exposure mode is utilized when the photographer wishes to control the shutter speed, either to freeze motion and/or to create blur. Once the desired shutter speed is chosen, the camera then determines the appropriate aperture based on the brightness of the scene. Similar to the program mode, alteration of various other settings is possible. Aperture Priority

This exposure mode is essentially the opposite of shutter priority, where the photographer determines the aperture and the camera determines the appropriate shutter speed. This mode is useful when wishing to determine and/or dictate the DOF present within the scene. Manual Mode

As implied, within this exposure mode the photographer has complete control and dictates all exposure parameters (e.g., shutter speed, aperture, ISO). It affords the greatest amount of flexibility and is the preferred choice of the authors.

Focus Obtaining the correct focus within the final image is fundamental, as it may be the difference between a good and an exceptional image. Several variables can affect focus, many of which have been discussed, including patient movement, shutter speed, and aperture selection. Aperture will be considered in more detail shortly as it pertains to DOF. There are several different methods for trying to obtain the correct focus; however, prior to this discussion an important point needs to be addressed. Simply put, the camera itself must be correctly focused for the refractive error of the photographer. This becomes extremely important when utilizing a manual mode and particularly relevant when multiple individuals

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light as its neighboring full stop. It is important to note when discussing aperture that an inverse relationship exists between the f‐number and the size of the lens opening (e.g., light intensity). Smaller f‐numbers equate to a larger lens opening and the transmission of more light. A simple way to think of this is “less is more.” While it may seem logical to maintain the widest aperture possible, thereby allowing more light and permitting faster shutter speeds, aperture also plays a key role in controlling depth of field (DOF) as will be discussed shortly.

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operate the same camera. Adjusting for one’s refractive error is easily performed by simply altering the dioptric control of the viewfinder. This is typically a small dial or knob located next to the viewfinder itself. Establishing the correct focus for the camera is comparable to adjusting a slit lamp, where attention is directed toward a series of points/marks (often focus points) located within the viewfinder. When proper focus has been obtained, these reference points will become sharp and crisp. However, while effective for most individuals, this dioptric adjustment may not be able to fully correct for one’s refractive error if it is significant. In general, one can use an automatic or manual approach to focus on the object of interest. Most current cameras in use today provide autofocus capabilities through a passive autofocus system, typically of the contrast detection type (Long, 2010d). These systems operate by focusing the lens until the image obtained demonstrates the greatest amount of contrast possible. A zone or spot is utilized to determine which part of the image will be analyzed for focusing purposes. These regions will beep or light up when focus has been obtained and can be varied as needed, either automatically or manually, based on the requirements of the photographer (e.g., if the object of interest is not centrally located). To activate the autofocus system (e.g., refocus), one simply needs to depress the shutter button halfway down. However, as the camera can only focus at one plane, it is important to pay attention to which zone/spot has achieved proper focus, as it may not coincide with the region of interest. In addition to altering the zone/spot used for establishing focus, one may alter the autofocus mode. Several different modes are available on most cameras; each varies by the mechanism by which the camera identifies the object of interest. Modes commonly available include single shot, continuous (Al Servo), and automatic (Al Focus) modes (Canon, 2009; Lowrie, 2007). Single shot is typically used for still subjects, as once the shutter is depressed halfway the focus remains constant (unless released and redepressed). Continuous mode is utilized for moving subjects, since the autofocus system is constantly changing the plane of focus as it tracks the object of interest. Automatic mode is a combination of the former two and may be used for a variety of situations. A review of the instruction manual will determine which modes are available on your particular model. While these automatic focus modes are effective in a number of different situations, they can become confused under certain circumstances. One of these is low‐light (low‐contrast) situations, as passive contrast autofocus systems are largely dependent on the availability of light to operate correctly. One method by which the camera may try to compensate for this limitation is to provide a series of short bursts of light from the pop‐up flash unit (pre‐flash), thereby allowing the system sufficient light to establish proper focus (Canon, 2009). However, despite this, use of a manual focus mode may be required and is the preferred mode for the

authors. Overriding the autofocus mode of the camera is performed by switching the AF/MF switch on the camera lens itself. This allows the photographer to set the focus plane by simply altering the focusing ring on the lens. An alternate approach, which is more applicable to ophthalmic photography, is to preset the plane of focus, based on the desired magnification and/or field of view, and to move to and from the object (e.g., globe) of interest. This provides the photographer complete control in determining which region of interest will be in perfect focus.

Depth of Field Another fundamental concept in photography is DOF. Based on the optical principles of the imaging system, only one plane of an object can be in perfect focus at any given point in time (Shaw, 2000). However, there is a zone in front and behind this plane of focus which is considered to be acceptably sharp. This zone is referred to as the DOF. Several factors applicable to ophthalmic photography that may affect the DOF include aperture, lens focal length, and working distance (Adams & Baker, 2003; Davis, 2010). A brief summary of their effects on DOF is given in Table 13.1. Of these, aperture is likely to play the most significant role. However, additional considerations include magnification and the angle at which the plane of focus (angle of camera to object) is oriented. When imaging at higher magnifications, as is common in ophthalmic photography, DOF is significantly reduced. As such, positioning the camera slightly off axis can render portions of the image out of focus. Knowing and understanding these variables as they pertain to DOF can significantly improve the photographer’s ability to control DOF and obtain the desired results. DOF may be accessed directly, prior to obtaining an image, using the DOF preview button. This button is present on most high‐end dSLR models, located on the front side of the camera body, and once depressed will stop down the ­aperture to the set f‐number. This allows the photographer to preview

Table 13.1  Depth of field (DOF) and its relationship to aperture, lens focal length, and working distance.

Parameter

How to Increase DOF

Aperture

Decrease

DOF inversely proportional to change in aperture; e.g., halving aperture doubles DOF

Focal length

Decrease

DOF inversely proportional to square of focal length

Working distance

Increase

DOF proportional to square of distance

Relationship to DOF

13: Digital Ophthalmic Photography

Lighting Lighting is another fundamental aspect of photography, although a detailed discussion of light and its spectral properties is beyond the scope of this section (Hattersley, 1979). Light within the scene may be described in several different ways. Harsh light is a term used to describe light emanating from a distant concentrated light source (e.g., a flash). Soft light is used to indicate light emanating from a more diffuse light source (London et al., 2010b). A summary of the effects on the object within a scene is given in Table  13.2. Most light employed in ophthalmic photography is generated from a flash unit and is therefore considered to be harsh lighting; however, soft lighting may be obtained by using a diffuser over the flash unit and may be preferred under ­certain circumstances (Mandell et al., 1976). More relevant to ophthalmic photography is the direction of lighting. The placement and/or direction of the light source can drastically alter the final image, impact one’s ability to visualize lesion(s) of interest, and/or result in the creation or placement of unwanted specular reflections. The direction of lighting as it pertains to ophthalmic photography can be characterized as follows: front lighting, side lighting (also known as tangential), and backlighting (e.g., retro illumination). Table  13.3 provides a summary of definitions, uses, and possible benefits.

Metering A light meter is a device that determines the amount of light present within a scene. Metering plays a crucial role in determining ideal settings for a proper exposure. However, while most metering systems allow for good exposure, that exposure may not be correct. There are two general types of meters, incident and reflective. Most metering systems present within digital cameras are of the reflective metering type. A reflective meter determines the amount of light reflected from the object within the scene (e.g., luminance; London et al., 2010a; Long, 2010a). These systems are referred to as through the lens (TTL) metering systems, as light must first pass through the lens of the camera prior to reaching the meter. Several types of TTL metering system may be available on your digital camera, and it is important to understand and know how these vary. Common metering methods are summarized in Table  13.4 and may include matrix/evaluative, center‐weighted, partial, and spot metering (Canon, 2009; Stansfield, 2010). It is important to note, however, that color plays no direct role in metering a scene. In fact, these metering systems assume that everything within the scene has a reflectance of 18% light (e.g., neutral gray). It is because of this fact that some images may be over‐ or underexposed, despite proper metering. White objects in a scene typically reflect 36% of the light, while black ones reflect 9% of the light (Shaw, 2000). If there is a strong bias to either one of these in a scene, the metering system assumes a reflectance of 18%, which translates into an incorrect exposure. To compensate for this, underexposing for black objects or overexposing for white objects may be necessary due to the assumptions of the metering system.

Table 13.2  Comparison between harsh and soft lighting. Textural Definition

Contrast

Shadows

Color

Harsh light

Improved

Improved

Sharp edged

Vibrant

Soft light

Reduced

Reduced

Soft edged

Dull

Table 13.3  Comparison between front, side, and backlighting techniques. Front

Side

Back (Retro Illumination)

Light source

Pop‐up flash and/or mounted accessory flash

Use of freely mobile accessory flash

Use of freely mobile accessory flash

Direction of lighting

Light strikes object straight on

Light strikes object from one side

Light almost coaxial with camera lens, reflecting from behind object of interest

Effects/ benefitzs

Flat effect; reduced contrast and textural detail

Improved contrast and textural detail

Silhouette effect

Good contrast and delineation of object borders

Good contrast and delineation of object borders

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how the final image will appear through the viewfinder and assess the DOF. It is important to note, however, that DOF becomes increasingly difficult to assess through the viewfinder at higher f‐numbers (smaller apertures) due to progressive light loss.

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Table 13.4  Common metering modes: Methods of metering and their benefits. Metering Mode

Matrix/Evaluative

Center Weighted

Partial

Spot

Method of metering

Divides scene into grid and meters each grid individually

Like matrix, with bias placed toward central 80% of the scene

Metering performed within the central 9% of the scene

Metering performed using extremely narrow angle of view (1–5 degrees)

Final metering based on array of predetermined scenes programmed into camera, judging best fit

Metering based on assumption area of interest is in center scene

Good for average scenes

Good for average scenes

Benefits/ uses

Flash As previously mentioned, proper lighting is fundamental to photography and demands special consideration. In ophthalmic photography, lighting within the scene is generally provided by a flash unit, as room lighting is not recommended (Christopherson, 1982). Flash photography is a complex and often misunderstood aspect of photography. This following section should serve as a brief introduction. Careful review of your flash unit’s manual is recommended to illustrate its full potential and any possible limitations. The flash unit is simply a device that can generate short bursts (e.g., 1/1000 second) of artificial light at a color temperature around 6000 K (Canon, 2008; Guy, 2010). These units vary in their capabilities, from simple auxiliary light sources to complex and quite sophisticated devices. The amount and duration of light generated from these units may be controlled automatically via the camera’s metering system (e.g., eTTL) or manually by the photographer. It is important to note, however, some fundamental concepts that pertain to flash photography. First, flash units and their effective area of coverage are dependent on the subject distance and obey the inverse square law (Guy, 2010). Simply put, doubling the subject distance translates into a reduction of light from the unit by a factor of 4. Second, due to the mechanics of the shutter, the maximum shutter speed obtainable is limited when the flash is employed. This maximum shutter speed is referred to as the flash sync speed, and is often about 1/200 to 1/250 second. Furthermore, while this is a difficult point to understand, the shutter speed does not limit the effective range of the flash; only the aperture and ISO do that (Guy, 2010). This is because the burst of light begins and ends while the shutter is open. Finally, metering of the flash unit may occur automatically (e.g., eTTL). However, the method by which this occurs differs from ambient light metering (e.g., evaluative metering). Metering of the flash is controlled by altering its light output, not by changing various exposure settings (e.g., aperture). In ophthalmic photography, use of a flash unit will likely be the primary means of generating light within the scene, ensuring proper exposure. To improve the unit’s ease of use

Provides very accurate metering of one specific spot in a scene Good for side or retro illuminated objects

Good for proper exposure of small object(s) within a scene

and understand its benefits, some additional points should be considered. These include the flash range, recycle time, integration with the camera, and placement/mounting of the flash unit. Flash Range

The flash range of a unit is described by its guide number (GN) and relates to the maximum subject distance that still maintains proper exposure. The GN is not a measure of the power of the flash; however, its value is dependent on sensitivity and angle of view (London et al., 2010b). While generally of little concern in ophthalmic photography due to small working distances, the GN will affect the range of apertures (and DOF) that may be utilized. Essentially, flash units with a low GN (e.g., pop‐up flash) may not allow for the desired DOF in the final image. A GN of at least 40 (at an ISO of 25) is recommended for ophthalmic photography (Gutner, 1977). Recycle Time

The recycle time of a flash unit is the duration needed to reach a full charge (e.g., maximum flash output). This time can range between tenths of a second to full seconds depending on the unit. Furthermore, these times are affected by the power setting of the flash (e.g., full vs. half) and the power supply (e.g., batteries vs. external power source) employed within the unit. As many of the patients imaged are not completely restrained/immobile (e.g., globes still freely mobile), rapid flash recycling time allows the greatest number of images to be obtained in the shortest amount of time. Integration with the Camera

Many options and choices are available when it comes to selecting a flash unit; however, regardless of the unit chosen, it is important to ensure that it is compatible with the metering system of the camera. As previously mentioned, these metering systems differ from those involved with ambient light, with metering of light occurring once the shutter has been opened (Guy, 2010). Ensuring proper compatibility allows for automatic metering to occur, where flash output is

regulated by the camera itself, based on predetermined exposure settings. Remember, automatic metering of the flash controls the flash output and does not alter exposure settings. Placement of the Flash

This last point of consideration is probably the most important, as the best images of the globe and/or adnexal regions are obtained with a single, carefully placed light source (Olsen, 1979). Common flash units employed today include the pop‐up flash, ring flash, and an accessory flash unit (which communicates via the hot shoe), the latter being the preferred choice of the authors. The pop‐up flash, while convenient and present on every camera, offers minimal power (low GN), is fixed in its location, and provides only frontal lighting. The frontal light generated from these units typically results in flat images, with poor textural detail. Additionally, use of these units at higher magnifications and short working distances often results in a marked shadowing effect due to the camera lens and poor exposure. The ring flash is an alternative and mounts directly in front of the camera lens. While these units provide uniform illumination on the subject, their shadowless illumination impairs one’s ability to assess depth in the final image. Furthermore, they generate centrally located specular reflections (flash artifact), which often obscure regions of interest in the final image (Mandell et  al., 1976). The third choice is an accessory or external flash. These flash units communicate via the hot shoe of the camera and may be mounted directly to the camera or be freely positioned via wired or infrared (wireless) communication systems. The latter creates an endless number of possible locations and/or positions for the flash, whereby the flash may be mounted away from the camera via a bracket or handheld by the photographer. Moving the flash unit not only allows for control of how the subject is illuminated (e.g., side light), but also facilitates variation in the location of specular reflections created. In summary, regardless of which flash unit is ultimately chosen, it should be of sufficient power, have controllable output, and not be obstructive in size or location (Gutner, 1977; Olsen, 1979).

Sensors and Generating the Image Most digital cameras today house either a charge‐coupled device (CCD) or a complementary metal oxide semiconductor (CMOS) sensor. Both are composed of a series of picture elements (e.g., pixels) in a grid‐like fashion. While the method of generating the electrical signal differs between these sensors, the basic concept is similar (Long, 2010c). Following exposure to light, each pixel within this grid samples the amount of light received, analyzes it, and assigns a numeric value (e.g., bit). The range of numeric values that may be assigned is referred to as the bit depth and relates to the pos-

sible tonal range within the final image (Gulbins, 2008). Each pixel within the sensor is covered by a filter (color filter array). This filter is often devoted to the three primary colors (red, green, and blue), such that each color neighbors the remaining two (Busch, 2004b). This arrangement results in a series of color channels, each of which has its own bit depth (bit per channel), typically 8 bits or higher for each of the red, green, and blue channels. As such, the sensor creates three incomplete color images (color channels). The camera determines the true color of each pixel by analyzing information obtained within each adjacent pixel, a process referred to as demosaicing (Long, 2010c). Because of this process, each pixel in the final image is a combination of three primary color channels, each of which has its own bit depth (e.g., 8 bits). The sum of each of their bit depths (bits per channel) is represented as the bits per pixel and defines the final color tonal range. Thus, a single pixel typically consists of 24 bits of color information (8 bits per channel). Finally, once this information has been obtained, it is amplified, then transferred to an analog–digital converter and onto the camera’s processor, where a number of final adjustments occur (e.g., mapping into color space) to create the final image (Busch, 2004b).

Resolution, Image Size, File Size, and Image Quality Several important concepts require a clear understanding when discussing photography, particularly in the digital realm, including resolution, image size, file size, and image quality. While these are all related, understanding their independent roles and how they are associated with one another is fundamental. Resolution is used to describe the amount of detail an image holds. This is denoted by the effective pixel count (W × H) of the sensor and should not be confused with the actual pixel count (total number of pixels of the sensor; Busch, 2004b). The effective pixel count refers to the number of pixels that contribute to the final image. This count is lower than the actual pixel count, as several pixels are unused and/or utilized for shielding purposes (Long, 2010c). The effective pixel count is therefore considered to be a more accurate representation of the resolution of the sensor (pixel resolution) and is defined as the number of pixels per unit of measure (e.g., pixels per inch or ppi; Gulbins, 2008; Standardization Committee, 2005). While pixel resolution is of consideration when discussing the final image resolution, spatial resolution is of greater importance. It is a measure of how closely lines can be resolved in the final image and is dependent not only on the capabilities of the sensor, but on the optical properties of the imaging system itself. Image size is simply the physical size in pixels of the final image and can be altered on most digital cameras (Busch, 2004b). Of note, however, is that reducing the image size will

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decrease the pixel resolution (e.g., the number of effective pixels) as well as the file size. File size is the actual space or amount of memory the final image will take up on the storage medium. This is affected by the image size and the degree of file compression. The latter may occur within the camera or during postprocessing through selection of the file format. While its primary purpose is to improve storage capacity, increasing file compression may significantly degrade the final image quality. As such, it is always preferred to obtain an image utilizing the least amount of compression possible. Table 13.5 lists common file formats, demonstrating the relationship between file size, degree of on‐camera processing, and compression (Gulbins, 2008; Long, 2010b). Image quality is a term used to describe the perceived degradation present within the final image. As such, it is affected by the resolution of the imaging system itself, in addition to any artifacts introduced during on‐board camera processing (e.g., amplification) and image compression. Furthermore, degradation of image quality may occur during postprocessing. While a detailed discussion of factors contributing to image quality is beyond the scope of this chapter, several of the factors describing image quality and relating to either the imaging system and/or postprocessing software programs may include sharpness, noise, dynamic range, contrast, and color balance.

White Balance White balance is a function of the camera that is often overlooked and/or misunderstood, yet it can significantly affect the results in the final image. White balance refers to how the camera interprets light within a scene, based on its color temperature (Long, 2010d). Specifically, it is how the camera determines what should be white. Once established, all other colors are reproduced from this point of reference. As such, proper white balance is essential for accurate color renditions in the final image. White balance may be altered

as needed to improve and/or correct for errors (e.g., blue color cast). All cameras have an automatic white balance function, in addition to several other preset configurations for various lighting conditions. Furthermore, several cameras offer the capability of creating a custom white balance, a function that may be useful or necessary for specific lighting conditions (e.g., infrared). Alteration of the white balance may also be conducted in a series of postproduction software programs when images are obtained in a RAW format (see below). A review of your camera’s operating manual will identify which configurations are present and how to go about altering them.

Color Space Color space and color management within the digital world are complex subjects and this section serves only as a brief introduction. The color space is the palate that provides the range of colors described by a particular color model (Kuehni, 2003). It is a mathematic model utilized by the camera and other reproduction devices to represent color. Most cameras today offer the choice of selecting between two common color spaces, sRBG and Adobe RGB. sRBG is a color space that encompasses only approximately 35% of the visible colors, according to the CIE (Commission Internationale de l’Eclairage, an international committee established to standardize colors). Its color gamut approximates that of most computer display devices and it is probably the most commonly utilized color space (Long, 2010c). Adobe RGB, on the other hand, encompasses approximately 50% of the visible colors according to the CIE. Its gamut provides an improvement within the cyangreens compared to sRGB (CIE, 2004). Regardless of which color space is utilized, proper selection is key to any color management system. By selecting the appropriate color space between devices, one ensures that the color values obtained from the original device (e.g., the camera) are accurately depicted by the reproducing device (e.g., the computer monitor).

Table 13.5  Common file formats and their impact pertaining to file size, degree of processing, compression, and quality. File Format

RAW

TIFF

JPEG

File size

Large (less than TIFF)

Large

Variable

On‐camera image processing

None

Yes

Yes

Compression

None

Minimal; compressed but information not discarded

Variable compression; low vs. high quality Low quality; high compression ratio (20 : 1) High quality; low compression ratio (4 : 1)

Image quality

High, preferred file format

High, good flexibility, free compression artifact

Variable, subject to compression artifacts

Equipment Considerations Digital Cameras for Ophthalmology The best camera to take any photograph is the one that is available when needed, regardless of whether it is professional equipment or a cell phone (Jarvis, 2010). It is often less the camera that is important as much the expertise of the photographer. A good photographer can obtain an acceptable (and often excellent) image even with an inexpensive camera or a cell phone with limited options. Conversely, an expensive, feature‐rich camera setup does not guarantee good image quality in the hands of someone who does not understand some basic principles of the art and science of photography. With the advent of digital photography and the explosion of various types of electronic camera systems, it has become much easier for most people to obtain acceptable ophthalmic images even on a limited budget. Nonetheless, there are equipment considerations that will facilitate acquisition of digital photographs in the veterinary clinical setting. This section will review our recommendations for external ophthalmic macrophotography at the time of publication. Although this is a rapidly changing field, most of the information will be applicable for the foreseeable future.

Digital Single Lens Reflex Cameras The basic components of any digital camera (dSLR, mirrorless, compact, or smartphone) are a lens to focus incident light reflected from the subject (eye and adnexa) onto the “digital film”/sensor, a controllable aperture within the lens to control the amount of light reaching the sensor and to maximize the DOF, a shutter system to allow a highly controllable duration of exposure of light on the sensor, a light‐tight enclosure (camera body) housing the sensor and electronic controls of the camera, a lens and a flash, and a means to view the subject (viewfinder or liquid crystal display [LCD] screen) and review the image (LCD screen). The most versatile camera for ophthalmic macrophotography remains the dSLR. Although dSLR cameras are made with fixed built‐in lenses, a dSLR with interchangeable lenses is more flexible. This enables attachment of a lens designed for close‐up (macro) photography. The camera should have reasonably high sensor resolution (most of the cameras available commercially have at least 20 megapixel sensors). Full control over lens aperture is important to enable adequate DOF. Digital SLRs offer by far the best control of aperture in photographic mode aperture priority (“A” on Nikon and “Av” on Canon dSLR) or manual control (“M” mode on most cameras) of aperture and shutter speed. A small aperture is needed to achieve a good DOF for the eye and adnexa when working with high magnifications. Although one might assume that the aperture is controlled on the lens itself (as

was the case using the aperture dial in the days before digital cameras), now the aperture is controlled electronically from the camera. Two basic types of sensor are found existing in digital cameras: CCD and CMOS sensors. These differ in various ways that may affect image quality, signal noise, and energy use. Many camera manufacturers use sensors that are smaller than the traditional “full‐frame” or 35 mm film size used previously in film SLR cameras. The commonest sensor sizes are full‐frame (35 mm film), used by several Nikon and Canon cameras, and APS‐C, with a crop factor of about 1.5×, used in various Nikon (DX format) cameras and those from other companies including Pentax, Sony, Samsung, and Fuji. Compact cameras have much smaller sensors and cell phones the smallest sensors of all. As the sensor size is reduced, the crop factor increases. Lenses (including most macro lenses) designed for 35 mm sensors project a circle size at the sensor plane that would illuminate a full 35 mm frame. When using these lenses with a smaller sensor (for instance, the APS‐C size sensor found in many dSLR cameras), the periphery of this circle of light falls beyond the edges of the CCD sensor. This means that the smaller sensor sizes effectively crop off the periphery of the image, introducing a crop factor dependent on the sensor size. The crop factor is the camera sensor’s diagonal size relative to a 35 mm full‐frame sensor. Most dedicated macro lenses are designed for full‐frame sensor sizes. This results in a shift in the effective focal length of the lens when using a smaller format sensor. For example, a 100 mm macro lens used on a camera with a small sensor with a 1.5× crop factor is comparable to using a 1.5 × 100 = 150 mm macro lens. Practically, the longer focal length increases the working distance to the subject and reduces the size of the flash reflection on the cornea. Whenever magnification is used in photography, there is a loss of DOF. Shallow DOF is sometimes needed to highlight part of an image (for instance, if the aim is to focus on a lesion in the cornea and blur deeper structures like the iris). In most situations, however, it is desirable to achieve good focus of ocular structures at different depths in the eye (lids, cornea, anterior chamber, iris), and a wide/deep DOF is needed, which in practice requires a small aperture (high f‐stop) setting on the camera (Fig.  13.2). Routinely with the lenses mentioned here, an f‐stop of f16 to f22 is recommended. Although a small aperture will enable good depth of field, there are potentially two problems associated with this. At very small apertures, diffraction becomes an issue, causing a decline in image sharpness. In addition, longer exposures using a slower shutter speed (which is not good when shooting without a tripod) or a more sensitive film/sensor (higher ISO number) may be needed for any level of illumination. Usually, the exposure issue is negated in ophthalmic macrophotography by leaving a fast shutter speed (to avoid blur

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A

B

Figure 13.2  Two images of the same eye and adnexa taken with identical settings other than varying aperture: (A) at f/5.6 (large aperture), (B) at f/20 (small aperture). Note also that with the smaller aperture (B), the fluorescent light artifact is less noticeable.

Figure 13.3  Examples of Canon (EOS 5D Mk II with 100 mm lens) and Nikon (D90 and D700 with 105 mm lens) digital SLR cameras.

from animal or photographer movement) and low ISO (to maximize image quality) and using flash illumination. Most digital cameras default to autofocus, which is very convenient for most uses other than macrophotography. It is important to have manual control over focus for ophthalmic photography of animals. The patient is likely to be moving, and using autofocus at high magnification and close range on a moving target (often with photographer movement added) will result in the autofocus continuously swinging on either side of sharp focus. It is much more efficient to set manual focus, then set the magnification on the lens and move the camera nearer or further from the subject. Another disadvantage of autofocus is that some in‐lens focusing motors are noisy and may scare the animal, making the process even more difficult. To achieve optimal exposures, dSLR cameras provide for exposure and/or flash compensation (to enable stepwise adjustments to exposure either manually or automatically over a sequence of images with exposure bracketing). This allows the user to set up a sequence of exposures where each

time the shutter release is pressed, the exposure will vary from the calculated exposure by some fraction (often 0.3–0.5) of a f‐stop (how much variance can be set ahead of time). This facilitates varying exposures without having to manually change ISO, aperture, or shutter speed. Many dSLR cameras are now available from several manufacturers. However, we decided to consider only those from the two largest manufacturers, Canon and Nikon, in this chapter (Fig. 13.3). There are two reasons for this: first, these companies make very high‐quality cameras with which we have most experience; and second – and this is quite important from the macrophotography perspective  –  both manufacturers make cameras, lenses, and flash systems that are fully compatible. The exact model of dSLR is of less importance than the type of lens and flash equipment chosen for ophthalmic (and general) macrophotography. Table 13.6 lists currently available and recommended macro lenses and flash units from both Canon and Nikon. We have chosen cameras in the mid‐ price range for dSLRs.

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Table 13.6  Canon and Nikon digital SLR cameras (2020). Digital SLRs (Body Price Only)

Features

Comments

EOS 5D Mark IV Estimated retail: $2,500

Full‐frame CMOS 30.4 MP APS‐H sensor Digic 6 image processor 100–32000+ ISO range, HD video, 3.2 in. clear view LCD, Canon EF lens compatible

Excellent choice in the mid‐price range of Canon dSLRs CF card type I and II Only if you are prepared to buy prime lenses to take advantage of high resolution

EOS 5DS R DSLR Estimated retail: $3,699

Full‐frame CMOS 50.6MP APS‐H sensor. Digic 6 Image Processor 100–32000+ ISO Range, HD Video, 3.2 in. clear view LCD, Canon EF lens compatible

Excellent choice in the high‐price range of Canon dSLRs. Dual card slots: SD and CF. Only if you are prepared to buy prime lenses to take advantage of high resolution

EOS 7D Mark II with Wi‐Fi adapter kit Estimated retail: $1,399

Small frame CMOS 20.2 MP APS‐C sensor Dual Digic 6 image processors 100–16000+ ISO range, HD video, 3.0 in. clear view LCD, Wi‐fi adapter image transfer, Canon EF lens compatible

Excellent (slightly less expensive) choice in the mid‐price range of Canon dSLRs CF card type I and II Wireless image transfer to phone or tablet

EOS 6d Estimated retail: $699 (used)

Small frame CMOS 20.2 MP APS‐C sensor Digic 5 image processor 100–25600+ ISO range, HD video, 3.0 in. LCD, Canon EF lens compatible.

Excellent lower‐price option SD/SDHC/SDXC card Built in Wi‐Fi transmitter

EOS 6d Mark II Estimated retail: $1,339

Small‐frame CMOS 26.2 MP APS‐C sensor Digic 5 image processor 100–25600+ ISO Range, HD Video, 3.0 in. LCD, Canon EF lens compatible

Excellent lower‐price option, SD/SDHC/SDXC card. Built‐in Wi‐Fi transmitter

Nikon USA (http://www.nikonusa.com/Nikon‐Products/Digital‐SLR‐Cameras/index.page) D850 Estimated retail: $2,999

45.7 megapixel FX‐format CMOS (full frame) sensor 64–25600+ ISO range 3.2 in. tilting LCD monitor

XQD and SD card (2 card slots) Only if you are prepared to buy prime lenses to take advantage of high resolution

D750 Estimated retail: $1,050

24.3 megapixel FX‐format CMOS (full frame) sensor 100–12800+ ISO range 3.2 in. VGA monitor

SD card (2 card slots) Built‐in Wi‐Fi

D7500 Estimated retail: $599

20.9 megapixel DX format CMOS sensor 100–51200+ ISO range HD video 3.2 in. VGA tilting touch‐sensitive LCD

DX (1.5x crop factor) sensor size SD/SDHC cards (2 slots) Built‐in Wi‐Fi

D5600 Estimated retail: $420

24.2 megapixel DX format CMOS sensor 100–25600+ ISO range HD video 3.2 in. vari‐angle LCD

DX (1.5× crop factor) sensor size 1 SD/SDHC card Built‐in Wi‐Fi

D3300S Estimated retail: $400

24.2 megapixel DX format CMOS sensor 100–25600+ ISO range HD video 3.20 in. LCD

DX (1.5× crop factor) sensor size 1 SD/SDHC card

Depth of Field Whenever magnification is used in photography, there is a loss of DOF. Shallow DOF is sometimes needed in highlighting part of an image (for instance, if the aim is to focus on a lesion in the cornea and blur deeper structures like the iris). In most situations, however, it is desirable to achieve good

focus of ocular structures at different depths in the eye (lids, cornea, anterior chamber, iris) and a wide/deep DOF is needed; this in practice requires a small aperture (high f‐stop) setting on the camera (Fig. 13.2). Routinely, with the lenses mentioned here, an f‐stop of f16–f22 is recommended. Although a small aperture will enable good depth of field, there are potentially two problems associated with this: a

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Canon USA (http://usa.canon.com)

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longer exposure (slower shutter speed, which is not good when shooting without a tripod) and/or more sensitive “film”/sensor (a higher ISO number may be needed for any particular level of illumination). Usually, the exposure issue is negated in ophthalmic macrophotography by leaving a fast shutter speed (to avoid blur from animal or photographer movement) and low ISO (to maximize image quality) and using flash illumination. Second, at very small apertures, diffraction becomes an issue, causing a decline in image sharpness. The only other approach to achieving good focus of all parts of a subject (eyes) at different distances from the lens is to use the technique of “focus stacking.” This involves combining several photographs of the same eye taken at very slightly different focus points – sequentially points at different depths in the object are in focus – and then combining the images in an editing application (Adobe Photoshop or Helicon Focus from Helicon Soft, Kharkiv, Ukraine) so that in the combined image all levels appear in focus. This is not practical for clinical photography in live moving animals, since the perspective in each image needs to be the same and requires that the camera and subject be relatively fixed. This can be achieved in two situations in ophthalmic practice: photographing an eye in an anesthetized patient with ocular fixation and for gross pathologic specimens of eyes. In both situations, it is possible to mount the camera on a tripod or operating microscope and fix the position of the eye being photographed.

Lenses for dSLR Cameras The lens chosen is often more important than the camera. A high‐quality lens, which allows focusing as close to a 1 : 1 magnification as possible, is ideal. Although this may be built in with a compact camera, the best options come as interchangeable lenses with dSLR systems. Prime macro lenses are optically some of the best lenses made. These lenses have a wide range of apertures, which is important to maximize DOF. Cameras with dedicated macro lenses (from the same manufacturer as the camera or with lenses designed for the particular camera) are recommended. A lens with a fixed focal length of about 100 mm is recommended for clinical photographs of companion animals. Shorter focal length macro lenses (e.g., 60 mm) can be used, but the working distance (camera to subject) is reduced. Lenses for macro use should be able to focus and provide a 1 : 1 life‐size image or larger. These are usually prime lenses (fixed focal length). These lenses tend to be higher quality, lower weight, and smaller in size. Prime macro lenses are highly corrected for optical aberrations that could occur when focused close up. This is achieved by a very specific design feature of the lens elements in the prime macro lens, which is missing in zoom lenses. The prime macro lenses mentioned here are some of the sharpest types of lens available and well worth the price for the quality of the images achieved. Alternatives are zoom lenses, which comprise more than one lens element that move relative to one another, are

larger and heavier, tend to be of lower quality, and introduce more chromatic and spherical aberration at larger aperture sizes, which may not be a big issue for macro work since we tend to use high f‐stops (smaller apertures). These lenses rarely approach a 1 : 2 reproduction ratio (many are nearer 1 : 4 or more). The macro zooms that do achieve a 1 : 1 ratio may only do so at certain focusing distances; generally, these are simply lenses with a fairly close focus ability. The image sharpness is usually less for macro zooms compared with true prime macro lenses. Both Canon and Nikon make excellent 50–105 mm prime macro lenses (Table 13.7). Generally,

Table 13.7  Canon and Nikon macro lenses for digital SLRs. Features

Comments

EF 100 mm f/2.8 macro USM Estimated retail: $600

Life size (1 : 1) with 5.9 in. working distance (minimum focus distance sensor plane to subject 12 in.)

Excellent 100 mm macro lens and reasonable price Auto focus not useful for ophthalmic imaging benefits, lost at high magnification

EF 100 mm f/2.8L macro IS USM Estimated retail: $749

Same lens with image stabilization

Little need for image stabilization for macro – benefits of image stabilization lost at high magnification

EF‐S 60 mm f/2.8 macro USM Estimated retail: $350

Life size (1 : 1) with 4 in. working distance (minimum focus distance sensor plane to subject 12 in.)

Good choice for small sensor cameras

AF‐S VR Micro‐Nikko 105 mm f/2.8 G IF‐ED Estimated retail: $810

Life size (1 : 1) with 12 in. minimum focus distance (sensor plane to subject)

Excellent 100 mm macro lens and reasonable price Sold as FX (full‐frame lens) Best Nikon lens for ophthalmic macro Little need for vibration reduction for macro – benefits of vibration reduction lost at high magnification

AF‐S Micro Nikkor 60 mm f/2.8 G ED Estimated retail: $600

Life size (1 : 1) with 7.2 in minimum focus distance (sensor plane to subject)

Excellent 60 mm macro lens FX (full frame) compatible

AF‐S DX Micro Nikkor 85 mm f/3.5 G ED VR Estimated retail: $560

Life size (1 : 1) with 10.8 in minimum focus distance (sensor plane to subject)

Excellent 85 mm macro lens DX (1.5× crop factor camera) compatible

Canon

Nikon

Flash Illumination Lighting is an extremely important aspect of the macrophotography system, as it is generally in photography. Regardless of how many features the camera has or the quality of the lens, if the lighting is wrong, the image will suffer. Unfortunately, it is also the part of the “macro equation” that can be most difficult to control. Natural lighting does not work well for ophthalmic macrophotography (see some of the artifacts discussed later). Flash is inevitably used in ophthalmic photography; ambient lighting is really not an option for ophthalmic work. Most eye photographs are taken in very reduced ambient lighting to avoid lighting artifacts; hence the need for flash. Even with flash lighting, it is still possible to introduce artifacts, which interfere with the quality of the image. A flash strobe with complete control over output intensity and direction of incident light on the subject (possible with most dSLR cameras; more difficult with compact and cell phone cameras) is the best choice. Proprietary flash units, designed specifically to work with the particular make of camera, are best. This will enable synchronization of the flash and TTL autoexposure (iTTL or eTTL), which considerably facilitates photography in the clinical setting. The in‐camera pop‐up flash present in many dSLR cameras (and almost all compact cameras and smartphones) is often a poor choice for macro illumination, especially if using a short working distance from camera to subject. Larger flash units

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attached to the camera hot shoe also do not fare much better. If using either pop‐up flash or one of the regular hot shoe flash units (as opposed to a macro flash unit), problems arise with either the flash reflex on the cornea interfering with the image or the camera lens actually being in the light path of the flash and causing a shadow of the lens on the subject. Flash units positioned near the end of the lens provide better illumination of the eye being photographed. This can be avoided with hot shoe regular flash units if handheld near the end of the lens or mounted on a flash bracket controlled from the camera, either wirelessly or with a cord connecting the flash to the hot shoe of the camera. This is one area where using a digital zoom lens may be beneficial, since it allows a longer working distance. Although the resulting image is small in the frame, with the high resolution available in most cameras the image can be cropped to concentrate on the area of interest: eye and adnexa.

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less costly macro lenses for both makes of camera are made by other manufacturers (Tokina, Tamron, and Sigma).

13: Digital Ophthalmic Photography

Macro Lighting Systems The best option for ophthalmic macrophotography is to use the proprietary macro flash units for name‐brand cameras (Canon’s Macro Twin Lite MT‐24EX and Nikon’s R1C1 Wireless Close‐ Up Speedlight System). Although these units are expensive, they are definitely worth the cost. They utilize TTL metering to make exposure simple (iTTL for Nikon and eTTL for Canon). These systems allow for variable control of the light output from each strobe unit; operation off the lens ring to enable more creative effects and reduce the rather flat lighting achieved with most ring flash units; diffusion of the incident light to reduce the effect of corneal flash reflexes; and, in the case of the Nikon R1C1, wireless control of the flash units (Fig. 13.4).

A Figure 13.4  A. Nikon R1C1 Speedlight. B. Canon Macro Twin Lite MT‐24EX.

B

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Both units have at least two strobe units (Nikon allows several units to be controlled wirelessly) that can be detached from the camera; Nikon is an even better option here, since the strobes are wirelessly controlled and can be positioned anywhere in relation to the camera and subject. The ratio of light output of each flash strobe can be independently varied. This allows the flash intensity from one direction to be less or more than that from another direction. Moving the flash unit further from the lens and eye both provides for a smaller flash reflex on the cornea and increases the depth and appearance of contour and texture in the image (Table 13.8). Flash units that can be removed from the camera to allow for variable direction of the incident light can aid in giving more depth to the image. Macrophotography and macro lenses tend to result in rather flat images, with limited DOF and little contour detail seen. Apart from increasing the depth of field via Table 13.8  Macro flash units for Nikon and Canon digital SLRs. Features

Comments

Canon Fits all Canon macro Macro Twin Lite MT‐24EX lenses Estimated Flash heads can be rotated retail: $990 around the eye, and angled for varied illumination depending on the working distance Can hold each flash strobe off camera Output of each flash head can be independently varied Incandescent focusing lights

Best option for Canon cameras Focusing lights ideal for ophthalmic photography in darkened room Flash head arrangement avoids “flat,” featureless images seen with traditional ring flash

Fits all Canon macro lenses Can hold entire ring off camera for directional lighting

Reasonable option for Canon lenses and cameras (if you like a ring flash)

R1C1 Wireless Close‐Up Speedlight System Estimated retail: $710

Fits all Nikon macro lenses Individual strobes can be detached from the lens ring to allow for convenient positioning to maximize detail and contour

Best option for Nikon cameras without wireless control built into the camera (otherwise use R1)

R1 Wireless Close‐Up Speedlight System Estimated retail: $460

Same as R1C1 but without the C1 wireless controller Can use with any dSLR with wireless Speedlight control built into the camera

Best option for Nikon cameras with wireless control built into the camera

Canon MR‐14EX Macro Ring Lite Estimated retail: $550 Nikon

reducing lens aperture, flat‐looking images can also be avoided by aiming the incident light from an angle to the ­subject–sensor axis. This happens to some degree even with a ring flash attached to the lens, since the flash strobe is a few degrees to the side of the lens–subject axis. This effect can be minimized by removing the flash from the camera and ­holding it to one side, at more of an angle. The Canon and Nikon macro flash units mentioned here incorporate a modeling light(s) in the flash strobes. This is of benefit for ophthalmic photography, which is usually performed in darkened rooms  –  the modeling lights provide adequate light to enable focusing on the subject, as well as showing the exact direction of the incident light, so the flash strobes can be oriented to illuminate the subject adequately when the flash actually discharges. Diffusers can be placed in front of the flash strobe (the Nikon R1C1 system comes with diffusers) to reduce the harshness of the flash reflex on the cornea. Various third‐ party flash diffusers are available to use with the Nikon and Canon macro flash lights. In general, the ophthalmologist will need to experiment with the flash direction and diffusers to determine what works best in any situation. Ring Flash Units

Many ring flash designs are available for macro work. The main problem with most of these is that the flash reflex in the cornea can be quite intrusive, obscuring lesions being photographed. Additionally, having two flash strobes on either side (or as a continuous ring around the flash unit) renders rather a flat‐looking image. Not all third‐party ring flash units work with the camera “TTL metering” for autoexposure. If this is the case, it is necessary to use manual mode and adjust the aperture and shutter speed settings, and then bracket exposures widely to obtain the results you would like; this is often not a realistic option in a clinical setting with a nervous animal and owner present and time at a premium. Some ring flash units (for instance the Sigma Flash Macro Ring EM‐140 DG) are available for Canon, Nikon, Pentax, Sigma, and Sony dSLR cameras and lenses. Although the results with the Sigma unit may not be quite as good as the macro flash units from Nikon and Canon (which only work with their respective dSLRs), the Sigma unit costs less and is a reasonable alternative. Pop‐Up Flash

For macrophotography, using the camera’s built‐in pop‐up flash is rarely a good option, mainly because the lighting is too far off axis from the macro lens to provide even illumination at the close‐up working distance used. The macro lens itself will often cast a shadow of the macro lens over part of the image when using pop‐up flash at a close working distance. However, there are times when a pop‐up flash will be the only option available. In this situation, the working distance from the camera to the patient should be increased to avoid

13: Digital Ophthalmic Photography

and actually move out of the frame between the pre‐flash and the exposure occurring, hence the need for good restraint.

Camera Settings Familiarity with the camera manual, although often difficult to read, is recommended to gain familiarity with the specific settings available for the camera, which vary by manufacturer. See Table 13.9. For the shooting mode, aperture priority (“Av” on Canon cameras and “A” on Nikon cameras) is the best choice for macro, since it allows for the best control over DOF. Apertures recommended for ophthalmic macrophotography are in the range of f/16–f/22. Even at these settings, there may be some introduction of reduced sharpness due to diffraction. Practically, this rarely matters for our images; it is more important to be able to quickly render decent DOF on the anterior segment in a potentially moving subject (for use printed small or viewed on screen), rather than an image which will be exceptionally well focused when made into a very large print. When using flash (as is usually the case with ophthalmic photography), the shutter speed should be relatively fast (1/120 second) to help freeze animal or photographer movement. As a rule of thumb, the shutter speed should match or be faster than the focal length of the lens – for 100 macro, use 1/120 second or faster. The best ISO (or sensor “speed”) setting is usually about 200 when using flash. This effectively provides for excellent image resolution and sharpness and minimal noise. The color space chosen may differ depending on image use: sRGB for patient records, prints, Microsoft PowerPoint,

Table 13.9  Manufacturers and supplier websites for equipment used in digital and macrophotography. Manufacturer/ Supplier

Website

Comments

Adorama

www.adorama.com

Reliable source for all camera equipment

Amazon.com

www.amazon.com

Reliable source for all camera equipment

B&H

www.bhphotovideo.com

Reliable source for all camera equipment

Canon‐USA

www.usa.canon.com

Manufacturer of very high‐quality dSLR, compact point and shoot, lenses, and dedicated flash units

Kolari Vision

www.kolarivision.com

Digital camera infrared conversion services

Life Pixel

www.lifepixel.com

Digital camera infrared conversion services and infrared photography resource

Nikon‐USA

www.nikonusa.com

Manufacturer of very high‐quality dSLR, compact point and shoot, lenses, and dedicated flash units

Ricoh

www.us.ricoh‐imaging.com

Manufacturer of Pentax K‐5 dSLR cameras, macro lenses, and macro flash

Sigma

www.sigmaphoto.com

Manufacturer of Sigma dSLR cameras, and lenses/flash compatible with Nikon and Canon dSLR cameras

Sony

www.store.sony.com

Manufacturer of Sony dSLR cameras, macro lenses, and macro flash

Tamron

www.tamron.com

Manufacturer of 60 mm prime macro lens for Nikon, Canon, and Sony dSLR cameras

Tokina

www.tokinalens.com

Manufacturer of 100 mm prime macro lens for Nikon and Canon dSLR cameras

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lens shadowing. Additionally, a light diffuser can be placed around the end of the macro lens. This will provide better lighting (the image will not look as flat), and the lens shadow will not be an issue. An inexpensive diffuser can be made from white, light‐transmitting plastic. TTL flash autoexposure is available on any camera for which there is a compatible flash unit produced by the same manufacturer (for instance, Nikon iTTL and Canon eTTL) and for some flash units made by third‐party manufacturers but with specifications for use with a particular manufacturer’s cameras (for instance Sigma ring‐flash units). When the shutter release is pressed, the flash unit will produce a rapid pre‐flash (small flash output from the unit). Light reflected into the camera “through the lens” is measured, and the amount of light needed for the actual flash during exposure of the sensor is calculated, then the flash fires again as the shutter opens. For ophthalmic macrophotography with flash, it is best to set the camera to “front‐curtain‐flash” mode. In “rear‐curtain mode,” the flash fires at the end of the exposure (just before shutter closes); if using a low shutter speed, this could result in a pupillary light reflex or reactive movement of the animal before the main flash occurs. Using cameras with a nondedicated flash unit, it may be necessary to make numerous exposures at varying shutter speeds or ISOs (keeping high‐stop/ small aperture for good DOF) to achieve an optimally exposed image – rarely an option in clinical practice with nervous animals. The pre‐flash output can be a problem in some situations, causing a blink reflex before the exposing flash/shutter opening occurs; this will require the lids to be held open in many situations. Some species of animal may be able to react

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Apple Keynote, or web use. For publication and research, Adobe RGB may be a better choice. The white balance needs to be set at flash or auto settings. The exposure metering mode chosen may vary with the luminance of the subject (part of eye, pupil color, iris color, periocular skin color) and may require some trial and error to get the area of the eye of interest adequately exposed. For instance, if the skin color is black and the setting is for matrix, which assesses the light needed to expose the entire frame, the light output may be higher than necessary for the central area of the image. This may result in blown highlights in the white conjunctiva or tapetal reflection in the pupil. Generally, matrix metering works well for most situations, and this is the preferred setting. Occasionally, there will be a need to experiment with center‐weighted and, rarely, spot metering. If an image appears too bright or dark in the LCD review (or on the computer screen if tethered), the exposure can be adjusted (exposure compensation) in various f‐stop increments (usually ± 0.3–0.5 to either darken or brighten the image, respectively). Flash compensation can also be used to achieve a similar effect. The histogram (see later discussion) is a useful way to assess whether to use exposure compensation. Incremental fractions of an f‐stop on either side of the iTTL/eTTL‐determined “correct” exposure allow a series of images (three or five) to be taken with automatic predetermined changes in the exposure for each image (exposure bracketing setting). This is particularly beneficial when photographing animals in the clinic, since it speeds up the process of taking a series of images. It is a good idea to use the superimposed histogram in the post‐image review, since it is often difficult to be sure of the adequacy of exposure, even on a 3 in. LCD screen on the camera, or on a tethered laptop, where the intensity settings of the screen may affect the distribution of brightness. The histogram allows a quick check that there is a good distribution of tones over the darks, midtones, and highlights. Autofocus should be turned off; use manual focusing. Generally, use the focusing ring to change the magnification and then move closer or further from the eye until adequate focus is appreciated, and then take the photograph. This is much more easily achieved with dSLR using the viewfinder than using the LCD. RAW or JPEG files (or occasionally, RAW and JPEG recorded simultaneously) are the best file type options to record in the camera. The image quality should be fine and the image size large. If the resulting images have too much data, some can be discarded (for instance, to compress files for use on the web). Conversely, low‐quality images cannot be improved in editing software. A list of valuable resources regarding photographic equipment, software reviews, and digital photography training (websites and printed resources) can be found in Table 13.10.

Compact Point and Shoot Cameras Although lacking the flexibility and user control of dSLR cameras, most current point and shoot cameras can produce good‐quality macro images. However, ophthalmic macrophotography with these cameras will rarely achieve the same results obtained with a dSLR camera/lens/flash system. Compact point and shoot cameras (CPAS) do have an inherent advantage for macro work due to the small sensor size and short focal length of the lens, which results in a wide DOF, but this is offset by several details of design and function CPAS are a good choice for work in the field with large animals, where it is convenient to carry a small camera tucked away in a pocket. For large eyes (horses and cattle), photographs can be taken at a longer working distance. CPAS cameras can also be convenient for surgical or histopathologic images taken through a microscope. Limitations of CPAS

CPAS cameras do, however, have some disadvantages. Of significance for clinical photography is that the shutter lag (time from when the shutter release button is fully depressed until when the image is captured) can be a problem. The shutter lag is considerably longer on a CPAS than a dSLR. Although a shutter lag of 0.5 second may seem short, it is 10 times slower than many dSLR cameras. To reduce shutter lag, always depress the shutter halfway to refocus  –  a rectangle appears on the LCD, which will change color (green on the Canon compact) when the subject area is in focus – then fully depress the shutter button. This may reduce shutter lag to about 0.1 second on some compact cameras. A parallax effect may be seen due to the offset between the viewfinder (if available) and the lens; the area centered in the viewfinder may be off center in the resulting image. This is not a problem if using the LCD screen to frame the subject and to focus the camera. Focusing on particular lesions of interest, using the LCD to frame the image on a compact camera can be difficult if the autofocus does not “choose” the area you want in best focus. Focusing can also be more difficult: a camera which allows manual focusing as well as autofocus (as with macro on a dSLR) may make it easier to achieve focus on the area/lesion of interest. Autofocus can be a problem with any digital camera due to continual refocusing because of unavoidable subject and photographer movement. The CPAS camera does have the advantage compared to a dSLR/macro lens combination in this regard, however, because the inherent greater DOF with a CPAS camera allows more structures to be in reasonable focus at any time. The highest f‐stop/smallest aperture available on compact cameras does not compare with a dSLR. DOF on these cameras is usually good, nevertheless, due to the very small sensor size and relatively wide‐angle lens.

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Name

Website

Comments

LinkedIn Learning

www.linkedin.com/learning

A subscription‐based site providing in‐depth (the best) video tutorials on a wide range of software, photographic equipment, and technique Excellent resource for learning Lightroom, Photoshop, Photos, and much more Able to subscribe monthly ($25) Perhaps the best photography learning site on the web – highly recommended

Adobe

www.adobe.com

Useful free tutorials and white papers on Adobe products

Digital Photography Review

www.dpreview.com

Reviews of cameras, lenses, and flashes from the major manufacturers Objective and useful reviews Recommended

Imaging Resource

www.imaging‐resource.com

Reviews of cameras, lenses, and flashes from the major manufacturers Objective and useful reviews

Ken Rockwell

www.kenrockwell.com

General photographic equipment review site – has reviews of most current Nikon and Canon dSLRs

Digital Photography School

www.digital‐photography‐ school.com

Interesting articles and forums for all aspects of photography

Photo.net

www.photo.net

Articles, forums, and reviews of equipment

The Digital Camera Resource Page

www.dcresource.com

Reviews of cameras, lenses, and flashes from the major manufacturers

The‐Digital‐Picture.com

www.the‐digital‐picture.com

Reviews of cameras, lenses, and flashes from the major manufacturers

The Lightroom Queen

www.lightroomqueen.com

Victoria Brampton’s site – everything Lightroom, including books to download on Lightroom Classic and Lightroom CC

Cambridge in Colour

www.cambridgeincolour.com

Interesting articles and tutorials on digital and macrophotography

Focus Photo School

www.focusphotoschool.com

A site with free tutorials and forums (and much other information) relevant to using Lightroom Notably recommends using an external hard drive for mobile catalogue access

Macrophotography and Digital Asset Management Books Victoria Brampton (2015) Adobe Photoshop Lightroom CC/6: The Missing FAQ: Real Answers to Real Questions Asked by Lightroom Users. Isle of Wight: LRQ Publishing. Victoria Brampton (2018) Adobe Photoshop Lightroom Classic CC: The Missing FAQ (Version 7/2018 Release): Real Answers to Real Questions Asked by Lightroom Users. Isle of Wight: LRQ Publishing. Martin Evening (2017) The Adobe Photoshop Lightroom Classic CC Book: The Complete Guide for Photographers. San Francisco, CA: Adobe Press. Fil Hunter, Steven Biver, & Paul Fuqua (2007) Light Science & Magic, 3rd ed. Waltham, MA: Elsevier (Focal Press). Peter Krogh (2009) The DAM Book. Sebastopol, CA: O’Reilly. Peter Krogh (2018) The DAM Book 3.0, available as PDF or CD, http://thedambook.com/the‐dam‐book. Bryan Peterson (2009) Understanding Photography Field Guide. New York: Amphoto Books. Bryan Peterson (2010) Understanding Exposure, 3rd ed. New York: Amphoto Books.

If using a CPAS camera very close to the subject, lighting from the offset flash location can be very uneven, resulting in marked shadowing of the side of the image furthest from the flash. Achieving optimum exposure with flash can be more difficult with CPAS than dSLR, especially if focusing close to the subject. Photographing from an increased distance helps reduce this. The lack of a focusing light on a CPAS camera

requires that photos be taken with some ambient lighting to enable focus on the lesion  –  lighting artifacts will then become more of a problem. Camera Settings for CPAS Cameras

Auto, program, or aperture priority shooting modes can be used with the camera set to “macro.” Matrix and center‐weighted

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Table 13.10  Websites and books providing equipment, software reviews, photographic training, and information about digital and ophthalmic photography.

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exposure modes are suitable (some degree of trial and error may be needed here to get the best exposure) and focus mode should be set to autofocus (which works quite well with CPAS cameras) or manual focus (Fig. 13.5). Autofocus aims an infrared beam at the subject and then determines the focus of the closest point when used in macro mode. When photographing animals, which tend to be moving targets even with good restraint, it is important that you use a camera with both a rapid autofocus mechanism and a short shutter lag. Autofocus works well with larger objects (equine eyes for instance) where the camera can be held slightly further from the eye and still fill a large area of the viewfinder/LCD. In most of the CPAS cameras, a focusing indicator appears on the LCD (white rectangular box on Canon cameras), which will turn green when the shutter release button is slightly depressed if the image is focused; then, the shutter can be fully depressed, and the photograph taken. Optical zoom should not be used with autofocus in macro mode, because the autofocus will usually only function when using the lens at a wide angle. It is important not to get too close to the subject with the CPAS; the autofocus mechanism will work, but only part of the image will be illuminated due to the offset position of the flash strobe (Fig.  13.6). It is better to take the image from further away to ensure good even lighting of the entire subject, and then use the zoom in playback to enlarge the image; when processing, the image can be cropped to remove extraneous adnexal tissues. Avoid using optical or digital zoom; the wide‐angle lens setting works best with autofocus. The minimum focus distance in macro mode will be found in the camera manual and, in most cases, macro with flash will work best at a greater distance than the minimum.

Figure 13.5  A compact point and shoot should not be held too close to the subject to avoid large flash reflexes, but the user should also avoid using optical zoom to ensure accurate autofocus.

Figure 13.6  Uneven illumination with a compact point and shoot camera (especially underexposed at lower left of image). This is avoided by increasing the working distance between the camera and the eye.

Since most of the images will be recorded in a darkened room, it may be necessary to illuminate the subject with a transilluminator or light from a slit lamp if using manual focusing to be able to see that the eye is in focus. With autofocus, this may still be needed to allow for rapid positioning of the camera to take the photograph before the patient moves. Focal illumination may also acclimate the patient to the light and thus elicit less of a reaction when the flash fires.

Smartphone Photography What the smartphone camera lacks in flexibility and user control of settings, it makes up for with ever‐improving image quality and immediate accessibility. The image quality obtained from smartphone cameras is inferior to that obtained using dSLRs. However, there are many instances when the images obtained are superior based on the fact that using a dSLR in some situations is much more time‐consuming (Fig. 13.7). Even so, ophthalmic macrophotography with these cameras will rarely achieve the same results obtained with a dSLR camera/lens/flash system. Smartphone cameras can take images that complement those taken with a dSLR in conjunction, resulting in more accurate case documentation. Smartphone cameras are a good choice for work in the field, especially with large animals where it is convenient to carry a small camera tucked away in a pocket. For large eyes (horses and cattle), photographs can be taken at a longer working distance using a modeling light without a flash to improve cooperation from the animal (Fig. 13.8). Since exposure lag time has become a thing of the past, obtaining good‐ quality images in rapid succession can be expected. Smartphone cameras can also be used to obtain handheld slit

be readily overcome with just a little practice. The speed and quality of modern smartphone cameras have allowed them to slowly become the “camera of choice” for most day‐to‐day situations. Focusing on particular lesions of interest, using the large smartphone screen is very straightforward and readily achieved merely by pressing the area of interest (on the screen) with your fingertip. Autofocus actually works quite well on most modern smartphones, being both fast and silent. The greater inherent DOF with a smartphone camera allows more structures to be in reasonable focus at any time. DOF on these cameras is usually good, due to the small sensor size and relatively wide‐angle lens. Lighting from the internal smartphone camera flash can result in significant overexposure when used for ophthalmic photography. This can be partially offset by applying a piece of transparent medical tape over the flash to decrease the intensity. However, because modern smartphones function very well in low‐light situations, good‐quality images can be obtained when using modeling or head‐mounted lights, without the need for the smartphone flash. Because using a smartphone camera is very intuitive, it will rapidly become an integral part of your everyday case documentation process. Images of a procedure or diagnostic test can be rapidly obtained, even when assistance is limited. Since these cameras have a wider field of view than dSLRs with a mounted macro lens, rapid procedure overview images can be obtained using a smartphone camera, without having to switch out your macro lens. Not only are such lens changes time con-

Figure 13.7  Cobalt blue filter illumination of a fluorescein‐ positive superficial corneal ulcer resulting from an improperly placed subpalpebral lavage system in a young Thoroughbred gelding. This image was taken 3 days after initial presentation.

lamp, surgical, or histopathologic images taken through a microscope (Fig. 13.9, Fig. 13.10, and Fig. 13.11). Smartphone Camera Limitations and Advantages

Limitations such as shutter lag (the time from when the shutter release button is fully depressed until when the image is captured) or focusing on a particular lesion/area of interest can be a problem. However, these minor inconveniences can

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Figure 13.8  A. Overview of upper eyelid location of tubing from a subpalpebral lavage (SPL) system that resulted in a large geographic superficial corneal ulcer in a young Thoroughbred gelding. This image was taken during the initial presentation (same horse as in Fig. 13.7). B. Footplate of the SPL tubing is visible approximately 12–15 mm proximal to the upper eyelid margin. Note the faintly fluorescein‐stained superficial corneal ulcer in the dorsal cornea.

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Figure 13.9  Slit lamp image of a subluxated lens with vitreal prolapse and peripupillary iris atrophy in a 9‐year‐old Quarter Horse gelding. The image was captured using an iPhone X held up to the ocular of a Kowa SL‐17 handheld slit lamp. Figure 13.11  Cytology sample from an infected corneal ulcer in a 15‐year‐old Missouri Foxtrotting Horse gelding. Multiple linear and branching fungal hyphae can be readily observed in this image taken with an iPhone X held up to the ocular of a microscope.

Figure 13.10  Postoperative image of a corneoconjunctival transposition to surgically treat a descemetocele in a young English Bulldog. This image was taken using an iPhone X held up to the ocular of a Zeiss operating microscope.

suming, they result in many images not being obtained due to personnel limitations, especially during examinations or surgery. Your smartphone camera will keep you from missing many of those shots in the future (Fig. 13.12).

Clinical Studio and Practical Aspects of Image Acquisition The “clinical studio” requires reduced ambient lighting (no overhead lighting and any ambient lighting in the exam room

Figure 13.12  This image of an intrastromal injection of voriconazole for the treatment of superficial keratomycosis was taken with an iPhone X.

should be at floor level). Photographs taken in brightly lit exam rooms (especially with overhead fluorescent tube lighting) or stalls or outdoors will usually have lighting artifacts and especially reflections from other light sources on the cornea. This necessitates the use of some form of modeling light on the flash unit or handheld light (Finoff transilluminator or slit‐lamp biomicroscope) to provide enough illumination of the subject to allow for focusing. In the clinical setting, it is rarely possible to use tripods to steady the camera: the patient tends to be a moving target

and, unlike in human photography, commands to avoid movement do not work. It cannot be emphasized enough that apart from the equipment and some knowledge of how to use it, successful clinical macrophotography depends on having helpers who can provide excellent restraint of the subject. Patience is essential from both the photographer and the helpers involved. Some practical suggestions will help in acquiring good‐ quality images (Fig. 13.13). Avoid photographing ophthalmic subjects outdoor or without flash illumination (Fig.  13.14), especially if wearing light‐colored clothing (white lab coats particularly). The patient should be well restrained. If restraining a small animal on a table, the holder should ideally be braced against the table with the animal’s head held against the body or, if possible, resting both arms on the examination room table. The photographer should also brace against the table or rest the elbows on the table, and use the elbows as a hinge point about which to move forward or backward to achieve adequate focus. For large animals, sedation is ideal (although not reasonable purely for taking photographs) and often will be required for the clinical examination per se. Support and relative immobilization of the head on a stack of hay bales work well. The photographer should not use one hand to hold the animal’s head or to open the eyelids (hands, arms, and fingers will appear reflected in the cornea; Fig. 13.15). The eyelids should be opened by the person providing restraint,

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by bringing the fingers over and under the head from the opposite side to the eye being photographed and placing the fingers above and below the eyelids. A third helper may be needed to provide modeling light to achieve focus. Although photographing eye lesions can occur at the time of anesthesia and surgery (in cases undergoing surgery to treat the disease), rotation of the eye may make it difficult to gain access to the lesions of interest. Additionally, some lesions may not be as evident in the anesthetized animal (for instance entropion), and the normal appearance of ocular structures relative to one another may be affected. Clinical photography should ideally be carried out on the awake animal whenever this is possible. Avoid taking photographs with ring flash units at very close working distances, to prevent the flash strobe reflection(s) appearing large on the corneal surface (Fig. 13.16). It is better to take the photograph from a slightly greater distance and then zoom into the image and crop as needed. Photographing from a slightly greater distance is also usually less stressful for the patient. Clinical photographs should not be performed immediately before animals undergo testing of retinal function, due to the photo pigment bleaching effects on the retinal photoreceptors. Electroretinography (ERG) should precede clinical photography; otherwise, ERG should be performed at least 60 minutes after photography (see Chapter 10, Part 4; Tuntivanich et al., 2005).

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Figure 13.13  A. Avoid use of fluorescent overhead lighting. B. Use a darkened examination room with any ambient lighting at floor level, not above the patient.

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Photographic Techniques

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External Macrophotography

Figure 13.14  Avoid photographing ophthalmic subjects outdoors or without flash illumination, to prevent loss of subject detail and appearance of artifactual reflections in the cornea.

Figure 13.15  The photographer should not use one hand to hold the animal’s head or to open the eyelids (or hands, arms, and fingers will appear reflected in the cornea).

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Macrophotography allows the photographer to capture detailed images of very small objects (e.g., lesions) and is an essential tool for the veterinary ophthalmologist. While it is possible to obtain usable and even relatively high‐quality images with different types of lenses, dedicated macro lenses allow even extremely small lesions to be visualized in detail. Most traditional macrophotography is done with the camera mounted on a tripod for stability, because even the slightest movement can result in motion blur. While tripod‐mounted shooting is possible for many different subjects and types of macrophotography, it is generally not feasible to routinely utilize a tripod when photographing animal eyes. As a result, most macrophotography performed in veterinary ophthalmology is done with the photographer stabilizing the camera in his or her hands and arms. This “handheld” method of camera stabilization requires a good deal of practice and patience before the technique is mastered. In addition to normal breathing and muscle movement from the photographer, subject movement also heavily influences the ability to capture a well‐focused image. While most modern lenses, including macro lenses, have quick and relatively quiet autofocus motors, one will achieve better and more consistent results if the lens is manually focused. Once the lens is set to the appropriate focal distance to capture the area of interest within the frame, subtle movement, toward or away from the subject, is all that is necessary to adjust, or fine‐focus, the image.

External Light Sources For most macro images taken of the adnexal and ocular structures, an external light source is essential. Since flash options

B

Figure 13.16  The size of the corneal flash artifact and its effect on the image (A) can be minimized by photographing the eye from a slightly greater distance (B).

were discussed earlier in the chapter, in this section we will focus on the effect of certain types and angles of external light that can be utilized to help highlight a lesion. While a table‐ mounted slit lamp is the instrument of choice for the human ophthalmic photographer, most veterinary ophthalmologists do not possess or have access to this piece of equipment. Table‐mounted slit lamp cameras are generally reserved for research or teaching purposes in an academic setting (Fig.  13.17). This does not, however, mean that one cannot capture informative, high‐quality handheld slit lamp images.

In addition to adequate manual restraint, a bright, handheld light source (e.g., a Finoff transilluminator) can be very useful, providing adequate illumination for the photographer to appropriately focus on the tissue or lesion to be photographed (Fig. 13.18). A transilluminator is bright enough to provide decent diffuse illumination and can be used as the sole light source to offer tangential (oblique) lighting. With a few minimal adjustments to the camera settings, clear, well‐ focused handheld images may be obtained. The sensor’s sensitivity to light (ISO) should be increased, the aperture size

Figure 13.17  Canine patient being manually restrained and positioned by a technician for table‐mounted slit lamp photography. (Courtesy of NC State University.)

Figure 13.18  A Finoff transilluminator is directed obliquely at the right eye in this horse to provide diffuse illumination. This improves the photographer’s visibility, and their ability to obtain a sharply focused image of the specific lesion of interest. (Courtesy of NC State University.)

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increased (a smaller f‐number represents a larger‐diameter aperture), and the shutter speed decreased (motion blur is more likely). Once the settings have been appropriately adjusted, it is essential that the camera (and the subject) is kept as still as possible to facilitate capture of a well‐focused image of the intended lesion or structure (Fig.  13.19). The graininess of the resulting image will depend on the ISO level, and motion blur can easily creep into the image due to even subtle movements from the subject, the camera, or both. A handheld slit lamp can be utilized to provide diffuse tangential lighting, as well as giving the photographer a means for obtaining handheld slit lamp images of the anterior segment (Fig. 13.20). This technique generally requires the help of at least one assistant (to restrain the animal and to steady the slit lamp), but the resulting images allow for more accurate documentation of many pathologic processes

(Fig. 13.21). This can be especially useful when consulting with colleagues via email. Alternatively, a smartphone can be held up or mounted to the slit lamp biomicroscope to obtain an image through the ocular. This method also requires the help of an assistant, but can result in some very useful images (Fig. 13.22).

Forms of Illumination Diffuse Illumination

Diffuse illumination is frequently utilized to accurately focus on the subject being photographed (Mártonyi et  al., 1984a, 1984b). While it helps with visualization of the lesion or area of interest, the light is rarely seen in the image due to the intensity of the flash. Frontal lighting provides diffuse, uniform illumination (Nicholl, 1985). While this is typically the most commonly utilized technique given the convenience of the pop‐up flash, the images generated are flat, lack depth, and generally include marked specular reflections, some of which may obscure regions of interest. Direct Focal Illumination with a Wide Beam

Figure 13.19  Oblique lighting from the Finoff transilluminator provided the sole source of illumination in this image and highlights the topographic features of the iris.

This technique is utilized frequently during the ophthalmic examination and is essential for localizing lesions within specific ocular tissues (Fig. 13.23). Two types of direct focal illumination, with a wide beam and with a narrow slit (optic section), are strategically implemented to highlight lesions within different tissues and various depths. Direct focal illumination with a wide beam of light helps to identify the limitations of the lesion being photographed, as well as putting the lesion into context with relation to its surrounding tissue. Additionally, the slit beam improves the examiner’s (and photographer’s) ability to determine the depth of a specific lesion within the cornea (Fig. 13.24) or lens (Fig. 13.25). Direct focal illumination may also be applied tangentially (Fig. 13.26) to provide visualization of the anterior chamber or iris through a cloudy cornea, or to highlight the topography of the iris and iridocorneal angle (ICA; Fig. 13.27). Direct Focal Illumination with a Narrow Slit

This technique allows for precise identification of the depth of a specific lesion within the light‐refracting tissue (cornea and lens) of the eye. Due to the differences in refraction at the anterior and posterior aspects of the cornea and lens, one can highlight a section of tissue using a narrow beam of light (optic section), which allows the examiner to determine the lesion’s depth based on its position relative to the anterior and posterior aspects of the tissue being evaluated (Fig. 13.28). Figure 13.20  A Kowa SL‐14 handheld slit lamp and a dSLR equipped with a macro lens are being used to capture handheld slit lamp images in a dog. (Courtesy of NC State University.)

Direct Focal Illumination Applied Tangentially

A focal light source can be directed at the eye from the nasal or temporal aspect of the globe and held roughly par-

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Figure 13.21  A. In this canine cornea, two circular lesions (medial descemetocele and axial corneal perforation plugged with fibrin) are readily visible. Mild corneal edema surrounds both lesions. Peripheral corneal vascularization and conjunctival hyperemia are prominent, and hyphema is present within the inferior anterior chamber. Anterior chamber depth is difficult to accurately determine in this conventional image. B. This handheld slit lamp image from the medial cornea in the same eye reveals the loss of corneal tissue down to the level of Descemet’s membrane and a collapsed anterior chamber.

Figure 13.23  Wide slit beam (parallelepiped) of light used to illuminate multifocal, punctate corneal endothelial opacities via direct retro illumination.

Figure 13.22  Slit lamp image of temporal vitreal prolapse in a horse obtained by holding an iPhone X up to the ocular of a Kowa SL‐17 handheld slit lamp.

allel to the surface of the iris. This method of illumination allows for a greater appreciation of the topography of the iris in the case of a clear cornea, and for indirect evaluation of the anterior chamber contents, even in the case of a cloudy cornea (Fig. 13.29). Diffuse, side illumination relies on the passage of light through a transparent media while observing scattered light from a dark background

(Christopherson, 1982). Under pathologic conditions, however, scattering within the corneal tissue may occur and is often best illustrated using a very oblique light source (Blaker, 1989; Mártonyi et al., 1984a). This type of lighting provides topographic information, yet fails to demonstrate the depth of a lesion. Demonstration of depth requires narrowing of the light source (as with use of a slit lamp), such that an optical section is created. This technique may be performed utilizing a dSLR camera and a handheld slit lamp as the primary light source; however, due to reduced lighting intensity, increased ISO settings (e.g., 800 and above) are often required.

Section II: Foundations of Clinical Ophthalmology

illumination. For simplicity, however, we will limit the discussion to direct retro illumination. Here, the light source must be coaxial (or close to it) with the imaging system, such that light reflecting from behind the lesion of interest is captured. Since the tapetum is present in most species examined, it often serves as the major reflecting structure. While this technique provides no information regarding depth, the silhouette effect created helps delineate extent and may provide information regarding the characteristics (e.g., obstructive vs. respersive) of the lesion(s).

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Infrared Macrophotography Figure 13.24  Note the brightly illuminated, punctate lesions along the posterior aspect of the optic section, localizing the lesions to the corneal endothelium. Lesion depth is precisely determined using the narrowest slit diaphragm (optic section) on the slit lamp.

Pinpoint Illumination (Tyndall Effect)

This highly specific form of illumination is utilized to help identify particulate/cellular matter within the aqueous humor, which may be otherwise invisible or very difficult to visualize (Fig.  13.30). The result of cellular accumulation within the aqueous humor is referred to as “aqueous flare” and is indicative of the presence of intraocular inflammation. It may be the only visible sign that the eye is actively inflamed and may be very subtle. Retro Illumination

This method of illumination is possible due to corneal transparency and is divided into direct and indirect retro

Most of the same principles as pertain to conventional macrophotography also apply to infrared macrophotography. Therefore, this section will cover specific points of consideration unique to infrared macrophotography. Digital cameras can be readily converted for infrared image capture (www.lifepixel.com; www.maxmax.com). Following conversion, digital infrared images can be obtained in the same manner as conventional color images. Following the recommended white balance calibration using green grass, the infrared converted camera is ready to use. When shooting in manual mode, aperture, shutter speed, and ISO can be readily adjusted, and the captured image is visible on the camera’s LCD viewing screen, similarly to that seen using a digital color camera (Fig. 13.31). A detailed description of the conversion process can be viewed at www.lifepixel.com. Briefly, the camera’s normal sensor, which contains filters to block out ultraviolet (UV) and infrared waves of light, enhancing the sensitivity to light within the visible spectrum,

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Figure 13.25  A. Note the multifocal, bright white, circular to linear opacities within the pupil margin in this horse’s eye. Additionally, a diffuse and dense, white cataract is present. B. This handheld slit lamp image from the same eye clearly demonstrates that the bright white, circular to linear opacities are located along the lens capsule epithelium, whereas the dense, white lens opacity involves the nucleus, but not the complete cortex. In the center of the image, clefting of the anterior lens sutures is readily visible.

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Figure 13.26  A. Conventional anterior segment image of an equine eye with chronic, nonulcerated keratitis and concomitant anterior uveitis. B. Tangential light is utilized as the sole source of illumination to highlight the changes within the anterior chamber in the same horse’s eye. Diffuse, dark, punctate to linear opacifications representing corneal endothelial pigment deposition and diffuse fibrin accumulation (network of pale strands) are highlighted within the anterior chamber.

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Figure 13.27  A. Conventional image of the left eye of a horse with a circular, inferior‐temporal area of corneal malacia, chronic peripheral corneal vascularization, and miosis associated with secondary anterior uveitis. B. Tangential lighting of the anterior segment of the same eye highlights the anterior surface of the iris and structures within the anterior chamber. Note the obvious presence of vessels along the surface of the inferior iris, just below the granula iridicae.

is removed and replaced with a sensor that contains filters for visible and UV waves of light, allowing infrared wavelengths to pass undisturbed. Since the captured image can be visualized on the camera’s LCD screen, immediate adjustments can be made to enhance its quality. Because of its longer wavelength compared to light within the visible spectrum, infrared light is less susceptible to scatter. This characteristic makes digital infrared photography an ideal means of visualizing the intraocular structures of the anterior segment (e.g., iris, lens) through a cloudy or opaque cornea (McMullen et  al., 2009; Fig.  13.32). Additionally, because of the ability of infrared light to pass through areas of edematous or fibrotic corneal tissue, essentially rendering them transparent, foci of cellular infiltrate can be made visible within these types of cornea lesions. This provides important information regarding a cornea’s

response to medical therapy, as well as postoperative lesion progression (Fig. 13.33). Infrared light is also absorbed by pigmented tissue, making it an ideal means for identifying small, often indiscernible areas of hyperpigmentation of the iris, even in animals with darkly pigmented (i.e., brown) irides (Fig.  13.34). Infrared photography of the iris provides a means of tracking the progression of pigmented lesions or masses (i.e., uveal melanocytomas/melanomas), as these areas of iridal hyperpigmentation are readily discernable from the surrounding, heavily pigmented, normal iris. This makes even subtle areas of hyperpigmentation along the lesion’s borders readily identifiable (Fig. 13.35). In diseases associated with pigment dispersion within the anterior chamber (e.g., pigmentary uveitis in the Golden Retriever) and iridal depigmentation resulting in corneal endothelial pigment

Section II: Foundations of Clinical Ophthalmology

the photographer to focus on the iris, while an external flash provides sufficient illumination to utilize moderate camera settings (e.g., ISO 200, f/16, and 1/250 shutter speed; Fig.  13.38). Alternatively, a Finoff transilluminator can be utilized to provide the sole source of illumination. This is especially useful for highlighting changes within the anterior segment using tangential illumination (Fig. 13.39). Plane of focus is important when shooting in infrared. Without using an external light source to illuminate intraocular structures (anterior chamber masses, iris, lens), the specific lesion or tissue structure to be photographed will likely be out of focus if the camera lens is parallel to the visual axis. Oblique infrared photographs taken medially or laterally at approximately 45degree angles from the globe allow the portion of the cornea closest to the lens as well as the iris and anterior lens surface to remain more in focus (Fig.  13.40). Using an external light source allows direct visualization of the specific tissue and structure(s) to be photographed, ensuring that the desired plane of focus is achieved.

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Figure 13.28  This handheld slit lamp image localizes these corneal opacities (diffuse, multifocal keratic precipitates in a 12‐year‐old Rat Terrier with chronic lens‐induced uveitis) to the corneal endothelium. Both direct (over the surface of the inferior iris) and indirect (over the pupil) retro illumination highlights the keratic precipitates located away from the optic section.

deposition (Fig. 13.36), infrared macrophotography may be useful in identifying subtle pigment changes present early in the disease process (Fig. 13.37). Similar lighting principles apply to digital infrared macrophotography as apply to digital color macrophotography. A Finoff transilluminator is used as a modeling light and allows

A

Slit Lamp Photography Table‐mounted slit lamp photography, while irreplaceable in human ophthalmology, is limited to research and academic settings in veterinary ophthalmology. Although there are several challenges to overcome, with a systematic approach and meticulous attention to detail it is possible to obtain handheld slit lamp images that provide useful additional information as well as enhancing case documentation. Therefore, in this section we will discuss some techniques that will enable documentation of both subtle and not so subtle changes in the anterior chamber using a dSLR and a handheld, portable slit‐lamp biomicroscope. Additionally, it is possible to obtain

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Figure 13.29  A. Conventional image of an 11‐year‐old Quarter Horse’s left eye following blunt force trauma. Temporal corneal edema, superior and medial areas of anterior synechiae, and a cataract are readily visible. Also note the mild accumulation of fibrin in the anterior chamber. B. Using tangential illumination of the anterior chamber, medial iris dialysis is readily visible. The mild fibrin accumulation identified in (A) is revealed to be more severe (moderate accumulation).

Figure 13.30  A thin slit beam of light is used to highlight the appearance of proteinaceous or cellular accumulation within the anterior chamber. Clinically this is referred to as aqueous flare and is a hallmark sign associated with anterior uveitis.

Good settings to start with are aperture f/11, shutter speed 1/640 of a second, and ISO 640, but these will constantly need to be adjusted based on the appearance of the image on the on‐camera LCD screen. If the image is overexposed (too bright), it may be necessary to decrease the aperture size (larger f‐stop number) and increase shutter speed, while at the same time decreasing the ISO. If the image is underexposed (too dark), adjustments in the opposite direction will be necessary: increase aperture size (smaller f‐stop number), decrease shutter speed, and increase ISO. The thickest slit beam of light will provide the most illumination, but will also offer the least amount of information pertaining to lesion depth (Fig. 13.42). By decreasing the size of the slit beam, the ability to assess lesion depth increases; however, it will also be necessary to increase the ISO, increase aperture size, and decrease shutter speed, due to the decreased illumination. It may be necessary to set the ISO at 1250, the aperture at f/4.5–5.6, and the shutter speed to between 1/80 and 1/200 of a second. This will lead to a grainier image with a shallow DOF, and it becomes increasingly more difficult to obtain a sharply focused image, due to motion blur (Fig. 13.43). Image stabilizers within the lens or camera significantly reduce the effects of motion blur, which results in well‐focused handheld images when using the previously described settings. Common artifacts associated with handheld slit lamp photography are reflections from the slit lamp or from surrounding objects or people, especially in a relatively clear, healthy cornea (Fig.  13.44). To prevent or minimize these artifacts, turn off all unnecessary overhead lights and cover all windows. Reflections from the light source (white slit lamp) can be more difficult to eliminate because of the proximity and angle of incident light necessary to illuminate the lesion or tissue for imaging. If this reflection cannot be completely avoided, try to confine the reflection to an area where it will have the least impact on the final image.

Goniophotography

Figure 13.31  Color image of the back of an infrared (IR) converted Nikon D200 with a black-and-white IR image on the LCD screen.

slit lamp images using a smartphone camera held up to or mounted to the ocular of the handheld slit lamp. While it is possible for the same individual to manage both the slit lamp and a dSLR, it is usually much more beneficial for an assistant to focus the slit lamp independently of the photographer (Fig. 13.41). This allows both the slit lamp and the camera to be individually stabilized and allows for greater control of the slit beam. Begin with the widest slit beam of light and with the camera in the manual mode of operation.

Many of the lighting and focusing challenges associated with handheld slit lamp photography are similarly encountered in goniophotography, due to the necessity of keeping the goniolens and the camera aligned while trying to simultaneously provide illumination with an external light source. With currently available handheld retinal cameras, it is possible to obtain acceptable gonio images. Using the Kowa Genesis‐D fundus camera set at a high flash output, the illumination is adequate to obtain diagnostically useful images of the ICA – notably the width of the anterior border of the cleft, presence of normal or dysplastic pectinate ligaments, or the presence of goniodysgenesis with sheets or partial sheets of mesenchyme across the face of the ICA. As with gonioscopy using any form of light source, the most easily imaged areas of the ICA are in the ventromedial, ventrolateral, and,

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Figure 13.32  A. In this conventional image of an equine eye with an axial amniotic membrane transplant (AMT), the pupil is not visible. B. Infrared photography of the same eye allows direct visualization of the pupil through an opaque cornea, or in this case through the AMT.

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C Figure 13.33  A. Conventional color image of an equine eye with chronic, ulcerative keratomycosis. B. Tangential illumination of the same eye. Note the enhanced visualization of the corneal vessels. C. Tangentially illuminated infrared image of the same eye. In addition to the dense area of cellular infiltration within the angle where the corneal vessels converge medially (3 o’clock position), there is also diffuse punctate cellular infiltrate within the cornea, axial to the superior corneal vessel terminations.

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Figure 13.34  A. Conventional color image of the left eye of a 19‐year‐old Cleveland Bay gelding 3 months following posterior lamellar keratoplasty. B. Digital infrared image of the same eye. Note the improved contrast within the darkly pigmented iris (e.g., granula iridicae) and the cornea. The notch defect in the medial aspect of the superior palpebral, which can be easily overlooked in the color image, is readily identifiable in the infrared image.

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Figure 13.35  A. Color image of the right eye of a 9‐year old, gray Quarter Horse gelding with multiple areas of iridal hyperpigmentation (1, 5, 6, and 9 o’clock positions), roughly halfway between the limbus and pupil margin. B. Digital infrared image from the same eye in which the described areas of hyperpigmentation are readily distinguished from the surrounding iris, despite its inherent level of pigmentation. The area of hyperpigmentation at the 5 o’clock position is raised from the surface (see the oblique view in Fig. 13.34), suggestive of an iris melanocytoma/melanoma.

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Figure 13.36  A. Color image of the right eye of an 11‐year‐old Quarter Horse mare with diffuse corneal edema and multifocal areas of superficial corneal ulceration associated with corneal bullae (e.g., small areas of fluorescein stain uptake). B. Digital infrared image from the same eye reveals diffuse punctate pigment deposition along the axial and inferior corneal endothelium. Infrared wavelengths of light pass through corneal edema with minimal scatter, allowing for a relatively clear view of the anterior segment despite a significant degree of opacification.

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Figure 13.37  A. Color image of the left eye of an 8‐year‐old male castrated Boston Terrier. A small translucent uveal cyst can be seen at the 3 o’clock position within the pupil margin (partially obscured by the flash reflection) and a larger, more heavily pigmented cyst can be seen within the inferior anterior chamber (5 o’clock position). A thin, interrupted line of hyphema can be seen spanning the distance between the two cysts. B. Digital infrared image of the same eye. Note that the translucent cyst seen at the 3 o’clock position within the pupil margin is closer to the cornea than to the iris (the pupil margin can be seen within the center of the cyst, and a curvilinear shadow from the cyst is being cast on the surface of the iris). Also, note the two additional uveal cysts medial and temporal to the larger cyst within the inferior aspect of the anterior chamber.

Figure 13.38  Digital infrared image taken with direct flash illumination. Note the presence of the large uveal cyst extending from the inferior pupil margin.

to a lesser extent, dorsomedial quadrants. The view of the dorsolateral quadrant can be more difficult due to the difficulty in positioning the head in such a way that the nose does not interfere with the positioning of the camera (Fig. 13.45). A Koeppe goniolens is applied to the topically anesthetized cornea using a viscous coupling solution (GonioGeL, Aurolab, Tamil Nadu, India) and held in place on the eye with the operator’s finger lightly applied to the top of the lens, which allows the lens to be moved over the cornea to obtain the best view of the ICA. A combination of the small movements of the lens and the camera itself will allow the ICA to be scanned.

Figure 13.39  Digital infrared image taken with tangential illumination. This is the same eye as in Figure 13.38. Note the increased surface detail of the iris and the three‐dimensional effect achieved by the creation of shadows within the anterior chamber. It is clear in this image that the uveal cyst has adhered to the corneal endothelium inferiorly (anterior synechia), and that there is a relatively large space between the cyst and the surface of the iris.

As with retinal photography, it is essential that the prism on the front of the camera is positioned as close to the goniolens (2–3 mm) as possible, to avoid a bright flash reflection artifact that will totally obscure the ICA. This is easily achieved with practice. Resting the camera against the hand holding the goniolens allows you to move with any small movements the animal may make (Fig. 13.46). A photograph is taken in each quadrant when the ICA appears at its widest extent. ICA photographs are taken

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Figure 13.40  Oblique digital infrared image of the same eye as in Figure 13.35. Images taken from this perspective help to create a three‐dimensional impression of any lesions present. In this image, it can be appreciated that the inferior‐medial area of hyperpigmentation is slightly raised above the surface of the iris. A small shadow is cast behind the lesion, suggesting elevation. Tangential illumination, as in Figure 13.39, can be used to further emphasize changes in surface elevation, as the shadows created are much more dramatic.

Figure 13.42  Handheld slit lamp set to the largest diaphragm setting, being demonstrated in a horse. (Courtesy of NC State University.)

relatively dark to minimize glare while the surgeon is working under the microscope. This requires that adjustments be made to the camera settings. Images taken during microsurgery can be obtained both with and without a flash. Illumination from the microscope is sufficient to obtain photographs highlighting specific procedural steps. However, these images are generally a bit darker and lack some of the detail that can be achieved with a flash (Fig.  13.48). Intraoperative flash photography readily provides the foundation for well‐focused, interpretive images representing the real‐time appearance of the subject. Both color and infrared digital images can be obtained peri‐ or intraoperatively with only minimal (if any) changes to the camera settings used for external photography (Fig. 13.49).

Fundus Photography Figure 13.41  Handheld slit lamp and oblique positioned dSLR utilized to obtain slit lamp images of the anterior segment in the horse. Note that the slit lamp and camera are being focused independently by separate individuals. (Courtesy of Silas Zee, Auburn University.)

before mydriasis and using the Genesis‐D camera, with a reasonably bright focusing light intensity and flash strobe set at about 12. Usually the flash intensity must be bracketed widely, depending on the extent of pigmentation in the anterior segment of the individual eye (Fig. 13.47).

Surgical Photography Peri‐ or intraoperative ophthalmic photography follows many of the same principles as macrophotography described earlier. One major difference is that the surgery suite is often

Most of the fundus photography performed in veterinary ophthalmology is obtained with specialized fundus cameras. One of the greatest disadvantages associated with digital fundus photography is the comparatively low image quality when compared to dSLR images. The dated technology of the currently available digital handheld, portable fundus cameras (e.g., the Kowa Genesis is a 2 megapixel camera) and the limited number of readily available, and affordable, fundus cameras that can obtain quality images contribute to this dilemma. Fundic images can be obtained with a dSLR and a condensing lens, but the results are inconsistent. Because it is extremely difficult (if not just about impossible) to visualize the exact portion of the fundus that is to be photographed while capturing the image in this manner, there are many necessary camera adjustments that must be made, and constant repositioning is necessary to obtain high‐quality images. The inherent difficulty associated with this technique, in addition to the relatively unpredictable results, generally

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Figure 13.43  A. Color image of the right eye of a 23‐year‐old Hanoverian Warmblood gelding with endotheliitis and anterior uveitis associated with pigment dispersion. B. Handheld slit lamp image from the same eye. The camera settings were adjusted to allow for image capture using the slit lamp as the sole source of illumination (ISO 1250, f/5.6 and 1/80 of a second). A relatively grainy image is to be expected.

Figure 13.44  Note the reflection of the white, handheld slit lamp, as well as the person holding the instrument, in this horse’s cornea. This can be minimized or avoided by using a Finoff transilluminator as a modeling light for focusing, and by having the assistant stand on the opposite side of the animal.

results in very few fundic images being obtained with this method. This practice has been all but superseded by dedicated handheld fundus cameras or smartphones. Although the image quality is inferior to those obtained with a dSLR, the availability of smartphones and the relative ease by which fundus images can be obtained has made this approach more feasible in a busy practice or even specialty referral center. However, while fundus images obtained in this manner are of acceptable quality for basic documentation and client education, they often lack detail and cannot be used to highlight subtle retinal lesions. Specific, digital handheld fundus cameras, such as the Smartscope (Optomed, Oulu, Finland) and

ClearView (Optibrand, Fort Collins, CO, USA), have been utilized in an attempt to bridge the gap in fundus photography that has resulted due to the decreased use of more sophisticated handheld fundus cameras in human ophthalmology. While the overall expense associated with the Smartscope and ClearView fundus cameras can be considered reasonable, the image quality does not rival that once obtained using film‐based handheld fundus cameras. That fact, coupled with the ever‐improving quality of smartphone cameras, has resulted in a general lack of dedicated, high‐quality (i.e., publishable image quality) digital fundus cameras for routine use in veterinary ophthalmology. Recently, a prototype lens adapter has been developed that allows exceptional fundic images to be obtained when mounted to a dSLR (Pirie & Pizzirani, 2011a). Imaging of the posterior segment using this adapter relies on the principles of indirect ophthalmoscopy. This system utilizes an indirect ophthalmic lens, common to the examiner, which is secured in front of a camera lens. The indirect ophthalmic lens forms a real, inverted aerial image at the object plane of the camera lens, which then forms the final image for the camera sensor. Alteration of the indirect lens is possible, allowing for alterations in magnification and field of view. Using lenses ranging from 28 to 90 D, an approximate magnification range between 1× and 4× and an approximate field of view range between 30 and 95 degrees (horizontal axis) are possible when imaging the canine eye (Pirie & Pizzirani, 2011b). The ClearView must be connected to a computer or laptop, where the images are automatically downloaded to a “ClearViewImages” folder and organized in subfolders labeled with the animal owner’s last name. Individual patient folders contain subfolders for each examination, organized by date of acquisition. Once the ClearView

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Figure 13.45  Photographing the iridocorneal angle and pectinate ligaments using a Genesis D fundus camera.

Figure 13.46  Goniophotography using a Genesis D fundus camera. The hand holding the camera is rested against the animal’s head. The iridocorneal angle is brought into focus by moving the camera and the goniolens on the cornea using the finger of the opposite hand, and rotating the focusing dial on the camera.

c­ amera is attached to the laptop/computer and the software application is opened, the images are readily obtained in a “burst” fashion. The shutter release button (located on the side of the camera) is depressed and held down to obtain a short burst of four sequential images. The camera is held up to the animal’s eye in a noncontact manner while the person obtaining the images confirms the correct location and focus by viewing the computer screen (Fig. 13.50). There is a short learning curve associated with this camera, but it does not take long to become comfortable using it. The ability (or necessity) to view the image directly on the computer screen makes this camera useful for teaching and client education purposes. The ClearView focuses automatically

Figure 13.47  Goniophotograph of a normal, open iridocorneal angle of a 6‐year‐old male neutered mixed‐breed dog.

on the retina of the animal being examined and the diopters cannot be manually adjusted (Fig.  13.51). As a result, the fundus cannot be accurately imaged in an aphakic or pseudophakic eye. The SmartScope/SmartscopePro is a self‐contained, nonmydriatic handheld unit with a 40 degree field of view. The camera has 5 megapixels of resolution and is capable of capturing color, red‐free, and infrared, still and video images. It has 8 GB of memory. Image transfer from the camera to a computer can be achieved via USB or over Wi‐ Fi. The camera back is fitted with a 2.4 in. LCD display that provides the photographer the ability to visualize the fundus in his or her line of site, thus allowing for direct control of the image focus. The SmartScope has autofocus, as well as allowing for manual diopter adjustments within a range of –20 D to +20 D.

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Figure 13.48  Intraoperative image using only the light from the operating microscope. High‐frequency diathermy is being used to perform an anterior capsulotomy in a 2‐year‐old Quarter Horse mare.

Figure 13.49  An external flash was utilized to capture this intraoperative image following intraocular lens implantation in an adult horse. Some corneal artifacts may be present (instrument reflection in the cornea) if the light from the operating microscope is not momentarily blocked while the image is being taken.

Over the past decade there has been increasing popularity, availability, and use of smartphones in clinical ophthalmology. These devices offer important and expanding diagnostic capabilities, allowing the user a fully embedded imaging system, capable of acquiring, storing, and transferring images wirelessly. Several ophthalmic applications are available for different examinations that can assess visual acuity, color vision, astigmatism, and pupil size, to name a few. More importantly, in conjunction with the use of various adaptors and apps, these devices are capable of imaging the posterior segment in a variety of species (Haddock et  al., 2013; Kanemaki et al., 2017). They offer the user a more cost‐effective means to capture images of the fundus. Most smartphone fundus cameras and photoadaptors rely on the principle of indirect ophthalmoscopy. Accessory

Figure 13.50  ClearView camera being used to image the fundus of a 7‐year‐old Icelandic Horse mare. The image is captured via a laptop connected via a USB cable (computer not shown).

Figure 13.51  ClearView fundus image of the right eye of a 10‐year‐old American Paint Horse gelding with equine motor neuron disease. Note the reticulated pattern of pigment clumping that is a consistent ocular finding in affected horses.

lens(es) employed may be mounted in a specific housing and/or held freehand. Various lens configurations have been assessed utilizing a number of different smartphone models/ suppliers and have been shown to produce a field of view comparable to that of conventional fundus cameras (Ludwig et  al., 2016). The imaging technique is detailed in a recent report (Haddock et al., 2013) and it is generally accepted that increased image quality is acquired with continued practice and patience. While these low‐cost smartphone systems offer the user a more affordable alternative, good image quality is a prerequisite for their diagnostic utility. In physician‐based medicine, comparative studies have demonstrated conflicting results pertaining to image quality. In one report, smartphone‐based

imaging generated images of low quality, compared to a standard fundus camera (Darma et al., 2015). An alternative report demonstrated no statistically significant difference (Adam et al., 2015). To date, no comparable study has been performed in veterinary medicine. An additional point of consideration is the photobiologic safety of conducting fundoscopy using these smartphone‐based systems. The light safety limits for ophthalmic instruments are set by the ISO (ISO 15004‐2.2) and it has been recommended that spectral irradiance on the retina be weighted separately for both thermal and photochemical hazards. To date, only one safety study has been performed, comparing retinal exposure levels of a smartphone‐based imaging system to those of conventional indirect ophthalmoscopy (Kim et  al., 2012). Based on this report, retinal exposure from a smartphone was one order of magnitude less than that of indirect ophthalmoscopy and within the ISO safety limits of thermal and photochemical hazards. Currently, it can only be assumed that the light intensity and energy levels generated by other, newer smartphone‐based systems are comparable. Similar light safety evaluations have not been conducted for other smartphone models. Fundus photography is difficult not only for the reasons listed, but also since even when utilizing a specialized fundus camera, many minor camera adjustments must be made to obtain consistent images, even from the same location within an individual eye. Depending on which part of the fundus is being photographed, several adjustments may be necessary from one image to the next. Often, it is necessary to frequently alternate lighting adjustments even at the same location within the fundus from the same eye, to obtain a well‐illuminated and sharply focused image. The following section is based on obtaining fundus images with the Kowa Genesis‐D digital fundus camera (Kowa Optimed, Torrance, CA, USA; Fig. 13.52). Prior to obtaining fundus images, ensure that the camera is properly set up and focused for use. There are focusing mirrors within each ocular (similar to most handheld portable slit‐lamp biomicroscopes). Adjust the oculars so that two sharply focused sets of lines are visible in each (rotate oculars clockwise or counterclockwise to focus). Once the camera has been focused, start with the flash level set to medium and the intensity level at 3 or 4 (right dial) when photographing a dog, or 4–5 when photographing a horse (for cats, set the flash level to low and the intensity level at 0.3 or 0.4 to start with), with the optic nerve head in the center of the image. The left dial on the base adjusts the amount of incident light, which allows the photographer to visualize and focus on the fundus. In order to make the imaging process easier, decrease this light intensity to as low as possible while still allowing visualization of the fundus. This will minimize resistance from the animal due to excessive light stimulation. If this light is kept as low as possible, most animals will tolerate the flash relatively well.

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Figure 13.52  Kowa Genesis‐D camera, assembled and ready for use. (Courtesy of NC State University.)

There is a significant learning curve associated with using a handheld fundus camera because of operator movement caused by triggering the on‐camera shutter, the delay associated with the foot pedal, and retraction of the globe by the animal. To trigger image capture on camera, it is necessary to activate a horizontal green lever, located on the grip, after ensuring that the image is in focus (manual adjustments can be made by adjusting the focusing wheel toward the front of the camera). To avoid the common flash artifact associated with images taken with this camera, the lens needs to be very close to the cornea (within 2–3 mm). This requires quite a bit of practice and a steady hand. Generally, this is achieved by resting the camera against the first finger (from the opposite hand) that is being used to hold the eyelids open. That ensures that you are always aware of where the camera is, and you can readily reposition following the regular breaks that are necessary to ensure that the cornea remains hydrated. Periodically, your view of the fundus will go from being in focus to blurry without any adjustments on the part of the photographer. This is generally associated with active globe retraction and movement of the nictitating membrane. Remain patient and do not make any major adjustments during this period. Instead, give the animal a short break and resume. Once the fundus has been brought into focus, only minor adjustments should be necessary.

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When photographing the tapetal portion of the fundus, the light intensity should be decreased incrementally to prevent overexposure. Light intensity will need to be increased accordingly to prevent underexposure when photographing the nontapetum (Fig. 13.53). As with any method of photography, regular use and critical evaluation of one’s techniques and settings are necessary to become proficient in obtaining high‐quality fundic images.

Photography of Specific Lesions Adnexal Lesions Accurate representation and depiction of adnexal lesions often require forethought and technical considerations on the part of the photographer. Composition of the final image(s) should always be planned from the beginning, with special attention given to the placement of the flash (Olsen, 1979). When imaging the adnexa, it is important first to obtain an overall representation of the lesion(s) such that a story is created. This entails imaging not only from several viewpoints, but also at varying magnifications. By doing so, the viewer obtains a greater appreciation of the “big picture.” Simply obtaining a close‐up image of an upper eyelid mass leaves the viewer with no perspective for comparison. One recommendation is to obtain at least two images (often several), one of low and one of high magnification (Christopherson, 1982; Fig.  13.54). Imaging at low magnification is performed to obtain an overall perspective of the lesion/abnormality that is being depicted. This is generally obtained by imaging the animal initially straight on using a front light source, with the plane of focus being the animal’s eyes. This method of illumination allows for uniform lighting (Mandell et al., 1976). From here, alteration in the point of view and/or angle of illumination (e.g., 45 degrees) may be performed to better relay information regarding depth and/or variations in profile. Magnifications typically employed for this purpose are approximately 1 : 8 to 1 : 5, utilizing an aperture setting of f/11– 22 (Gutner, 1977; Mandell et  al., 1976; Olsen, 1979). From here, imaging of the region of interest should be conducted at higher magnification(s). These images may involve a series of incremental increases in magnification and are obtained to more accurately depict pathologic changes of the lesion(s) of interest. Use of side lighting is preferred here as it creates shadows, improving textural detail and depth within the image. The specific location of the light source (e.g., left vs. right side) may vary, depending on the desired effect and specific location of the lesion. Magnifications typically employed will vary depending on the size of the lesion, typically ranging between 1 : 4 and 1 : 2 (Christopherson, 1982; Olsen, 1979). However, one must always bear in mind the effects of increasing magnification and DOF. As such, higher aperture settings

(e.g., f/32) may be required to ensure the maximum amount of DOF within the image. Some potential artifacts present in the final image while photographing adnexal lesions often relate to the light source. As previously mentioned, use of a point light source (e.g., flash) often results in harsh lighting, which generates pronounced specular reflections. Use of a diffuser may be of benefit while working at lower magnifications (Mandell et  al., 1976). A diffuser will not only decrease the intensity of these reflections, but also provide more uniform illumination.

Corneal Lesions Imaging the cornea creates some additional considerations, as the goal may be not only to illustrate the presence, size, depth, and/or morphology of a particular lesion, but also to demonstrate its transparency. The latter point is of the greatest difficulty, but is achievable with careful placement of the light source. Two methods often employed to photograph the cornea include utilizing a standard camera (e.g., dSLR) and/or a slit‐ lamp biomicroscope. However, the latter produces a limited DOF, due to the optical design of the system (Tate & Safir, 1980). Regardless of which modality is employed, the concepts and methods are comparable. When composing the final image, the lesion of interest should be centrally located, demonstrating its size, topography, and relationship with surrounding tissues (e.g., conjunctiva, sclera, and eyelids). Magnifications required for this purpose typically range from 1 : 1 to 2 : 1, utilizing an aperture around f/22–32 (Gutner, 1977; Olsen, 1979). A 1 : 1 magnification ratio will allow for the globe and surrounding tissues to be imaged (small animal), while a 2 : 1 ratio will result in the cornea filling the image (Christopherson, 1982). Most available macro lenses will allow for a 1 : 1 ratio to be obtained; however, going beyond this (e.g., 2 : 1) requires some modification. Several methods may be employed for this purpose and include the use of extension tubes, teleconverters, close‐up lenses, and/or reversing lenses. While each has its own advantages and disadvantages, it is the authors’ preference to utilize extension tubes, if needed. Table  13.3 provides a brief summary. One additional point of consideration is proper alignment between the corneal lesion and the camera lens as magnification increases (and DOF decreases). The axis of the lesion should be oriented perpendicular to the camera lens (e.g., sensor), thereby maximizing focus. This nevertheless becomes somewhat difficult with unrestricted ocular movements. Due to the spectral properties of the cornea, a number of lighting techniques may be employed, each revealing often dramatically different features/properties of the lesion(s). These may include frontal, side, and retro illumination lighting techniques. Figure  13.55 provides examples of these

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D Figure 13.53  Normal fundic images from (A) canine, (B) feline, (C) color‐dilute equine, (D) bovine, and (E) camelid (alpaca).

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Figure 13.54  A. A 12‐year‐old Golden Retriever with upper and lower eyelid masses of the left palpebrae. B. Close‐up of left eye. The smooth upper eyelid mass involving approximately 50% of the upper eyelid can be readily distinguished from the multilobulated pink to partially pigmented mass affecting the central and lateral aspect of the inferior palpebra, extending into and involving the lateral canthus.

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C Figure 13.55  Images obtained from the same patient demonstrating the effects of different lighting techniques. While the following series illustrates changes involving the lens, similar effects are noted with corneal lesions as well: frontal lighting (A), side lighting (B), and retro illumination (C). Note in (A) the lack of detail, marked flash artifact, and poor illustration of regions of interest (e.g., cataracts). Using side lighting (B), displacement of the flash artifact and the direction of light allow for improved visualization and depth. In (C), improved visualization and illustration of more subtle details are clear.

while preventing ocular movement is not often possible, limiting head movement can be of great benefit. Last and generally speaking, the shutter speed should be no slower than the focal length of the lens being used. This is true while working at low magnifications and becomes of increasing consideration at high magnifications. Another artifact, in addition to motion artifact, is specular reflections involving the cornea, some of which may obscure regions of interest. These reflections (e.g., flash artifact) simply demonstrate the ability of the cornea to act like a convex mirror. As such, it is important to pay particular attention to the location of the flash (and subsequent artifact), as simply relocating its position may largely reduce these reflections. Similarly, it is important to instruct the person restraining not to peer over the animal’s head, since reflections of this individual’s face (or anyone in close proximity) may be reflected in the cornea. These reflections, however, can largely be eliminated through the use of specialized equipment and/or cross‐polarization (Fariza et  al., 1989; Pirie & Pizzirani, 2011a; Shun‐Shin et al., 1992), the latter being a relatively simple technique that utilizes two linear polarizers, one over the light source (e.g., flash unit) and the other over the camera lens, as demonstrated in Figure 13.57. It should be pointed out that while specular reflections often obscure details of interest, they may serve some purpose in the determination of refractive indices, measurement of binocular misalignment, and corneal diameter (Howland, 1980; Quick & Boothe, 1992; Robinson et al., 1989).

lighting techniques, illustrating their primary effects. To capture a sharply focused image of a corneal surface lesion, ensure that the first Purkinje–Sanson image (reflection from precorneal tear film or corneal epithelial surface) is in focus. The source of the Purkinje–Sanson image may originate from incidental light, a handheld light source, or the focusing light emitted by the camera. It is generally helpful to turn off any overhead lights when photographing an animal’s eyes, as this will eliminate unwanted reflections in the cornea. A clear, healthy cornea has an extremely reflective surface. Overhead or natural light shining onto the cornea results in the reflection of surrounding objects appearing on the corneal surface of the final image (Fig.  13.56). White objects will reflect strongly from the corneal surface, and a conscious effort must be made to prevent capturing the reflection from the slit lamp or bystanders wearing light‐colored clothes in the final image (see Fig. 13.44). As discussed, imaging the cornea typically involves a magnification ratio of 1 : 1 or above (Gutner, 1977; Olsen, 1979). At these magnifications, DOF is limited and may be compensated to some extent by reducing the aperture size (e.g., increasing f‐number). However, as the magnification of the image increases, so does the magnification of any movement. This movement may be on the part of the photographer and/ or the patient. As such, some general guidelines should be employed in an effect to maintain a sharp image and minimize motion artifacts. First, always ensure that you, as the photographer, are stable. This may require leaning on the examination table or wall to prevent body movements or hand tremors. Second, proper animal restraint is important;

Anterior Uveal (Iris) Lesions

Figure 13.56  This image was taken of a horse’s left eye in an open stall. The blue sky, with clouds as well as surrounding pine trees, can be seen within the pupil. Additionally, there is a very bright flash artifact on the cornea, over the temporal iris. Due to the amount of incidental light, the lashes and vibrissae also cast their reflection onto the cornea. (Courtesy of Erin Matheson‐Barr.)

The iris is a unique structure within the eye, in that it is a well‐textured surface in an array of colors (Fig. 13.58). Typical magnifications required to image the iris are comparable to those for the cornea and include magnification ratios of 1 : 1 and above. Recall, however, that DOF is significantly reduced at these magnifications. This creates an additional challenge when imaging the iris, due to its normal convex profile. Therefore, to ensure proper focus within the final image, it is imperative to ensure correct alignment of the camera lens to the iris plane. When composing the final image, the iris should fill the frame within the viewfinder, placing the pupil centrally. The final image obtained should provide the viewer with an overall representation of the lesion as it pertains to the iris itself, and any surrounding tissue(s). Higher magnification, focusing on the lesion of interest, may then be obtained to provide greater pathologic detail. The iris is best illuminated using either side lighting (tangential lighting) and/or retro illumination techniques. As previously discussed, side lighting creates sharp‐edged shadows, improving on textural detail and depth perception within the final image. This method of illumination is particularly useful when demonstrating topographic changes

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Figure 13.57  Images obtained from the same patient demonstrating the effects of nonpolarized (A) and polarized lighting (B). Note the improved detail within (B) due to a significant reduction of corneal specular reflections (e.g., no reflection of palpebral conjunctiva, reduced flash artifact, etc.).

(e.g., raised anterior uveal melanoma), and also allows visualization of the anterior chamber and surface of the iris through an opaque cornea (Fig. 13.59). Although the specific location of the light source will vary based on the location of the lesion, it is important to pay attention to specular reflections generated on the corneal surface, as these may obscure regions of interest. An external, handheld light source used to illuminate the globe from the side generally requires a slower shutter speed and larger aperture to ensure adequate illumination of the subject (Fig. 13.60). Alternatively, camera settings routinely utilized for photographing the anterior iris (i.e., f/16 and 1/250 exposure) are selected, while an off‐­ camera flash positioned nasally or temporally from the globe provides the appropriate illumination to capture a similar image (Fig. 13.61). Retro illumination may be useful instead, relying on light reflecting from the fundus (e.g., tapetum). While not a transparent tissue, this illumination technique may demonstrate both structural and pathologic abnormalities of the anterior uvea

Figure 13.58  Conventional image of a horse’s iris with adjusted camera settings (f/13; 1/160 second; ISO 640) to better visualize the details of this darkly pigmented tissue using an external flash.

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Figure 13.59  A. This image was taken using an external flash, an aperture setting of f/20, and a shutter speed of 1/200 second. B. This image of the same eye was taken without a flash and with the aperture set to f/5.6 and the shutter speed reduced to 1/200 second. Tangential illumination allowed for direct visualization into the anterior chamber.

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Figure 13.60  A Finoff transilluminator is shown providing tangential illumination as the sole source of lighting in this canine patient. (Courtesy of Silas Zee, Auburn University.)

Figure 13.61  Tangential lighting is provided with an off‐camera flash held temporally to this horse’s eye. This technique is useful in highlighting changes on the surface of the iris. (Courtesy of NC State University.)

(Fig. 13.62). It requires some considerations, including the position of the light source and pupil size. For light to pass first through the pupil and onto the reflective surface (e.g., fundus), it must be positioned as close to the camera lens as possible (or be coaxial to it). Furthermore, the pupil must be of sufficient size to allow enough light to pass. While pupillary dilation allows a greater amount of light to be transmitted, less iris tissue is visualized due to peripheral displacement. As such, the preferred time to conduct this imaging technique is shortly after the instillation of a dilating agent, prior to its maximum effect. This provides a balance between the pupil size and degree of iridal tissue still visualized and thus capable of being retro illuminated. Additional imaging techniques may rely on altering

Figure 13.62  Retro illumination image of the left eye of a 14‐year‐old Paint Horse gelding. The red fundic reflex is due to the lack of tapetum and pigment in the retinal pigmented epithelium. The areas of increased transparency within the iris are due to a lack of iridal pigment (heterochromia irides) and subsequent iris atrophy. The dark curvilinear band that is visible midway between the ventral edge of the pupil and the lower eyelid margin represents the ventral aspect of the lens. This structure is not normally visible.

the illumination source and/or use of special filters (e.g., red free; Fig. 13.63). Furthermore, advanced imaging techniques, such as fluorescein angiography, may be conducted to assess the iris vasculature (Fig. 13.64; Alario et al., 2012).

Lens Lesions The lens is normally a biconvex transparent structure located behind the anterior uvea. Under various disease states, alteration in its transparency and/or position may occur and can

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Figure 13.63  Red‐free image of the feline iris.

Figure 13.65  Image of a posterior cortical cataract in a dog via retro illumination. Note the subtle detail and improved visualization of lens involvement obtainable using retro illumination.

the lens, maximum pupillary dilation (unless contraindicated) is recommended. This will limit any masking effect by the anterior uvea and improve the photographer’s ability to retro illuminate the lens.

Retinal Lesions

Figure 13.64  Image demonstrating anterior segment fluorescein angiography of the feline iris (same eye as Fig. 13.63) during the early venous phase. Note the clear visualization of the major arterial circle, iris arterioles, and venules.

be documented photographically. This may be performed utilizing either direct and/or retro illumination techniques. Direct illumination may be conducted using either front or side lighting, with the latter being preferred. Utilizing this method of illumination, light is either refracted or scattered within the lens. The former often results in the overall bluish appearance typically seen with nuclear sclerosis, while the latter causes opacities (e.g., cataracts) to appear white. Retro illumination, on the other hand, is not subject to refraction, only obstruction, and results in lenticular opacities appearing dark/black (depending on the density of the lesion). This method of illumination provides improved visualization of subtle changes in lens transparency (Fig. 13.65). Magnifications typically employed to image the lens are comparable to those required for both the cornea and the iris. However, due to its biconvex nature, only a small plane of focus is maintained within the final image. As such, it is imperative to maximize the DOF (e.g., smaller apertures) where possible. Of final note is that when specifically imaging

Imaging of the retina typically relies on the use of a devoted fundus camera; however, newer alternatives are becoming increasingly available (Chalam et al., 2009; Guyomard et al., 2008; Pirie & Pizzirani, 2011a). Conventional fundus cameras are based on the principle of reflex‐free indirect ophthalmoscopy (Gullstand, 1910). Magnifications and fields of view that may be obtained are dependent on the imaging system and may range from 2× (low magnification) to 5× (high magnification; Allen, 1964). Some units are fixed and do not allow for any such variation. Similarly, flash settings available will vary depending on the power of the flash unit within the system. As such, it is important to review the manual of the system being used to ensure a clear understanding of these parameters. Prior to attempting to image the posterior segment, it is important to ensure the fundus camera has been correctly focused for the photographer. This procedure is like that required for use of a slit lamp and relies on the presence of crosshairs/lines within the objective of the camera. Once proper focus of the camera has been obtained, the photographer is now ready to image the posterior segment. If utilizing a portable unit, this process involves axial movement of the system toward the patient until proper focus of the retina has been obtained, a technique like direct ophthalmoscopy. Fine‐ tuning using the dioptric adjustment on the unit may be required due to the refractive error of the patient. Alternatively, because of the inherent shallow DOF provided by these units, changing the plane of focus may be needed depending on the lesion of interest.

The final image obtained should ideally be sharply focused, evenly illuminated, and deeply saturated in color (Leutwein & Littmann, 1980). While these imaging systems can obtain high‐quality images, it is important to acknowledge that the globe itself plays a vital role in the quality of the final result. As such, any alteration in the normal transparency of the cornea, lens, and/or vitreous may significantly reduce image quality. The final image should provide an overall representation of the lesion(s) of interest and include the optic nerve head as a point of reference (Nicholl, 1985). If illustrating changes in topography (e.g., swollen optic nerve head), it is common practice to obtain the initial image(s) at the most elevated surface within the field, followed by a series of images altering the depth of field as needed. Additional photos, varying the field of view and/or magnification, may then be obtained. Several techniques have been recommended whereby a series of standardized overlapping images are obtained to describe fundus abnormalities (Diabetic Retinopathy Study, 1981). Furthermore, with the use of a digital‐based imaging system, these standardized approaches may allow for the creation of collages via several imaging software programs (Hackel & Saine, 2005; Mahurkar et al., 1996; Fig. 13.66). Common artifacts that may be noted in the final image of the fundus generally relate to incorrect axial positioning of the camera and/or misalignment. If the camera is too close to the eye, a bright bluish‐white reflection will occur within the center of the image (Fig. 13.67). If the camera is too far away, the image obtained will be poorly saturated and contain a bluish‐gray ring around its periphery. If the camera is misaligned, an orange crescent will result within the final image. Correction of this artifact requires movement of the camera in the opposite direction from the side of the crescent (Justice, 1982).

Image Capture, Storage, Archiving, and Retrieval Digital Darkroom The cataloguing, processing, and output of images in a digital environment require various considerations relating to

Figure 13.66  Fundus montage of a heterochromic canine eye. This image was generated from a series of five images and blended using Adobe Photoshop CS4.

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B Figure 13.67  Fundus images demonstrating the effects of improper positioning. Imaging system too close (A) and too far (B) from the patient.

the computer system chosen. Most image cataloguing and editing applications are best used on computers with a fast‐ central processing unit (multicore processors) and large amounts of high‐quality random‐access memory (RAM). High‐quality graphics cards are recommended for image processing applications. Hard drives need to be of high capacity and have speeds of 7200 rpm or more. Internal connections with serial advanced technology attachment (SATA) provide fast processing, although these may be replaced by faster serial‐ attached (SAS) small computer system interface (SCSI) drives. In the future, we may expect to see more use of solid‐ state drives (SSDs) for the operating system and applications in desktop computers, with data (including image) storage on other (SATA or SAS) internal and/or external hard drives. External hard drives used for accessing imaging collections should at least aim to use eSATA or USB 3 connections for speed of access. For imaging processing on laptops or connecting to multiple computers, external hard drives can be used and should have eSATA or USB 3 connections. Laptops with SSDs are fast enough for the cataloguing/editing software, although the actual image collection (which may become large) is

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­ etter housed on an external hard drive. Laptops should ideb ally have two external hard drives connected so that images can be mirrored on both drives in case of drive failure. A high‐quality monitor (or monitors) is required, generally light‐emitting diode (LED) backlit with at least 12 bit color depth and internal calibration ability. A monitor profiler (X‐Rite i1Display Pro, www.xrite.com, or Data Color S5P100 Spyder 5PRO Elite, spyder.datacolor.com) can be used to ensure that the colors seen on the monitor are as close to reality as possible.

File Types For most veterinary ophthalmologists, the easiest and most easily managed files are JPEG – these have the advantage of a relatively small file size and yet adequate quality (data retention) for storage in medical records, publications, or use in slideshow presentations. This is a lossy format (data are discarded at the time the photograph is taken), and the downside to the format occurs if you plan further pixel editing (e.g., in Photoshop), which will further degrade the image. If any editing is done on virtual images in parametric image editing applications (e.g., Lightroom), this is not an issue since the imported master images are not “damaged” in the editing process (and all edits are easily reversible). If you plan on creative editing with images, some form of RAW file format would be preferable for capture in the camera – for Canon files, the file name ends with .CR2, and for Nikon, .NEF. These files are ideal if you intend to open the files in Photoshop (which requires conversion in Photoshop or Lightroom to a PSD or TIFF format) and to make significant adjustments. These RAW files have the disadvantage of being large and consuming a lot of space on a hard drive. The other concern is that these formats are proprietary to particular companies and potentially might change or not be supported in the future. Regardless, if you want the best data that the camera can capture, use RAW files and convert or view in Lightroom. If file size and hard drive space are a concern and you are more interested in a convenient image of a case that can be stored with a patient record, printed, used in slide presentations, or uploaded to a web album, JPEGs are quite adequate. One additional alternative to the proprietary RAW file formats is the Adobe DNG (digital negative) file type. This is comparable to the basic RAW file, but is an open source format and is thus less susceptible to individual camera company vagaries and more likely to be supported in the future. It offers the benefits of a RAW file, but with more peace of mind for the future. One option is to take photographs in both RAW and JPEG formats in the camera, storing them on the CompactFlash (CF) or Secure Digital (SD) card, and then to back up the RAW files to archival optical media (DVD discs) and import into Lightroom as DNG files. DNG files are optimal for use in the Adobe applications Bridge and Lightroom.

In summary, for most uses in ophthalmology (patient files, PowerPoint, storage), the highest‐quality JPEGs are adequate. To use in publications where submission to a publisher or journal is involved, the best options are TIFFs, portable network graphics (PNG) files, or high‐quality JPEGs. If you plan to use the images for creative or artistic purposes, RAW files are recommended. These can be backed up to retain a master copy of the original data, and a second set can be converted to DNG for any further processing in an editing process. If in doubt about how images may eventually be used, it is best to capture them as RAW files. Many cameras now enable each image to be recorded as both RAW and JPEG files.

File Naming Conventions Maintain the original file name as part of any conversion. This is most important when you capture the image in more than one format (RAW and JPEG), or if you keep master copies (RAW) but also make DNG copies for use in the cataloguing database (you may even end up with RAW + DNG + JPEG copies of your images). If the original file name is always maintained, it is possible to revert to the original RAW file if needed (if the JPEGs are lost or corrupted, for instance). So, a RAW Canon image file imported as MG_5409. cr2 might be changed to Smith_Freddy_10687_MG_5409. DNG or .CR2 or converted to Smith_Freddy_10687_ MG_5409.JPG (case name/hospital case number/original file name/number/file format). Professional media photographers often catalogue based on the date the photo was taken. For instance, vacation shots might be catalogued by year_month_location: 2012_1_ Naples_Carnival. The date has less value for ophthalmology file naming, since that information can be recorded as part of the metadata in the cataloguing software. Of more importance in locating images are the patient’s name and hospital case number. For all other aspects of file identification, one can rely on the metadata. It rarely makes sense to include the diagnosis in the file name, since that is more than adequately covered in the keyword tag applied to the photographs. In fact, the information contained in metadata is so complete that one could dispense with any change in file name at import and simply include all of the patient information in the metadata. The disadvantage to this approach, however, is that you end up with a very bloated set of keywords, which includes patient name and reference numbers that may only ever be applied to a single small group of patient photos.

Image Cataloguing and Organization: Digital Asset Management Digital imaging allows a photographer to capture a large number of photographs easily and inexpensively (compared to film). Just as with film imaging, it is possible to end up with a large image collection, but then to have little time to be

able to organize and easily locate specific photos in the future. The approach taken to organizing and retrieving images will depend on how the images will be used. The process has been referred to as digital asset management (DAM). One option is to store the image collection on one hard drive (hopefully with at least a second drive as a backup copy) in a folder arrangement accessible via a browser application such as Windows Explorer, Mac Finder, or Adobe Bridge. Folders for an ophthalmology collection might cover species, anatomic parts of the eye, and disease processes, with file naming based on the patient name with or without the ocular condition. This would allow the database to be searched by a browser based on the file or folder name criteria. However, this can be limiting when it comes to locating particular images. Adobe Bridge works well to connect different types of files in the various applications found in the Adobe Creative suite. These might be graphics, website design, and photography, audio, and video applications. These can all be browsed in Bridge, which supports many more file types than the parametric image editing (PIE) applications. In any network situation where multiple users might need to access the same files for particular projects, Bridge works very well. Lightroom can only be accessed by one user at a time (catalogues cannot presently be used on a network). PIE applications such as Lightroom are better organization applications than Bridge for photographers, because they allow you to do all the things that you need to within the DAM application. However, if you use other applications for multimedia presentations (e.g., website design in Adobe Dreamweaver, illustration in Adobe Illustrator), you might also access images from within Bridge to integrate them into the file formats of these other applications. Bridge is included with purchases of Adobe Photoshop. In the clinical setting, it may be adequate to import images into whichever practice management and electronic medical record (EMR) software is used. This will attach images to patient files and visits, which is ideal to be able to follow the progression of an ophthalmic case photographically. In most practice management software applications, it is possible to tag or keyword images to facilitate retrieval of conditions later. Image editing is less often supported in practice management software, partly because of the need to preserve the original data and avoid issues of falsification where a record could be unethically changed. This issue is complicated by differences in both human and veterinary medicine and the country where the patient lives. Veterinary medicine in the United States follows the human Health Insurance Portability and Accountability Act (HIPAA) guidelines, which specify privacy and accuracy requirements for medical records. Any editing of images should take place outside the medical record itself to avoid the charge of record falsification. One approach to image organization, retrieval, and backup in the clinical setting is to store images in both the practice

management software and in a separate DAM application with more extensive organizational and editing features. This allows for not only easy access in the clinic when reviewing cases, but also considerable flexibility for the use of images in other software applications. When the photograph is taken, it should be added to the dated visit for the patient in the medical record; this may simply require that the image is printed for inclusion in a paper medical record or preferably appended as a JPEG to the patient/visit in an EMR. Concurrently, the image can be copied to at least one other separate hard drive (and preferably two for an extra backup) for access by one of the cataloguing applications discussed here. The images accessed or referenced by the cataloguing application are then available for editing, grouping by disease process by tagging or keywording, and output for use in publications, presentations, or online, within the guidelines for the ethical use of medical images (see later in this chapter). DAM applications have various common features. Most notable is the concept that the actual image files and the application files are separate entities. There is a catalogue or library folder of files with information about the images that is separate from the image files themselves. Changes to the information (which can include any editing of the images) happen in the catalogue/library files and reference the image files, but do not change the image file data. Image capture or taking the photograph is obviously the first step. The actual processing on images also begins in the camera with the proprietary programs built in. These will take the digital data and store it in a format that is specific to the camera and manufacturer (the RAW data file). The camera software may also (depending on the file acquisition settings chosen) process the raw data and store the image in a format that can be read by most software applications (JPEG). At the time an image is taken, it is essential to identify and record the subject in some way. A simple approach is to photograph the patient information/case number from the physical, paper record as the first photograph in the sequence pertaining to the case. Some DAM applications (including Lightroom) enable the simultaneous capture of images to the camera and a computer or laptop. This can be achieved with either a wired (usually USB) or wireless connection between the camera and computer (which depends on the camera). This is useful for macrophotography, where it is often difficult to assess focus on the small LCD screen on the camera, and removes the additional step of taking photographs and having to download the images to the computer later (Fig.  13.68). Tethered capture starts the image organization process the moment the photograph is taken, and avoids the accumulation of disorganized images that is commonly seen with digital photograph collections. Ideally with tethered capture the file naming is established, keywords assigned, and a destination folder specified in the catalogue before the images are

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Figure 13.68  Tethered capture setup. Camera is connected via USB or wirelessly to laptop computer with Lightroom and catalogue files installed on the internal hard drive. Images are directly transferred as acquired to a folder on one external hard drive. The second hard drive backs up both the internal drive Lightroom catalogue and the images on the first external drive.

Figure 13.69  Tethered capture settings in Lightroom. Files can be renamed, have metadata applied, and be imported to a folder on the hard drive. (Adobe product screen shot reprinted with permission from Adobe Systems Incorporated.)

taken; each is identified by a file name with an appended sequence number as they are imported (Fig. 13.69). Importing images into the catalogue/library database happens either as the photograph is taken via tethered capture, or later when image files are copied from the camera to a

computer hard drive. In either case, the term “import” implies that the image is copied to a location of your choosing on the hard drive and an entry generated in the DAM database that references the master image file. The image per se is not “in the database,” although, depending on the

application, the “master” image may be stored within the application file (for instance, as a managed image in Aperture) or anywhere else on the hard drive (a referenced image in Aperture). The proprietary camera file names (for instance DSC or MG on Nikon or Canon cameras, respectively) are changed to something meaningful for your cataloguing system. Metadata (information about the image) are added. Metadata include keywords to facilitate retrieval and organization by subject, copyright information, and ways to group or rate images by color coding or on a numeric scale. At the same time, files can be copied or rearranged into whatever organizational arrangement (for instance, by anatomic location or disease process) is preferred. For the DAM application to keep track of the individual images, it is essential that any rearrangement of the image files on the hard drive be done from within the DAM software. Although it is best to rename files and add metadata when images are copied from the camera to the hard drive and imported to the DAM catalogue, this may not always be practical. If images from many different cases are imported at the same time, making changes to filenames and assigning keywords at that time does not easily work, since the information will be different for the groups of images pertaining to each case. In this instance, use the DAM software to copy to a folder identified by the date on which the images were taken and import all images to the catalogue/library. Later, these images can be keyworded and moved to a more logical folder‐ based organizational structure (based on species/location of lesion/specific disease). Images can be backed up to another location (a separate external hard drive is a good option) at the time of transfer from the storage card in the camera, to protect against accidental loss from the card or primary image location directory. Again, ideally, if images can undergo renaming and addition of metadata before the initial backup, there is less chance of getting confused between the backup of the downloaded images and any subsequent backups of the archival images that will be accessed by the DAM software. For additional backup protection of images, a copy of the “virgin” (RAW and/or JPEG) files can be made directly from the camera to another hard drive or optical medium before any renaming is done. Once images are in the cataloguing application, they can be quickly reviewed. Poor images (out of focus, poor DOF, severely over‐ or underexposed, or otherwise deemed inadequate) are rejected and deleted from the catalogue (and hard disk drive). Organization of images within the catalogue can occur at import or later (or both), and this is easily done from within the DAM application (in fact, resist the temptation to do any organization from outside the DAM application). For instance, photographers might import initially into a folder system that is based on the date the image was taken and

then organize into the folder system (species, anatomic location, disease process) later. Alternatively, images might be imported directly into a destination folder at import (or immediately when captured via tethering). DAM applications use various systems for organizing images, including dated albums, tree or hierarchy‐based lists of folders and albums, geotagged locations or places, and facial recognition (little used for ophthalmology libraries). Many applications utilize smart albums/collections, which automatically add images to albums or collections as they are imported based on predetermined criteria. For instance, all images keyworded with “iris atrophy” would automatically move into the “uveal diseases” or “iris atrophy” folder on import. Taking time to set up smart albums or collections can make it much faster to organize images into the relevant folder in the catalogue. Metadata (and especially keywords) applied to every image in a catalogue or library enable numerous ways to retrieve images from within a collection. For instance, if every image is keyworded on import by breed and disease process and the better photographs are given a numeric rating as to quality, it becomes easy to search the catalogue for the best examples of breeds with specific diseases. Most cataloguing programs enable some degree of image editing. The extent of image editing in which you should engage is very much determined by the subsequent use of the image (see ethical considerations in image editing below). Editing may be very rudimentary – for instance, changes in brightness, fill light, contrast, color hue, and saturation (this is the case with programs such as Apple Photos) – or done in a program that allows for considerable control (such as Lightroom). Automated (manufacturer‐embedded programming instructions) editing options are available in most programs, and although these quickly and easily change images, they are of limited value and often result in an edit that does not bring out the feature you may want to emphasize in the photograph. The most important consideration here is that any image editing should be nondestructive (this excludes Adobe Photoshop, which makes changes to the actual pixels in the image). This means that the original image data are left untouched and edits are simply written as separate files within the cataloguing program, which reference the original image. This is referred to as PIE. In some DAM applications, copies of the original images can be made before any image editing is applied (which is easily done in PIE applications). For instance, in Lightroom, virtual copies of images can be created for further editing, and then the edited images can be compared back to the original images. After image organization and any further editing in the software, the files should again be backed up on a regular basis. This entails backup of both the original/archival image files and the catalogue index files (the files that refer to the original data, contain metadata and keywords or tags, and have instructions about image edits that have been applied).

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Most applications enable direct output as slideshows of images, the ability to print images within the program (or send online to a printing facility), reproduce images in slideshow applications such as PowerPoint or Keynote, publish images to web galleries, export images to other applications such as email, blogs, messaging, and telemedicine, and upload images to social networking sites.

Cataloguing, Image Organization, and Parametric Image Editing Software Several DAM applications are available to catalogue and organize images. Applications such as Apple Photos and Google Photos are consumer products, whereas Adobe (Photoshop) Lightroom is intended for the more serious or professional photographer. The DAM application reviewed here is Lightroom, due to its popularity with professional photographers. Other DAM applications that have many of the same features are also mentioned to provide the spectrum from inexpensive but functional software up to the best applications available. Lightroom creates a database of small file size previews and metadata, which reference the master image files and may reside anywhere (on either a connected or a disconnected drive or even on a DVD). Lightroom is a DAM and PIE database (referred to as a library or catalogue, respectively) which contain all the information about your images. The database (which can only be accessed by single users as no networking is available) stores the name, hard drive location, and all information (metadata, editing, all versions, and thumbnail previews of the master image). File information is stored using the Extensible Metadata Platform (XMP) for all file formats supported by Lightroom (JPEG, TIFF, PSD, and DNG). XMP metadata are written into the files in the location where the images are stored. For RAW files, the data are written into “sidecar” files, which are associated with the individual RAW image files. The application allows users to have multiple databases (for instance, to group images related to diagnosis, research project, species, breed), although only one can be in use at any one time. The program allows the master image files to be stored either within the program database or at any other location (files can even be referenced on a different hard drive or even other storage media). Nondestructive editing of images is possible (master files are never altered), and multiple versions of any image (for instance, with different edits applied to each) can exist in the database. With all the power of the most recent versions of this application, there is now little need to edit images in Photoshop (unless interested in creative and artistic use). Adobe Photoshop Lightroom

Lightroom was originally a desktop application (it cannot be run on a network), but recently Adobe has moved to a subscription format for its photography applications. The Adobe

Creative Cloud Photography Plan includes Lightroom for local use (now called Lightroom Classic CC) as well as a more recent addition of the cloud‐based Lightroom CC (which is only compatible with more recent versions of Windows). Photoshop CC and Bridge are also included in the photography plan. The two versions of Lightroom (Lightroom Classic and Lightroom CC) are different in several respects. Lightroom Classic is essentially the same version of the application that has been available for some years, but as part of the subscription undergoes periodic updates. Lightroom Classic CC

Lightroom Classic CC is a versatile and powerful cataloguing and imaging application that can be used on either Mac or Windows platforms. Lightroom initially was a cataloguing and organization application, but each version has added more parametric image editing features. In the latest versions the editing options are powerful enough to be sufficient for most photographers without the need to further edit images in Photoshop. Some features present in Photoshop are currently absent in Lightroom (for instance, the ability to use layers when compositing and editing images). Lightroom is designed to follow the photographer’s workflow using modules (Library for image importation cataloguing and organization, Develop for advanced image editing, Map for image geotagging, Book for publishing images, Slideshow to allow grouping and presentation of images in a slideshow format, Print to set up printing options, and Web where images are grouped and published as web albums (Fig. 13.70). The interface is divided into a central pane (2 in Fig. 13.70), which can either show a grid of photograph previews or enlarged views of individual or groups of images for examination and editing, two side panels (1 and 3), the content of which changes depending on the module in use, and a filmstrip at the bottom of the interface (4), which allows selection of the images to be worked on in any of the modules. The side panels contain information about the images (keywords, camera, and capture data) and commands to perform functions in the different modules as you progress through the workflow (for instance, editing changes in the Develop module; Fig.  13.71). The left side panel (1) is for navigation in Lightroom Classic (based on the existing folder structure). The right side panel (3) contains information about a highlighted image (histogram, metadata including keywords) and image editing options (either quick develop in the Library module for basic editing or the more comprehensive editing options of the Develop module). The menu bar at the top of the interface (5) has the modules, which follow a typical workflow from left to right. In the Library module, the navigation panel on the left allows the user to see the organizational structure of the library in a folder format (as might already exist on the hard

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Figure 13.70  Lightroom interface. The areas of the interface (1–5) are described in the text. (Adobe product screen shots reprinted with permission from Adobe Systems Incorporated.)

Figure 13.71  In Lightroom Classic CC, images follow a photographic workflow through modules to organize, modify, and output to print, slideshow, or the web. (Adobe product screen shots reprinted with permission from Adobe Systems Incorporated.)

drive; Fig. 13.72). Images could all be in a single large folder if preferred, and can still be found utilizing the powerful metadata search options in the application. Most users will probably adopt a folder format, particularly if importing images into the database from previous organizational structures based on folders (in which case the actual location of the drive does not change). An advantage of Lightroom is that it is possible to move images and folders within the application and change their location on the hard drive and still have Lightroom keep track of the changes. Lightroom’s reliance on accessing the actual location of the image file does, however, mean that moving image files from outside of the program (e.g., in Explorer) will cause problems with the

database being able to find the moved image on the hard drive. In other words, all rearranging of image files on the hard drive should be done inside Lightroom. Importation of images in Lightroom can occur from existing locations on an internal or external hard drive, from a memory card in a digital camera, or directly as the photograph is taken (in tethered or wireless mode). The importation process occurs in the Library module. Options allow for copying of images to a specific location on the internal or external hard drive. Images already on the hard drive in a folder structure can simply be added to the Lightroom catalogue at their present location in the existing folder‐based organization (Fig. 13.73). Images can be imported as RAW (NEF or CR2), JPEG, TIFF, PSD (native Photoshop format), or even CMYK. At import, images can optionally be converted to DNG files. Alternatively, RAW images can be viewed and processed in the Develop module (which is essentially the Adobe Camera Raw application). After an initial backup of the virgin files from the camera in RAW or JPEG format, conversion of RAW files to DNG in Lightroom is a good option to consider (smaller files, embedded metadata, file verification). In the large center pane (2 in Fig.  13.70), all images in a folder or collection can be viewed in a grid, or individual images can be enlarged in loupe view (single image on screen) or arranged in pairs or small groups for comparison when grading. The panels around the central pane can all be

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Figure 13.72  Lightroom Library Module – the navigation panel is where images are organized and rearranged in the catalogue and physically in folders on the hard drive. (Adobe product screen shot reprinted with permission from Adobe Systems Incorporated.)

viewed or hidden to show images in full‐screen mode. At this stage, the images are either flagged as picks to keep or rejected from the catalogue (and hard drive if of poor quality), and then can be further ranked on a 1–5 star system or color coded into groups if so desired. Basic editing can also occur in the Library module, and this is often more than sufficient for most editing needs. The power of applications such as Lightroom Classic lies in their ability to organize images in numerous ways and to be able to find images wherever they are located (hard drives, optical media, etc.) by tagging images with metadata. Some of the metadata (IPTC) is applied automatically in the camera when the photograph is taken, while other metadata (keywords, and preset information such as your copyright and contact information) is added either at the time of importation (best practice) or later when working on images in the library. The keywording option in Lightroom Classic is the most powerful feature for a collection of ophthalmology images. It is possible to tag images by species, breed, age, sex, part of the eye, and type of disease process involved (or any other

keyword combinations you choose). Groups of keywords (sets) likely to be used for particular diseases (e.g., a glaucoma set of keywords could include epistler injection, corneal edema, mydriasis, optic nerve cupping, lens luxation, etc.) speed up the process of applying groups of keywords to single files or groups of images. Using metadata tags in combination with renaming on import to identify by patient name and hospital case number allows for fast and easy retrieval of any image (Fig. 13.74). Apart from the organization of images into folders within the catalogue, separate collections of images can also be generated from the master image files (the location of the master images is not altered, but rather “virtual” copies of the master images are created in the separate collections). Individual images (which can only reside in one folder) can be referenced in multiple collections. For instance, when putting together a talk requiring numerous images, the images can be put into a collection for temporary access while preparing the presentation without affecting their original location. Smart collections can be populated by images based on predetermined metadata criteria. In this way, collections of images can be automatically generated as images are imported to the catalogue. Lightroom’s Develop module is the area where all detailed editing occurs. The editing capabilities of the Develop module are adequate for almost all the editing needs of the photographer, without the need to further edit in Photoshop or other pixel editing software. Various editing options are available using parametric nondestructive changes, and the histogram‐oriented level adjustments, tone curves, and hue and saturation of the editing options offered here are well beyond the needs of the ophthalmic photographer (Fig. 13.75). Versions of the images (virtual copies) can be created for editing and can be grouped into collections (e.g., all images of a particular topic might be selected and grouped into a collection for export and use in presentation or published to a web gallery to be shared). These “copies” are much smaller than the copies that would be generated in a nonparametric image editor (such as Photoshop), and therefore creating multiple virtual copies take up very little space on the hard drive. Apart from straight collections you create to house groups of images, the Library module also can contain user‐generated “smart collections.” These are automatically generated based on criteria you specify. For instance, you might set up a smart collection for iris melanoma – any image added to the catalogue that has iris and melanoma in the filename or keywords is automatically added to your smart collection. You choose the type of metadata to filter with (keywords, date image taken, camera used, aperture used, etc.), and then specify conditions for the metadata (e.g., all images with keyword phaco shot at aperture f/22). See Table 13.11. Output options in Lightroom include the Slideshow, Web, and Print modules. Although the slideshow module is helpful in generating slideshows that will present a group of

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Figure 13.73  Lightroom images are imported (and copied) from a digital camera to the hard drive or can be added to the image catalogue without moving if already located on the hard drive. Images are renamed, tagged with metadata, and the location of the copied files is specified. (Adobe product screen shots reprinted with permission from Adobe Systems Incorporated.)

A

B

Figure 13.74  The Lightroom Keywording panel (A) is where keywords are added to images. This is facilitated with keyword suggestions and groups (sets) for frequently used keyword combinations. The catalogue is searched (B) using filenames, keyword combinations, ratings, or metadata. (Adobe product screen shots reprinted with permission from Adobe Systems Incorporated.)

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Figure 13.75  Lightroom’s Develop module provides several means to edit images and apply corrections for specific lenses. (Adobe product screen shots reprinted with permission from Adobe Systems Incorporated.) Table 13.11  Organizational summary for Adobe Lightroom Classic CC. Catalogues (Ophthalmology, Veterinary, Family, Travel, etc.) Folders: Ophthalmology by species (Dog, cat, horse, exotics, etc.) ●● ●●

Subfolders: Part of eye (Orbit, Eyelids, and Cornea, etc.) Subfolders: Normal, type of disease – congenital/acquired, etc. or disease type (developmental uvea, uveitis, neoplasia, etc.)

Collections: groups of images you are working with, for instance to put in book chapter or into slideshow for PowerPoint or Keynote. You can have multiple virtual copies of the master images to edit or manipulate. Smart collections: predetermined collections that auto‐populate based on specified criteria. For example, every time you add a photo with the word “cyst” in the filename or metadata keyword tag, the image will also appear (as a copy in the catalogue) in the smart collection for cysts – even if the image was imported to a file location/folder for uveal cysts or elsewhere in the library.

images in a variety of formats that may be useful for professional and commercial photographers, most ophthalmologists will be more interested in utilizing images in applications such as PowerPoint and Keynote. Drag and drop is possible from Lightroom on Mac into either Keynote or PowerPoint for Mac, but at present this is not possible when using Lightroom on a Windows platform. On either Mac or Windows, images can be exported as a JPEG slideshow and then inserted into PowerPoint slides.

Lightroom CC

The more recent version of Lightroom, now called Lightroom CC, is quite different to the existing Lightroom Classic. This is a cloud‐based application that imports and stores all of the images (including RAW files) in the cloud (local copies can and should also be stored on a local hard drive). This does have the benefit of providing an immediate cloud‐based backup of images rather than the user having to do this as a separate step in Lightroom Classic. Whereas Lightroom Classic imports and will use a conventional folder structure, Lightroom CC imports based on the date and time of the import. Images are stored in albums that can be further organized into folders and subfolders (although these have to be set up manually in the navigation pane; Fig.  13.76). Metadata cannot be added during the import of images and it is not possible to specify the destination of images with the same specificity in Lightroom CC (basically to the cloud rather than specific folders on the local hard drive). The ability to keyword images is also not available in Lightroom CC, the “find” feature being replaced by a search box that utilizes artificial intelligence to locate specific features of the image. At this time, this is not a useful feature for a collection of ophthalmology images – whereas the search feature might find all images with dogs or cats, it will not locate (for example) any images with hypopon or retinal hemorrhage as the search criteria (at least as yet; Fig. 13.77).

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Figure 13.76  Lightroom CC main window with folder structure and grid view. (Adobe product screen shot reprinted with permission from Adobe Systems Incorporated.)

Figure 13.77  Lightroom CC window with artificial intelligence–based search box and edit panel. (Adobe product screen shot reprinted with permission from Adobe Systems Incorporated.)

The editing options in Lightroom CC are also far more limited than in Lightroom Classic and are more typical of the simple editing options available in other applications such as Apple Photos and Google Photos (Fig. 13.77).

It has for some time been possible in some previous versions of desktop‐based Lightroom to synchronize a collection of images to a mobile application, to view images on a tablet or cell phone. This has been taken much further in Lightroom

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CC and it is a definite advantage of this version. Since the images are all uploaded to the cloud‐based servers, they are readily accessible to any mobile platform, not just for viewing but also to be edited and distributed. The downside to this approach is found with a very large collection of images, which will require more investment in online storage capacity with Adobe, and hence higher cost than when storing images on a local drive. Several other DAM applications are available as alternatioves to Lightroom. These vary from free or low‐cost consumer applications such as Apple Photos and Google Photos to more advanced professional applications. A web search will reveal numerous applications that can perform in a similar way to Lightroom. However, it should be remembered that Adobe Photoshop and Lightroom have been present for a long time and hopefully the company will continue innovating and improving its products. The same cannot always be said for smaller, less‐established companies in the digital imaging field.

Image and Catalogue Storage Options, Imaging Workflow, and Data Backup Original Image (Master) Storage and Catalogue Backup

Most photographic images will be stored primarily on a hard drive – often the main drive in a computer. Hard drives are prone to eventual failure and can have bad sectors on the disc, which may adversely affect the image collection. It is therefore important to have some form of backup system in place to ensure that images are not lost or corrupted. There are numerous approaches that can be taken to image backup, which vary in complexity and reliability. For a comprehensive review of best backup practices, see The DAM Book 3.0 (2017; http://thedambook.com/the‐dam‐book). There is no “right way” of image cataloguing, editing, and backup. Images on an internal hard drive with a backup copy on an external hard drive is the minimum backup recommended. More redundancy in the system can be achieved with multiple backups both onsite and offsite, with permanent backup on optical media. Two data backups are needed with PIE applications – one for the actual image files (RAW, JPEG, PNG, etc.) and the other for the cataloguing software data files (the database). It is important to recognize that while the cataloguing software application usually has a built‐in feature for backing up the catalogue files, this does not necessarily back up the actual image files. Backup of the original or master image files (in “virgin” form) may require other actions and software. In Lightroom, a backup, which can be set to occur every time the catalogue is closed, only applies to the catalogue files, not the individual image files. Backup of images can start in the camera. There are several cameras that include a slot for a second memory card and an

option built into the camera software to use this second card (which should be same capacity of card) for an exact backup copy of the original image (this protects against failure of one or other card). Images should be copied (not moved) to a computer hard drive as soon as possible after they are recorded on the memory card to avoid accidental deletion. Images should not be “moved” from card to hard drive in case errors occur during the transfer. No images should be deleted from the memory card until they are transferred to the hard drive, and preferably not until an additional backup has been made. A decision must now be made as to whether to back up the “virgin” images (to a hard drive or optical medium) or wait until the files have been imported into Lightroom and have undergone metadata additions and filename changes. Images can be simply copied to a folder on the hard drive in Mac Finder or Windows Explorer. There is a small risk of errors during the transfer and no way to verify that the transfer occurred without error using this approach. Alternatively, copy and verify software can be used to ensure that the copied files are identical to those on the memory card. Once on the hard drive, the images can be imported (without necessarily changing the location on disc) into the DAM application. If a small number of images are to be transferred from camera to hard drive on a frequent basis (possibly nightly or weekly), they may be copied into the final location on the hard drive using whatever organizational/folder structure is chosen using the DAM application (e.g., Lightroom), creating an entry in the catalogue with a changed filename, and adding keywords as necessary. For instance, feline uveal cyst images are renamed, keyworded as “uvea,” “cyst,” and “feline,” and imported to a “subfolder: cyst” in the “subfolder: uvea” or the “folder: feline ophthalmology.” One hour spent each week performing this task is more efficient, less exhausting, and less likely to cause data loss than infrequent downloads of vast numbers of patient images. If, however, images are only downloaded infrequently or when the memory card is nearly full (hence large numbers of images of many different cases and diseases), with the intent to return to them later and make the metadata/filename changes, an alternative option is to use Lightroom to copy the original camera files to a dated download folder on the internal hard drive. The copied files are identified in the download folder in the Lightroom catalogue by subject and year, with subfolders to identify the month (e.g., into a folder called “Ophthalmology 2020” with subfolders for the month “Ophthalmology 3–12”). These files are then backed up to an external hard drive or optical medium. When time permits, the images in the dated folders are renamed and metadata applied, and then they are moved in Lightroom to a permanent folder on the internal hard drive more relevant to the subject (remember that this must be done in Lightroom and not in Windows Explorer or Mac Finder). Individual images can be identified from the camera by including a photograph

of the patient file information or a card with the patient’s information. Renaming the image files and adding keywords can then be done at a later date. If importing RAW files into Lightroom, this is the time to convert them to DNG if that is the preferred file format. One of the benefits of using DNG format for your image files inside Lightroom is that a validation code is embedded in the DNG file. The DNG file has a source image that never changes (regardless of other edits or changes to the metadata). Any future backups of the DNG file will automatically enable data verification. Once images have had renaming/keywording changes made, they are again backed up as a finished/archival file. Several applications are available for backup of the image files to either additional external hard drives, optical media, or online (e.g., Acronis True Image, Acronis, Schaffhausen, Switzerland, or Nova Backup Pro, NovaStor, Agoura Hills, CA, USA). Although it is more convenient simply to use backup software to make compressed image backups, a better approach is to make exact copies of the image files to the backup location with backup or file synchronization and verification software; this ensures that the copies in the backup are indeed identical to the original images, with no errors detected in the backup or copy process. Any further work on these image files will be parametric in Lightroom for either JPEG or RAW images (i.e., no changes to the archival/master file, only edits in the Lightroom catalogue file). The DAM application will also make a backup of the catalogue/library file that is separate from the actual image collection. If any RAW file from the archive is subsequently changed in a pixel editing program like Photoshop, the edited version should be saved as a separate copy with the same file name, plus a designation to indicate that it is a copy that has been edited (e.g., Heidi_Snooks_MG6705_editcopy.PSD). To keep any copies edited in Photoshop organized in the Lightroom catalogue, the editing should be initiated in Lightroom and then saved back to the catalogue as an edited image. It is good practice to store the archival images on optical media once they have been renamed (this is not a copy of the Lightroom catalogue file, but simply the renamed master images, the same as will be in the archive) so that one additional copy exists on a different medium. At present, the most convenient optical backup is DVD (4.3 GB). With increasing digital image file size in high‐resolution dSLR cameras, it is now only practical to use DVD storage, and certainly so if shooting RAW or RAW + JPEG files. CDs may be a reasonable option for collections of JPEG images, although if shooting 4 MB images a CD will accommodate fewer than 200 images. For archiving purposes only, use “R” (read‐only) discs to avoid inadvertent overcopying of data. We have little reliable data on the longevity of optic media – estimates of a 50‐ to 100‐year storage life seem optimistic. In general, it seems that at present, DVD‐R discs with silver or gold

r­ eflective coatings may be the most stable. Companies with archival quality DVD‐Rs popular with photographers include MAM‐A (Colorado Springs, CO, USA). Soon it seems likely that Blu‐Ray will start to replace CDs and DVDs for image archiving due to the higher storage capacity (up to 50 GB at present and expected to rise in the future). If backing up to a laptop or computer hard drive, it is fast and easy to attach an external hard drive and immediately make an exact copy (mirror) of the files to the external drive. At this stage of the workflow, the images should be copied to the external drive as an additive backup. This simply requires adding the new files from the memory card to the existing files on the internal and/or external drive. One way to organize these additions is to place each data transfer of new files in a dated folder on the hard drive. The same organizational structure should then be copied to any other external drives or optical media. An even better practice is to back up the original files to two external drives set up in a RAID 1 configuration. Various external hard drives that facilitate this are available (Fig. 13.78). It is possible to copy the images and validate that the copied files are identical using software such as ViceVersa (TGRMN Software, Fullarton, Australia) or SyncBack (2BrightSparks, Singapore) on Windows, and ChronoSync (Econ Technologies, Winter Springs, FL, USA) on Mac. It is also good practice periodically to copy one other backup of the original master files to another external drive that is maintained offsite at another location to avoid the possibility of data loss from theft, fires, and so on. In the clinical setting, an additional backup may occur if the patient images are also copied into the patient record in the practice management software. Ideally, as much as possible of the subsequent image transfer and modification should be handled from within the imaging software. It is important not to move or edit images outside of the catalogue application or the images will not be referenced correctly in the catalogue.

Catalogue and Image Library Configurations The simplest arrangement for any image collection is on the primary hard drive of the laptop or computer. In this configuration, both the catalogue files and the image library files are on the same drive (as well as the operating system and other applications and documents). The main drawback with this arrangement is that image collections can easily become so large that they fill up the entire drive. Various other configurations are possible, however, with most parametric cataloguing and imaging software. The most reliable, stable, and easily organized approach is to use one computer as the imaging workstation  –  a good option is to have two to four hard drives in the tower as well

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Hard Drive

Attached Hard Drive Backup

Offsite Hard Drive Backup

Archive Backup

Figure 13.78  Simple backup configuration for one computer imaging system. (Reproduced with permission from The DAM Book, Peter Krogh, O’Reilly, 2009.)

as USB or Firewire connections for external backup hard drives, and an internal DVD‐RW drive (or even an internal Blu‐Ray drive) for optical backup. If most of the imaging workflow is done on one desktop computer, the primary drive houses all the usual application software, including the Lightroom catalogue. This can either be a regular hard disk drive (HDD) or a solid state drive (SSD). The master image collection is then located on a separate internal hard drive (usually a HDD drive, since this allows for a large volume of images at lower cost than SSD). Using internal drives for the catalogue and the image collection additionally has the advantage of speed of processing. Both the catalogue/library and the master image collection need to be backed up regularly to external hard drives. The simplest recommended organization and backup configuration for one computer use is shown in Figure 12.74. Images are imported onto the laptop or PC hard drive (the catalogue is kept here as well). The entire drive is cloned to two separate external drives – one remains online, and backups are continuous; the other is updated on a regular schedule (weekly or monthly) and then taken and kept at a different location (home or work). Separate periodic optical drive backups of the image collection and the catalogue are also recommended. Essentially, all the parametric imaging is done in the DAM catalogue on the internal drive, and backup of the catalogue and image collection to the external hard drives occurs on a regular schedule. Backup is all about ensuring redundancy  –  that is, multiple backups of images – so that if the worst happens and the primary collection of images and the DAM catalogue are lost, destroyed, or corrupted, they can be restored intact. Offsite backup can be achieved using the cloud. The first time a large collection of image masters is backed up to the

cloud it can take some considerable time, but subsequent continuous backup ensures an additional offsite set of images. Various cloud backup and synchronization applications are available, including CrashPlan (Code42 Software, Minneapolis, MN, USA), Backblaze (San Mateo, CA, USA), and Carbonite (Boston, MA, USA). All charge a monthly fee for storage space, certainly worth the peace of mind of an additional offsite backup in case of failure of the primary system. These cloud systems in no way guarantee your data if lost and should never be used as the primary backup system for original image (or any other) files. One further option for local backup is network access storage (NAS). Images and catalogues (and any other files you like) are kept on a NAS drive that can be accessed online. An example would be the Synology DiskStation (Synology, New Taipei City, Taiwan), which has replaceable SATA hard drives in an external network‐connected enclosure. This can be accessed anywhere online for image and catalogue access and backup, and is effectively a personal cloud backup.

Multiple Computers for Catalogue and Image Library If images are viewed and edited on more than one computer (e.g., on a laptop at home or when traveling and a computer at work), a different storage arrangement is needed to avoid errors of synchronization between the catalogues of each computer. One way to achieve this is to keep the primary copy of the catalogue and the image collection (masters) on an external hard drive (preferably with a Firewire, USB 3.0, or Thunderbolt interface) rather than on the internal drive of

one of the computers used. The external drive is moved from computer to computer, where the DAM application (Lightroom) is installed on internal drives. The main drawback is that accessing the catalogue and the image collection on an external drive tends to be slower than using internal drives. Other issues that have been noted are problems when using USB connections to external hard drives on a Mac and the risk of major file corruption if USB drives are inadvertently disconnected from the computer or laptop. It may be necessary to ensure that the drive letter and path are the same for the external drive when used on different computers for the Lightroom library to function normally. Multiple backups are recommended if a traveling external hard drive is used for the images and the catalogue. A better and simpler approach if using Lightroom Classic CC is to set up the catalogue either on Dropbox (www. dropbox.com) or in the Adobe Creative Cloud folder, which is automatically added to Windows Explorer or Mac Finder when you install the Creative Cloud Photographer’s Plan. This enables a single Lightroom Classic catalogue to be viewed across multiple devices (computer, tablet, cellphone) in much the same way as can be achieved with Lightroom CC, but using Creative Cloud also has the benefits of all the additional features of Lightroom Classic (editing and keywording) that are valuable for an ophthalmology collection. Large collections need more storage space on either Dropbox or Adobe Creative Cloud, but the benefits may outweigh the additional cost.

Ethics of Editing and Use of Images The need may arise to edit images that are of slightly poor quality (mostly inadequate exposure, or occasionally to do with focus and sharpness) and attempt to improve on the camera’s output. With applications such as Photoshop and Adobe Fireworks, it is possible to make many adjustments to the image, but it is important to remember that this is changing the pixels themselves (vs. the parametric image editing performed by Lightroom). In the interest of scientific honesty, it is generally accepted that photographic editing should be limited, in order not to use the editing process rather than the actual captured image as a basis for interpretation of results in experimental studies. However, the change to digital imaging has not significantly affected the way image editing and output have historically been used to illustrate (and possibly in some instances falsify) research findings. Even subtle changes in the exposures used for printing and techniques such as burning and dodging have been available ever since photography was first invented. It is easier now to make editing adjustments to final images because of computer technology, but overall nothing has changed with the advent of digital imaging.

It should also be remembered that image editing can be very valuable in enabling interpretation of scientific and diagnostic images that would be difficult if these techniques were not applied. There are some rules that should be adopted when considering image editing (also known as enhancement or manipulation). Simple adjustments to the entire image are generally acceptable. For documentation in a medical record, there should be very limited if any image enhancement, no more than changes to exposure applied to the entire image. All enhancements must be made to a copy of the unprocessed original image and saved in the record along with the original (unedited) image. For illustration purposes, it is acceptable to enhance images. For instance, in teaching ophthalmology, enhancement may be used to bring out certain aspects of pathology that might be difficult to illustrate otherwise. This can easily be done in applications such as Lightroom on a desktop or laptop to illustrate lesions to students or clients. Applications exist for tablet use, which enable photo enhancement for illustrative purposes. Depth of focus using focus stacking techniques and high dynamic range processing can be especially useful in illustrating lesions recorded in gross histopathology images of the eye, where multiple images can be captured with a camera mounted to a photo table or tripod. For image documentation of scientific research, enhancements are only acceptable if exact details are included with the images of what adjustments were made. Ideally, a copy of the original image should accompany the edited/enhanced version of the image, or a statement be made that particular edits have been applied to the image. Individual publishers and journals vary in what image manipulation they will accept. These are usually detailed in the author guidelines for each publisher. Images of the same subject that will be compared from one to another (e.g., to determine changes in pathology over time) should be acquired and processed identically each time (this can be difficult to achieve in the clinical setting). Images collected as RAW data will need to be processed for publication; generally it is recommended that for publication images are submitted as TIFF or EPS, and that lossy compression techniques (e.g., JPEG) that change pixel data are avoided. JPEG images should never be edited and resaved; each time this happens, more data are lost. Several types of image manipulation are not permitted in publications or research presentations. Combining different images to portray a single case or experimental result is definitely prohibited. Changes should not be selectively made to the brightness or contrast of selected areas of an image. Concealing, cropping, or adding data to an image (e.g., using layers and cloning and healing tools in Photoshop) that affects the interpretation of the image is considered unethical, particularly if the image is to be used to support research findings.

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Generally, all image manipulation for publication should be used as little as possible, relying instead on good photographic technique to record important details of the case pathology or experimental results.

Image Use and Publication Although privacy issues about use of images and medical data may not be as restrictive and regressive in veterinary versus human medicine, it is recommended that before taking photographs of ophthalmic cases, permission is obtained to acquire and use patient images. This is easily done by including a permission statement to be signed at the time of the patient’s admission to the hospital. The statement should assign all rights to use images in a way that does not identify the patient (necessarily), but also enables use in various

print and online media. Privacy rules in veterinary medical records obviously still must apply. An example of permission to acquire and use patient images is as follows: I consent for medical photographs to be made of my pet(s) by XYZ Veterinary Hospital. I understand that these images may be used in the medical record, for purposes of medical teaching, research into animal eye disease, publication in books or journals and electronically online. I understand that I will not receive payment from XYZ Veterinary Hospital or any other individual or entity for photographs taken of my pet(s). The statement should be signed and dated and kept on the patient’s medical record.

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Hattersley, R. (1979) Photographic Lighting: Learning to See. Englewood Cliffs, NJ: Prentice‐Hall. Howland, H.C. (1980) The optics of static photographic skiascopy. Comments on a paper by K. Kaakinen: A simple method for screening of children with strabismus, anisometropia or ametropia by simultaneous photography of the corneal and the fundus reflexes. Acta Ophthalmologica, 58, 221–227. Jarvis, C. (2010) The Best Camera Is the One That’s with You: iPhone Photography by Chase Jarvis. Berkeley, CA: New Riders. Justice, J. (1982) Ocular fundus photography. In: Ophthalmic Photography (ed. Justice, J.), pp. 41–52. Boston, MA: Little, Brown. Kanemaki, N., Inaniwa, M., Terakado, K., et al. (2017) Fundus photography with a smartphone in indirect ophthalmoscopy in dogs and cats. Veterinary Ophthalmology, 20, 280–284. Kim, D.Y., Delori, F., & Mukai, S. (2012) Smartphone photography safety. Ophthalmology, 119, 2200–2201. Kuehni, R.G. (2003) Color Space and Its Divisions: Color Order from Antiquity to the Present. Hoboken, NJ: Wiley‐Interscience. Leutwein, K. & Littmann, H. (1980) The fundus camera. In: Refraction and Clinical Optics (ed. Safir, A.), pp. 1–16. Hagerstown, MD: Harper & Row. London, B., Upton, J., & Stone, J. (2010a) Exposure, sensors, and film. In: Photography (eds. London, B., Upton, J., & Stone, J.), 10th ed., pp. 66–89. Upper Saddle River, NJ: Prentice Hall. London, B., Upton, J. & Stone, J. (2010b) Lighting. In: Photography (eds. London, B., Upton, J., & Stone, J.), 10th ed., pp. 220–251. Upper Saddle River, NJ: Prentice Hall. Long, B. (2010a) Advanced exposure: Learning more about your light meter and exposure controls. In: Complete Digital Photography (Long, B.), 5th ed., pp. 158–185. Boston, MA: Cengage Learning. Long, B. (2010b) Camera anatomy: Holding and controlling your camera. In: Complete Digital Photography (Long, B.), 5th ed., pp. 32–67. Boston, MA: Cengage Learning. Long, B. (2010c) Image sensors: How a silicon chip captures an image. In: Complete Digital Photography (Long, B.), 5th ed., pp. 92–105. Boston, MA: Cengage Learning. Long, B. (2010d) Program mode: Taking control of exposure, focus, and more. In: Complete Digital Photography (Long, B.), 5th ed., pp. 120–157. Boston, MA: Cengage Learning. Lowrie, C.K. (2007) Canon EOS Digital Rebel XTi Digital Field Guide. Chichester: John Wiley. Ludwig, C.A., Murthy, S.I., Pappuru, R.R., et al. (2016). A novel smartphone ophthalmic imaging adapter: User feasibility studies in Hyderabad, India. Indian Journal of Ophthalmology, 64, 191–200. Mahurkar, A.A., Vivino, M.A., Trus, B.L., et al. (1996) Constructing retinal fundus photomontages: A new computer‐based method. Investigative Ophthalmology & Visual Science, 37, 1675–1683.

Mandell, A.I., Foster, C.W., & Luther, J.D. (1976) External photography of the eye. International Ophthalmology Clinics, 16, 133–143. Mártonyi, C.L., Bahn, C.F., & Meyer, R.F. (1984a) Clinical Slit Lamp Biomicroscopy and Photo Slit Lamp Biomicrography. New York: Ophthalmic Photographers’ Society. Mártonyi, C.L., Bahn, C.F., & Meyer, R.F. (1984b) Forms of illumination: Principles and applications. In: Slit Lamp Examination & Photography (eds. Mártonyi, C.L., Bahn, C.F., & Meyer, R.F.), 3rd ed., pp. 34–76. Sedona: Time One Ink. McMullen, R.J., Jr., Clode, A.B., & Gilger, B.C. (2009) Infrared digital imaging of the equine anterior segment. Veterinary Ophthalmology, 12, 125–131. Nicholl, J. (1985) Document ocular pathology with ophthalmic photography. Journal of Ophthalmic Nursing & Technology, 4, 4–7. Olsen, O.J. (1979) External ophthalmic photography. American Journal of Optometry and Physiological Optics, 56, 548–558. Peterson, B. (2010) Understanding Exposure: How to Shoot Great Photographs with Any Camera. New York: Amphoto Books. Pirie, C.G. & Pizzirani, S. (2011a) Anterior and posterior segment photography: An alternative approach using a dSLR camera adaptor. Veterinary Ophthalmology, 14, 1–8. Pirie, C.G. & Pizzirani, S. (2011b) Reflex‐free digital fundus photography using a simple and portable camera adaptor system: A viable alternative. Journal of Visual Communication in Medicine, 54, 146–155. Quick, M.W. & Boothe, R.G. (1992) A photographic technique for measuring horizontal and vertical eye alignment throughout the field of gaze. Investigative Ophthalmology & Visual Science, 33, 234–246. Robinson, J., Gilmore, K.J., & Fielder, A.R. (1989) Validation of a photographic method of measuring corneal diameter. British Journal of Ophthalmology, 73, 570–573. Shaw, J. (1987) John Shaw’s Closeups in Nature. New York: Amphoto Books. Shaw, J. (2000) John Shaw’s Nature Photography Field Guide. New York: Amphoto Books. Shun‐Shin, G.A., Brown, N.P., & Benjamin, L. (1992) Anterior segment photography using the Oxford retro‐illumination camera. International Ophthalmology, 16, 191–193. Standardization Committee (2005) The term “resolution” shall not be used for the number of recorded pixels. Guideline CIPA DCG‐X001‐2018. Tokyo: Camera & Imaging Products Association. Stansfield, A. (2010) Canon Rebel T1i/EOS 500D: The Expanded Guide. Lewes: Ammonite Press. Tate, G.W. & Safir, A. (1980) The slit lamp: History, principles, and practice. In: Refraction and Clinical Optics (ed. Safir, A.), p. 14. Hagerstown, MD: Harper & Row. Tuntivanich, N., Mentzer, A.L., Eifler, D.M., et al (2005) Assessment of the dark‐adaptation time required for recovery of electroretinographic responses in dogs after fundus photography and indirect ophthalmoscopy. American Journal of Veterinary Research, 66, 1798–1804.

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14 Diseases and Surgery of the Canine Orbit Simon A. Pot1, Katrin Voelter2, and Patrick R. Kircher3 1

Ophthalmology Section, Equine Department, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland Equine Department, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland 3 Clinic for Diagnostic Imaging, Department of Clinical Diagnostics and Services, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland 2

Orbital diseases are not uncommon in the dog. The close vicinity of the oral and nasal cavity, tooth roots, and paranasal sinuses renders orbital structures susceptible to disease processes extending from any of these structures through the orbital wall. The dog has an incomplete bony orbit. The orbital rim consists of bone for approximately four‐fifths of its circumference and is completed by the orbital ligament. The rest of the orbit is enclosed by bone only on the dorsomedial and cranioventral sides. The rest of the roof and floor and the lateral wall of the orbit are formed by the temporal, masseter, and medial pterygoid muscles of mastication and by the zygomatic salivary gland (Murphy et  al., 2012). As a result, the orbital contents are relatively susceptible to penetrating trauma through the surrounding soft tissues (Fig. 14.1). The orbit can be divided into an intraconal and an extraconal space, separated from each other by the fascial sheets that envelop the extraocular muscles and fuse with Tenon’s capsule anteriorly, and with the periorbita around the annulus of Zinn at the orbital apex. The orbital muscle cone contains the extraocular muscles, such as the four rectus muscles, the two oblique muscles, and the retractor bulbi muscles, CN II through VI, the internal ophthalmic artery, the anastomotic branch of the external ophthalmic artery, and the orbital venous plexus. The extraconal space is enclosed by the periorbita, which is a fascial layer covering the osseous and soft tissue walls of the orbit. Certain structures that cross the caudal orbital floor area are of major significance and are to be avoided during surgery, including the maxillary artery and nerve, the pterygopalatine ganglion, and the associated parasympathetic, sympathetic, and somatic nerves. Unoccupied spaces within the orbit are filled with fat, which cushions the globe and other susceptible intraorbital structures.

Clinical Signs/Examination A full history, obtained from the patient caregiver, needs to include information on the duration, onset, and progression of the disease, any signs of pain and systemic disease, a possible history of trauma, any initiated treatments, the response to those treatments, and the results of any diagnostic tests that have been performed. Clinical signs of orbital disease are relatively nonspecific with regard to etiology. Orbital diseases result in altered orbital volume, impaired function of orbital structures, or both. Changes in orbital volume manifest as exophthalmos or enophthalmos, depending on whether the orbital volume has increased or decreased, and depending on the location of a volume change within the orbit. Diffuse orbital volume increases, or intraconal mass lesions located inside the muscle cone behind the globe, typically displace the globe in an anterior and axial direction. Focal lesions outside the muscle cone in a more nasal, temporal, inferior, or superior position in relation to the globe will displace or rotate the globe off‐ axis into a direction opposite the mass lesion (Fig.  14.2). These changes can be quite subtle, but they can help localize the lesion within the orbit and help plan an approach for biopsy acquisition and surgical exploration. Careful evaluation of any asymmetries or aberrations in axis orientation of both eyes needs to be performed by observing both pupils at an arm’s‐length distance. The degree of exophthalmos or enophthalmos is usually estimated by determining the position of the axial cornea relative to the orbital ligament and the other eye, both from a distance and from above (Fig. 14.3). It can also be measured directly with a Luedde or Hertel exophthalmometer (McCalla & Moore, 1989; Musch et  al., 1985). A bilateral orbital volume decrease and subsequent enophthalmos can be caused by a trigeminal neuropathy or

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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Figure 14.1  Canine skull demonstrating the lack of an osseous orbital floor, rendering the orbital contents susceptible to penetrating trauma through the roof of the mouth.

cachexia, or age‐related orbital fat and masticatory muscle atrophy (Fig.  14.4). Unilateral masticatory muscle atrophy and enophthalmos are typically caused by dysfunction of the mandibular branch of the trigeminal motor nerve. Secondary entropion can occur (Fig. 14.5). Nictitating membrane protrusion also typically accompanies orbital volume changes. An extraconal volume increase displaces the nictitans anteriorly, causing protrusion as well (Fig. 14.6), whereas an intraconal volume increase typically does not cause nictitans protrusion. With a volume decrease, passive nictitans protrusion occurs due to enophthalmos. The orbital contents can be palpated both caudal to the orbital ligament and from the oral cavity through the pterygoid muscle. The immediate retrobulbar tissues can be palpated by retropulsion of the globe. In normal mesaticephalic and dolichocephalic dogs, the globe can be displaced caudally for some distance. This is usually not possible in brachycephalic breeds. In the presence of space‐occupying orbital lesions, retropulsion of the globe will be restricted or impossible, and may also be painful. The bony rim of the orbit and the walls of the nasal cavity and paranasal sinuses should be carefully palpated and evaluated for the presence of any asymmetry. Percussion of the paranasal sinuses can be helpful to determine the presence of sinus‐occupying inflammatory or neoplastic material. The presence of a symmetric flow of air through both nostrils should be evaluated, as sinonasal tumors can cause tumor invasion of the orbit. The oral cavity is routinely inspected, because disease processes from the oral cavity or teeth may adversely affect the orbit and its contents (Ramsey et  al., 1996). Conversely, orbital diseases may affect, or be visualized through observation of, adjacent structures, such as the oral cavity, for instance pterygopalatine fossa swelling behind the last upper molar tooth. Restrictive myopathies, like masticatory muscle myositis, can cause restrictions or even an inability to open

the mouth. The degree to which the mouth can be opened should be recorded during the initial and follow‐up examinations in such cases. Inflammatory changes within the orbit are usually accompanied by pain, especially upon globe retropulsion and when opening the mouth. Movement of the vertical ramus of the mandible into the orbital space upon opening the mouth increases pressure on the orbital contents. Most dogs with orbital pain will therefore display difficulties with, or will vocalize during, some activities requiring jaw movement: chewing and eating (especially dry food, rawhides, bones), playing with balls and sticks, barking, or yawning. Thorough inspection of the oral cavity needs general anesthesia in these patients. Inflammatory changes in the orbit (cellulitis, abscess formation), which cause tissue edema, can be accompanied by conjunctival chemosis and periocular swelling. Impaired function of orbital structures manifests as reduced ocular motility, strabismus, abnormal globe position, anisocoria, blindness, and increased or reduced tear production. These signs can be caused by mechanical entrapment, pressure atrophy, loss of nerve function, and neural stimulation of affected tissues. Congestion of episcleral vessels is caused by a decreased venous return, which is due to increased orbital tissue and intravenous pressure. In more extreme cases of exophthalmos, lagophthalmos ensues due to a decreased ability to close the eyelids. This quickly results in exposure keratitis, ulceration, and potential loss of the eye. Indentation of the globe can be observed by ultrasound or ophthalmoscopically as an area of fundus elevation and altered reflectivity due to the altered angles of incident and reflected light. This indented fundus area should be observed during spontaneous eye movements. The indentation will not change position if it is caused by a mass attached to the globe, whereas unattached masses will cause an indentation that shifts position during globe movement. The presence of retinal detachments secondary to orbital mass lesions has been described (Attali‐Soussay et al., 2001). Even with marked deformation of the globe, the intraocular pressure usually remains within the normal range (Spiess et al., 1995). However, in dogs with a relatively short palpebral fissure, the globe can be pressed against the lids by a space‐occupying lesion, elevating the intraocular pressure. In rare cases of pulsating or intermittent exophthalmos associated with arteriovenous fistula or varix, auscultation of the orbit may be useful.

Ancillary Diagnostic Tests Because the orbit cannot be visualized directly, thorough general physical, ophthalmic, and neuroophthalmic examinations must be followed by a variety of diagnostic tests.

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Figure 14.2  Globe displacement caused by focal mass lesions in the orbit. A. Localized inside the muscle cone. B, C, and D. Localized outside the muscle cone, in a more nasal or temporal (B), inferior (C), or superior (D) position in relation to the globe. (Source: Adapted with permission from Miller, P.E. (2008) Orbit. In: Slatter’s Fundamentals of Veterinary Ophthalmology (ed. Maggs, D.J., Miller, P.E., & Ofri, R.), 4th ed., pp. 352–373. St. Louis, MO: Saunders.)

A  combination of diagnostic imaging and cytology/biopsy sample acquisition is usually employed to localize and identify orbital pathologies. Although almost always available, x‐ray films are not the modality of choice for ocular disease. Nevertheless, in cases of orbital disease it may serve as a first survey modality. The limitations are the same as for any other part of the skull. Soft tissue swelling with depiction of the lesion center will be possible. Also, changes in the bony structures, such as periosteal reactions, fractures in cases of trauma, aggressive bone lesions causing osseous proliferation or destruction, and lesions containing radiopaque material will be depicted (Fig.  14.7; Dennis, 2000; Johnston &

Feeney, 1980; Ruehli & Spiess, 1995a). Still, we have to consider that changes visible on films are usually rather advanced. Being confronted with such lesions, a decision to continue or not may be taken with the owners. Contrast radiography of orbital tissues, such as pneumoorbitography, orbitography, orbital arteriography, venography, optic nerve thecography, and sialography, has frequently been used to diagnose orbital diseases (Ackerman & Munger, 1979; Gelatt et  al., 1970; Johnston & Feeney, 1980; LeCouteur et  al., 1982b; McCalla & Moore, 1989). However, these methods have largely been displaced by more recent cross‐sectional imaging techniques, including orbital ultrasonography

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Figure 14.3  Exophthalmos of the left eye (OS) caused by orbital neoplasia. A. Frontal view, demonstrating left‐sided nictitans membrane protrusion and a slight “off‐axis” position OS. B. Dorsal view showing a mild degree of forward displacement OS.

Figure 14.4  Age‐related loss of retrobulbar fat and marked muscle atrophy in both eyes.

(Cottrill et al., 1989; Dziezyc & Hager, 1988; Dziezyc et al., 1987; Schmid & Murisier, 1996), computed tomography (CT; LeCouteur et  al., 1982a), and magnetic resonance imaging (MRI; Grahn & Wolfer, 1993).

Diagnostic Ultrasound The basic principles of diagnostic ultrasound have been described in Chapter  10, Part 2. Various approaches for B‐mode ultrasonography of the orbit exist. The ultrasound probe can be placed: 1) On the anesthetized corneoconjunctival surface for a direct corneoconjunctival contact approach, which eliminates attenuation of the ultrasound beam by the skin and decreases potential reverberation artifacts due to air trapping between the probe and the skin.

Figure 14.5  Unilateral cranial nerve V lesion leading to marked unilateral masticatory muscle atrophy and enophthalmos.

2) On the upper eyelid skin with the eyelids closed for a transpalpebral approach, which can decrease patient discomfort. 3) Caudal to the orbital ligament for a temporal approach, which allows visualization of the deeper orbital structures, including the optic canal and orbital fissure (Stuhr & Scagliotti, 1996). 4) On the oral mucosa behind the last upper molar, directed toward the orbit, for a transoral approach (Fig.  14.8), which is useful for fine needle aspirate (FNA) guidance and foreign body searches in retrobulbar abscess or cellulitis suspects. Two scanning planes should routinely be obtained. For the corneoconjunctival and transpalpebral approaches, a vertical and horizontal axial scan should be obtained to gain an overview of the globe, optic nerve head, optic

Figure 14.6  Bilateral orbital disease causing exophthalmos and nictitans protrusion in both eyes. (Courtesy of the University of Wisconsin‐Madison Comparative Ophthalmology Service.)

nerve, ­extraocular muscles, orbital fat, and bony orbital walls. Scans in additional planes can be obtained depending on the localization of the lesion of interest. In human patients a transverse and longitudinal/paraxial probe orientation is used for a more detailed evaluation of the extraocular muscle bellies (Byrne & Green, 2002). When using a temporal or transoral approach, the probe is oriented along the longitudinal and transverse planes of the orbit. Scanning along the craniocaudal axis of the orbit yields the best results when evaluating the optic nerve and deeper parts of the orbit. Both eyes should be imaged routinely to compare the normal and abnormal sides and to identify or rule out the presence of bilateral disease. Ultrasound is a useful technique to image the orbit, especially for an initial screening for the presence of lesions. The normal orbit is characterized by a relative hypoechogenicity of the extraocular muscles and optic nerve, compared to the orbital fat (Fig.  14.9). The bony orbital wall presents as an uninterrupted reflecting interface, which can be scanned for surface irregularities and defects. In the presence of lesions, the normal ultrasound anatomy of the orbit is usually altered or absent. Ultrasound characteristics of inflammatory and neoplastic lesions have been described in specialized texts (Byrne & Green, 2002; Nyland & Mattoon, 2002; Spaulding, 2008). In cases of orbital lesions, when the exact location and tissue of origin of a lesion need to be defined, as well as the extension (including bony involvement) and the nature of the lesion (benign vs. malignant), ultrasonography has many limitations. In situations in which these questions need to be answered, cross‐sectional imaging techniques (CT and MRI) are indicated. In cases of cellulitis, either a generalized loss of contrast between the orbital contents or no ultrasonographic abnormalities are observed (Dennis, 2000). Abscesses are identified as lesions with a well‐demarcated echogenic wall, hypoechogenic corpuscular contents, and signal enhancement distal to

the lesion. Cavitary lesions with a fluctuant center are found in dogs with cystic lesions and orbital abscesses, but are also identified in more than 10% of neoplasms (Boroffka et  al., 2007; Mason et  al., 2001). Cavitary lesions are described as typical lesions in orbital myxosarcoma in dogs (Dennis, 2008). When the suspicion of a retrobulbar abscess or cellulitis is high and the presence of a foreign body needs to be determined, ultrasound seems to be a relatively sensitive diagnostic tool (Boroffka et  al., 2007). Foreign bodies are often identified as hyperechogenic linear structures with distal signal attenuation (shadowing). However, old wooden foreign bodies do not necessarily cause distal shadowing and can be difficult to identify. CT or MRI studies are indicated for an evaluation of the size, number, and exact localization of retrobulbar foreign bodies (Dennis, 2000; Hartley et  al., 2007). Sometimes both modalities, CT/MRI and ultrasonography, may be complementary, as cases exist where ultrasound depicts the foreign body and CT/MRI does not, and vice versa (Fig. 14.10 and Fig. 14.11). Neoplastic lesions were most commonly hypoechoic and homogenous, and globe indentation was identified more often than with inflammatory lesions (Fig. 14.12). However, these features are by no means distinctive. Orbital bone defects and tissue mineralization were almost exclusively seen in neoplastic lesions (Boroffka et al., 2007; Mason et al., 2001). In one study, the sharper delineation of lesion margins was the most discriminating feature of neoplasms compared to inflammatory lesions, with both ultrasound and CT (Boroffka et  al., 2007). Color Doppler ultrasound used to characterize orbital blood flow can be useful for the differentiation of orbital lesions (Byrne & Green, 2002; Gelatt‐ Nicholson et al., 1999). The advantages of ultrasound over some of the more advanced imaging techniques are its relatively low costs, general accessibility in practice, the fact that general anesthesia is usually unnecessary, and its use for real‐time guidance during FNA or tissue biopsy acquisition. Ultrasound can be used to evaluate the intraorbital extension and localization of disease, but more accurate tools are available for this purpose. Another limitation of ultrasound is the inability to image beyond the bony orbital wall, precluding the evaluation of extraorbital lesion extension and the evaluation of adjacent structures in general (Richter et al., 2003).

Computed Tomography and Magnetic Resonance Imaging Both CT and MRI allow multiplanar imaging, and therefore complete assessment of the anatomic structures of interest beyond the bony margins (nasal and cranial cavities) can be readily achieved (Fig. 14.13). When we need to decide which of these two modalities we should use, the

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Figure 14.7  A, B. Mineralized space‐occupying lesion right nasal cavity: laterolateral view (A) and ventrodorsal view (B). Note the marked, well‐defined, inhomogenously mineralized space‐occupying lesion visible on the radiographs (white arrows). With these findings, a suspicion of an aggressive neoplastic lesion can be raised, preparing a discussion on how to proceed with the patient. Only if continuation and therapy are planned is further imaging, such as computed tomography (CT), necessary. C, D. Transverse CT images of the region, indicating the exophthalmus (white arrows in C), the osteolysis, and the large mineralized space‐occupying lesion (white arrows in D).

advantages and disadvantages of both techniques must be considered. CT is fast, thus requires less time under general anesthesia, and it offers very good bony detail. The main disadvantages are the use of ionizing radiation and poor soft tissue contrast. In contrast, MRI obtains an excellent soft tissue contrast, and characterization of the lesions (hemorrhagic, cystic, necrotic, mineralized) can be performed with exquisite detail thanks to different sequences. The main disadvantages of MRI are that it is less available,

more expensive, and slower than CT, requiring longer general anesthesia times. The basic principles of CT and MRI have been described in Chapter 10 Part 2 and will not be repeated in this chapter. The normal anatomy of the orbit in CT and MRI studies has been described (Boroffka & Voorhout, 1999; Boroffka et al., 2008; Joslyn et al., 2014; Morgan et al., 1994). Reference values for normal canine eyes have been published (Chiwitt et al., 2017; Salguero et al., 2015). Globe size was correlated

Figure 14.8  Ultrasound probe placement for a transoral approach to the orbit.

with weight and showed significant differences between small, medium, and large‐breed dogs (Chiwitt et al., 2017). Periorbital length was equal across brachycephalic, mesaticephalic, and dolichocephalic dog breeds and was positively correlated with both bodyweight and cranial length (Klaumann et  al., 2017). Some characteristics of CT and MRI in respect to specific orbital pathologies will be highlighted here.

A

Due to the natural contrast between bone, soft tissues, air, and fat, CT has superior contrast resolution qualities, enabling excellent visualization of orbital structures, especially bone. MRI provides better soft tissue contrast resolution compared to CT. MRI scans are therefore superior to CT scans in cases in which an exact evaluation of soft tissue tumor extension into the surrounding soft tissues, including intracranial extension (Fig. 14.14), is needed (Dennis, 2000). An MRI scan is recommended for patients that show neurologic signs indicating central nervous system involvement. Cysts and abscesses are also more easily identified with MRI. Despite the fact that osseous changes can be evaluated on MRI scans (cortical bone presents as a signal void on MRI; see Fig. 14.14), CT is the modality of choice for the evaluation of traumatic injury, osseous changes, and the visualization of foreign bodies (especially metallic ones, where MRI is contraindicated; Boroffka et al., 2011; Malhotra et al., 2011). Tissue perfusion can be assessed using both imaging modalities by comparing pre‐ and postcontrast studies. Well‐­ perfused tissues (most tumors, granulomatous lesions, abscess walls, tissue reactions surrounding foreign bodies, vascular lesions) will contrast enhance after contrast injection (Hoyt et al., 2009). As with other imaging modalities, due to a lack of specificity neither CT nor MRI is straightforward for distinguishing between inflammatory and neoplastic processes when mass lesions are identified. As with any rule there exist ­exceptions,

B

Figure 14.9  Ultrasound images of a normal canine orbit. A. Axial scan: the optic nerve (asterisk) and extraocular muscle bellies (arrows) are hypoechogenic compared to the surrounding orbital fat. B. Paraxial scan facilitating examination of the extraocular muscles (arrows). The optic nerve can be seen as an S‐shaped hypoechogenicity (arrowheads). Note that the lens is not visible in this probe orientation. (Courtesy of M. Dennler.)

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E Figure 14.10  Orbital foreign body in a 5.5‐year‐old Eurasier dog. A. Ultrasound demonstrated a clean shadow in the deeper part of the orbit (asterisk). A definitive distinction between a shadow caused by a foreign body or by the normal bony contours of the skull was not possible. B–D. Magnetic resonance imaging (MRI): transverse, dorsal, and oblique T1‐weighed postcontrast planes show a linear signal void surrounded by marked contrast uptake (black arrows). This was identified as a foreign body. In this case MRI confirmed the diagnosis. E. A wooden foreign body was delivered via modified lateral orbitotomy.

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E Figure 14.11  Orbital abscess due to a foreign body in a German Shepherd dog. A. T2‐weighed dorsal plane. B. T1‐weighed postcontrast transverse plane of the abscess with T2 hyperintense and T1 hypointense content with marked rim enhancement (white arrows). A foreign body could not be identified in these sequences. C, D. Ultrasound images of the abscess. In the center of the cavity a hyperintense linear structure is visible (white arrows) representing the foreign body. In this case ultrasound confirmed the diagnosis. E. A piece of grass was extracted during surgery.

Section IIIA: Canine Ophthalmology

orbital and periorbital masses using CT scans to facilitate surgical planning (Dorbandt et al., 2017). Whether CT or MRI is used for further diagnostics often depends on various factors, including suspected diagnosis, therapy planning purposes, machine availability, costs, and clinician preference. Future applications of MRI could include the use of microcoil‐assisted MRI for high‐resolution imaging of the cranial orbit and globe (Ivan et  al., 2019; Lavaud et  al., 2019; Fig. 14.16). Table 14.1 lists the clinical value of various diagnostic imaging modalities in various situations (Gonzalez et al., 2001; Morgan, 1989; Penninck et al., 2001).

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Fine Needle Aspiration and Tissue Biopsy

Figure 14.12  Ultrasonography of an orbital neoplasm (meningioma) in a 10‐year‐old Collie. Note the marked indentation of the caudonasal globe.

such as melanotic tumors, which are almost pathognomonic in MRI: intraocular melanomas have a unique signal behavior of T1 hyper‐ and T2 hypointensity. Sensitivity and specificity for the detection of optic nerve and intracranial lesions are high in MRI. In a study evaluating CT signs associated with inflammatory and neoplastic orbital conditions, Lederer et al. (2015) identified increased attenuation of orbital fat (fat‐stranding) to be associated with inflammatory and bone defects with neoplastic lesions. Osteolysis is typically interpreted as a sign of neoplastic disease, which is supported by most publications describing and comparing orbital imaging techniques (Boroffka et al., 2007; Calia et al., 1994; Dennis, 2000). Winer et al. (2018) identified both osteolysis and new bone formation to be highly associated with neoplasia. However, in endemic areas fungal granulomas, causing clinical symptoms and displaying imaging characteristics similar to those of neoplastic lesions, need to be considered as a differential diagnosis (Baron et al., 2011; Hecht et al., 2011; Fig. 14.15). In general, MRI scans require more time than CT scans, but allow the acquisition of images in various planes, without the need for repositioning the patient. CT imaging allows the acquisition of guided biopsies, through the acquisition of short scans ascertaining the correct placement of the biopsy needle. This is a possible advantage of CT over MRI imaging. A diagnostic scan should be performed prior to needle placement and aspiration, to ensure that tissue changes (e.g., hemorrhage) or the introduction of air into the biopsy area does not interfere with the results of the scan. Also, if radiation therapy is part of the therapeutic plan, a diagnostic CT scan can be used for radiation planning as well (Boston, 2010). A recent paper described the three‐dimensional printing of

Biopsy specimens can be obtained via the oral cavity, through bulbar conjunctiva, or through the skin caudal to the orbital ligament, with or without the use of ultrasound or CT guidance (Boydell, 1991). With the advent of modern imaging techniques, diagnostic orbitotomies have become almost obsolete. Some publications providing data on the diagnostic sensitivity of FNAs and tissue biopsies show that an FNA yields diagnostic results in approximately 50% of cases, whereas tissue biopsies provide a definitive diagnosis in approximately 75% of cases (Armour et  al., 2011; Attali‐ Soussay et al., 2001; Gilger et al., 1992). In a study by Hendrix and Gelatt (2000) a definitive diagnosis was derived from 49% of the cytologies, 56% of the nonsurgical biopsies (trephine, biopsy needle), and 100% of the surgical biopsies performed. When cytology and a nonsurgical biopsy were both performed, the diagnostic yield increased to 79%. Sufficient amounts of tissue can be obtained with an ultrasound‐guided tru‐cut core biopsy technique, which was found to be of equal diagnostic value compared to excisional biopsies in lesions with a maximum diameter of 25–38.5 mm (Cirla et al., 2016). FNAs were found to be less likely to yield a definitive diagnosis when performed on mesenchymal tumors, likely due to the fibrous and cell‐poor nature of these masses (Attali‐ Soussay et al., 2001). A recent study showed that tumor diagnosis based on core needle and surgical biopsy samples was superior to FNAs. A discordance between cytologic and histopathologic diagnosis was reported in 53% of cases (Flaherty et al., 2020). The use of special stains and immunohistochemical markers can increase diagnostic accuracy (Dubielzig et al., 2010; Giudice et al., 2005).

Congenital Anomalies of the Orbit and Globe Anophthalmos Complete absence of the eye, or anophthalmos, is very rare. In most cases, some remnants of ocular tissue can be identified histologically (Kern, 1991).

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D

Figure 14.13  Computed tomography study of a squamous cell carcinoma invading the dorsocranial orbit and nasal cavity. A, B. Three‐ dimensional (3D) reconstructions outlining the tumor (yellow) in relation to the skull and eye (white). Osteolysis is evident underneath the tumor mass. C, D. Cross‐section of 3D reconstruction and transverse bone window demonstrating the enophthalmos and globe indentation (arrowheads) due to the tumor mass effect. Osteolysis (arrows) and nasal involvement (asterisk) are clearly identified in D. (Courtesy of M. Dennler.)

Cystic Eye, Microphthalmia, and Nanophthalmia If remnants of ocular tissue are present histologically, a diagnosis of either a cystic eye or microphthalmia can be made. Cystic eyes are structures that consist of an outer mesenchymal layer, lined internally with a single layer of undifferentiated neuroectoderm. In these cases, development has been arrested at the optic vesicle stage.

In true microphthalmia the globe contains evidence of the presence of surface ectoderm (lens), neural crest migration, and neuroectodermal differentiation (Grahn & Peiffer, 2007). Microphthalmia therefore presents as an abnormally small globe, with various other ocular anomalies involving the cornea, lens, uvea, vitreous, and retina (Slatter, 1990). Vision may be normal, reduced, or absent. In contrast, a small but otherwise normal globe is called nanophthalmia.

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E

Figure 14.14  A–C. Magnetic resonance imaging (MRI), transverse plane, T1‐weighed precontrast (A), T2‐weighed (B), and T1‐weighed postcontrast (C) sequence: exophthalmos caused by a nasal adenocarcinoma (asterisk) with orbital and intracranial tumor extension. D, E. MRI T1‐weighed postcontrast reconstructions in the (D) sagittal and (E) dorsal plane. The tumor is highlighted by marked contrast uptake (white arrow) and shows invasion into the neurocranium and also into the retrobulbar space, where the nasal bone, observed as a clear signal void on the contralateral side, is almost completely destroyed.

In the Doberman Pinscher, microphthalmia is associated with anterior segment and retinal dysplasia (Arnbjerg & Jensen, 1982). The cause of this anomaly remains unknown, but a genetic trait is suspected (Lewis et al., 1986). Congenital cataracts and microphthalmia in the Miniature Schnauzer (Gelatt et al., 1983; Shastry & Reddy, 1994; Zhang et al., 1991) and microphthalmia in the Australian Shepherd (Gelatt & McGill, 1973; Gelatt et al., 1981) are recessively inherited. In the Australian Shepherd dog, microphthalmia is associated with equatorial staphylomas, persistent pupillary membranes, and retinal dysplasia (Gelatt & Veith, 1970). Poorly pigmented animals are most affected (Bertram et al., 1984). Collies and Shetland Sheepdogs with Collie eye anomaly often exhibit variable degrees of microphthalmia (Kern, 1991); this is especially true for merles. Microphthalmia has also been observed in the Beagle (Saunders & Rubin, 1975), Akita (Laratta et al., 1985), Chow Chow (Collins et al., 1992), Cavalier King Charles Spaniel (Narfström & Dubielzig, 1984), Irish Wolfhound (Kern, 1981), and a number of other breeds of dog (Bayon et al., 2001; Boroffka et al., 1998).

Vascular Anomalies Orbital varices and arteriovenous fistulas are very rare orbital anomalies with few reported cases. Varices can be congenital (Adkins et  al., 2005) as well as acquired. In humans, they are often a sequel of head trauma (Troost & Glaser, 1995), which has also been suspected in orbital varix (Millichamp & Spencer, 1991) and arteriovenous fistulation cases in dogs (Tidwell et al., 1997). In contrast to humans, dogs typically present with a nonpainful, pulsating, or intermittent exophthalmos (Komar & Schuster, 1967; Ruehli & Spiess, 1995b). A decrease in venous return from the head can influence the extent of exophthalmos if an orbital varix is present, with the exophthalmos worsening when the head is kept low or pressure applied to the jugular vein region (Adkins et al., 2005). In arteriovenous fistula cases, not varices (Millichamp & Spencer, 1991), a systolic murmur (“bruit”) can be auscultated in the orbital region (McCalla & Moore, 1989; Rubin & Patterson, 1965).

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C Figure 14.15  Postcontrast computed tomography (CT) study, transverse plane, soft tissue window: extensive osteolysis (B; arrows) and a mass lesion (asterisks) extending into the nasal cavity (A), orbit (A, B), and cranial vault (B, C). Based on the nasal extension of the mass, identified on this CT examination, tissue samples were acquired via rhinoscopy. Histologic examination yielded a diagnosis of blastomycosis. (Courtesy of R. Drees.)

The diagnosis of these vascular anomalies is made on the basis of clinical signs and results of diagnostic imaging, including dynamic contrast CT imaging and magnetic resonance angiography (Tidwell et al., 1997). Treatment can be difficult and the prognosis is guarded. Ligation of orbital vessels can cause massive hemorrhage, necessitating enucleation of the globe and/or ligation of the common carotid artery. Orbital exenteration and careful hemostasis should be curative. The successful use of guided coil embolization with or without subsequent application of intravenous sclerosing foam has been described in dogs with an orbital varix (Adkins et al., 2005; Saunders et al., 2018).

Table 14.2 lists the most important differential diagnoses for exophthalmos.

Orbital Cysts A retrobulbar dermoid cyst (Walde, 1997), microphthalmia‐ associated orbital cysts of neural tissue (Regnier et al., 2008), and medial canthal cysts originating from lacrimal glandular or nasolacrimal ductal tissue in young dogs (Ota et al., 2009) have been reported. Surgical excision is recommended. Intralesional injection of a sclerosing agent (1% polidocanol) was recently reported to be successful in resolving a suspected nasolacrimal duct cyst in a dog (Zimmerman et al., 2019).

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A

B

Figure 14.16  High‐resolution magnetic resonance imaging in a healthy, 8‐year‐old Beagle dog: T1 (A) and T2‐weighed (B) images. Note the detailed depiction of the ocular and cranial orbital structures. Table 14.1  Diagnostic imaging: Added value beyond clinical examination/indications. Radiography

Ultrasound

Computed Tomography (CT)

Magnetic Resonance Imaging (MRI)

Cellulitis

–

+/–

+

++

Abscess

–

+

++

++

Metallic

++

+

++

Xa

Bone

+

+

++

++

Glass/plastic

–

+/–

++

++

Plant (grass awn/wood)

–

+/–

+

+

Salivary cyst

–

+

+

++

Foreign body

Neoplasia Intraorbital

+/– (mineralization) +

++

++

Affecting bone

+/– (size, location)

+/– (location)

++

+

Extraorbital extension

+/–

+/–b

++

++

b

Intracranial extension

–

+/–

+

++

Biopsy/aspirate guidance

–

+c

+d

–

Three‐dimensional reconstruction

–

+

++

++

–, No added clinical value beyond what can already be deduced based on clinical examination findings; +, of added diagnostic value; ++, significant addition of diagnostic information. a  An MRI is contraindicated in the presence of a metallic foreign body, as those can possibly dislodge under influence of the strong magnetic field. b  In cases where major bone lysis has taken place, extraorbital structures may become visible on ultrasound. In such cases the suspicion of involvement can be raised. c  Aspirates and biopsies can be guided in real time (or as the needle is being advanced) with ultrasound assistance. d  Real‐time guidance is not possible with CT assistance. Rather, the needle will be placed and its position assessed with a quick scan. Needle position can then be adjusted and reassessed as needed. Delineation of the lesion, on the other hand, is much more precise with CT compared to ultrasound. Source: Information from Armour et al. (2011); Attali‐Soussay et al. (2001); Boroffka et al. (2007); Byrne & Green (2002); Calia et al. (1994); Dennis (2000, 2008); Drees et al. (2009); Gonzalez et al. (2001); Grahn et al. (1993); Hendrix & Gelatt (2000); Malhotra et al. (2011); Mason et al. (2001); Morgan (1989); Penninck et al. (2001); Stuhr & Scagliotti (1996).

Table 14.2  Causes of exophthalmos. Vascular anomalies Orbital varix Orbital arteriovenous fistula Cystic lesions Salivary retention cyst and mucocele Inflammatory lesions Abscess Cellulitis Granuloma Extraocular muscle myositis Masticatory muscle myositis Neoplasia Primary orbital Metastatic or primary multifocal Locally invasive tumor invading orbit Traumatic causes Orbital fracture Hematoma Emphysema Miscellaneous Craniomandibular osteopathy

Acquired Orbital Diseases Inflammatory Lesions: Orbital Cellulitis/Abscess In contrast to large animals, orbital inflammatory diseases are rather common in small animals, especially in dogs. According to most studies, dogs presenting with non‐­ neoplastic orbital diseases are significantly younger than dogs presenting with neoplastic diseases. In one representative study, dogs presented with orbital abscesses at a mean age of 4 years, whereas the mean age of tumor patients was 9.5 years (Boroffka et  al., 2007; Dennis, 2000; Ruehli & Spiess, 1995b). Other studies showed no significant age difference between these two groups of patients (Calia et  al., 1994; Mason et al., 2001). Typically, dogs present with acute, unilateral exophthalmos (Fig.  14.17), protrusion of the nictitating membrane, conjunctival hyperemia and chemosis, episcleral venous congestion, periocular swelling, serous to mucopurulent ocular discharge, and pain. The globe itself is generally normal and normotensive. Affected dogs are usually febrile and inappetent, although in one study none of the 12 animals with orbital cellulitis presented with these signs (Armour

et  al., 2011). This underlines the potential inaccuracy of a diagnosis based on clinical symptoms alone. A white blood cell count usually reveals neutrophilia. The underlying cause often remains unidentified (Koch, 1980), but foreign material is sometimes encountered (Grahn & Wolfer, 1993; Ruehli & Spiess, 1995b; Stades et  al., 2003). The point of entry of such foreign bodies is not always easily identified. Foreign bodies may enter the orbit from the oral cavity, percutaneously, or through the conjunctival sac. Hematogenous infection of orbital tissues has been suspected as well. Microorganisms may invade from the oral cavity, sinuses, or tooth roots, notably the caudal roots of the upper fourth premolar and the roots of the upper first and second molar teeth (Grahn et  al., 1995a; Hakanson, 1994; Ramsey et  al., 1996). The presence of a swelling or fistula on the surface of the maxillary bone (Fig. 14.18) anterior to the orbital margin is a typical sign of an apical tooth root infection. Overly aggressive or improper dental extraction techniques can result in inadvertent penetration of, and introduction of an infection into, the orbit and potentially even the globe (Ramsey et al., 1996; Smith et al., 2003). Infections of the zygomatic gland may present as orbital cellulitis or abscess (Simison, 1993), and in these cases a swollen excretory duct may be seen lateral to the second molar tooth. In another study the majority of dogs with zygomatic sialadenitis were male and of medium or large breeds. The disease was unilateral in 9/11 dogs and a sialocele formed in 7/11 dogs. Both MRI and CT were excellent diagnostic methods to identify sialadenitis. Medical treatment with antimicrobials and anti‐inflammatory drugs resolved clinical signs within 3 weeks in most dogs (Cannon et  al., 2011). Significant inflammatory diseases of the globe itself (panophthalmitis, scleritis) can also cause orbital cellulitis. Ultrasound can be useful in confirming typical globe abnormalities in combination with signs of cellulitis, including retrobulbar fluid accumulation (Fig. 14.19). Wang et  al. (2009) identified extension from adjacent structures, exogenous trauma, and foreign bodies as the most common causes of infectious orbital disease. Staphylococcus spp. were isolated in 25%, E. coli in 16.7%, Pasteurella multocida in 8.3%, and anaerobic bacteria (mostly Bacteroides and Clostridium spp.) in 30.5% of the canine patients in this study. In another study, Pasteurella spp. were the most common isolates from orbital abscesses (Ruehli & Spiess, 1995b). Fungal organisms are an uncommon cause of orbital disease (Baron et  al., 2011; Bruchim et  al., 2006; Dubielzig et al., 2010; Roberts & Thompson, 1969) and the clinical signs are usually pathognomonic for orbital inflammatory diseases. Onchocercosis seems to be an emerging disease in the southwestern United States and south‐central Europe. In chronic cases, the worms are incorporated in

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C Figure 14.17  A. Clinical presentation of a 2‐year‐old dog presenting with a sudden, painful exophthalmos of the left eye. B. Ultrasound of the left retrobulbar space, occupied by a large hypoechoic lesion with a relatively well‐defined cranial border and demonstrating a loss of orbital tissue contrast. C. Postcontrast computed tomographic study revealing lesion extent: generalized swelling and hypoattenuation of the soft tissues along the left side of the face, and an abscess with hypoattenuating center (white arrow) and contrast‐enhancing capsule (black arrow) is identified along the dorsal and lateral surfaces of the frontal bone. Sinus involvement (asterisk) is seen (intracranial extension was present on other slices), the peribulbar area is compartmentalized, and the globe itself severely compressed. D. Abscess drainage caudal to the last upper molar. All images represent the same patient. (Courtesy of the University of Wisconsin‐ Madison Comparative Ophthalmology Service.)

subconjunctival, episcleral, and orbital granulomas, causing corresponding clinical symptoms. Treatment consists of surgical excision and the postoperative use of macrofilaricid drugs (Dubielzig et al., 2010; Komnenou et al., 2002; Sreter & Szell, 2008). Other parasites are rarely identified in orbital disease (Laus et al., 2003). Ultrasonography is a cost‐effective method to determine the presence of a drainable retrobulbar abscess and to screen for the presence of a foreign body (see Fig. 14.17B). The type of foreign body material dictates which imaging modality is most useful for identification. Most foreign bodies are not recognized on plain radiographs, but metallic foreign bodies are easily demonstrated. MRI scans are contraindicated when a suspicion for a metallic FB exists,

due to the risk of FB displacement under the influence of the strong magnetic field (Malhotra et al., 2011). Low‐field (0.4 Tesla) MRI tends to overestimate the presence of foreign bodies, according to a recent publication (Fischer et al., 2019). A CT scan can directly pick up foreign bodies that are sufficiently dense (metal, glass, bone). Foreign bodies of lower density (plant material, wood, plastic, porcupine quills) may be identified in postcontrast studies as a filling defect with a contrast‐enhancing rim of reactive tissue (Boroffka et al., 2011). In patients that show clinical signs consistent with extraorbital involvement, CT or MRI studies to evaluate the extent of periorbital tissue involvement and to determine the prognosis are indicated (see Fig. 14.17C; Kneissl et al., 2007). Intracranial extension of

A

B

Figure 14.18  Clinical appearance of a suborbital fistula (A) originating from a tooth root abscess of P4 with apical alveolar bone lysis (B). (Courtesy of S. Grundmann.)

Figure 14.19  Ultrasound B‐scan image of a patient with blastomycosis panophthalmitis and secondary orbital cellulitis. Note the hyperechogenicity of the vitreous (asterisk), the lack of contrast between the orbital tissues, and the fact that the outer contour of the sclera and optic nerve is visible due to retrobulbar fluid accumulation (thin black arrow). (Courtesy of the University of Wisconsin‐Madison Comparative Ophthalmology Service.)

fungal and bacterial orbital disease is possible and significantly decreases the prognosis for survival (Baron et  al., 2011; Hecht et al., 2011; Oliver et al., 2009). As with ultrasound, a loss of definition of orbital structures, increased attenuation of orbital fat, and a diffuse, poorly defined mass effect are the typical feature of orbital cellulitis on CT and MRI images (Fig.  14.20; Armour et  al., 2011; Lederer et al., 2015). Obtaining samples for cytology and culture/sensitivity assays is an important step in the diagnostic process. FNAs and tissue biopsies can be used for these purposes. A surprisingly high number of submitted cultures yield negative results, however (Armour et  al., 2011; Wang et al., 2009).

Figure 14.20  Postcontrast computed tomography study, transverse plane of a dog with orbital cellulitis: mild exophthalmos and a loss of definition of orbital structures. (Courtesy of M. Dennler.)

The first and most important step in treating an orbital abscess is drainage, which is performed in general anesthesia with protection of the airways through intubation and tube cuffing. The oral mucosa behind the last upper molar tooth, which may show a fluctuating swelling, is incised. A closed hemostat is advanced through the pterygoid muscle (Fig. 14.21) and then opened and withdrawn without closing (see Fig. 14.17D). The hemostat is advanced in a blind fashion into an area richly supplied by blood vessels and nerves, but complications are rarely encountered. However, damage

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Figure 14.21  Transoral abscess drainage technique.

to the optic and ciliary nerves has been observed (Kern, 1991; Ruehli & Spiess, 1995a, 1995b). Irrigation of the retrobulbar area is a controversial issue. Exacerbation of the exophthalmos and spreading of infectious organisms are potential complications. On the other hand, irrigation with crystalline penicillin has been beneficial (Slatter, 1990). When orbital ultrasonography fails to reveal an abscess, drainage of the orbit may be postponed, and systemic antibiotic therapy instituted instead. Most orbital inflammations respond within 2–3 days with systemic antibiotic therapy. Systemic antibiotic therapy using broad‐spectrum antibiotics is usually indicated pending the results of bacterial culture and sensitivity testing. A relatively high incidence of mixed aerobic/anaerobic and pure anaerobic bacterial infections has been reported (Jang et al., 1997; Wang et al., 2009). Use of cephalosporins, extended‐spectrum penicillins (e.g., ticarcillin), potentiated penicillins (e.g., amoxycillin‐­ clavulanic acid), and carbapenems was therefore recommended based on aerobic and anaerobic culture sensitivity results in these and other studies. Additionally, if no contraindications exist, these patients are usually treated with nonsteroidal anti‐inflammatory drugs (NSAIDs). Hot packs also are beneficial and well tolerated by most dogs (Ruehli & Spiess, 1995a, 1995b). The globe itself must be treated symptomatically. In cases of lagophthalmos, lubrication of the ocular surface is important. The degree of exophthalmos often increases temporarily after drainage, and a temporary tarsorrhaphy may be necessary. Soft food should be offered until the globe is back in its normal position. The prognosis is usually good. In a series of 17 cases, 15 healed within a week, one healed after one recurrence, and

one was lost to follow‐up (Ruehli & Spiess, 1995a, 1995b). In most cases, the exophthalmos regresses within 36–48 hours, and the general condition of the animal markedly improves. Long‐term ophthalmic pathology was observed in 30% of dogs following retrobulbar cellulitis and abscessation in a recent retrospective study, with 5/41 dogs suffering permanent blindness due to suspected optic nerve compression. This highlights the need for initial ophthalmic assessment and follow‐up examinations (Fischer et al., 2018). If foreign material is retained in the orbit, recurrences are to be expected. An attempt to identify and localize a potential foreign body via ultrasound, CT, or MRI is warranted in such cases. Surgical retrieval of an identified foreign body can be performed via abscess drainage or any of the orbitotomy techniques described later in this chapter. Surgical exploration via orbitotomy and flushing of the retrobulbar space was effective in curing patients with recurrent retrobulbar abscesses in one case series (Tremolada et al., 2015). Patients presenting with chronic purulent ocular discharge should be checked for the presence of a conjunctival fistulous tract, along which foreign body material may be retrieved via surgical exploration (Fig. 14.22; Stades et al., 2003).

Salivary Retention Cysts and Mucoceles (Sialoceles) Cystic structures in the orbit or periorbital tissues can arise from any glandular or epithelial tissue, including lacrimal, third eyelid, and salivary glands, and conjunctival or paranasal sinus mucosa. The main clinical signs relate to the mass effect created by the volume and location of the cyst. Mucoceles (or sialoceles) usually result from trauma to the head, with or without skull fractures (Knecht et  al., 1969; Schmidt & Betts, 1978). In a mucocele, leakage of saliva from the zygomatic gland or its excretory duct causes inflammation and tissue fibrosis (Slatter & Basher, 2003), resulting in a thick fibrous capsule, but no true epithelium, surrounding the cavitary lesion. A mucocele is therefore not a true cystic lesion (Dubielzig et  al., 2010). Mucoceles must be distinguished from salivary retention cysts, caused by inflammation and ulceration of the oral mucosa and obstruction of salivary outflow, with subsequent cyst formation (Bartels, 1990; Nell & Walde, 1994). Salivary retention cysts are true cysts, which are lined with a true epithelium when viewed histologically (Dubielzig et al., 2010). These cysts are caused by obstruction of the salivary duct, typically due to sialoliths or inflammation of the oral mucosa. The reaction of tissues surrounding the cysts is minimal. A distended excretory duct of the zygomatic gland can sometimes be seen in the oral mucosa. The clinical distinction is not always possible, since the clinical signs of retention cysts and mucoceles are similar: a fluctuating swelling with a variable position within the orbit and possible conjunctival or oral presentation. Exophthalmos and

A

B

C

D

Figure 14.22  Orbital foreign body in a 6‐year‐old dog. A. Initial presentation with chronic purulent discharge from the right eye. B. Fistulous tract in the dorsal conjunctival fornix. C. Surgical exploration of the fistulous tract. D. Foreign material (wood) retrieved from the orbit.

protrusion of the nictitating membrane are usually present, and pain on opening the mouth or palpation of the globe is variable, but usually minimal. In one case, strabismus and secondary iritis were observed (Nell & Walde, 1994). The diagnosis is made on the basis of clinical signs and results of orbital ultrasonography, CT. and/or MRI. Tissue characteristics identified via MRI can assist with disease differentiation (Boland et al., 2013). Aspiration of a yellowish and slightly tenacious fluid with variable amounts of blood is typical for mucoceles (Schmidt & Betts, 1978). True cysts usually yield clear to mucoid fluid. Mucoceles are best treated by surgical excision of the cystic cavity and associated gland (Slatter & Basher, 2003). In cases of salivary retention cysts, treatment of the oral mucosal disease is essential; at the same time, the cyst can be drained from the oral cavity, similar to an orbital abscess. Successful use of sclerotherapy after aspiration of cyst contents has been described (Stuckey et al., 2012). The prognosis appears to be favorable. In most reported cases,

healing occurred within a short time following surgical and medical therapy.

Myositis Because of the absence of a temporal bony orbital wall, swelling or atrophy of the muscles of mastication will displace the globe (Fig.  14.23A). Eosinophilic myositis of the muscles of mastication, or masticatory muscle myositis (MMM), predominantly affects young German Shepherds and Weimaraners, but has also been described in Labrador Retrievers and Golden Retrievers (Koch, 1980). MMM is an immune‐mediated inflammatory myopathy targeting the temporalis, masseter, and pterygoid muscles of mastication. These muscles contain type 2M myofibers, which are composed of myosin heavy and light chains unique to the masticatory muscles. This unique myofiber‐type composition provides the basis for the preferential susceptibility of masticatory muscles to myositis (Orvis & Cardinet, 1981). Type

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Figure 14.23  A. Masticatory muscle myositis in a German Shepherd. There is marked swelling of the masticatory muscles and bilateral exophthalmos, which is more marked in the left eye. (Courtesy of I. Walde.) B, C. Postcontrast magnetic resonance imaging T1‐weighed study of a different patient, dorsal (B) and transverse (C) planes: note the marked irregular contrast enhancement of the inflamed muscle bellies (white arrows) accentuated in the peripheral muscle areas.

2M fiber‐specific autoantibodies against masticatory muscle myosin heavy and light chains are routinely found in dogs with MMM, but not in dogs with polymyositis, using immunoblotting and enzyme‐linked immunosorbent assay (ELISA; Shelton, 2007; Shelton et al., 1987). A major target for autoantibodies in canine MMM has been identified and named masticatory myosin binding protein‐C (Wu et  al., 2007). In acute myositis, a leukocytosis with peripheral eosinophilia, elevated serum levels of creatine phosphokinase, and a positive 2M antibody test are typically present. Histopathology of temporal muscle biopsies reveals degeneration of muscle fibers as well as neutrophilic and eosino-

philic infiltration (Carter, 1981). The digastricus muscle does not contain type 2M fibers (Bubb & Sims, 1986), which likely explains the results of a study describing CT findings in dogs with MMM, in which abnormalities were identified in the temporalis, masseter, and pterygoid muscles of mastication, but not in the digastricus muscle (Reiter & Schwarz, 2007). MMM is usually an acute disease accompanied by fever, lethargy, anorexia, and weight loss. Pain and swelling of the  masseter and temporal and pterygoid muscles causes ­painful and restricted jaw movements and exophthalmos, ­respectively. Optic neuritis and subsequent blindness have been described in association with acute MMM (Lescure,

1985). Despite the fact that this is a bilateral disease, symptoms of bilateral muscle involvement are not always appreciable clinically. Without treatment, inflammatory episodes persist for 1–3 weeks (Carter, 1981). Acute myositis must be differentiated from orbital cellulitis or abscesses, temporomandibular joint disease, and (extraocular) polymyositis. Cross‐sectional imaging (ultrasound, CT, MRI) can assist with an early diagnosis of MMM (Fig. 14.23B, C). Changes in size, signal attenuation, and inhomogenous contrast enhancement have been identified via CT in the masticatory muscles of dogs with MMM (Czerwinski et al., 2015; Reiter & Schwarz, 2007). Masticatory muscles were swollen and hyperintense on T2‐weighted and gradient echo short tau inversion recovery (GE STIR) sequences in MRI, indicating inflammation‐induced muscle edema (Cauduro et al., 2013). Fibrosis of the muscles of mastication causes muscle atrophy, enophthalmos, and an inability to open the mouth in chronic cases. Muscle fibrosis without inflammatory infiltrates is evident histologically, and leucocyte, creatine phosphokinase, and 2M antibody levels are unlikely to be elevated. This situation must be differentiated from neurogenic and steroid‐induced muscle atrophy, and from atrophy secondary to endocrine diseases. Difficulties in opening the mouth can handicap a dog and negatively impact its quality of life. Severe enophthalmos causes secondary entropion and may impair vision in combination with nictitans protrusion. In some cases, muscle fibrosis and atrophy occur without clinically detectable antecedent inflammation (Kern, 1991; Whitney, 1970). Extraocular polymyositis has been described in 37 dogs, of which 29 were female and 21 were Golden Retrievers (Williams, 2008; Fig. 14.24). Affected dogs are typically young. Bilateral exophthalmos with anterior globe displacement, retraction of the upper eyelid without protrusion of the nicti-

Figure 14.24  Bilateral extraocular polymyositis in an 8‐month‐ old Golden Retriever. Note the bilateral symmetric exophthalmos without nictitans membrane protrusion.

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Figure 14.25  Ultrasonographic image of the swollen rectus muscles (outlined by asterisks) in a 5‐year‐old Great Dane with extraocular polymyositis.

tating membrane, and congestion of episcleral vessels are common presenting signs. A predominantly CD3+ ­lymphocytic infiltrate dominates the muscle histopathology (Dubielzig et  al., 2010). In chronic cases, fibrosis of the extraocular muscles can cause mild enophthalmos and strabismus. In contrast to Graves’ disease in humans, extraocular polymyositis is not associated with either hyper‐ or ­hypothyroidism (Carpenter et  al., 1989). Ultrasonography, CT, or MRI will reveal swollen extraocular muscles in cases of extraocular polymyositis (Fig. 14.25). Restrictive nasoventral strabismus has been described as a uni‐ or bilateral (Fig. 14.26), progressive esotropia in young dogs, which can lead to blindness within a few weeks (Allgoewer et al., 2000). Extraocular muscle fibrosis was histologically diagnosed in all specimens in this case series, and signs of either acute or chronic lymphocytic inflammation (extraocular muscle myositis) were present in most cases. Radical surgical transection of the affected muscles resulted in a central eye position in 9/12 treated eyes, although most eyes remained enophthalmic. Three of the treated eyes returned to the original preoperative position following surgical correction. In the acute stages, myositides respond well to immunosuppressive doses of oral corticosteroids over 3–4 weeks. Azathioprine can be given at a dose of 1–2 mg/kg body weight for 10–14 days and then tapered off. The prognosis is guarded. Recurrence rates have traditionally been reported to be quite low (Koch, 1980), but relapses may occur (Kern, 1991). Uncontrolled myositis will invariably lead to atrophy of the affected muscles. Advanced muscle atrophy and fibrosis cannot be influenced medically. Silicone or glass beads

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Figure 14.26  Bilateral esotropia in an 18‐month‐old field trial Labrador Retriever. Clinically, this patient demonstrated limited spontaneous abduction of both eyes (OU) and forced duction toward the temporal side was restricted OU. A slight posterior movement of the globe was noticed while rotating the globe in a temporal direction. A nasal rotation of the superior retinal veins was observed OU. This was interpreted as evidence of dorsal oblique and medial rectus muscle shortening and likely fibrosis. (Courtesy of the University of Wisconsin‐Madison Comparative Ophthalmology Service.)

have been implanted in the orbit to correct the enophthalmos, but migration of these implants has been a major problem in both humans and animals (Helms et al., 1987). Neospora caninum has been associated with extraocular polymyositis in a litter of German Shorthaired Pointers (Dubey et  al., 1990). Infectious causes of myositis, like neosporosis, toxoplasmosis, leishmaniasis (Naranjo et al., 2010), and lyme borreliosis (Raya et al., 2010), need to be considered as a differential diagnosis for masticatory and extraocular muscle myositis.

Orbital Neoplasia Tumors represent the most common group of orbital diseases. Primary tumors can arise from any orbital tissue, and secondary neoplasms either invade the orbit from adjacent structures or metastasize to the orbit from distant sites. In general, orbital neoplasms occur in older animals (Attali‐ Soussay et al., 2001; Boroffka et al., 2007; Calia et al., 1994; Cirla et al., 2016; Dennis, 2000; Mason et al., 2001; Ruehli & Spiess, 1995a). Depending on the localization, orbital tumors cause slowly progressive, unilateral exophthalmos or enophthalmos, with variable displacement and indentation of the globe (Slatter & Basher, 2003). Nictitans protrusion is present and retropulsion of the globe is decreased or impossible. Bilateral orbital neoplasia appears to be extremely rare. In contrast to orbital inflammatory diseases, neoplasms tend not to be painful. However, a diagnosis of orbital neoplasia cannot reliably be made based on clinical signs alone. In a retrospective study of 44 dogs with orbital neoplasia, Hendrix and Gelatt (2000) found that one‐third of patients with neoplastic disease

showed acute symptoms of pain, purulent inflammation on cytology, and/or a favorable initial response to antibiotics. Osteolytic processes are usually associated with pain as well. Vision can be retained even in chronic cases, depending on the level of pressure or tension on the optic nerve. Tumors arising from the optic nerve or its meninges will cause blindness at an early stage (Spiess et al., 1995). On top of the clinical signs already described, nasosinal tumors can cause epistaxis, altered percussion tones, and pain upon palpation and/or percussion of the nasosinal cavities, and a decreased or absent airflow through the nose. The frequency of occurrence of the various types of orbital tumors in dogs, as diagnosed in some larger case series, is listed in Table 14.3 (Armour et al., 2011; Attali‐Soussay et al., 2001; Boroffka et  al., 2007; Calia et  al., 1994; Cirla et  al., 2016; Dennis, 2000; Flaherty et al., 2020; Gilger et al., 1992; Hendrix & Gelatt, 2000; Kern, 1985; Mason et  al., 2001; O’Brien et  al., 1996; Ruehli & Spiess, 1995a). According to these studies, the most common orbital tumors in dogs are: 1) Tumors of mesenchymal origin (osteosarcoma, fibrosarcoma, multilobular osteochondrosarcoma). 2) Tumors of epithelial origin (mostly adenocarcinoma, among which primary nasosinal tumors were common). 3) Miscellaneous (peripheral nerve sheath tumor, orbital meningioma, mastocytoma). Most of these tumors are of primary orbital origin, with the exception of nasal and paranasal sinus tumors. All of the tumors listed above are malignant. A complete general physical exavmination, including evaluation of regional and distant lymph nodes, and a search for possible metastases via thoracic and abdominal imaging are part of a routine workup. Characteristics of orbital neoplasia, identifiable with the various imaging modalities, have been described in “Ancillary Diagnostic Tests” (see Fig.  14.7, Fig.  14.12, Fig.  14.13, and Fig.  14.14). MRI characteristics of some major tumor types (carcinoma, sarcoma, lymphoma) have been described in detail (Armour et al., 2011). After localization of the lesion, an FNA or tissue biopsy is obtained. The diagnostic sensitivity of the various sampling procedures is discussed in “Ancillary Diagnostic Tests”. On cytology, lymphoma can sometimes be difficult to distinguish from a benign reactive proliferation of lymphocytes. In such cases, a polymerase chain reaction assay for antigen receptor rearrangement (PARR) can be used to determine the clonal origins of lymphocyte populations. Since clonal lymphocyte replication is a hallmark of neoplasia, this test can confirm the monoclonal origin (and thus tumorous nature) of lymphocytes. The test can be performed on blood, FNA, biopsy, and aqueocentesis samples (Burnett et  al., 2003; Pate et al., 2011). Unfortunately, many orbital neoplasms are discovered in an advanced stage at which euthanasia or palliative surgery

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901

Table 14.3  Neoplastic orbital diseases. Referencesa

1

2

3

Nasal adenocarcinoma 14/112

Osteosarcoma 12/112

Anaplastic/undifferentiated sarcoma 11/112 Flaherty et al. (2020)

B‐cell lymphoma 10/23

Fibrosarcoma 5/23

Soft tissue sarcoma 3/23

Carcinoma 13/53

Sarcoma 8/53

Peripheral nerve sheath tumor 5/53

Armour et al. (2011)

Nasosinal tumor 9/29

Sarcoma 8/29

Carcinoma (not nasosinal) 6/29

Boroffka et al. (2007)

b

Cirla et al. (2016)

Adenocarcinoma 3/13

Osteosarcoma 2/13

Various 1/13 each

Attali‐Soussay et al. (2001)

Nasosinal tumor 14/26

Sarcoma 6/26

Various 2/26 each

Mason et al. (2001)

Osteosarcoma 6/44

Fibrosarcoma 5/44

Nasosinal tumor 5/44

Hendrix & Gelatt (2000)

Adenocarcinoma 4/12c

Fibrosarcoma 2/12

Various 1/12 each

Dennis (2000)

Osteosarcoma 3/24

O’Brien et al. (1996)d

Multilobular osteochondrosarcoma 10/24 Fibrosarcoma 4/24 Meningioma 4/19

Mesenchymal mass 4/19 Fibrosarcoma 3/19

Ruehli & Spiess (1995a)

Nasosinal tumor 3/13

Various 1/13 each

Calia et al. (1994)

Osteosarcoma 6/23

Mastocytoma 4/23

Squamous cell carcinoma 8/21

(Adeno‐)carcinoma 5/21 Malignant lymphoma 3/21

Reticulum cell sarcoma 3/23

Kern (1985) Gilger et al. (1992)e

a

 Cats were excluded from this table for all but the last reference.  Of these carcinomas, eight were suspected to be of nasosinal origin. c  Three of these four adenocarcinomas showed (para‐)nasal involvement. The fourth was a recurrence of a previously incompletely removed third eyelid adenocarcinoma. d  A population bias exists in this study, since these patients were all candidates for orbitectomy surgery. e  This reference was incorporated for comparison: 21 cases of orbital neoplasia in cats. Note: Top‐tier orbital tumors in dogs: ●● Tumors of mesenchymal origin (osteosarcoma, fibrosarcoma, multilobular osteochondrosarcoma) ●● Tumors of epithelial origin (mostly adenocarcinoma, among which primary nasosinal tumors were common) ●● Miscellaneous (peripheral nerve sheath tumor, orbital meningioma, mastocytoma) b

is the only option. Osteolysis is a poor prognostic indicator and is associated with a significant decrease in survival time (Hendrix & Gelatt, 2000). Localized neoplasms without evident distant metastasis may be surgically removed via orbitotomy or orbitectomy and reconstruction procedures while preserving the globe and, possibly, the animal’s vision. If preservation of the globe is not possible, exenteration of the globe or radical orbitectomy must be considered (for references, see “Orbitotomy and Orbitectomy”). Surgical management of orbital neoplasia can be combined with radiation therapy, chemotherapy, or both. For some tumor types, including nasosinal tumors, irradiation yields favorable results when used as monotherapy. Nasosinal tumors are graded on a scale from 1 to 4, based on local tumor extension. Tumors involving the orbit are minimally classified as Stage 3. The median survival time after cobalt irradiation is significantly decreased for Stage 3 and 4 tumors (315 days), compared to Stage 1 and 2 tumors (745 days; Adams et al., 1998). A diagnostic CT scan can be used for radiation planning and was considered to be superior to MRI for nasal tumor staging (Drees et al., 2009). It is therefore important for treatment planning and prognostic purposes to include a CT scan in

the diagnostic workup of a patient suspected of having a nasal tumor. Helical tomotherapy and modern linear accelerators with sophisticated treatment planning are different from older irradiation devices, like cobalt units, in that the avoidance of critical structures within the treatment field is an achievable treatment goal (Deveau et al., 2010). The use of such image‐guided intensity‐modulated radiation therapy modalities has resulted in survival times comparable to those attained using older methods, while massively reducing the occurrence of severe ocular side effects, including cataracts, retinal degeneration, keratoconjunctivitis sicca, and blindness (Lawrence et al., 2010; Pinard et  al., 2012). Recently, canine sinonasal tumors were treated using image‐guided intensity‐modulated radiation therapy with an integrated boost technique in which the gross tumor volume was exposed to 20% additional ­irradiation. Only mild ocular side effects were observed during the first 3 months after treatment (Soukup et  al., 2018). The ­tolerability of the simultaneously integrated boost ­technique for canine sinonasal tumors using image‐guided intensity‐­modulated radiation therapy and improved local tumor control is predicted based on theoretical calculations (Gutierrez et al., 2007).

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Tumor Frequency

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Canine lobular orbital adenomas are benign tumors of lacrimal or salivary gland origin, consisting of multiple individual friable lobular units dispersed into the orbital connective tissues. Dogs typically present with painless eyelid and nictitating membrane swelling and anterior orbital involvement. Metastasis has not been reported. The risk for recurrence after surgical excision is high, unless the tumor is completely resected, which potentially requires orbital exenteration (Headrick et al., 2004). Orbital myxosarcoma is a rare, slowly progressive neoplasm in dogs. Typically, large fluid‐filled cavities are seen in the orbit and along fascial planes. The main differential diagnosis is zygomatic sialocele. Advanced cross‐sectional imaging identified involvement of the temporomandibular joint in 6/7 cases in two studies. Osteolytic changes to the temporomandibular joint were identified on standard radiographs in two dogs. These tumors usually are not amenable to resection, but also typically show a slow and largely pain‐free progression (Dennis, 2008; Parslow et al., 2016). Benign orbital hibernomas are rare neoplasms of brown adipose tissue occurring in older dogs. Surgical excision should be curative (Ravi et al., 2014). Canine orbital rhabdomyosarcoma is a malignant neoplasm predominantly of young dogs. Surgical resection had a favorable prognosis in older dogs in a recent case series (4/4 dogs alive 8–13 months after diagnosis), whereas the majority of younger dogs (9/11) were euthanized within 6 months (median 2.5 months) after diagnosis (Scott et al., 2016). In most cases of orbital neoplasia, the prognosis is guarded at best. In one study of 12 cats and 13 dogs with retrobulbar tumors, the overall average survival time was 8.6 months, with a range of 1 month to 3 years. The average survival time was 1 month in cats and 13 months in dogs (Attali‐Soussay et  al., 2001). Most dogs with orbital neoplasms are euthanized shortly after diagnosis. With early diagnosis and surgical therapy, however, the survival time increases to several months to years (Kern, 1985; Lawrence et al., 2010; O’Brien et al., 1996; Spiess et al., 1995). Hendrix and Gelatt (2000) showed that, of the dogs that either died or were euthanized within 6 months of diagnosis, 78% (14/18 dogs) did not receive treatment. Of the dogs that survived for longer than 6 months, 86% (12/14 dogs) did undergo some form of therapy.

Traumatic Lesions Orbital Fractures and Hematomas

Orbital fractures and hematomas usually result from road accidents. The frontal, temporal, and zygomatic bones are most commonly involved, and clinical signs include skin lacerations, pain, facial asymmetry, lacrimation, exophthalmos or enophthalmos, strabismus, proptosis, lagophthalmos, and secondary xerophthalmia. Contusions of the globe are often

associated with lens luxation, intraocular hemorrhage, and retinal detachment. In severe cases, scleral ruptures, usually extending from the lamina cribrosa, may occur (Rampazzo et al., 2006). Fractures involving the paranasal sinuses may cause orbital or subcutaneous emphysema with crepitus (Ruehli & Spiess, 1995a; Slatter & Basher, 2003). Animals with orbital fractures should be kept quiet to prevent further swelling and hemorrhage, and cold compresses should be administered. The eye must be cleansed immediately and kept lubricated. Local and systemic antibiotics and systemic corticosteroids should be given. Topical steroids are administered if the corneal epithelium is intact. NSAIDs may increase the risk of further hemorrhages. Topical application of atropine sulfate is controversial, because secondary glaucoma may be a complication of marked hyphema. As soon as the overall condition of the patient is stable, the eyes and orbit need to be further evaluated. CT is the fastest and most comprehensive imaging modality when dealing with trauma patients: an exact evaluation of fracture topography, a reliable assessment of globe integrity, and a complete evaluation of the entire head are possible. MRI would be the most useful imaging modality if intracranial changes are suspected. Ultrasonography of the globe may be indicated when hyphema prevents examination of the posterior segment. The reader is referred to “Ancillary Diagnostic Tests” for references. Small, nondisplaced fractures stabilize spontaneously and do not require surgical reduction and fixation. Small, displaced, and offending bone fragments need to be removed surgically and large, unstable fractures may require internal fixation. Entrapment of extraocular muscle bellies is a possible complicating factor. A strabismus may be present and eye movements can be restricted, as are forced ductions in the opposite direction. Chronic entrapment can result in permanent loss of muscle function and even fibrosis, leading to a persistence of clinical signs. In cases of muscle entrapment, surgical therapy is indicated. Orbital fractures can induce an oculocardiac reflex in dogs, as evidenced by bradycardia and an atrioventricular block (Selk Ghaffari et  al., 2009). To prevent serious exposure keratitis, a third eyelid flap or a temporary tarsorrhaphy is indicated. In cases with extensive trauma to the globe, the prognosis for long‐term comfort is poor, phthisis bulbi is a common sequel, and enucleation is usually recommended. Spontaneous orbital hematoma formation can occur as a result of rodenticide ingestion. Conjunctival or subcutaneous hematomas, exophthalmos, orbital pain, and typical clinical pathologic abnormalities (prolonged prothrombin time, normal to prolonged partial thromboplastin time, and normal to decreased platelets) are suggestive of the diagnosis. A favorable response to vitamin K1 treatment is typically quick and complete (Griggs et al., 2016).

Orbital Emphysema

Orbital emphysema is usually a complication of enucleation. Brachycephalic dogs appear to be predisposed. This may result from increased pressure in the nasal cavity of such dogs during expiration. Air is pressed into the orbit via the nasolacrimal duct. Fractures of the paranasal sinuses may also cause orbital emphysema (Barros et al., 1984; Bedford, 1979; Martin, 1971; Slatter & Basher, 2003). The soft swelling of an orbital emphysema often reveals crepitus when palpated. If clinical signs are equivocal, plain radiographs will show air in the orbit and, at the same time, may demonstrate orbital fractures. Orbital emphysema resolves spontaneously in most cases. If an emphysema persists or occurs later after enucleation, the proximal end of the nasolacrimal duct must be identified and ligated (Gornik et al., 2015; Slatter & Basher, 2003). In brachycephalic breeds, prophylactic ligation of the nasolacrimal duct at the time of enucleation could be considered. Proptosis

Proptosis results from a sudden, forward displacement of the globe with simultaneous entrapment of the eyelids behind the equator (Gilger et al., 1995). This entrapment prohibits spontaneous repositioning of the globe (Fig. 14.27). Proptosis must be differentiated from exophthalmos, in which the lid margins remain in a physiologic position. Proptosis of the globe is a true ophthalmic emergency, which requires rapid assessment of the situation as well as immediate medical and surgical therapy. Even if vision cannot be preserved, the globes can often be salvaged for cosmetic purposes by early and correct management.

Figure 14.27  Proptosis of the right globe in a young Golden Retriever. There is entrapment of the eyelids as well as severe swelling and hyperemia of the bulbar conjunctiva. The cornea has already been protected with an ointment.

Though proptosis is usually the result of some traumatic incident, trauma may be minimal in brachycephalic breeds. In one series of 29 dogs, 14 dogs were brachycephalic (Fritsche et  al., 1996). In dolichocephalic breeds, greater trauma is necessary to cause proptosis. The diagnosis of proptosis is relatively easy to make. Determination of the prognosis, as well as the appropriate medical and surgical management, may be more difficult. The prognosis for vision is guarded to poor in general and depends on the extent of (peri‐)ocular tissue damage. As an approximation, only 20% of proptosed globes regain some functional vision (Fritsche et  al., 1996; Gilger et  al., 1995). Hence, prognosis refers to the possibility of salvaging the globe for cosmetic purposes, as opposed to enucleation. Salvaged globes must be free of discomfort to the dog and cosmetically acceptable to the owner. The degree of proptosis may provide some idea regarding the amount of extraocular muscle damage. Usually, the medial rectus muscle is the first to be avulsed. If more than two rectus muscles are avulsed, the vascular supply and innervation to the anterior segment are compromised due to the extensive tissue trauma, and the globe should be enucleated (Fig.  14.28; Fritsche et  al., 1996; Gilger et  al., 1995). Scleral ruptures are often associated with intraocular hemorrhage and loss of shape and turgor of the globe. Enucleation is recommended in these cases (Rampazzo et al., 2006). Globes with intraocular hemorrhage, especially if combined with avulsion of more than one extraocular muscle, have a guarded prognosis. Such eyes may still be repositioned. If an acceptable status does not result, enucleation can be performed at a later date. Keratitis sicca and neurotrophic keratitis due to corneal desensitization are common sequelae and may be difficult to

Figure 14.28  Severe proptosis with avulsion of the optic nerve and several extraocular muscles in an American Cocker Spaniel. Despite the clear and intact anterior segment, enucleation was inevitable.

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manage. The long‐term prognosis must be discussed with the owner in such cases. Some owners may prefer enucleation rather than a blind eye that is salvaged, but requires constant attention for many years. Eyes with only a minor or moderate degree of proptosis and with avulsion of no more than one muscle and either no or minor intraocular hemorrhage have a better prognosis for salvaging the globe. Usually, such eyes remain blind. Size of the pupil itself is no indicator for prognosis. Eyes that have direct or indirect pupillary light reflexes and vision on initial examination have a better long‐term prognosis for vision. Positive direct and indirect pupillary light reflexes as well as assessment and operation performed by a veterinary ophthalmologist were the sole factors correlated with a favorable prognosis in a recent study (Pe’er et al., 2020). Proptosed eyes should be repositioned under general anesthesia as soon as possible. Until anesthesia is induced, proptosed globes must be kept lubricated with a viscous gel or ointment. The globe is cleansed with sodium chloride solution, and the eyelids are engaged with strabismus hooks or Allis forceps and pulled both up and away from the globe. Gentle pressure will cause the globe to settle back into the orbit. A lateral canthotomy may be necessary. Orbital hemorrhage and tissue swelling usually prevent the eye from returning to an absolutely normal position; therefore, a temporary tarsorrhaphy must be performed using 4‐0 to 2‐0 (depending on the size of the animal) monofilament nonabsorbable suture material. Two or three horizontal mattress sutures with stents are usually required. At the medial canthus, a small opening should be left to facilitate topical medication. Immediately after completing the temporary tarsorrhaphy, a cold pack is applied to the eye to decrease swelling until the animal recovers from anesthesia. Postoperative care is identical to that given to orbital fracture and hematoma patients. Depending on the amount of orbital swelling and degree of exophthalmos, all sutures should remain in place for at least 1 week and are then removed one at a time, starting medially, on subsequent visits and dependent on the return of a healthy blink. Long‐term sequelae of proptosis include blindness, strabismus, mild exophthalmos, lagophthalmos, sensory deficits of the cornea, keratoconjunctivitis sicca, exposure keratitis, glaucoma, and phthisis bulbi (Fritsche et  al., 1996; Gilger et  al., 1995). Exotropia is a common sequel resulting from avulsion of the medial rectus muscle, the shortest of the four rectus muscles (Fig. 14.29). Globe position often returns to near normal over the course of several months. With the brachycephalic breeds, bilateral medial or lateral canthoplasty in order to shorten the palpebral fissure and thus prevent future proptosis should be discussed with the owner at the time of repositioning the proptosed globe.

Figure 14.29  Exotropia following proptosis of the right globe and medial rectus muscle avulsion in a Shih Tzu. Due to the medial rectus avulsion, the globe now lacks a force rotating the globe in a nasal and pulling it in a posterior direction. The result is a subtle exophthalmos and chronic erosion on the nasal (now central and most protruding) part of the cornea. (Courtesy of the University of Wisconsin‐Madison Comparative Ophthalmology Service.)

Miscellaneous Lesions Orbital Fat Prolapse

Prolapse of orbital fat is uncommon in dogs; only a few cases have been described (Boydell et al., 1996; Grahn et al., 1993). Orbital fat is separated from the subconjunctival space by Tenon’s capsule. In humans, senile weaknesses of Tenon’s capsule are responsible for herniation of orbital fat within the eyelids. The cause of orbital fat prolapse in the dog is unknown. Prolapsed fat presents as a subconjunctival swelling (Fig. 14.30). Inflammatory reactions and ocular discharge are lacking. The swelling is easily movable and usually nonprogressive, but enophthalmos and protrusion of the nictitating membrane can be present. FNA is typically diagnostic. If necessary, orbital fat prolapse can be treated surgically, by excision of the prolapsed fatty tissue and suturing the conjunctiva to the episcleral tissue or orbital rim to prevent recurrences (Boydell et al., 1996). Excessive removal of orbital fat should be avoided, as enophthalmos could ensue. The prognosis is good, and recurrences have not been described. Craniomandibular Osteopathy

Craniomandibular osteopathy is a non‐neoplastic, proliferative bone disease that predominantly affects Scottish Terriers and West Highland White Terriers at the age of 3–6 months. Other breeds can also be affected. Affected pups are often lethargic, inappetent, and slightly febrile. The mandibular lymph nodes are enlarged, and the temporal muscles may be atrophied. Because of their inability to open the mouth, affected dogs salivate profusely, have difficulty eating and drinking, and are often dehydrated and

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Figure 14.30  Orbital fat prolapse in a dog. A soft mass that was not attached to the globe caused significant swelling of the ventral bulbar conjunctiva. (Courtesy of B.M. Spiess.)

e­ maciated (Manley & Amundson Romich, 1993). The orbit is rarely involved, but exophthalmos has been described (Mould, 1993). The etiology is unknown, but hereditary factors are suspected to play a role (LaFond et  al., 2002; Padgett & Mostosky, 1986). The diagnosis is made on the basis of plain radiographs or CT images of the skull showing typical periosteal lesions of the mandible and temporal bone. In severe cases, the temporomandibular joint can be damaged. Recently, MRI was used to diagnose craniomandibular osteopathy (Matiasovic et al., 2016). The disease is self‐limiting. However, supportive therapy during the active stage of the disease is important. In many cases, administration of analgesic drugs suffices. In severe cases, nutrients and fluids need to be administered parenterally (Slatter & Wolf, 1993). The prognosis is good, except in cases affecting the temporomandibular joint, in which food intake may permanently be problematic. Due to the clinical and pathologic similarities between the two diseases, it seems likely that craniomandibular osteopathy and calvarial hyperostosis are manifestations of the same disease with different predilection sites (Fig. 14.31; Mathes et al., 2012; McConnell et al., 2006; Thompson et al., 2011).

Surgery of the Globe and the Orbit Surgical Preparation For all orbital surgeries, the periorbital skin and eyelids are clipped, shaved, and prepared for aseptic surgery in a ­routine

Figure 14.31  Three‐dimensional computed tomographic reconstruction of a dog with craniomandibular osteopathy (white arrows) and calvarial hyperostosis (yellow arrows pointing at cross‐sectioned temporal bones, caudal view). (Courtesy of M. Dennler.)

manner. The ocular surface and conjunctival sac are copiously flushed with sterile saline solution; a 1 : 50 aqueous povidone‐iodine solution can also be used as part of the chemical preparation of the eye for surgery.

Local and Regional Anesthesia A preoperative retrobulbar block with a sodium channel blocker (bupivacaine, lidocaine, etc.), with or without adrenaline, improves perioperative analgesia and reduces the need for additional postoperative analgesics (Myrna et  al., 2010). The inferior‐temporal palpebral (ITP) route has been shown to give the most consistent intraconal drug placement. A ~4 cm, 22‐gauge spinal needle is bent at the midpoint in an approximate 20° angle. The needle is positioned at the inferior orbital rim and inserted through the inferior lid; it is advanced 1–2 cm in total, depending on patient size and the depth of the orbit, until a slight popping sensation is detected, which indicates piercing of the orbital fascia. The needle is then directed slightly dorsally and nasally toward the apex of the orbit (Fig. 14.32). After drawing on the syringe plunger, the medication is slowly injected.

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Section IIIA: Canine Ophthalmology

Figure 14.32  Frozen skull, sectioned through the eye and orbit. Needle placement for a retrobulbar injection via the inferotemporal palpebral route is demonstrated. (Reproduced with permission from Accola, P.J., Bentley, E., Smith, L.J., et al. (2006) Development of a retrobulbar injection technique for ocular surgery and analgesia in dogs. Journal of the American Veterinary Medical Association, 229(2), 220–225.)

There should be no resistance and the eye should move forward slightly and rotate centrally while the pupil dilates (Accola et al., 2006). A supratemporal approach for retrobulbar anesthesia has recently been evaluated in canine cadavers and appears to be a valid alternative to the ITP approach (Fig.  14.33A; Chiavaccini et  al., 2017). A canine cadaver study demonstrated that retrobulbar anesthesia provided marginally better injectate volume distribution compared to peribulbar anesthesia (Fig.  14.33B). However, the study predicted an inadequately reliable success rate of 40%–60% even for the retrobulbar technique (Shilo‐Benjamini et  al., 2017). In a later study, the same authors demonstrated that peribulbar injection produced notable anesthesia more reliably than retrobulbar injection (Shilo‐Benjamini et al., 2019). To avoid the risks associated with retrobulbar blocks, intraoperative bupivacaine splash blocks and intraorbital lidocaine‐bupivacaine–infused absorbable gelatin sponges have been evaluated and demonstrated similar pain control efficacy compared to retrobulbar blocks with bupivacaine

A

B

C Figure 14.33  Needle position for retrobulbar anesthesia (A), peribulbar anesthesia (B), and sub‐Tenon’s anesthesia (C).

(Chow et  al., 2015; Ploog et  al., 2014). However, a recent study demonstrated that a preoperative retrobulbar bupivacaine block is more effective than an intraoperative bupivacaine splash block at controlling intraoperative and postoperative pain perception in dogs undergoing enucleation (Zibura et al., 2020). Vezina‐Audette et al. (2019) demonstrated that an oculocardiac reflex occurred less frequently in animals receiving retrobulbar nerve blocks compared to animals without such blocks. An ultrasound‐guided posterior extraconal block was demonstrated ex vivo to successfully deliver contrast close to the main nerves that provide sensory and motor innervation to the eye (Viscasillas et al., 2019). A sub‐Tenon’s capsule injection of lidocaine resulted in mydriasis and extraocular muscle akinesia and intraoperative analgesia, thus providing an alternative to retrobulbar blocks in certain surgeries (Fig.  14.33C; Ahn et  al., 2013a, 2013b, 2013c). In a recent review, Shilo‐Benjamini (2019) concluded that there is little evidence for choosing one ophthalmic regional anesthesia technique over another, due to a lack of controlled clinical trials and adverse events reported in the veterinary literature.

Enucleation Enucleation is the most common orbital surgery performed in animals. Removal of the globe is indicated in any case involving blind, painful eyes (e.g., uncontrollable glaucoma, endophthalmitis, severe ocular trauma with hemorrhage, and so on). It is also indicated for treatment of intraocular tumors not amenable to other forms of surgical or medical treatment. The most commonly used surgical technique is the subconjunctival approach (Fig. 14.34; Kuhns, 1976; Slatter & Basher, 2003). The main objectives are to remove the globe, nictitating membrane, conjunctival sac, and lid margins, while leaving as much soft tissue behind as possible to minimize postoperative depression of skin over the orbit. A lateral canthotomy is performed to facilitate exposure of the globe, and a lid retractor is inserted. Beginning in the dorsal quadrant, the bulbar conjunctiva is incised approximately 5 mm posterior to the limbus. The conjunctiva and Tenon’s capsule are bluntly dissected from the globe, and the extraocular muscles are identified and transected close to their scleral insertion. Dissection of these muscles allows the globe to be mobilized and displaced in an anterior direction. Undue traction on the extraocular muscles is better avoided due to the risk of inducing an oculocardiac reflex, which is a well‐known phenomenon in pediatric strabismus surgery in humans (Choi et  al., 2009). The retractor bulbi muscle is then identified and dissected in a similar fashion. Medial rota-

tion of the globe will expose the optic nerve, which is clamped with curved hemostats and then transected a few millimeters behind the globe. The surgeon must avoid tension on the optic nerve, so as not to damage contralateral optic nerve fibers at the crossover point in the optic chiasm (Stiles et al., 1993). Blunt dissection of soft tissue and transection of the muscles close to the sclera will minimize hemorrhage. Once the globe is removed, the orbit is packed with gauze sponges to control diffuse hemorrhage, and the nictitating membrane is grasped with forceps and dissected at its base (to include the gland of the third eyelid). The lacrimal gland is usually not removed. In addition, 3–5 mm of eyelid margin are removed with scissors. The conjunctival sac is removed as thoroughly as possible. After removal of the gauze package, the periorbital/deep fascial layers and subcutis are sutured with 4‐0 absorbable suture material in a continuous pattern. The skin is closed with simple continuous or interrupted sutures using 4‐0 nonabsorbable monofilament suture material. Postoperative care is symptomatic, and sutures are removed after 10–14 days. Owners should be informed that serosanguinous secretions from the ipsilateral nostril may occur over the first few postoperative days, until the nasolacrimal duct is obliterated. An alternate technique is the transpalpebral approach in which the eyelids are sutured together in a continuous suture pattern (Fig. 14.35; Wolf, 1990). Two elliptical incisions approximately 5 mm behind the lid margins are joined near the medial and lateral canthus. Deep dissection will identify the bulbar conjunctiva. After transection of the medial and lateral canthal ligaments, forward traction of the eyelids will help with dissection of the conjunctiva, until the sclera is encountered at the limbus. Further dissection, globe removal, and wound closure are the same as for the subconjunctival approach. The globe, conjunctival sac, nictitans, and lid margins are removed en bloc. The transpalpebral approach has the advantage of minimizing exposure of the orbit to contaminants from the ocular surface. This method is therefore employed in cases of ocular surface infection. The most common postoperative complication is hemorrhage within the first few hours after surgery, which results in swelling of the surgical site and serous discharge from the suture line. Cold compresses, pressure bandages, and sedation of the patient are usually sufficient to control hemorrhage. Icing the wound between wound closure and recovery may help to reduce swelling. Warm compresses applied to the orbit during the days following surgery can also help to reduce swelling. Draining fistulas from the orbit can result from incomplete removal of the caruncle at the medial canthus or of the remaining secretory tissues (e.g., conjunctival goblet cells, third eyelid gland) within the orbit. Postoperative orbital

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Figure 14.34  Enucleation: subconjunctival approach. A. Incision of the bulbar conjunctiva. B. After transection of the extraocular muscles close to their scleral attachments, the optic nerve is clamped and severed. C. The orbit is packed with a gauze sponge and the nictitating membrane resected. D. Excision of the lid margins. E, F. Closure of the periorbital and deep fascial layers with a continuous suture pattern, after removal of the gauze sponge. Skin closure with simple interrupted or continuous sutures. (Adapted with permission from Slatter, D.H. & Basher, T. (2003) Orbit. In: Textbook of Small Animal Surgery (ed. Slatter, D.H.), 3rd ed., pp. 1430–1454. Philadelphia, PA: W.B. Saunders, Figure 95‐25.)

infection is a rare complication. In brachycephalic breeds, orbital emphysema may also be a complication of enucleation. Orbital sialoceles have been reported as a complication of enucleation surgery associated with prior parotid duct transposition, for which parotid duct transposition reversal has been described and proposed as a preventive measure (Guinan et al., 2007; Young et al., 2018). A recent comparative

study identified carprofen as a more effective postoperative pain treatment than tramadol (Delgado et al., 2014). A recent evaluation of owner perceptions and satisfaction following bilateral enucleation demonstrated that 90% of owners were satisfied with the procedure, perceived their dogs to have a good quality of life, and would consent to the procedure again (Hamzianpour et al., 2019).

A

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Figure 14.35  Enucleation: transpalpebral approach. A. The eyelids are sutured or clamped together and an elliptical incision is made around the lid margins. B. After transection of the extraocular muscles close to their scleral attachments, the optic nerve is clamped and severed. The globe, conjunctival sac, nictitans, and lid margins are removed en bloc. Bilayered closure of the orbit is identical to that during subconjunctival enucleation (Fig. 14.34E, F). (Adapted with permission from Slatter, D.H. & Basher, T. (2003) Orbit. In: Textbook of Small Animal Surgery (ed. Slatter, D.H.), 3rd ed., pp. 1430–1454. Philadelphia, PA: W.B. Saunders, Figure 95‐27.)

Exenteration Exenteration involves removal of the conjunctiva, periorbita, extraocular muscles, and globe. In case of an orbital tumor, exenteration may be extended to involve all orbital contents. A transpalpebral approach is used, in which the eyelids are sutured together in a continuous pattern. An incision is made around the palpebral fissure and approximately 5 mm from the lid margins. Dissection is then advanced caudally through the orbicularis oculi and orbital fascia toward the orbital rim, involving all extraocular muscles, the globe, conjunctiva, nictitating membrane, and lacrimal gland (Slatter & Basher, 2003). If necessary, the remaining orbital connective tissues and fat can be excised. Closure of the subcutis and skin is routine, as described for enucleation. The orbital depression is more marked following exenteration than following enucleation, and a prolene or Dacron mesh can be anchored to the orbital rim to avoid an unsightly depression. A novel surgical approach for an extensive orbital exenteration was described in detail in a recent publication (Berggren & Wallin‐Hakansson, 2019).

Orbital Prosthesis To improve the postoperative cosmetic appearance of enucleation or exenteration surgery, silicone or methyl methacrylate spheres may be implanted (Hamor et  al., 1993; Moore, 1990; Nasisse et  al., 1988; Oria et  al., 2016). This reduces the extent of the depression of skin over the orbit, commonly seen after enucleation surgery. Silicone spheres are most commonly used today. The size of the implant is selected according to the size of the orbital space to be filled; the diameters in dogs vary between 12 and 28 mm. These implants are placed into the orbit after hemostasis has been achieved. To improve the cosmetic

appearance and avoid rotation of the implant, the anterior quarter of the sphere is removed using scalpel blades and Mayo scissors, until a flat, anterior surface with smooth, rounded edges is produced. After placement, the sphere should snugly fit into the orbit without causing undue compression of orbital tissues and the anterior surface of the sphere should not protrude from the orbital rim. The wound is then closed in a routine manner. Postoperative care is the same as for enucleation and exenteration. Possible complications include traumatic dislocation and rotation of the implant, orbital seroma formation, and infection. The latter can result in wound dehiscence and extrusion of the implant (Hamor et al., 1994; Nasisse et al., 1988). Contraindications to the placement of an orbital prosthesis include the presence of neoplasia or infection in the orbit, or extraorbital sources of a systemic bacteremia.

Evisceration and Implantation of Intrascleral Prostheses Evisceration involves replacing the intraocular contents with an appropriately sized silicone sphere, leaving only the fibrous tunic. The diameter of the silicone sphere should equal the horizontal diameter of the opposite healthy cornea (Ruoss et  al., 1997), or be 1 to 2 mm larger (Wilkie et  al., 1994). Blind and painful eyes of an approximately normal size, without septic endophthalmitis or intraocular neoplasia, are candidates for evisceration and implantation of a silicone prosthesis (McLaughlin, 1990; Ruoss et  al., 1997). A blind eye with early phthisis bulbi can be fitted with an intrascleral prosthesis to prevent further globe shrinkage and secondary adnexal problems (Lettow, 1987). Animals are premedicated with systemic flunixin meglumine and antibiotics. After routine preparation and draping

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release the uvea and retina. A lens loop is used to remove the lens, and the scleral shell is irrigated with lactated Ringer’s solution and inspected for residual uveal tissue. The prosthesis is inserted into the globe using a special sphere introducer. Some hemorrhaging will occur during evisceration, and blood will usually fill the space between the sclera or cornea and the silicone sphere. The scleral incision is closed with 6‐0 absorbable suture material in a simple interrupted pattern. Tenon’s capsule and the limbal‐based conjunctival flap are sutured with the same suture material in a continuous pattern. The canthotomy is closed with 4‐0 nonabsorbable suture material. Complications, including regrowth of unidentified intraocular neoplasms, scleral wound dehiscence, and postoperative intrascleral infections, have been reported to occur in 10% of cases (Hamor et  al., 1994; Koch, 1981). Corneal erosions and septic keratitis were identified as the most common postoperative complications in 9/20 patients in a retrospective study (Lin et al., 2007). In general, corneal integrity is a prerequisite for implantation of a prosthesis, but such devices have been used to

of the eye for intraocular surgery, a lateral canthotomy is performed (Fig. 14.36). A 5–8 mm, 120°, limbal‐based flap of bulbar conjunctiva and Tenon’s capsule or, alternatively, a fornix‐based flap of equal size is then prepared. The sclera is incised parallel to and 5 mm behind the limbus with a #64 Beaver blade over a length of 2–3 mm. Care is taken not to incise the uveal tract. Up to this point, no aqueous humor should escape. A cyclodialysis spatula is then inserted between the uvea and sclera and carefully advanced into the anterior chamber. At this point some aqueous humor will escape. Alternatively, a lens loop can be used, which necessitates a slightly larger scleral incision. While avoiding the corneal endothelium, careful rotating movements of the spatula are used to bluntly separate the uveal tract from its scleral attachments, except for its attachment at the optic papilla. The scleral incision is enlarged with scissors to a length 1–2 mm larger than the diameter of the prosthesis. The uveal tract is then grasped with forceps and removed in one piece by slow, gentle, continuous traction. Vitreous and retina are usually removed together with the uvea. Transection at the optic nerve head may be necessary to

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Figure 14.36  Evisceration and implantation of an intrascleral silicone prosthesis. A. Outline of the limbal‐based conjunctival flap. B. The sclera is incised down to the uveal tract. C. A cyclodialysis spatula is inserted between sclera and uvea and advanced into the anterior chamber. The uveal tract is separated from its scleral attachments with sweeping movements of the spatula. D. After enlargement of the scleral incision, the uvea is grasped with serrated forceps and removed by slow, continuous traction. E. After irrigation of the globe, an appropriately sized silicone prosthesis is inserted using a Carter sphere inserter. F. The scleral and conjunctival wounds are closed with 6‐0 absorbable suture material.

Extrascleral Prosthesis Extrascleral prostheses are more commonly used in horses than in small animals. Such devices are acrylic or porcelain shells designed to fit into the conjunctival sac and cover a noninfected blind and phthisic eye, an intrascleral or orbital implant, or an empty socket (Gilger et  al., 2003; Hamor et al., 1992; Lavach & Severin, 1984; Romkes & Eule, 2012;

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B Figure 14.37  A. Portrait of a dog bearing intrascleral silicone prostheses in both eyes, 5 months postoperatively. B. Close‐up of the right eye, demonstrating mild neovascularization, fibrosis, and pigmentation of the cornea.

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Slatter & Wolf, 1993). Pegged extrascleral prosthesis systems, in which a peg anchored to an orbital implant protrudes through the conjunctiva and couples the orbital implant to an extrascleral prosthesis, facilitate statistically, but not clinically, significant movement of the prosthetic shell (Yi et al., 2009). The use of such pegged implants in dogs should be discouraged, since the physician‐based literature contains evidence that patients receiving pegged implants have a high risk of experiencing complications unique to pegging, and therefore a significantly higher rate of complications overall when compared with patients who received a nonpegged implant (Fahim et al., 2007). Species‐ related problems with hygiene and potential self‐trauma would likely influence the postoperative complication rate that is to be expected in dogs.

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s­ alvage globes with corneal lacerations (Riggs & Whitley, 1990). Also, intraocular neoplasms have to be carefully ruled out prior to evisceration and implantation of a silicone prosthesis. However, a report of nine cases with intraocular neoplasia suggests that such tumors may not be an absolute contraindication to placement of an intrascleral prosthesis (McLaughlin et al., 1995). The cosmetic results are usually acceptable (Fig. 14.37). In a retrospective study, most clients were satisfied with the result (Ruoss et al., 1997).

14: Diseases and Surgery of the Canine Orbit

Orbitotomy and Orbitectomy Several approaches to the orbit are possible, depending on lesion localization (Gelatt & Gelatt, 2011). A transconjunctival approach will provide access to lesions anterior to the equator of the globe (Slatter & Basher, 2003). Dorsal, ventral, nasal, or temporal approaches can be chosen (Williams & Haggett, 2006). Masses within the extraocular muscle cone necessitate transection of the respective rectus and oblique muscles. Even then, visualization is limited using this route (Fig. 14.38). Ventral transpalpebral anterior orbitotomy was described as alternative means to gain moderate access to space‐occupying lesions in the ventral anterior orbit. Tissue dissection was minimal and postoperative complications were few (McDonald et al., 2016). A wider access to the orbit is gained through a lateral approach, with transection of the lateral orbital ligament. If deep orbital structures such as the zygomatic salivary gland must be accessed, a portion of the zygomatic arch can be removed with a rongeur (Bistner et al., 1977). Removal of localized orbital neoplasms usually requires a more radical approach. Three‐dimensional printing to create a model of the surgical site might become a useful surgical planning tool (Dorbandt et al., 2017). Adequate access to the ventral and caudal aspects of the orbit can be gained by lateral orbitotomy with resection of the zygomatic arch (Fig. 14.39A, B; Slatter & Abdelbaki, 1979). This technique has been used to remove orbital tumors and, at the same time, retain both the globe and vision (Spiess et al., 1995). In a modification of this technique, the orbital ligament is transected and the zygomatic arch deflected ventrally after osteotomy. Extensive tissue dissection of the temporal muscle is prevented, thus decreasing closure time and sparing and safeguarding the palpebral branch of the facial nerve (Fig.  14.39C, D; Gilger et  al., 1994). Another advantage of this modified lateral approach is the fact that the zygomatic arch remains attached to the masseter muscle, leaving the blood supply intact. The modified lateral orbitotomy

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C Figure 14.38  Transconjunctival orbitotomy. A. The conjunctiva and Tenon’s capsule are incised in the desired quadrant, and the extraocular muscles are identified. B. Transection of the extraocular muscles allows limited visualization of the anterior orbit. C. After the transected muscles are sutured, the conjunctiva is closed with resorbable suture material in a continuous pattern. (Adapted with permission from Slatter, D.H. & Basher, T. (2003) Orbit. In: Textbook of Small Animal Surgery (ed. Slatter, D.H.), 3rd ed., pp. 1430–1454. Philadelphia, PA: W.B. Saunders, Figure 95‐28.)

c­ urrently seems to be the most widely used technique to gain access to the orbit (Barnes et  al., 2010; Bartoe et  al., 2007; Gelatt & Gelatt, 2011; Hartley et  al., 2007; Lassaline et  al., 2005). An adaptable three‐step procedure to gain access to almost the entire orbit, called transfrontal orbitotomy, has been described (Fig.  14.39E, F; (Håkansson & Håkansson, 2010). Surgical exposure was excellent and postoperative recovery uneventful in 9/9 patients. Possible complications of orbitotomies include hemorrhage, transient lagophthalmos, postoperative swelling and infection, enophthalmos, and strabismus (O’Brien et  al., 1996; Slatter & Abdelbaki, 1979; Spiess et al., 1995).

In cases with local extraorbital tumor extension and/or bone involvement, extensive and aggressive tumor resection, in the form of partial or total orbitectomy (Fig.  14.40), is indicated. These are invasive surgical procedures that involve opening of the (para‐)nasal sinuses, calvarium, and/or oral cavity, up to complete resection of the orbit, including its osseous delineation (orbital rim, frontal bone, maxillary bone including last molar(s), zygomatic arch, etc.). The main intraoperative risk is profuse bleeding from the maxillary artery or one of its tributaries when working in the ventral orbit. These arteries need to be ligated if they are (to be) severed. If they cannot be identified, the ipsilateral carotid

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Figure 14.39  Orbitotomy techniques. A, C, E. Skin incisions are indicated in red, and cerclage hole, osteotomy, and orbital ligament transection sites are indicated in blue. B, D, F. Demonstrating surgical exposure after tissue reflection and retraction. Lateral orbitotomy (Slatter & Abdelbaki, 1979): A. The skin incision is made along the ventral rim of the zygomatic arch and is continued along the orbital ligament and sagittal crest. After preplacing cerclage holes, an osteotomy is performed rostrally and caudally to the orbital ligament. B. The skin, fascia, and temporal muscle are reflected caudally and the zygomatic arch is reflected dorsally, exposing the orbital fascia and muscle cone. The retractor bulbi muscles, optic nerve, and caudal globe are exposed by incising the orbital fascia and transecting the lateral rectus muscle. This approach necessitates the sacrifice of the palpebral branch of the facial nerve, leading to postoperative lagophthalmos. Modified lateral orbitotomy (Gilger et al., 1994): C. The skin incision runs along the dorsal rim of the zygomatic arch. The subcutaneous palpebral branch of the facial nerve is preserved by blunt dissection from the surface of the temporal muscle and dorsal retraction together with the skin. D. After transection of the orbital ligament and the temporal muscle aponeurosis, an osteotomy is performed and the zygomatic arch is deflected ventrally. Transfrontal orbitotomy (Håkansson & Håkansson, 2010): E, F. The skin is incised along the ventrolateral zygomatic arch, followed by a modified lateral orbitotomy, as described by Gilger et al. (1994). A second skin incision follows the course of the palpebral branch of the facial nerve, to preserve a strip of skin protecting that nerve (outlined in yellow in E). This incision is then continued to facilitate elevation and caudal retraction of the temporal muscle from the orbital ligament and sagittal crest. In order to maximize exposure of, and room for surgical manipulation in, the cranial and ventromedial orbit, an osteotomy and cranial reflection of the zygomatic process of the frontal bone are finally performed.

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C Figure 14.40  Illustration of surgical margins observed when performing a total orbitectomy. (Adapted with permission from O’Brien, M.G., Withrow, S.J., Straw, R.C., et al. (1996) Total and partial orbitectomy for the treatment of periorbital tumors in 24 dogs and 6 cats: A retrospective study. Veterinary Surgery, 25, 471–479.)

artery may need to be occluded to control hemorrhage and obtain a bloodless surgical field (Slatter & Basher, 2003). In a case series of 30 orbitectomies, the postoperative complications were relatively minor in most patients (O’Brien et al., 1996). When partial orbitectomy is performed, the globe will be sacrificed if a neoplastic process involves the globe or structures that are critical to globe survival. A superior orbitectomy involving the soft tissue structures dorsal to the eye (including eyelid) usually warrants eye removal. Loss of the inferior eyelid can be remedied using a lip‐to‐lid procedure, as described by Pavletic et al. (1982). Wound closure can be routine if no large skin defects were created during tumor resection. In those cases no special care needs to be taken to close the nasal or frontal sinuses (Boston, 2010; O’Brien et  al., 1996). Reconstructive techniques are indicated in cases where calvarial bone was resected and the brain is relatively unprotected, or where large skin defects were created during tumor resection. A temporalis muscle flap can be used to reconstruct the calvarial wall or reconstruct nasal and paranasal cavities and the

orbital rim (Bentley, 1991). Caudal auricular axial pattern flaps can be used to close large skin defects in the head and neck region (Stiles et al., 2003). A masseter muscle flap was used to stabilize the ventral orbit and support the globe after caudal maxillectomy and ventral orbitectomy (Sivagurunathan et al., 2014). Another technique to support and maintain the eye in a normal position following ventral orbitectomy involved the use of a temporalis fascia transposition flap (Dent et  al., 2019). An adaptable three‐step method for the reconstruction of bone and soft tissue defects resulting from partial orbitectomy procedures not involving structures critical to globe survival was described in a recent case series. The authors reported excellent tectonic, functional, and cosmetic results, with mild postoperative complications. Step one involved the reconstruction of the orbital rim and facial contours with cerclage wires. A prolene mesh covering the wires and reestablishing the inner orbital and outer facial contours was placed in step two. A collagen sheet was placed over the mesh followed by subcutis and skin closure over the construct in step three (Fig.  14.41; Wallin‐Hakansson & Berggren, 2017).

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Figure 14.41  Reconstruction of orbital and facial features. A. Facial features to be reconstructed: a, orbital rim; b, ventral edge of zygomatic arch; c, facial crest overlying maxillary canal; d, dorsolateral ridge of nasal bridge; e, midline of nasal bridge; f, flat area of maxilla. B. Schematic representation of ostectomy. C. Intraoperative view after placement of cerclage wires: a, b, c, f, cerclage wires at facial features indicated in A; MA&N, maxillary artery and nerve; ZA, posterior cut end of zygomatic arch. D. View after placement of prolene mesh inside orbit. E. View after prolene mesh has been folded down over the facial bone defect, trimmed, and sutured. (Reproduced with permission from Wallin‐Hakanson, N. & Berggren, K. (2017) Orbital reconstruction in the dog, cat, and horse. Veterinary Ophthalmology, 20(4), 316–328.)

References Accola, P.J., Bentley, E., Smith, L.J., et al. (2006) Development of a retrobulbar injection technique for ocular surgery and analgesia in dogs. Journal of the American Veterinary Medical Association, 229, 220–225. Ackerman, N. & Munger, R.J. (1979) Intraconal contrast orbitography in the dog. American Journal of Veterinary Research, 40, 911–918. Adams, W.M., Miller, P.E., Vail, D.M., et al. (1998) An accelerated technique for irradiation of malignant canine nasal and paranasal sinus tumors. Veterinary Radiology & Ultrasonography, 39, 475–481. Adkins, E.A., Ward, D.A., Daniel, G.B., et al. (2005) Coil embolization of a congenital orbital varix in a dog. Journal of the American Veterinary Medical Association, 227, 1952–1954.

Ahn, J., Jeong, M., Lee, E., et al. (2013a) Effects of peribulbar anesthesia (sub‐Tenon injection of a local anesthetic) on akinesia of extraocular muscles, mydriasis, and intraoperative and postoperative analgesia in dogs undergoing phacoemulsification. American Journal of Veterinary Research, 74, 1126–1132. Ahn, J., Jeong, M., Park, Y., et al. (2013b) Comparison of systemic atracurium, retrobulbar lidocaine, and sub‐Tenon’s lidocaine injections in akinesia and mydriasis in dogs. Veterinary Ophthalmology, 16, 440–445. Ahn, J.S., Jeong, M.B., Park, Y.W., et al. (2013c) A sub‐Tenon’s capsule injection of lidocaine induces extraocular muscle akinesia and mydriasis in dogs. Veterinary Journal, 196, 103–108.

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Allgoewer, I., Blair, M., Basher, T., et al. (2000) Extraocular muscle myositis and restrictive strabismus in 10 dogs. Veterinary Ophthalmology, 3, 21–26. Armour, M.D., Broome, M., Dell’Anna, G., et al. (2011) A review of orbital and intracranial magnetic resonance imaging in 79 canine and 13 feline patients (2004–2010). Veterinary Ophthalmology, 14, 215–226. Arnbjerg, J. & Jensen, O.A. (1982) Spontaneous microphthalmia in two Doberman puppies with anterior chamber cleavage syndrome. Journal of the American Animal Hospital Association, 18, 481–484. Attali‐Soussay, K., Jegou, J.P., & Clerc, B. (2001) Retrobulbar tumors in dogs and cats: 25 cases. Veterinary Ophthalmology, 4, 19–27. Barnes, L.D., Pearce, J.W., Berent, L.M., et al. (2010) Surgical management of orbital nodular granulomatous episcleritis in a dog. Veterinary Ophthalmology, 13, 251–258. Baron, M.L., Hecht, S., Westermeyer, H.D., et al. (2011) Intracranial extension of retrobulbar blastomycosis (Blastomyces dermatitidis) in a dog. Veterinary Ophthalmology, 14, 137–141. Barros, M., Matera, J.M., Alvarenga, J., et al. (1984) Orbital pneumatosis in a dog. Modern Veterinary Practice, 65, 38. Bartels, P. (1990) Abflussstörungen der Glandula zygomatica als ursache von Exophthalmus. Kleintierpraxis, 35, 77–80. Bartoe, J.T., Brightman, A.H., & Davidson, H.J. (2007) Modified lateral orbitotomy for vision‐sparing excision of a zygomatic mucocele in a dog. Veterinary Ophthalmology, 10, 127–131. Bayon, A., Tovar, M.C., Fernandez Del Palacio, M.J., et al. (2001) Ocular complications of persistent hyperplastic primary vitreous in three dogs. Veterinary Ophthalmology, 4, 35–40. Bedford, P.G. (1979) Orbital pneumatosis as an unusual complication to enucleation. Journal of Small Animal Practice, 20, 551–555. Bentley, J.F. (1991) Use of a temporalis muscle flap in reconstruction of the calvarium and orbital rim in a dog. Journal of the American Animal Hospital Association, 27, 463–466. Berggren, K. & Wallin Hakansson, N. (2019) A surgical approach for extensive orbital exenteration in dogs: A description of technique and its application in 4 cases. Veterinary Ophthalmology, 22, 238–245. doi: 10.1111/vop.12583. Bertram, T., Coignoul, F., & Cheville, N. (1984) Ocular dysgenesis in Australian Shepherd dogs. Journal of the American Animal Hospital Association, 20, 177–182. Bistner, S., Aguirre, G., & Batik, G. (1977) Atlas of Veterinary Ophthalmic Surgery. Philadelphia, PA: W.B. Saunders. Boland, L., Gomes, E., Payen, G., et al. (2013) Zygomatic salivary gland diseases in the dog: Three cases diagnosed by MRI. Journal of the American Animal Hospital Association, 49, 333–337. Boroffka, S.A., Dennison, S., Schwarz, T., et al. (2011) Orbita, salivary glands and lacrimal system. In: Veterinary Computed Tomography (eds. Schwarz, T. & Saunders, J.), pp. 137–152. Ames, IA: Wiley‐Blackwell.

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Chiwitt, C.L.H., Baines, S.J., Mahoney, P., et al. (2017) Ocular biometry by computed tomography in different dog breeds. Veterinary Ophthalmology, 20, 411–419. Choi, S.R., Park, S.W., Lee, J.H., et al. (2009) Effect of different anesthetic agents on oculocardiac reflex in pediatric strabismus surgery. Journal of Anesthesia, 23, 489–493. Chow, D.W., Wong, M.Y., & Westermeyer, H.D. (2015) Comparison of two bupivacaine delivery methods to control postoperative pain after enucleation in dogs. Veterinary Ophthalmology, 18, 422–428. Cirla, A., Rondena, M., & Bertolini, G. (2016) Automated tru‐cut imaging‐guided core needle biopsy of canine orbital neoplasia: A prospective feasibility study. Open Veterinary Journal, 6, 114–120. Collins, B.K., Collier, L.L., Johnson, G.S., et al. (1992) Familial cataracts and concurrent ocular anomalies in Chow Chows. Journal of the American Veterinary Medical Association, 200, 1485–1491. Cottrill, N.B., Banks, W.J., & Pechman, R.D. (1989) Ultrasonographic and biometric evaluation of the eye and orbit of dogs. American Journal of Veterinary Research, 50, 898–903. Czerwinski, S.L., Plummer, C.E., Greenberg, S.M., et al. (2015) Dynamic exophthalmos and lateral strabismus in a dog caused by masticatory muscle myositis. Veterinary Ophthalmology, 18, 515–520. Delgado, C., Bentley, E., Hetzel, S., et al. (2014) Comparison of carprofen and tramadol for postoperative analgesia in dogs undergoing enucleation. Journal of the American Veterinary Medical Association, 245, 1375–1381. Dennis, R. (2000) Use of magnetic resonance imaging for the investigation of orbital disease in small animals. Journal of Small Animal Practice, 41, 145–155. Dennis, R. (2008) Imaging features of orbital myxosarcoma in dogs. Veterinary Radiology & Ultrasound, 49, 256–263. Dent, B., Wavreille, V.A., & Selmic, L.E. (2019) Use of a temporalis fascia transposition flap for ventral orbital stabilization after ventral orbitectomy in a dog. Veterinary Surgery, 48, 1058–1063. doi: 10.1111/vsu.13162. Deveau, M.A., Gutierrez, A.N., Mackie, T.R., et al. (2010) Dosimetric impact of daily setup variations during treatment of canine nasal tumors using intensity‐modulated radiation therapy. Veterinary Radiology & Ultrasound, 51, 90–96. Dorbandt, D.M., Joslyn, S.K., & Hamor, R.E. (2017) Three‐ dimensional printing of orbital and peri‐orbital masses in three dogs and its potential applications in veterinary ophthalmology. Veterinary Ophthalmology, 20, 58–64. Drees, R., Forrest, L.J., & Chappell, R. (2009) Comparison of computed tomography and magnetic resonance imaging for the evaluation of canine intranasal neoplasia. Journal of Small Animal Practice, 50, 334–340. Dubey, J.P., Koestner, A., & Piper, R.C. (1990) Repeated transplacental transmission of Neospora caninum in dogs. Journal of the American Veterinary Medical Association, 197, 857–860.

Dubielzig, R.R., Ketring, K.L., McLellan, G.J., et al. (2010) Veterinary Ocular Pathology: A Comparative Review. Cambridge, MA: Elsevier. Dziezyc, J. & Hager, D.A. (1988) Ocular ultrasonography in veterinary medicine. Seminars in Veterinary Medicine and Surgery (Small Animal), 3, 1–9. Dziezyc, J., Hager, D.A., & Millichamp, N.J. (1987) Two‐ dimensional real‐time ocular ultrasonography in the diagnosis of ocular lesions in dogs. Journal of the American Animal Hospital Association, 23, 501–508. Fahim, D.K., Frueh, B.R., Musch, D.C., et al. (2007) Complications of pegged and non‐pegged hydroxyapatite orbital implants. Ophthalmic Plastic and Reconstructive Surgery, 23, 206–210. Fischer, M.C., Adrian, A.M., Demetriou, J., et al. (2018) Retrobulbar cellulitis and abscessation: Focus on short‐ and long‐term concurrent ophthalmic diseases in 41 dogs. Journal of Small Animal Practice, 59(12), 763–768. doi: 10.1111/jsap.12924. Fischer, M.C., Busse, C., & Adrian, A.M. (2019) Magnetic resonance imaging findings in dogs with orbital inflammation. Journal of Small Animal Practice, 60(2), 107–115. doi: 10.1111/jsap.12929. Flaherty, E.H., Robinson, N.A., Pizzirani, S., & Pumphrey, S.A. (2020) Evaluation of cytology and histopathology for the diagnosis of canine orbital neoplasia: 112 cases (2004–2019) and review of the literature. Veterinary Ophthalmology, 23(2), 259–268. Fritsche, J., Spiess, B.M., Rühli, M.B., et al. (1996) Prolapsus bulbi in small animals: A retrospective study of 36 cases. Tierärztliche Praxis, 24, 55–61. Gelatt, K.N. & Gelatt, J.P. (2011) Veterinary Ophthalmic Surgery. Philadelphia, PA: Saunders‐Elsevier. Gelatt, K.N., Guffy, M.M., & Boggess, T.S.D. (1970) Radiographic contrast techniques for detecting orbital and nasolacrimal tumors in dogs. Journal of the American Veterinary Medical Association, 156, 741–746. Gelatt, K.N. & McGill, L.D. (1973) Clinical characteristics of microphthalmia with colobomas of the Australian Shepherd Dog. Journal of the American Veterinary Medical Association, 162, 393–396. Gelatt, K.N., Powell, N.G., & Huston, K. (1981) Inheritance of microphthalmia with coloboma in the Australian shepherd dog. American Journal of Veterinary Research, 42, 1686–1690. Gelatt, K.N., Samuelson, D.A., Bauer, J.E., et al. (1983) Inheritance of congenital cataracts and microphthalmia in the Miniature Schnauzer. American Journal of Veterinary Research, 44, 1130–1132. Gelatt, K.N. & Veith, L.A. (1970) Hereditary multiple ocular anomalies in Australian shepherd dogs (preliminary report). Veterinary Medicine and Small Animal Clinician, 65, 39–42. Gelatt‐Nicholson, K.J., Gelatt, K.N., MacKay, E., et al. (1999) Doppler imaging of the ophthalmic vasculature of the normal dog: Blood velocity measurements and reproducibility. Veterinary Ophthalmology, 2, 87–96.

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McDonald, J.E., Knollinger, A.M., & Dees, D.D. (2016) Ventral transpalpebral anterior orbitotomy: Surgical description and report of 3 cases. Veterinary Ophthalmology, 19, 81–89. McLaughlin, S. (1990) Evisceration and implantation of intrascleral prosthesis. In: Current Techniques in Small Animal Surgery (ed. Bojrab, M.), 3rd ed., pp. 117–119. Philadelphia, PA: Lea & Febiger. McLaughlin, S.A., Ramsey, D.T., Lindley, D.M., et al. (1995) Intraocular silicone prosthesis implantation in eyes of dogs and a cat with intraocular neoplasia: Nine cases (1983–1994). Journal of the American Veterinary Medical Association, 207, 1441–1443. Millichamp, N. & Spencer, C.P. (1991) Orbital varix in a dog. Journal of the American Animal Hospital Association, 27, 56–60. Moore, C. (1990) Orbital exenteration and insertion of intraorbital prosthesis. In: Current Techniques in Small Animal Surgery (ed. Bojrab, M.), 3rd ed., pp. 123–126. Philadelphia, PA: Lea & Febiger. Morgan, R.V. (1989) Ultrasonography of retrobulbar diseases of the dog and cat. Journal of the American Animal Hospital Association, 25, 393–399. Morgan, R.V., Daniel, G., & Donnell, R.L. (1994) Magnetic resonance imaging of the normal eye and orbit of the dog and cat. Veterinary Radiology & Ultrasound, 35, 102–108. Mould, J. (1993) Conditions of the orbit and globe. In: Manual of Small Animal Ophthalmology (eds. Peterson‐Jones, S. & Crispin, S.M.), pp. 45–64. Cheltenham: British Small Animal Veterinary Association. Murphy, C.J., Samuelson, D.A., & Pollock, R.V.S. (2012) The eye. In: Miller’s Anatomy of the Dog (ed. De Lahunta, A.), pp. 1009–1057. Philadelphia, PA: W.B. Saunders. Musch, D., Frueh, B.R., & Landis, J.R. (1985) The reliability of Hertel exophthalmometry: Observer variation between physician and lay readers. Ophthalmology, 92, 1177. Myrna, K.E., Bentley, E., & Smith, L.J. (2010) Effectiveness of injection of local anesthetic into the retrobulbar space for postoperative analgesia following eye enucleation in dogs. Journal of the American Veterinary Medical Association, 237, 174–177. Naranjo, C., Fondevila, D., Leiva, M., et al. (2010) Detection of Leishmania spp. and associated inflammation in ocular‐ associated smooth and striated muscles in dogs with patent leishmaniosis. Veterinary Ophthalmology, 13, 139–143. Narfström, K. & Dubielzig, R. (1984) Posterior lenticonus, cataracts, and microphthalmia: Congenital ocular defects in the Cavalier King Charles Spaniel. Journal of Small Animal Practice, 25, 669–677. Nasisse, M.P., Van Ee, R.T., Munger, R.J., et al. (1988) Use of methyl methacrylate orbital prostheses in dogs and cats: 78 cases (1980–1986). Journal of the American Veterinary Medical Association, 192, 539–542. Nell, B. & Walde, I. (1994) Retentionszyste der Glandula zygomatica eines Hundes mit sekundärem Exophthalmus und Starbismus. Kleintierpraxis, 39, 569.

Nyland, T.G. & Mattoon, J.S. (2002) Small Animal Diagnostic Ultrasound. Philadelphia, PA: Saunders. O’Brien, M.G., Withrow, S.J., Straw, R.C., et al. (1996) Total and partial orbitectomy for the treatment of periorbital tumors in 24 dogs and 6 cats: A retrospective study. Veterinary Surgery, 25, 471–479. Oliver, J.A., Llabres‐Diaz, F.J., Gould, D.J., et al. (2009) Central nervous system infection with Staphylococcus intermedius secondary to retrobulbar abscessation in a dog. Veterinary Ophthalmology, 12, 333–337. Oria, A.P., De Souza, M.R., Dorea Neto Fde, A., et al. (2016) Polymethylmethacrylate orbital implants with interconnecting channels: A retrospective study following enucleation in dogs and cats. Veterinary Ophthalmology, 19, 102–109. Orvis, J.S. & Cardinet, G.H.D. (1981) Canine muscle fiber types and susceptibility of masticatory muscles to myositis. Muscle Nerve, 4, 354–359. Ota, J., Pearce, J.W., Finn, M.J., et al. (2009) Dacryops (lacrimal cyst) in three young labrador retrievers. Journal of the American Animal Hospital Association, 45, 191–196. Padgett, G.A. & Mostosky, U.V. (1986) The mode of inheritance of craniomandibular osteopathy in West Highland White Terrier dogs. American Journal of Medical Genetics, 25, 9–13. Parslow, A., Taylor, D.P., & Simpson, D.J. (2016) Clinical, computed tomographic, magnetic resonance imaging, and histologic findings associated with myxomatous neoplasia of the temporomandibular joint in two dogs. Journal of the American Veterinary Medical Association, 249, 1301–1307. Pate, D.O., Gilger, B.C., Suter, S.E., et al. (2011) Diagnosis of intraocular lymphosarcoma in a dog by use of a polymerase chain reaction assay for antigen receptor rearrangement. Journal of the American Veterinary Medical Association, 238, 625–630. Pavletic, M.M., Nafe, L.A., & Confer, A.W. (1982) Mucocutaneous subdermal plexus flap from the lip for lower eyelid restoration in the dog. Journal of the American Veterinary Medical Association, 180, 921–926. Pe’er, O., Oron, L., & Ofri, R. (2020) Prognostic indicators and outcome in dogs undergoing temporary tarsorrhaphy following traumatic proptosis. Veterinary Ophthalmology, 23(2), 245–251. doi: 10.1111/vop.12713. Penninck, D., Daniel, G.B., Brawer, R., et al. (2001) Cross‐ sectional imaging techniques in veterinary ophthalmology. Clinical Technicians, Small Animal Practice, 16, 22–39. Pinard, C.L., Mutsaers, A.J., Mayer, M.N., et al. (2012) Retrospective study and review of ocular radiation side effects following external‐beam Cobalt‐60 radiation therapy in 37 dogs and 12 cats. Canadian Veterinary Journal, 53, 1301–1307. Ploog, C.L., Swinger, R.L., Spade, J., et al. (2014) Use of lidocaine‐bupivacaine‐infused absorbable gelatin hemostatic sponges versus lidocaine‐bupivacaine retrobulbar injections for postoperative analgesia following eye enucleation in dogs. Journal of the American Veterinary Medical Association, 244, 57–62.

Rampazzo, A., Eule, C., Speier, S., et al. (2006) Scleral rupture in dogs, cats, and horses. Veterinary Ophthalmology, 9, 149–155. Ramsey, D., Maretta, S.M., Hamor, R.E., et al. (1996) Ophthalmic manifestations and complications of dental disease in dogs and cats. Journal of the American Animal Hospital Association, 32, 215–224. Ravi, M., Schobert, C.S., Kiupel, M., et al. (2014) Clinical, morphologic, and immunohistochemical features of canine orbital hibernomas. Veterinary Pathology, 51, 563–568. Raya, A.I., Afonso, J.C., Perez‐Ecija, R.A., et al. (2010) Orbital myositis associated with Lyme disease in a dog. Veterinary Record, 167, 663–664. Regnier, A., Raymond‐Letron, I., & Peiffer, R.L. (2008) Congenital orbital cysts of neural tissue in two dogs. Veterinary Ophthalmology, 11, 91–98. Reiter, A.M. & Schwarz, T. (2007) Computed tomographic appearance of masticatory myositis in dogs: 7 cases (1999– 2006). Journal of the American Veterinary Medical Association, 231, 924–930. Richter, M., Stankeova, S., Hauser, B., et al. (2003) Myxosarcoma in the eye and brain in a dog. Veterinary Ophthalmology, 6, 183–189. Riggs, C. & Whitley, R.D. (1990) Intraocular silicone prostheses in a dog and a horse with corneal lacerations. Journal of the American Veterinary Medical Association, 196, 617–619. Roberts, S.R. & Thompson, T.J. (1969) Pneumonyssus caninum and orbital cellulitis in the dog. Journal of the American Veterinary Medical Association, 155, 731–734. Romkes, G. & Eule, J.C. (2012) Followup of a dog with an intraocular silicone prosthesis combined with an extraocular glass prosthesis. Case Reports in Veterinary Medicine, 2012, Article ID 762452. Rubin, L. and Patterson, D.F. (1965) Arteriovenous fistula of the orbit in a dog. Cornell Veterinarian, 55, 471–481. Ruehli, M. & Spiess, B.M. (1995a) Retrobulbar space‐occupying lesions in dogs and cats: Clinical signs and diagnostic work‐ up. Tierärztliche Praxis, 23, 306–312. Ruehli, M.B. & Spiess, B.M. (1995b) Treatment of orbital abscesses and phlegmon in dogs and cats. Tierärztliche Praxis, 23, 398–401. Ruoss, E., Spiess, B.M., Rühli, M.B., et al. (1997) Intrascleral silicone prosthesis in the dog: A review of 22 cases. Tierärztliche Praxis, 25, 164–169. Salguero, R., Johnson, V., Williams, D., et al. (2015) CT dimensions, volumes and densities of normal canine eyes. Veterinary Record, 176, 386. Saunders, L. & Rubin, L.F. (1975) Ophthalmic Pathology of Animals: An Atlas and Reference Book. Basel: Karger. Saunders, R.S., Scansen, B.A., Jung, S.S., et al. (2018) Use of an intravenous sclerosing foam (3% sodium tetradecyl sulfate) for treatment of orbital varix in a dog. Veterinary Ophthalmology, 21, 194–198. Schmid, V. & Murisier, N. (1996) Color doppler imaging of the orbit in the dog. Veterinary & Comparative Ophthalmology, 6, 35–44.

Schmidt, G.M. & Betts, C.W. (1978) Zygomatic salivary mucoceles in the dog. Journal of the American Veterinary Medical Association, 172, 940–942. Scott, E.M., Teixeira, L.B., Flanders, D.J., et al. (2016) Canine orbital rhabdomyosarcoma: A report of 18 cases. Veterinary Ophthalmology, 19, 130–137. Selk Ghaffari, M., Marjani, M., & Masoudifard, M. (2009) Oculocardiac reflex induced by zygomatic arch fracture in a crossbreed dog. Journal of Veterinary Cardiology, 11, 67–69. Shastry, B.S. & Reddy, V.N. (1994) Studies on congenital hereditary cataract and microphthalmia of the Miniature Schnauzer dog. Biochemistry and Biophysics Research Communications, 203, 1663–1667. Shelton, G.D. (2007) From dog to man: The broad spectrum of inflammatory myopathies. Neuromuscular Disorders, 17, 663–670. Shelton, G.D., Cardinet, G.H.D., & Bandman, E. (1987) Canine masticatory muscle disorders: A study of 29 cases. Muscle Nerve, 10, 753–766. Shilo‐Benjamini, Y., Pascoe, P.J., Wisner, E.R., et al. (2017) A comparison of retrobulbar and two peribulbar regional anesthetic techniques in dog cadavers. Veterinary Anaesthesia and Analgesia, 44, 925–932. Shilo‐Benjamini, Y. (2019) A review of ophthalmic local and regional anesthesia in dogs and cats. Veterinary Anaesthesia and Analgesia, 46(1), 14–27. doi: 10.1016/j.vaa.2018.10.004. Shilo‐Benjamini, Y., Pascoe, P.J., Maggs, D.J., et al. (2019) Retrobulbar vs peribulbar regional anesthesia techniques using bupivacaine in dogs. Veterinary Ophthalmology, 22(2), 183–191. doi: 10.1111/vop.12579. Simison, W.G. (1993) Sialadenitis associated with periorbital disease in a dog. Journal of the American Veterinary Medical Association, 202, 1983–1985. Sivagurunathan, A., Boy, S.C., & Steenkamp, G. (2014) A novel technique for ventral orbital stabilization: The masseter muscle flap. Veterinary Ophthalmology, 17, 67–72. Slatter, D. (1990) Fundamentals of Veterinary Ophthalmology. Philadelphia, PA: W.B. Saunders. Slatter, D. & Wolf, E.D. (1993) Orbit. In: Textbook of Small Animal Surgery (ed. Slatter, D.), pp. 1245–1263. Philadelphia, PA: W.B. Saunders. Slatter, D.H. & Abdelbaki, Y. (1979) Lateral orbitotomy by zygomatic arch resection in the dog. Journal of the American Veterinary Medical Association, 175, 1179–1182. Slatter, D.H. & Basher, T. (2003) Orbit. In: Textbook of Small Animal Surgery (ed. Slatter, D.H.), 3rd ed., pp. 1430–1454. Philadelphia, PA: W.B. Saunders. Smith, M.M., Smith, E.M., La Croix, N., et al. (2003) Orbital penetration associated with tooth extraction. Journal of Veterinary Dentistry, 20, 8–17. Soukup, A., Meier, V., Pot, S.A., et al. (2018) A prospective pilot study on early toxicity from a simultaneously integrated boost technique for canine sinonasal tumours using image‐ guided intensity‐modulated radiation therapy. Veterinary and Comparative Oncology, 16(4), 441–449. doi: 10.1111/ vco.12399.

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Spaulding, K. (2008) Eye and orbit. In: Atlas of Small Animal Ultrasonography (eds. Penninck, D. & D’Anjou, M.A.), pp. 49–90. Ames, IA: Blackwell. Spiess, B., Rühli, M.B., & Bauer, G.A. (1995) Zur Therapie von retrobulbären Neoplasien beim Kleintier. Tierärztliche Praxis, 23, 509–514. Sreter, T. & Szell, Z. (2008) Onchocercosis: A newly recognized disease in dogs. Veterinary Parasitology, 151, 1–13. Stades, F.C., DjajadiningraT‐Laanen, S.C., Boroffka, S.A., et al. (2003) Suprascleral removal of a foreign body from the retrobulbar muscle cone in two dogs. Journal of Small Animal Practice, 44, 17–20. Stiles, J., Buyukmihci, N.C., Hacker, D.V., et al. (1993) Blindness from damage to optic chiasm [letter]. Journal of the American Veterinary Medical Association, 202, 1192. Stiles, J., Townsend, W., Willis, M., et al. (2003) Use of a caudal auricular axial pattern flap in three cats and one dog following orbital exenteration. Veterinary Ophthalmology, 6, 121–126. Stuckey, J.A., Miller, W.W., & Almond, G.T. (2012) Use of a sclerosing agent (1% polidocanol) to treat an orbital mucocele in a dog. Veterinary Ophthalmology, 15, 188–193. Stuhr, C. & Scagliotti, R.H. (1996) Retrobulbar ultrasound in the dolichocephalic dog using a temporal approach. Veterinary & Comparative Ophthalmogy, 6, 91–99. Thompson, D., Rogers, W., Owen, M., et al. (2011) Idiopathic canine juvenile cranial hyperostosis in a Pit Bull Terrier. New Zealand Veterinary Journal, 59, 201–205. Tidwell, A.S., Ross, L.A., & Kleine, L.J. (1997) Computed tomography and magnetic resonance imaging of cavernous sinus enlargement in a dog with unilateral exophthalmos. Veterinary Radiology & Ultrasound, 38, 363–370. Tremolada, G., Milovancev, M., Culp, W.T., et al. (2015) Surgical management of canine refractory retrobulbar abscesses: Six cases. Journal of Small Animal Practice, 56, 667–670. Troost, B. & Glaser, J.S. (1995) Aneurysms, arteriovenous communications, and related vascular malformations. In: Duane’s Ophthalmology on CD‐ROM (ed. Jaeger, T.). Philadelphia, PA: J.J. Lippincott. Vézina‐Audette, R., Steagall, P.V.M., & Gianotti, G. (2019) Prevalence of and covariates associated with the oculocardiac reflex occurring in dogs during enucleation. Journal of the American Veterinary Medical Association, 255(4), 454–458. doi: 10.2460/javma.255.4.454. Viscasillas, J., Everson, R., Mapletoft, E.K., & Dawson, C. (2019) Ultrasound‐guided posterior extraconal block in the dog: Anatomical study in cadavers. Veterinary Anaesthesia and Analgesia, 46(2), 246–250. doi: 10.1016/j.vaa.2018.09.045. Walde, I. (1997) Retrobulbar dermoid cyst in a Dachshund. Veterinary & Comparative Ophthalmology, 7, 239–244. Wallin‐Hakansson, N. & Berggren, K. (2017) Orbital reconstruction in the dog, cat, and horse. Veterinary Ophthalmology, 20, 316–328.

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15 Diseases and Surgery of the Canine Eyelid Frans C. Stades1 and Alexandra van der Woerdt2 1 2

Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands The Animal Medical Center, New York, NY, USA

The primary function of the eyelids is the protection of the globe. The eyelids cover the orbit and globe, and surround the palpebral fissure through which the globe contacts the environment. When the palpebral fissure is fully open in the normal adult dog and the eye is looking forward, the eyelid margins should just cover the dorsal and ventral external limbi. It is normal for the lateral limbus and sclera to be exposed, and when the globe is deviated laterally, the medial sclera is seen. The hairless margins of the lids should be well aligned to the curvature of the cornea and should move smoothly across the globe. The inside of the lids is covered by the very loose (except the area over the Meibomian glands–tarsal “plate”) palpebral conjunctival mucosa connecting to the corneal limbus and allowing movements of the globe behind the lids. Compared to other species, eyelid diseases in dogs are frequent, of considerable significance, and represent an important part of the practitioner’s and eye specialist’s ophthalmic case load. The initial diagnosis of lid disease is not usually difficult; however, determining the inciting cause of deterioration in the subtle interactions of conjunctiva, muscles, ligaments, hairs, and folds may be less simple. The eyelid diseases can be divided into congenital‐­ developmental and hereditary, trauma, inflammatory, immune‐mediated and others, and neoplastic disorders. Clinical management of most of the eyelid diseases, except for the inflammatory and immune‐mediated types, is primarily surgical. Lid surgery can be challenging. The selection of the surgical technique for a particular condition may be influenced not only by the most effective procedure, but also by the experience of the surgeon, the surgical instrumentation available, the quality (3–5× magnification) of the operating loupe or operation microscope (5–20× magnification), the timing of the surgical intervention, and the optimal surgical procedure, all of which are critical for the final result. Most of the small animal eyelid surgical procedures were adapted from techniques performed in humans, such as

the Celsus procedure for entropion (Celsus, cited by Zeis, 1839; Patel & Anderson, 1996). In older dogs, eyelid neoplasms are much more common than in other companion animals. The majority of neoplasms can be excised by reasonably simple surgical procedures when performed at an early stage. Surgical procedures for the canine eyelids have been reported in several comprehensive chapters and reviews in the veterinary literature in recent years (Aquino, 2007, 2008; Gelatt & Gelatt, 2011; Hamilton et  al., 2000; Lackner, 2001; Martin, 2005; Moore, 2000; Moore & Constantinescu, 1997; Slatter, 2001; Stades et al., 1998; van der Woerdt, 2004; Wyman, 1979, 1990). In this chapter, we describe the procedures available in both Europe and America, those with which we have personal experience and success, and those that the veterinary ophthalmologist would be expected to perform.

Structure and Function The anatomy of the eye is covered in detail in Chapter  2. Here, the more clinical and functional aspects are discussed (Fig. 15.1), especially as they relate to lid surgery (Gelatt & Gelatt, 2011; Stades et al., 1998). The eyelids are composed of skin, palpebral conjunctiva, collagen, muscle, and glandular tissue. They can be divided into the larger, 2–5 mm longer, and more mobile dorsal, superior, or upper eyelid; and the ventral, inferior, or lower eyelid. The circular muscle surrounding the palpebral fissure is the orbicularis oculi muscle. However, the eyelids do not close by circular contraction. Because of the subcutaneous tissues and a ligament in the medial canthus attached to the nasal bones and the retractor anguli lateralis muscle plus a lateral palpebral ligament in the lateral canthus, it narrows to a horizontal slit. This lateral ligament may contribute to eyelid distortion, particularly in mesocephalic breeds (Robertson & Roberts, 1995a, 1995b).

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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Figure 15.2  Lid length measurement using unsharpened calipers in a St. Bernard. The stretched lid fissure in this St. Bernard is almost 45 mm. Courtesy of Frans C. Stades.

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Figure 15.1  Cross‐section through the canine lid: 1. eyelash‐like hair on the lateral part of the upper lid; 2. Zeis/Moll glands; 3. Meibomian gland; 4. mucus cells conjunctiva; 5. fornix; 6. scleral conjunctiva; 7. nictitating membrane gland; 8. orbicularis oculi muscle; and 9. tarsal “plate.” Copyright Frans C. Stades.

The average length of the palpebral fissure when stretched by calipers is approximately 33 mm in most medium to large breeds of dogs. In breeds with a distinct lack of contact of the lower lid to the globe, the palpebral fissure length is usually over 39 mm (Fig.  15.2; Stades et  al., 1992). The orbicularis oculi muscle enables the closing phase of blinking, a movement in which the upper eyelid plays the most important part. During closure there is a lateral‐to‐medial zipper‐like movement, bringing the tear surplus to the lacrimal puncta. The levator palpebrae (innervated by the oculomotor nerve), levator anguli oculi medialis (Müller’s muscle), and other superficial facial muscles help open the upper eyelid, thus maintaining the precorneal tear film. The malaris muscle opens the lower eyelid (Fig. 15.3).

Skin and Cilia The eyelids are thin and of pliable skin, enabling blinking and following the corneal surface smoothly. Fine and short hairs normally cover the eyelid skin. In dogs, the borderline of the “eyelash” hairs and regular hairs in the upper lid begins about 1 mm away from the free lid margin (and not at the outer free rim of the edge itself, as in human eyelashes). In the lower lid, hairs start about 2 mm away from the free margin. Cilia or eyelashes occur primarily on the lateral part of the upper eyelid, usually in two or four irregular rows. These cilia are normally the same color as the

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Figure 15.3  Muscles of the lids of the left eye: 1. orbicular oculi muscle; 2. lateral palpebral ligament or retractor anguli oculi lateralis; 3. medial palpebral ligament; 4. malaris muscle; 5. levator palpebrae muscle; and 6. levator anguli oculi medialis muscle. Copyright Frans C. Stades.

adjacent ­eyelid hair coat. Long tactile hairs (pili supraorbitales or vibrissae) appear as a tuft along the dorsomedial orbital margin.

Margin The free margins (margo intermarginales) of the eyelids are generally pigmented (usually nonpigmented if the skin around the eye is nonpigmented, for example in the area of a white spot around the eye), and they are hairless. Furthermore, the margins are smooth, glossy, and fatty, but dry. Some 30–40 orifices of the Meibomian glands open into the free lid margin in a fine groove, also named the “gray line.” This groove and the openings are important surgical landmarks used to reappose lid margins in surgical procedures. In case of doubt, pressure by anatomic forceps on the lid margin will produce sebaceous

15: Diseases and Surgery of the Canine Eyelid

Canthus Both canthi are composed of the lid margins converging together in the medial canthus, leaving 3–5 mm of skin, which continues into the conjunctiva in a minor eminence at the base of the nictitating membrane, called the lacrimal caruncle. The hair growth in the area is short and soft. The hairs point outward medially. In the lateral canthus over 2–3 mm, there are no Meibomian glands or tarsal “plates.”

Blood Supply and Lymphatic Drainage The blood supply to the eyelids primarily originates from the medial and lateral palpebral arteries. Additional blood supply to the lateral canthus and upper and lower eyelid is derived from branches from the external ethmoidal artery. The medial aspects of the canine eyelids are also supplied by branches of the malaris artery, a branch of the infraorbital artery, which anastomose with the inferior palpebral and transverse facial arteries and branches of the external ophthalmic artery. Limited blood supply to the eyelids originates from the deeper orbital blood vessels. All these together provide a profuse vascular supply of the lids and result in marked hyperemia and edema in inflammatory reactions. The lymphatic drainage from the eyelids converges at the medial and lateral canthal areas. Lymphatic drainage is mainly to the parotid lymph node as well as to the mandibular lymph nodes. Both lymph nodes need to be examined if regional metastases from eyelid neoplasia are suspected.

Lid Functions The functions of the eyelids include the following: ●●

Lid Sensation The main sensation of the canine eyelids is provided by several branches of the trigeminal (V) nerve. Sensation of the lateral two‐thirds of the upper eyelids is provided by the trigeminal nerve. The medial canthus and medial aspects of the upper eyelids are also served by the largest branch of the ophthalmic nerve. The sensation for the entire lower eyelid is provided by the maxillary division of the trigeminal nerve. This concentration of trigeminal nerve endings around the palpebral fissure guarantees an extreme sensitivity to stimuli and provides the afferent limbs of the palpebral reflex that stimulate the orbicularis oculi to close the lids when touched. The palpebral branch of the facial (VII) nerve innervates the majority of the muscles (e.g., orbicularis oculi) that control the palpebral fissure size, except for the levator palpebral superioris muscle, which is innervated by the oculomotor (III) cranial nerve. The levator anguli oculi medialis is under sympathetic control as loss of sympathetic innervation in Horner’s syndrome results also in ptosis of the medial upper lid.

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The direct protection of the eye and the active blink reflex to tactile stimuli applied to the cornea, conjunctiva, or nictitating membranes, or following a strong light and/or loud stimuli, all resulting in protection of the globe. When direct stimuli are applied to the eyelids, conjunctival, and corneal surfaces, the eyelids blink. This reflex is subcortical, involving the ophthalmic division of the trigeminal nerve (afferent portion) and palpebral division of the facial nerve (efferent portion). In domestic animals, eyelid closure may be very powerful, particularly when the animal is in pain (blepharospasm). Both enophthalmos and microphthalmos may result in reduced support for the lid margin, allowing the lid to turn in toward the globe (secondary entropion), producing pain and thus contraction of the orbicularis oculi. Entrapment and removal of material from the conjunctival sac and cornea to the medial canthus. Production of glandular secretions by the tarsal glands, keeping the lid margin fatty, and reduction of evaporation of the tear film. Distribution of the tear film and the removal of tears toward the lacrimal puncta.

Principles of Lid Surgery Exactly how lid surgery is conducted may vary somewhat among ophthalmologists, but the general principles are similar.

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material, revealing their position. On the conjunctival surface of the lid margin, the Meibomian glands are visible, below the conjunctiva, as 3 to 4 mm long, whitish yellow lines running perpendicular to the margin. Just outside the groove are the even smaller orifices of the glands of Zeis and Moll (modified sweat glands). The oily material secreted by these three glands coats the margin of the lid with a lipid layer, preventing the tear fluid from flowing across it. Meibometers to measure the delivery rate of lipids on the lid margin are available for use in humans, but the precision in dogs is still questionable (Benz et al., 2008). The Meibomian gland secretion of dogs is biochemically very similar to that of humans (Butovich et  al., 2011). This secretion also forms an extremely thin oily film on the watery tear fluid, thereby reducing evaporation. The eyelids of humans are quite similar to those in dogs, with one major difference. In humans, the tarsal layer consists of a distinct cartilaginous plate that provides internal support for the eyelids. In domestic animals, the tarsal plate consists of a thinner and more flexible fibrous tarsus, but it does provide a surface for muscle attachment.

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Anesthesia

Magnification Equipment and Light

In general, sedation and local anesthesia are insufficient for lid surgery, especially because sufficient muscle relaxation is needed for the correct estimation of, for example, the lid fissure length, the amount of tissue to be removed, or the degree of correction necessary. However, in geriatric or debilitated patients, light sedation plus local 2% lidocaine infiltration anesthesia may be useful for minor procedures (Giuliano, 2008; Swinger & Carastro, 2006).

One of the most important factors for eyelid surgery is good magnification; 3× to 5× magnification is sufficient in most cases. Powerful, well‐focused operating lights, a head‐ mounted light, or operating microscope lights are essential during surgery.

Preparation of the Operative Field The lid skin is usually shaved or clipped by very small hair clippers. The last row of eyelash hairs may be cut by scissors, with some ointment on the blades so that the cut hairs will stick to the ointment. Afterward, the conjunctival sac and the skin are washed copiously with hand‐warm saline. Diluted baby shampoo (1 part diluted with 20 parts water) can be used to clean the eyelids if excessive dirt is present. The skin is then dried with gauze sponges. Starting at the margins, the lids are penciled by the standard water‐based surgical povidone‐iodine solution. Care should be taken not to allow iodine to reach the conjunctival sac or the other eye. An alternative method prepares the eyelid surface with 1 : 50 aqueous povidone‐iodine solution, which is not toxic if corneoconjunctival contact occurs.

Surgical Instruments These may include the Kalt, Arruga, or Castroviejo needle holders, strong modified (teeth shortened to 0.3 mm) Castroviejo’s suture, cilia and Graefe fixation forceps, calipers, chalazion and Stades nictitating membrane and small towel clamps, short‐beaked Stevens tenotomy scissors, electroepilator, and lid plate/spoon (Jaeger or Gränitz). Cutting by rounded scalpel blade easily causes folding of tissues. Using a pointed scalpel blade from the inside to the outside provides a more precise incision. Cutting by scissors causes crushing of the tissues and nonperpendicular incision edges (Fig. 15.4).

Suture Material For eye (lid) surgery, atraumatic suture material is always used. However, the surgeon must be aware that the introduction opening of the needle is always approximately double

Positioning For lid surgery, the lid fissure has to be positioned more or less horizontally and the medial canthus lower than the forehead. The positioning of the head is best carried out by using a vacuum pillow. In lid surgery, the surgeon works in a sitting position, at the ventral side of the head, with the hands resting, as much as possible, on the animal’s head, thus preventing the risk of uncontrolled movements and minimizing tremor. The lid fissure can be stretched by closed Castroviejo forceps and stretched ventrally, or dorsally, by a finger of the surgeon. Also, special lid plates or spatulas (Jaeger or Gränitz) can be used to support the lid. However, undesired cutting onto a lid plate, resulting in perforation of the conjunctiva, is possible.

A

B

Draping Special ocular drapes with an opening for the eye, or disposable drapes with a preexisting hole or a hole cut during surgery, can be used for eye surgery. The drapes may be fixed by towel clamps (Jones or Scheadel). During surgery, the drapes are secured below the head; otherwise, they may be pulled downward by the knees of the surgeon, thus influencing the shape of the lid fissure or position of the eye. Adherent (windows) sheets are less desirable in lid surgery because they place traction on the lids, influencing the position.

C Figure 15.4  A. Cutting by rounded scalpel blade, causing folding. B. Cutting from inside out by pointed scalpel blade. Both methods result in perpendicular wound edges. C. Fold cutting by scissors results in nonperpendicular wound edges. Copyright Frans C. Stades.

the size necessary for the suture material. For lid skin, which may be extremely leathery, 10–16 mm, 3/8–1/2 circle, extra‐ sharp‐pointed round, micropointed, or extra‐fine‐cutting needles are used. Their behavior in tissues is illustrated in Fig. 15.5. If there is any likelihood of postsurgical irritation of the cornea by the suture material (e.g., recurrence of entropion), soft material such as silk is advised. If strength is important, 5‐0 or 6‐0 monofilament nylon can be used. For difficult‐to‐handle animals, absorbable material, such as polyglactin 910 or polyglycol acid, can be used, eliminating the need for suture removal. However, these materials and their ends are more abrasive and can irritate the cornea in case of contact. Also, the resorption process can cause more reaction of the surrounding tissues. If there is a higher risk of infection, monofilament nylon 6‐0 is used (blepharoplasties). The needle should be handled at its flattened middle area. Capturing the conic tip of the needle with the hardened beak of the needle holder will roughen its surface and badly hamper skin passage. Handling the rounded back part of the needle, where the suture material is clamped/glued in, may result in uncontrolled rotation of the needle and unwanted trauma by its tip.

Suturing Wound edges must be closed very precisely (Fig. 15.6). As eyelids are moving continuously, the knots of the suture must be well secure. The surgical knot consists of a double throw, closed by a square knot (Fig. 15.8). Suture ends are left long to allow easy removal and thus hang downward, or they are gathered together in the upper lid or canthi (Fig. 15.7); short ends may “brush‐irritate” the cornea. If wounds are unequal in length (e.g., in the Celsus–Hotz or Stades procedures), the longer wound edge has to be “smuggled” away over the total

A

B

C Figure 15.5  Surgical needles (A and B) and monofilament suture material (C) and their behavior in tissues. Left to right: round, cutting, reversed cutting, and spatula needle sections. C2 is especially hazardous in thin covering layers like the free lid margin. Copyright Frans C. Stades.

A

B

Figure 15.6  A. Asymmetric suture. After suturing, the wound levels will not be equal, resulting in delayed and scarring wound healing. B. Symmetric suture, resulting in exact apposition. Copyright Frans C. Stades.

(also see later Fig. 15.22, Fig. 15.28, and Fig. 15.8C), thus preventing folding on either side of the wound (dog‐ears). Special attention is necessary to appose the edges of eyelid margin defects (Fig. 15.8 and Fig. 15.9). Sliding flaps should be pulled into the defect and bulge within the contour of the lid margin. If there is traction on the flaps or sliding grafts, it should be gradually minimized by the direction of the sutures and/or traction sutures (Fig.  15.11A and B). The posterior aspect of the skin graft postsurgically will be covered by conjunctival cells spontaneously, or it can be lined with mucosa from adjacent palpebral conjunctiva, buccal mucosa, or an island graft from bulbar conjunctiva of the opposite eye. However, the latter methods are more time‐consuming and may lead to unwanted traction bands and secondary graft edge entropion. A single‐layer wound closure (starting at the eyelid margin with a figure‐of‐eight or horizontal mattress suture with nonabsorbable or absorbable suture material and the remaining wound by single, interrupted sutures) was compared to a two‐layered wound closure (starting by apposing the deeper tarsoconjunctival layer with a simple continuous suture or one horizontal mattress suture, with buried knots of an absorbable suture material, and further closure as described in the first method). No significant difference was present in wound recovery, eyelid structure, and function after wound healing (Romkes et al., 2014).

Hemostasis Hemostasis is usually achieved by direct pressure. Excessive hemorrhage can also be stopped by (bipolar) electrocoagulation. For hemorrhages of very fine vessels, special ophthalmic (battery) disposable microcautery units are available. Cautery of vessels will cause a local area of necrosis, and for this reason cauterization should not be done too quickly or excessively. Diffuse hemorrhages during lid surgery will usually clot spontaneously. To avoid delay caused by waiting for the hemorrhage to stop spontaneously, cutting by scalpel should be done from the lowest to the highest point.

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A

B

C Figure 15.7  A. The surgical knot consists of a double throw, closed by a square knot. B, C. Both ends of the knot should be pulled equally, avoiding capsizing or spilling of the knot that would result in a potentially slipping knot. Courtesy of Frans C. Stades.

Diffuse hemorrhages during lid surgery will generally result in swelling of the weakest adjacent tissue. In entropion and ectropion correction, the area of swelling is usually the conjunctiva behind the skin wound. In entropion, the conjunctival swelling may displace the lid margin beneficially away from the often painful cornea, which may appear as an overcorrection initially. However, in ectropion and macroblepharon corrections, this swelling may result in recurrent ectropion. Therefore, in the latter  procedures, more thorough hemostasis should be achieved before the final closure of the wound, or a small drain must be placed, especially following extensive blepharoplasties.

Cryosurgery Figure 15.8  The ends of upper lid or lateral canthus sutures can be caught or linked together in an outer‐placed suture to prevent irritation of the cornea. Copyright Frans C. Stades.

In cryosurgery, the destructive effect of freezing the intracellular water ruptures the cell membrane in unwanted tissues. In general, two cycles of rapid freezing and slow, spontaneous thawing are used. The tissues are frozen to at

1

A

B Figure 15.9  Suturing of a free lid margin wound. Methods of suturing using a figure‐of‐eight‐like (A) or a U‐form (B) suture. The conspicuous points of the wound are sutured first (1). The remaining wound is sutured by halving the intervals. Copyright Frans C. Stades.

least −25 °C, but no more than −30 °C (possible necrosis), by the use of carbon dioxide or nitrous oxide. Cryosurgery may be of use for the destruction of hair follicles, the destruction of reactive granulation, or several types of neoplasia. The main advantages of cryosurgery are the relative simplicity and repeatability of the method. Potential disadvantages are severe postoperative swelling; depigmentation, which may be permanent; and the unwanted loss of normal tissue.

Postoperative Care During recovery from general anesthesia or later during unsupervised moments, the patient may loosen or lose stitches, or worse, tissues, resulting in wound dehiscence and infections. Routine use of an Elizabethan or E‐collar may prevent such complications.

Congenital and Presumed Hereditary Structural Abnormalities Ankyloblepharon: Physiologic The canine palpebral fissure is sealed at birth. A pinhole‐ sized patency at the medial canthus may be the earliest indication of the later separation. This period of natural

ankyloblepharon is required in the dog because of the relative immaturity of the ocular and adnexal tissues at parturition. The bridge of tissue in the palpebral fissure between the already developed margins of the eyelid normally regresses at 10–14 days postpartum. Because the canine and feline palpebral fissure is not patent at birth, the term congenital with reference to disease in these animals should apply for a period of approximately 6–8 weeks after birth, until the main structures of the eye have developed. Premature opening of the palpebral fissure is usually accompanied by exposure keratoconjunctivitis and severe corneal ulceration; globe perforation and uveitis are possible complications. In such cases, wetting ointments or gels must be used to protect the ocular surfaces. On occasion, temporary tarsorrhaphy with long and adjustable sutures may be necessary, particularly if the palpebral fissure opens within the first few days postpartum. When surgical closure proves to be necessary, mattress sutures are used to appose the lid margins for approximately 10–14 days, and it may prove necessary to maintain topical wetting therapy for several days after the sutures are removed. If the condition is accompanied with a tear film deficiency, prognosis is less favorable.

Ankyloblepharon: Pathologic Ankyloblepharon is delayed or complete failure of opening of the palpebral fissure. Even though little is known about the cause of this regressive defect, some epidermal growth factor must be involved. The anomaly occurs infrequently and is usually bilateral. Conjunctivitis or ophthalmia neonatorum must be considered in the differential diagnosis, but in this condition the closed eyelids will bulge as a result of the exudate that accumulates behind the adhered eyelids. This often staphylococcal keratoconjunctivitis may result from an intrauterine infection or from the dam’s genital tract during partum. The bacteria enter the conjunctival sac, presumably via the patent opening in the medial canthus. The first indication of its presence may be a bead of purulent material at the medial canthus and the bulging lids (Fig. 15.12). The lid fissure should be carefully opened without delay; otherwise, the lacrimal gland, cornea, and even the whole globe can be irreversibly damaged. Therapy

Treatment consists of gently massaging the fissure cautiously until it opens. If this fails, mechanical spreading with mosquito forceps in the spontaneous first opening and/or into the groove of the future fissure starting in the medial canthus will open the fissure. Sometimes, an incision at the medial canthus with a pointed scalpel is necessary. Care is required to follow the line of separation between the two lid margins accurately, using Stevens scissors, and to avoid any contact with the cornea. The conjunctival sac can be swabbed to determine the cause of infection

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Section IIIA: Canine Ophthalmology

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C

D

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Figure 15.10  Suturing of a free lid margin wound as it should not be done. Suturing at unequal intervals and too far away from the margin’s first figure‐of‐eight suture (A) and the result (B). Incongruous suture: at the left side, 1 mm outside of the margin; at the right side, in the line of the Meibomian gland openings or gray line (C) and its result (D). Suture located in the line of the Meibomian gland openings but too far away from the wound (E) and its possible results (F). Copyright Frans C. Stades.

and to establish antibiotic sensitivity. The conjunctival sac may be irrigated with 10% acetyl cysteine. All debris is removed using sterile saline or a 1 : 50 povidone‐iodine aqueous solution. The eye is examined for corneal damage, and a broad‐spectrum topical antibiotic is applied four to six times per day for as long as necessary. Specific antibiosis can be substituted once the sensitivity has been established. Prognosis

The prognosis is favorable. There are no known means of preventing this condition.

Eyelid Coloboma or Aplasia In eyelid coloboma or aplasia palpebrae, or lid agenesis, the lid margin and the lid itself are completely or partly undeveloped. This rare anomaly is congenital, presumed hereditary,

usually bilateral, and in the canine affecting the lateral part of the lower eyelid; the condition is not infrequent in cats. Eyelid coloboma is often associated with other congenital anomalies such as microphthalmia, absence of the lacrimal gland, keratoconjunctivitis sicca, persistent pupillary membrane, cataract, retinal dysplasia, and optic nerve head colobomata. The pups are often born with the palpebral fissure partly or fully open. Sometimes, the margin of the eyelid is developed but without Meibomian glands. Therapy

If the margin of the eyelid is developed without Meibomian glands, no surgical therapy is necessary. If there are ectopic hairs in the area, they should be removed. If the cornea is only slightly irritated, administration of topical lubricants, to effect, on a daily basis will be sufficient. If the lesions are larger, a substitute eyelid should

15: Diseases and Surgery of the Canine Eyelid

be created by ­blepharoplasty. Many methods have been described, using skin, skin with orbicularis and tarsus, and, in the more sophisticated but also more complicated procedures, skin posteriorly lined with adjacent conjunctiva or homologous conjunctiva/mucosa from elsewhere (see reconstructive blepharoplasties, later Fig.  15.75, Fig.  15.77, and Fig.  15.83, and Chapter  28, “Feline Ophthalmology”).

B

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In cases of minor defects, the prognosis is favorable. In larger lesions, the substitute eyelid can function reasonably well. In some cases, lifelong administration of topical lubricants will be necessary. In case of failing lacrimation, prognosis is less favorable. If there are other congenital anomalies, they should be considered in the prognosis.

3 A

Figure 15.11  Surgical correction of wounds and the order of suturing (1–3). If there is traction on the wound, U‐figure relaxation sutures can be used; silicon or infusion tubing prevents sutures from cutting into the skin (A). If flaps are to be positioned (B), the sutures should pull the flap into the defect (B, 1, 2), relieving traction on the leading edge of the graft. The leading wound edge (C), to be the new lid margin, should bulge slightly within the lid margin contour, resulting in a continuous lid margin line after cicatrization. Copyright Frans C. Stades.

Osteoma Cutis Eyelid Deformation Osteoma cutis is a rare ossification within the deep dermis. Osteoma cutis in the eyelid may be cause trichiasis, keratitis, and even strabismus (Hindley et al., 2016). Therapy

Local resection of the abnormal tissue appears to be curative.

Dermoids and Dysplasia Palpebrae Dermoids or choristomas of the lids are ectopic and abnormally developed islands of skin in or at the margin of the eyelid, frequently associated with some dysplastic deformities of the adjacent conjunctiva. They are rare, possibly hereditary, anomalies, usually of the lower lid near the lateral canthus (Fig. 15.13). Genetic predisposition exists in the French Bulldog, Shih Tzu (Badanes & Ledbetter, 2019), German Shepherd, Wirehaired Dachshund, Dalmatian, and St. Bernard, with the latter breed demonstrating a familial relationship between lower eyelid coloboma and dermoid formation (Brandsch & Schmidt, 1982). An island or fold of skin often disrupts the lid margin and is continuous with the conjunctiva. The fissure length itself is sufficient in most cases. Blinking is abnormal, and hairs generally grow toward the cornea, causing chronic irritation and resulting in edema, vascularization, and pigmentation. Therapy

Figure 15.12  Pathologic ankyloblepharon. Delayed eyelid opening in a puppy has resulted in ophthalmia neonatorum with pus extruding from the medial canthus. Courtesy of Frans C. Stades.

Treatment consists of removal of the abnormal parts of the eyelid and conjunctiva, and especially the hair follicles in the involved area. Thereafter, the lid margin wound is closed with extreme care. Blepharoplasties are necessary when the lid margin has insufficient length. If a normal upper lid is available, the stretched lid margin length can be measured by calipers. If the normal part of the lower lid

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Prognosis and Prevention

Section IIIA: Canine Ophthalmology

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Figure 15.13  Dermoid and eyelid dysplasia of the lateral canthus and conjunctiva in a 6‐month‐old French Bulldog. Courtesy of Frans C. Stades.

margin is 2–3 mm too short, the defect can be closed directly. Otherwise, the defect can be closed using a sliding (graft) procedure. If the condition does not produce overt corneal disease, the operation is often delayed until 10–12 weeks of age, when anesthesia risks are lower. For patients with severe defects, it may be best to operate soon. Postoperative treatment consists of topical initial choice, antibiotic eye ointment, or lubricating solutions four times daily for 10–14 days. Prognosis and Prevention

The prognosis is favorable. Parents and littermates should also be examined. Affected animals and, ideally, also members of their immediate family should not be used for breeding.

Distichiasis and Conjunctival Ectopic Cilia Distichiasis refers to single or multiple hairs arising from the free lid margin. They usually arise singly or with two or more hairs from the Meibomian duct openings (Fig.  15.14). The follicle itself is located 4–6 mm behind the margin of the lid in the posterior distal tarsal “plate,” in or near the base of the Meibomian glands. The Meibomian glands are modified hair follicles, and distichiae develop from undifferentiated mesenchymal gland tissue and are not associated with histologic changes of the tarsal glands (Raymond‐Letron et  al., 2012). Both lids can be affected, and the condition usually demonstrates a bilateral presence (Bedford, 1971; Gelatt, 1969; Halliwell, 1967; Schmidt, 1980). In dogs affected with soft distichiae, directed away from the cornea, the condition appears to have limited clinical significance. Hairs floating

on the corneal surface in the precorneal tear film in humans are known to irritate significantly. Stiff hairs that rub the cornea can irritate and cause injury (Bedford, 1971). This type of cilia may be coated with some mucin. Irritation leads to increased lacrimation, blepharospasm, and epiphora. Distichiasis may also act as a wick, resulting in an overflow of tears over the lower lid margin, moistening the margin and the exterior skin of the eyelid. Occasionally, corneal ulceration will present with distichiasis, and though the cilia may be directly responsible for loss of epithelium, self‐trauma may also be involved. Secondary entropion may be present, or in primary entropion distichiasis may cause severe irritation, resulting in a vicious circle. Although distichiasis is considered to be inherited, the exact mode of transmission is unknown. It occurs frequently, and predisposed breeds (1995–2000, 27,087 pure‐bred dogs) include the American (69%) and English (49%) Cocker Spaniels; Welsh Springer (48%) and Cavalier King Charles Spaniels (24%); Flat‐Coated Retriever (31%); Boxer, English Bulldog, Havanese, and Shetland Sheepdog (25%); Shih Tzu, Pekingese, and Tibetan Terrier; and Spaniel, Dachshunds, Poodles, and Jack Russell Terrier. Distichiasis may be present in puppies during litter screening at 6 weeks of age. Dogs with distichiasis are prone to having ectopic cilia in the conjunctiva. Breed predispositions to ectopic cilia are as for distichiasis in the Flat‐Coated Retriever, Pekingese, Shih Tzu, English Cocker Spaniel, Boxer, English Bulldog, Poodle, and Jack Russell Terrier. Irritation caused by distichiae leads to variable degrees of frequent blinking, moisture on the margins of the lower eyelid, and corresponding corneal lesions such as edema, vascularization, ulceration, and pigmentation. Distichiae may be difficult to detect without magnifying glasses and strong focal illumination. A common sign of distichiasis is the mucin that adheres to the hairs, revealing their presence. The mucus can effectively mask, but on the other hand betray, their existence. Straight, tough hairs, directed toward the cornea, however, can cause trigeminal irritation, as witnessed by excessive lacrimation, blepharospasm, mild conjunctivitis, and superficial keratitis. Trichiasis and entropion must be considered in the differential diagnosis, but in these conditions no hairs arise from the free lid margin. Therapy

The simplest treatment is manual epilation by rounded‐tip epilation forceps at regular intervals (4–5 weeks). The advantages of this method are that it allows detection of irritation caused by the hairs, it needs no anesthesia, and, if there are only a few hairs, it can be performed by skillful owners themselves. Manual epilation may also be used to confirm that the clinical signs are related, in fact, to the distichiae. For permanent treatment of distichiasis, the hair follicle is destructed, removed, or redirected. The methods vary from

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Figure 15.14  A. Distichiasis (hairs in or on the lid margin) emerging from the Meibomian (1), Zeis, or Moll (2) gland openings; 3. tear film; 4. cornea. B. Distichiasis of the lower lid in a dog. Mucus adheres to several of the distichiae, revealing their presence and proving their corneal contact and irritation. Copyright Frans C. Stades.

diathermy‐electroepilation to electrocautery, high‐frequency radiohyperthermia, electrolysis, cryotherapy, partial resection of the distal tarsal “plate,” eyelid split, transpalpebral conjunctival dissection, and Celsus–Hotz repositioning, but all have various limitations. All these methods require general anesthesia and, more important, adequate magnification (5–10×) to detect the orifice of the hair and the follicle (Halliwell, 1967). In electrocautery, the hair follicle is destroyed by coagulation. A simple battery‐powered device is the Perma Tweez (Stades et al., 1998). A very thin, stiff steel wire, mounted on a fragile spring, is introduced along the hair about 3 to 5 mm deep (not deeper!) into the lid margin to the follicle. If incorrectly positioned, the wire will move backward because of the spring instead of into the root of the hair follicle (Fig. 15.15A). It is disadvantageous that destruction of the follicle must be assumed rather than observed. The tip is rotated slightly in each follicle for at least 15 seconds, and when the tip is retracted the hair ideally should adhere to the steel wire. When the hair is removed by an epilation forceps, it should provide no resistance. Otherwise, the procedure has to be repeated, or it has to be combined with another method, such as the destruction of the follicle via the conjunctiva. Electrocautery and high‐frequency radiohyperthermia units for hemostasis, provided with a needle, are usually too powerful and will easily lead to destruction of the free edge of the lid margin and result in nasty distortion and scarring (Fig. 15.15B), often without destroying the ­follicle.

Bipolar electrolysis apparatus, as advocated to destroy “mustache” hairs in humans, are usually not powerful enough for the destruction of the more deeply located hair follicle in distichiasis. Cryosurgery is a popular technique. It is performed through the conjunctival surface directly over the follicle, 3–4 mm behind the free margin of the lid (Chambers & Slatter, 1984; Wheeler & Severin, 1984). The lid margin is stabilized and everted, using a Von Graefe forceps or Desmarres eyelid clamp (Fig. 15.16). A double freeze–thaw cycle using (nitrous oxide) specific probes produces a −25 °C freeze, which can destroy the follicles but spare the adjacent eyelid tissue. Because temperatures below −30 °C will easily produce necrosis and eyelid distortion, the use of thermocouple needles may ensure that tissue temperature does not fall below −25 °C. A 60‐second freeze is followed by a brief thawing period and then a second freeze for 30 seconds. The immediate postoperative effect is considerable swelling of the cryosurgery site, sometimes so much that blinking is impaired. Preoperative systemic nonsteroidals or postoperative topical treatment with corticosteroid initial choice antibiotic eye ointment is helpful. The swelling usually lasts no more than 2–4 days. Depigmentation of the frozen areas occurs within 72 hours. Repigmentation usually takes up to 6 months to complete. Permanent depigmentation, scarring, and distortion are possible complications. Two variations of lid splitting can be effective in patients with substantial eyelid thickness and if the cilia are more localized (Bedford, 1973, 1979; Campbell, 1977; Long, 1991).

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Figure 15.15  A. Distichiasis. Destruction of a single hair follicle by battery‐powered needle coagulator (Perma Tweez) via the opening of the gland (1) or by electrocautery (cutting) via the conjunctiva–tarsal “plate” (2). Alternatively, cryodestruction can be done at the same location. B. Lid margin damage after distichiasis‐hair follicle destruction using an overpowered needle cautery. Specific blank tip‐isolated shaft needles do exist for follicle destruction, but the diameter is less fine than the Perma Tweez. Copyright Frans C. Stades.

Figure 15.16  Cryodestruction of multiple distichiae in the conjunctiva–tarsal “plate” in a dog. Courtesy of Frans C. Stades.

The eyelid “wedge” removal requires a special lid clamp, and the free lid margin is damaged. Very precise parallel incisions, approximately 5 mm deep, are made anterior and posterior to the involved Meibomian ducts. A wedge of tarsal tissue is removed together with the hair follicles; however, the location of the follicle must be assumed rather than observed. The posterior eyelid margin is left intact; thus, postoperative eyelid distortion is avoided. In the removal of the involved tarsal “plate,” including the Meibomian glands, very precise incisions, approximately 4 mm deep, are made

outside the involved Meibomian ducts and just behind the base of the glands, and the tarsal “plate” removed (Bedford, 1979). In both procedures the wounds are allowed to heal by granulation, and the partial loss of Meibomian function seems to have no demonstrable effect on the stability of the precorneal tear film. These techniques should not be attempted in breeds with relatively thin eyelids because of the risk of cicatricial distortion or distortion of the entire length of the lids. In the removal of a tarsal “plate” strip, including the base of the Meibomian glands, the palpebral conjunctiva is incised 2 mm behind and parallel to the free lid margin over the involved area. A second incision, 4 mm behind and parallel to the first incision, allows removal of a strip of tarsoconjunctival tissue, with the assumed distichia follicles. If performed over most of the length of the eyelids, postoperative cicatrization may cause secondary entropion. A sliding tarsoconjunctival graft may be incorporated to prevent this complication (Long, 1991). A simpler method to remove the root of the distichia is to use an electric knife or electrocautery pen, 3–4 mm behind the location of a distichia into the tarsal “plate” until the follicle is visualized and destroyed (Stades et al., 1998). These methods can also be combined with the Perma Tweez method when the destruction of the follicle is uncertain. The defect will be refilled by secondary granulation and be re‐ epithelized after 10 days.

15: Diseases and Surgery of the Canine Eyelid

Ectopic Cilia Dogs with distichiasis are predisposed to having ectopic cilia in the conjunctiva as the same hair follicles are involved. Here, one or multiple cilia emerge through the palpebral conjunctiva and impinge directly on the cornea, causing severe corneal irritation (Bellhorn, 1965; Gwin et al., 1976a, 1976b; Helper & Magrane, 1970; Playter & Ellett, 1972). They are usually pigmented in the same color as the rest of the hairs of the dog and located in a small, pigmented spot of conjunctiva (Fig.  15.17). Predisposed breeds (also for distichiasis) are Flat‐Coated Retriever, Pekingese, Shih Tzu, Cavalier King Charles Spaniel, Boxer, English Bulldog, English Cocker Spaniel, Poodle, and Jack Russell Terrier. The upper eyelid is primarily involved. Single, multiple ciliae, bundles (Shih Tzu), or knots of hairs (Poodle) emerge through the conjunctiva, approximately 4 mm behind the

free lid margin. The condition is usually in the young dog, accompanied by acute, intense blepharospasm and lacrimation, and may resemble a foreign body. It easily results in a superficial, rounded (no scratch) corneal defect, without undermined edges, and is accompanied by vessels. The clock‐hour position of the corneal defect usually reveals the position of the cilia in the corresponding tarsal conjunctiva. Sufficient cooperation of the patient, light, and magnification are important factors for diagnosis. Therapy

In treatment, the lid is everted by Von Graefe’s forceps, a chalazion, or an eyelid clamp. From the palpebral conjunctival surface, using an electric knife, the covering conjunctiva is removed until the hair follicle is visualized and then destroyed. Alternatively, the assumed follicle area is excised en bloc by scalpel, by a dermal biopsy punch (D’Anna et al., 2007), or destroyed by cryosurgery. In the latter method, the cilia have to be removed by epilation afterward. Manual epilation may work in very easy‐to‐handle dogs (Park & Beckwith‐Cohen, 2015). However, much more thorough inspection is possible under general anesthesia as multiple ectopic cilia are common, and permanent destruction of the aberrant hair follicle is preferable. Aftercare consists of topical initial choice antibiotic ointment 4 times daily for 7 days. Prognosis and Prevention

The prognosis is favorable; however, the owner should be informed that other adjacent hair follicles may be invisible at the first session or, when not visualized, the germinal bud may not be destroyed and the hair shaft may regrow. The prevalence of distichiasis in 799 English Cocker spaniels from Denmark, examined between 2004 and 2013, was shown to be 49.31%. The relative risk of developing the disease was 1.3 and 1.8 for offspring of one or two affected parents, respectively. This, together with the moderate to high heritability (0.22 to 0.51) of the condition, indicates that selective breeding can be used to reduce the incidence of distichiasis (Petersen et  al., 2015). Affected animals, even with “only” one or two distichiae, should not be used for breeding, especially for breeds in which the percentage of affected dogs is still low.

Entropion

Figure 15.17  Ectopic cilia in the middle of the upper eyelid in a dog. Therapy is to excise or destroy the cilia follicles by cautery or cryothermy. Courtesy of Kirk N. Gelatt.

Entropion is the inversion of all or part of the eyelid margin, such that the free rim of the lid margin or the outer skin contacts the conjunctival or corneal surface, or both. The degree of entropion is considered to be mild when the margin is tilted by about 45°, moderate when it is tilted by about 90°, and severe when the margin is turned inward by about 180° (Fig. 15.18). Entropion may be lateral, medial, angular, or total, and may affect the lower or upper lid, or both. Entropion can be divided into categories: primary, such as congenital or developmental entropion; and secondary or

SECTION IIIA

Alternatively, a transconjunctival strip involving the area between 2 and 4–5 mm from the free lid margin bearing the ciliae can be resected (Gómez et al., 2020). The wound closes by secondary intention. Appearance of new distichiae occurred in 14/30 eyes (46.3%). Recurrence of distichiae only occurred in one eye (3.3%). Postoperative complications included trichiasis and cicatricial entropion, which developed in two eyes (6.6%). The Celsus–Hotz procedure can also be used to evert the lid margin with distichiae involving nearly all of the eyelid margin, to break the corneal contact and relieve the clinical signs. However, the necessary eyelid eversion may prove to be unacceptable and the distichiae remain in place. The Stades forced granulation procedure (Stades, 1987b) can be used both to remove the hair follicles and to evert the lid margin (see later Fig. 15.58), but it will result in a marked scar formation just outside the lid margin, which may or may not pigment.

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1

2

3

4

A

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Figure 15.18  A. Positions of the lid margin: 1. severe entropion; 2. mild entropion; 3. normal position; and 4. ectropion. B. Severe, high‐degree lower lid entropion, masked by exudate in a Rottweiler. Copyright Frans C. Stades.

acquired, such as spastic and cicatricial entropion. Entropion may result from a difference in tension between the orbicularis oculi muscle and the malaris muscle (lower lid entropion) and is influenced by multiple conditions such as the length of the lid fissure, conformation of the skull, the orbital anatomy, gender, and the extensiveness of folds of facial skin around the eyes. Epidemiology

Primary, congenital, or developmental entropion is a common condition in pure‐bred dogs. A hereditary defect is common, but the genetic basis is not well understood. It is commonly present in one or two littermates, with sound parents, excluding simple, dominant inheritance. It is more likely polygenic, but a dominant inheritance with incomplete penetrance or a recessive trait is not impossible. Severe entropion of the entire lower lid (Fig. 15.18B and Fig.  15.19A) occurs in breeds including the Chow Chow, Shar Pei, Bouvier des Flandres, Neapolitan Mastiff (Guandalini et al., 2016), and Rottweiler. In these breeds, the lid fissure is usually relatively short. In hunting breeds like the German Pointer, Labrador, Golden Retriever, and others, the lateral three‐fourths of the lower lids are commonly involved. In large or giant breeds, such as the Great Dane, St. Bernard, and Leonberger, entropion is often associated with an oversized palpebral fissure length, and is commonly found in the lateral half of the lower lid and the lateral canthus (see later Fig.  15.44A). Upper eyelid entropion (Fig.  15.19B) (usually in combination with trichiasis; see also later Fig.  15.59A) occurs in the Bloodhound, Chow Chow, and Shar Pei, and in the older English Cocker Spaniel and Basset Hounds, in which the looseness of the circum

orbital skin, the presence of loose facial folds (see later Fig. 15.65A), and the long and heavy ears contribute to upper lid distortion. Medial entropion occurs frequently in the Pekingese, Shih Tzu, Pug, Toy and Miniature Poodle, Cavalier King Charles Spaniel, and English Bulldog. In breeds like the Shar Pei and Chow Chow, the lower and upper eyelid entropion can be present as early as 2–6 weeks of age. In the other breeds, the onset of entropion is usually at 4–7 months. However, sudden onset of entropion, also unilateral, in 4‐ to 6‐year‐old or even older dogs, possibly initiated by secondary spasm caused by minor trauma, is also possible. Infrequently, the entropion is secondary or acquired as a result of severe (corneal) pain, such as occurs in primary corneal ulceration. It can also be secondary to a loss of lid support (e.g., in microphthalmos, phthisis bulbi, retrobulbar fat resorption, or muscle atrophy secondary to chronic myositis). In rare cases, conjunctival and skin scarring (caused by wounds or surgery) may cause traction to the lid margin and cause secondary cicatricial entropion, trichiasis, or both. Clinical Signs

The inverted position of the lid margin against the palpebral conjunctiva of the nictitating membrane and the bulbar conjunctiva and cornea results in irritation, excessive lacrimation, mucopurulent discharge, and blepharospasm. There is increased conjunctival vascularity and signs of chronic irritation of the cornea such as edema, vascularization, granulation, pigmentation, and even ulceration. The margin and exterior surface of the eyelid are moist, often discolored, and there may be mucopurulent discharge

A

B

Figure 15.19  A. High‐degree, entire lower lid entropion with secondary corneal ulceration in an Rhodesian Ridgeback. B. High‐degree upper lid entropion in a German hunting dog. Courtesy of Frans C. Stades.

dependent on the severity of the inversion and degree of irritation. Where hairs contact the cornea, corneal defects are common. Because of the trigeminal irritation, the patient will be in constant pain, resulting in excessive lacrimation, enophthalmos, a loss of support of the lid margin, and subsequently a further increase of the entropion. Moreover, self‐trauma in an attempt to relieve pain will contribute to the overall damage. This leads to a vicious circle that can be resolved only by surgical correction of the entropion. The corneal lesions may be filled by granulation tissue or they may deepen until perforation occurs. The final stage is the formation of scar tissue and pigmentation or, sometimes, loss of the eye. Diagnosis

Diagnosis is based on clinical signs, history, and breed. The patient should be observed without restraint to determine the degree of entropion. After the evaluation has been done at a distance, during closer examination the animal should not be held too tightly by the nape of the neck, because traction on the skin may evert the entropion. In case of doubt (e.g., when only the outside of the eyelid margin is moist), an entropion provocation test should be performed. For this purpose, a small skin fold, approximately 10 mm below the lower lid margin, is retracted slightly so that the lid margin inverts and the outer edge lies against the cornea. This inversion should be corrected by a single blink, and its persistence indicates (habitual) entropion. The instillation of a topical anesthetic is another diagnostic method to differentiate the structural component from the secondary spastic or pain contribution of the entropion. Trichiasis, distichiasis, and eyelid coloboma must be considered in the differential diagnosis, but in these conditions the cilia and the free lid margin, or absence of lid margin, can be visualized.

Therapy

In mild entropion, the cornea may be protected by a topical lubricant. It is usually best to postpone surgical correction until the head has grown to full size (1.5–2 years of age). However, if there are signs of distinct conjunctival or corneal irritation, surgical intervention is certainly indicated. Tacking Lids or Stay Sutures

In puppies (mainly Shar Pei and Chow Chow) less than 12 weeks old (when the anesthesia risk is relatively high) with severe entropion, temporary retraction sutures (“tacking”; Fig. 15.20; Johnson et al., 1988; Lenarduzzi, 1983) can be placed to gather up the skin of the lid and thereby evert the lid, thus preventing corneal lesions. Alternative staple or skin‐crushing methods are considered unpredictable, irritating, and animal‐unfriendly methods. Usually, two to four 5‐0 to 6‐0 nonabsorbable or absorbable (but they last for less time) tacking sutures are placed adjacent to the involved lid margin. Simple, interrupted (needle direction away from the cornea, thus less risk for corneal trauma) mattress sutures or interrupted, vertical mattress sutures are placed in the lower and less frequently in the upper eyelids. The “bites” are about 5 mm long to ensure adequate retraction and tissue holding occur. Often, the sutures are left long to permit multiple adjustments. When the sutures are removed (4–6 weeks) or lost, the surrounding “scar tunnel” will remain, thus still causing correcting traction on the lid margin. Therefore, this procedure must be considered a surgical intervention for entropion and the patient so identified. In some cases, the entropion will not need further correction. Persistent entropion requires further surgery. The tacking procedure is also indicated in adult dogs to treat spastic entropion or to prevent secondary trichiasis‐ entropion of the upper lid to the lower lid after lower lid

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B A Figure 15.20  Entropion correction by retraction sutures (tacking). The sutures can be maintained for at least 2–3 weeks. The scar tissue “tube” formed around the suture material will result in moderate permanent correction. A. Simple interrupted sutures. B. U‐figure suture, with the disadvantage that the needle also points in the direction of the cornea during suturing. Copyright Frans C. Stades.

entropion correction. Severe entropion should be corrected when there are corneal lesions, even in very young animals. Special care must be taken to avoid overcorrection, particularly in very young animals. Before operating, the entropion is evaluated before and after application of a topical anesthetic to determine the extent and degree of entropion. In long‐standing lesions, the entropic lid hairs are coated with a mucoid material that appears whitish tan and gives the surgeon an indication of the amount of eversion necessary to correct the defect. Quickert–Rathbun Procedure

As reported by Williams (2004), the Quickert–Rathbun technique can be used in dogs for lower lid entropion using fornix‐based sutures. This technique may be an alternate procedure to the tacking method in young puppies (especially those where entropion recurs after tacking) or may be employed in older dogs. In this procedure, double‐ended 4‐0 absorbable suture is positioned from the deep fornix to exit externally 1–2 mm from the eyelid margin, immediately everting the lid margin and entropion (Fig. 15.21). The tension by the sutures can be varied to effect normalcy or slight ectropion. Further work is necessary to evaluate the long‐ term success. The use in the upper lid, as done in humans, may be harmful to the lacrimal gland ductuli. Many methods and variations are available for the correction of entropion (Veenendaal, 1936). There is no “cookbook” method to fit every patient. Complicated entropion cases, such as combinations of upper and lower lid entropion, medial entropion, and combinations with severe corneal lesions (e.g., ulcer, corneal pigmentation), require more surgical skills and experience. Surgical Procedures

Entropion correction was described by Celsus in the first century ad as a technique by which only skin was removed and the skin wound sutured (Zeis, 1839). Hotz improved the

Figure 15.21  In the Quickert–Rathbun technique, a double‐ ended 4‐0 absorbable suture is extended from the deep fornix to exit just in front of the lower lid margin, immediately everting the lid margin and entropion. The tension by the sutures can be varied to effect normalcy or slight ectropion. Disadvantage: less predictable after removal of the suture. Copyright Frans C. Stades.

procedure to include removing a strip of the orbicular oculi muscle and closing the wound with simple, interrupted sutures anchored in the remaining muscle (Hotz, 1879). In the veterinary literature, the excision of a somewhat circular section of skin to effect correction of entropion was described by Fröhner around 1900 (Fröhner, 1900). At least three different surgical procedures were described and illustrated for entropion for animals by Nicholas (1914). The excision of an oval portion of skin involving the lateral lower eyelid and lateral canthus for entropion was referred to as the Berlin– Mégnin method. A simple method to repair entropion in the dog was reported by Veenendaal (1936). The excision of an arrowhead‐shaped section of lateral canthus skin for the treatment of entropion has been referred to as the Schleich method (Carter, 1967; Dixon, 1948; Halliwell, 1965; Menges, 1946; Miller & Albert, 1988; Mitchell, 1931). The Celsus–Hotz procedure and its modifications are currently the basic surgical techniques for the treatment of most types of entropion. This procedure and its modifications

15: Diseases and Surgery of the Canine Eyelid

­ igmentation of the skin ceases and the first eyelid hair p begins; Fig. 15.22), extending at least 1 mm medial and lateral to the entropic part of the lid. The lid may be stretched by closed forceps in the lateral canthus and a fingertip adjacent to the area of entropion, or by an entropion clamp, or it can be held taut and the eye protected by, for example, a Jaeger or Gränitz lid plate. If the first incision is too close to the margin, there will not be enough tissue for suturing, and there is a greater possibility of the sutures touching the SECTION IIIA

­ rovide consistent and beneficial results. Others claim the p Celsus method alone to be sufficient for correction (Martin, 2005). Lid procedures in dogs must consider that this species lacks a cartilage tarsal plate and a well‐developed lateral canthal ligament that are present in humans. Often the presence of enophthalmos can further complicate the correction of entropion. Surgical correction is begun with an incision 2–2.5 mm from and parallel to the margin of the lid (where the

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A

C

2 1

4 3

D B

5 5

E Figure 15.22  Celsus–Hotz procedure for the correction of severe lower lid entropion with corneal ulceration. A. The skin is incised at about 2.5 mm (as near as possible to the margin for better prediction of the entropion correction, but with enough space for skin suturing) from and parallel to the lid margin (B). C. The skin plus orbicularis muscle are excised; not deeper: canaliculus and (sub‐) conjunctival tissues should not be damaged. The lid margin should no longer show spontaneous intention of inward rolling. D. The skin is sutured with material not exceeding 5‐0 (e.g., nonabsorbable or absorbable, especially in difficult‐to‐handle animals, mono‐ or polyfilament), using a fine, round‐body needle with or without a micropoint. Continuous sutures alone are not used because of the risk of rupture of the suture material when rubbed, resulting in dehiscence of the entire wound. The first sutures are placed at the medial and lateral ends, and the rest of the wound is closed by halving the intervals in the following order: 1, 2, 3, 4, and so on. The distance between sutures is 2–2.5 mm. Alternatively, the intervals of the simple interrupted sutures can be made at about 4 mm, and thereafter the remaining wound intervals closed by a continuous suture. E. Secondary upper eyelid trichiasis to the lower, caused by postoperative lower lid conjunctival swelling, can be prevented by tacking of the upper lid (5). Copyright Frans C. Stades.

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cornea. If the first incision is too far from the margin, the lid may not evert sufficiently, and the result will be less than anticipated. Overcorrection may cause ectropion, which may result in additional, less predictable surgery. Therefore, correctly estimating the amount of tissue to be removed is most important. The following methods can be used as an aid:

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●●

●●

The most entropic part of the skin that lies against the cornea before surgery can be marked. The eyelid is replaced in its entropion position after the first incision has been made (Fig. 15.23). Using forceps, a small amount of blood is applied to mark the margin of the skin of the inverted lid. The second or external, elliptical‐shaped incision is then made just along the edge of this mark (Stades et al., 1996). The rule‐of‐thumb technique (Fig. 15.24) is performed by placing digital pressure on the lid skin adjacent to the entropic margin and pulling down until the free lid margin is exposed. The distance the thumb moves to evert the lid is the widest portion of the lid skin excised. The second incision is made in an elliptical fashion, joining the two ends of the primary incision (Wyman, 1979, 1990).

A

B

D

C

A

Figure 15.24  Entropion correction estimation: rule‐of‐thumb method (Wyman). A. Correction is accomplished by placing digital pressure on the lid skin adjacent to the entropic margin and pulling down until the free lid margin is exposed. B. The distance the thumb moves to evert the lid is the widest portion of the lid skin excised. C. An “arrow pattern” of suturing can be used, starting in the middle of the wound. The first two sutures are placed at an angle of 45°, pointing to the pupil. Disadvantage: the wound may not perfectly appose in between. D. The remaining sutures are placed parallel to each of the first two on the corresponding sides. Advantage: simple, moderate estimation of necessary correction. Copyright Frans C. Stades. ●●

B Figure 15.23  Entropion correction estimation: blood‐staining method (Stades). After the primary incision parallel to the lid margin, the lid is replaced in the entropion position. Using forceps, blood is applied to mark the skin at the line where the lid rolls inward. The second incision is made just along the edge of this mark. Advantages: simple, proper estimation of necessary correction. Copyright Frans C. Stades.

Sufficient skin can be grasped with Allis forceps, for example, until the eyelid returns to its normal position (Fig. 15.25). The resulting fold of skin is removed by cutting with scissors (Miller & Albert, 1988).

The part of the skin around which the incisions have been made is further excised with a scalpel or with scissors (“fold” method), including a superficial strip of the orbicularis muscle (see Fig. 15.22 and Fig. 15.25). The palpebral conjunctival sac should not be perforated. After removal, the remaining lid margin should conform to the corneal surface and not tend to invert. Hemorrhage is usually minor and occurs from the lateral and medial ends of the incisions. Temporary clamping of the larger blood vessels by hemostats or digital pressure is usually sufficient. Thermocautery (or ligatures) of these bleeders is seldom necessary and may cause local fibrosis in the lid.

A

and lateral ends, and then the rest of the wound is closed by halving. In lateral canthal entropion, the first suture is positioned at the lateral canthus. Some surgeons advocate an arrow pattern starting in the middle of the wound. The first two sutures are placed at an angle of 45° to each other, pointing to the eye. However, this may result in less perfect wound apposition between those stitches. The remaining sutures are placed parallel to each of the first two on the corresponding sides. They should be spaced as described previously. The edges of the wound should be joined together carefully so that no parts of the edge remain visible. Some postoperative swelling of the conjunctiva is normal and even desirable because it keeps the eyelid margin off the cornea, which is often still painful, thus allowing the cornea to heal quickly. Surgery for Central Entropion

In the orbicularis pedicle traction strip or Wyman procedure, the central tarsal pedicle is combined with the Celsus–Hotz procedure to treat central lower entropion (Fig.  15.26; Wyman & Wilkie, 1988). The technique involves construction B

A

B

C

D

C Figure 15.25  Entropion correction estimation: fold‐grasping method. A. Sufficient skin can be grasped, for instance with an Allis forceps (not a hemostat), until the eyelid returns to its normal position. B. The resulting fold of skin is removed by cutting with scissors. C. A strip of the orbicular oculi muscle is removed. Advantage: simple, moderate estimation of necessary correction. Disadvantage: imprecise, nonperpendicular wound edges due to cutting with scissors. Copyright Frans C. Stades.

The wound is closed with interrupted sutures of material that will effectively reappose the wound edges and should be 5‐0 or 6‐0 (e.g., absorbable or nonabsorbable mono‐ or polyfilament), using a fine, round‐body needle with or without a micropoint (see Fig.  15.22 and Fig.  15.24). The sutures are placed at intervals of not more than 2 mm. Alternatively, the intervals of the simple interrupted sutures can be made at about 4 mm, and thereafter the remaining wound intervals closed by a continuous suture. Continuous sutures alone are not recommended because of the risk of dehiscence of the entire wound when it is rubbed. Placement of the sutures must accommodate the shorter eyelid margin wound and the longer distal incision. The first sutures are placed at the medial

Figure 15.26  The central tarsal pedicle procedure for entropion (Wyman procedure). A. A tarsal pedicle anchored at the eyelid margin is combined with the Celsus procedure. The initial skin incision is performed about 2.5 mm from the eyelid margin. A tarsal pedicle is constructed by scalpel, with its base at the eyelid margin of the most extensive entropion. The second skin incision of the Celsus method is performed, and the section of skin is removed using tenotomy scissors. The width of the surgical wound varies with the extent of the entropion. B. A subcutaneous tunnel is made below the pedicle. C. Through the tunnel, a 5‐0 cruciate suture attached to the tarsal pedicle is secured with a stent or silicone or infusion tubing below the surgical wound. D. The skin wound, to correct the remainder of the entropion, is apposed with simple interrupted, 5‐0 to 6‐0 sutures. Disadvantage: complicated and less predictable results. Copyright Frans C. Stades.

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of a pedicle of tarsus to evert the eyelid margin. The pedicle is secured in the subcutaneous tissues. This procedure is mainly recommended for severe and previously operated, recurrent entropion. To correct mild central entropion of the upper and lower eyelids, the Wharton–Jones or Y to V method (not to be confused with the V to Y method for ectropion) has been advocated. The initial Y incision is made, starting from just below the eyelid margin, including eyelid skin and orbicularis oculi layers (Fig.  15.27). The tip of the flap is sutured outward, thus everting the lid margin outward. The procedure is traumatic to the orbicularis muscle, and because the middle of the flap does not control traction to the margin optimally, the result is difficult to predict.

A

Surgery for Medial Entropion

In cases of medial entropion, a little more of the skin can be removed to counteract any tendency to develop nasal folds, and without the risk of overcorrection. The Celsus– Hotz procedure may be modified for medial entropion and epiphora in miniature breeds of dogs. The objective of the technique is to evert the medial lower eyelid margin enough to assist the lower lacrimal punctum to conduct tears to its orifice (Peiffer et al., 1978a, 1978b). The extent of the lower eyelid skin–orbicularis oculi muscle to be excised is determined preoperatively by estimating the millimeters of correction to evert the medial lower eyelid. The incision should not be deeper than the orbicularis oculi muscle to avoid damage to the lower lacrimal punctum and canaliculus. Alternatively, pads of skin plus muscle can be removed by trephining. Medial canthus entropion combined with relative oversize of the lid fissure and caruncle trichiasis, as in breeds such as the Pekingese or Shih Tzu, should be corrected by medial canthoplasty (see “Trichiasis”). Alternative methods such as the Bigelbach and Stades Diabolo procedures also can be used in the medial canthus, but are more complicated, less predictable, and do not remove the caruncle trichiasis. Surgery for Entropion and Macro‐ and Microblepharon

In many large and giant‐breed patients with lateral lower lid entropion, the palpebral fissure is oversized. In these dogs, the stretched fissure length often varies from 40 to 50 mm. If the lid fissure is shortened in these patients, the lateral entropion usually disappears without specific correction. For additional details, see “Ectropion and Oversized Palpebral Fissure (Macro‐ or Euryblepharon”). In miniature breeds with microblepharon, this abnormality is usually accompanied by upper lid entropion. When the lid fissure is lengthened in these patients, the entropion disappears ­without specific correction. For additional details, see “Microblepharon, Blepharophimosis, or Blepharostenosis.”

B

C Figure 15.27  The Y to V plasty (Wharton–Jones) for entropion may be used for mild entropion of the central to lateral portion of the lower lid. A. The initial incision of the lid skin and orbicularis oculi muscle layers starts about 1–2 mm from the eyelid margin. The lower part of the incision will determine the extent of the lid eversion. B. A triangular section of skin and orbicularis oculi muscle, based at the eyelid margin, is dissected from the underlying tarsus by tenotomy scissors. C. The tip of the skin– muscle flap is apposed in a V shape to effect eversion of the eyelid margin with simple interrupted, 5‐0 to 6‐0 sutures. Disadvantage: unpredictable results. Copyright Frans C. Stades.

Surgery for Lateral Canthal Entropion

The Celsus–Hotz procedure may be adapted for entropion of the lateral one‐third of the upper and lower eyelids and the lateral canthus (Fig. 15.28). This modification is ­recommended when the palpebral fissure size is normal and an additional

3

1

and zygomatic arch, and a wedge of the tendon excised near its base. An alternative technique is to sever the tendon (tendonotomy) by scissors midway between its original and the insertion. The conjunctival wound is not apposed by sutures. Other entropion techniques may be combined with this method. In macroblepharon combined with lateral entropion, a lateral canthoplasty may be indicated (Grussendorf, 2004; see later Fig. 15.51; Gutbrod & Tietz, 1993; see later Fig. 15.31). In these procedures, the newly created lateral canthus is more or less anchored to the lateral ligament. Surgery for Entropion Combined with Shortening of the Lower Lid

2 4

Figure 15.28  Arrowhead Celsus–Hotz surgical correction of lateral angular entropion with a secondary corneal ulcer and the order of suturing (1–4). The correction does not change the size of the palpebral fissure. Advantage: predictable. Disadvantage: no lateral traction to the lateral canthus. Copyright Frans C. Stades.

enlargement of the palpebral fissure is not necessary. It has been proposed that transection of lateral palpebral ligament band or transconjunctival lateral canthal tenonectomy will reveal the true dimension of the palpebral fissure, and that a combination of this technique with the more conventional blepharoplasties offers a much better approach to correction of lateral canthus entropion (Robertson & Roberts, 1995a, 1995b). In the lateral canthoplasty procedure by Wyman (Fig. 15.29A–D), the lateral canthoplasty and construction of a lateral canthal ligament can be useful for large and giant breeds with minor central ectropion and lateral entropion of the lower and upper lids and the lateral canthus (Wyman, 1971). In this method, two strips of lateral canthal orbicular muscle are sutured to the zygomatic arch periosteum to retract the lateral canthus outward. The latter method can be modified, using one, or preferably two, nonabsorbable traction sutures attaching the lateral canthus to the periosteum of the zygomatic arch (Fig. 15.29E), thus stabilizing the lateral canthus (Peiffer et  al., 1978a, 1978b). This reduces the time for surgery, and with less tissue dissection the postoperative wound swelling is reduced. An alternative method is to use a section of frozen scleral homograft. The lateral canthal tendonectomy procedure (Robertson’s procedure) is to treat lateral canthal entropion that releases the tension in large and giant breeds of dogs by transection of the lateral canthal tendon (Robertson & Roberts, 1995b). The lateral canthus is everted by forceps to expose the palpebral conjunctiva. With curved Stevens or tenotomy scissors, the palpebral conjunctiva is separated from the deeper tarsus in a 9 mm arc. The fibrous band is located by blunt dissection that extends from the lateral canthus to the orbital ligaments

In the partial Celsus–Hotz full‐thickness lateral wedge resection procedure of Read and Broun (Fig. 15.30), the entropion is corrected by a combination of a Celsus–Hotz procedure and a lateral lid margin shortening of 20%–30% using a wedge resection, directly adjacent to the lateral canthus. The crescent of skin and the underlying orbicularis muscle of the partial Celsus–Hotz procedure and the full‐thickness wedge are removed. The partial Celsus–Hotz wound is closed using simple interrupted, rapidly absorbable sutures. The wedge is closed double‐layered, with a figure‐of‐eight suture at the margin. The success rate was 94% and especially effective in breeds with macroblepharon. Mild entropion recurrence was present in 6% of dogs. Recurrences were most common in breeds with short to average‐sized stretched palpebral fissure length. The advantage of a more time‐consuming and less easy to estimate method including lid shortening was not clarified (Read & Broun, 2007). In the lateral canthoplasty Gutbrod and Tietz (1993) procedure (Fig. 15.31), the lower lid is shortened over 2–6 mm, and a full‐thickness triangular area, including the lateral canthus, is removed, inducing lateral traction on the lateral canthus. The canthus is closed using 4‐0 absorbable material. The conjunctiva, the orbicularis oculi muscle plus subcutaneous layers, and the skin wound are separately apposed by simple interrupted sutures of the same material. The method appeared to have good results, mainly in the correction of entropion in a variety of breeds. The procedure has also been used for the correction of ectropion‐macroblepharon. Postoperative Management

Aftercare for entropion correction consists of applying topical initial choice antibiotic ointment (more lubricating than drops) at least 4 times daily for 14 days. Systemic antibiotics may be indicated in lateral canthoplasty techniques when surgical time and trauma are more excessive. If corneal ulceration is present, appropriate mediations are instilled. Even when sutured with great care, a protective E‐collar is recommended to prevent self‐trauma and possible wound dehiscence. The sutures are removed between 10 (especially silk) and 14 (monofilament, nonabsorbable) days after surgery.

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E Figure 15.29  The lateral canthoplasty and construction of a lateral canthal ligament by Wyman can be useful for large and giant breeds with central ectropion and lateral entropion of the upper and lower lid and the lateral canthus. A. An arrowhead of skin is removed at the lateral canthus over 3–5 mm. The width of the surgical wound should approximate the amount to effect correction of the entropion. B. Two myotomies are performed with their bases at the lateral canthus. These strips of muscle will form the new lateral canthal ligament. C. After subcutaneous dissection by tenotomy scissors, the pedicle of orbicularis oculi is secured by a cruciate suture to the periosteum of the zygomatic arch by a simple interrupted, 5‐0 nonabsorbable suture. D. The skin layers are apposed by simple interrupted, 5‐0 to 6‐0 sutures. E. As an alternative to the pedicle of orbicularis oculi muscles in the lateral canthoplasty procedure, one or preferably two sutures or a section of frozen scleral homograft can be used to attach the lateral canthus to the periosteum of the zygomatic arch and stabilize the lateral canthus. Advantages: both methods provide sufficient traction on the lateral canthus; the Wyman procedure is more complicated but stronger because of the tissue bridge. Anticipate postoperative lid swelling. Copyright Frans C. Stades.

Absorbable materials will not absorb very quickly in the skin, and the dissolution process causes more reaction and irritation, but removal is avoided, which is especially useful in uncooperative and/or ­anesthesia‐risk patients. Complications

The primary goal of these procedures is a functional, nonirritating eyelid, and a secondary goal is cosmetic acceptability. Complications with all of these procedures are often associated with overcorrection or undercorrection and undesired scar formation, leading to extensive and complicated repair surgery. Recurrent wound dehiscence in entropion correction has been described due to sebaceous adenitis

(Carmack et al., 2010). Directly after lower lid entropion correction, there will be wound swelling, mainly of the more elastic conjunctiva, enabling the upper lid cilia to irritate the lower lid margin and/or conjunctiva during blinking. This temporary trichiasis phenomenon can be prevented by tacking the lateral upper lid (Stades et al., 2007, p. 82) until the lower lid conjunctival swelling has resolved (see Fig. 15.22, E5). Large and giant breeds of dogs with entropion and enophthalmos present additional challenges because the globe– lower eyelid contact is often absent and entropion repair is less predictable. Breeds with excessive forehead skin folds also complicate entropion surgery that may require concurrent excision of large amounts of the forehead skin, which is

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90° %

0 –2 10

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m m

2–3

mm

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B

C Figure 15.30  The Celsus–Hotz full‐thickness lateral wedge resection by Read and Broun can be useful in entropion combined with an oversized lower lid, shortening the lower lateral lid margin over 20%–30%. A. The lateral lower lid is grasped and retracted laterally to establish how much the lid can be shortened. The partial Celsus–Hotz procedure and the lateral wedge resection incisions are made. B. The lateral incision of the wedge is 10–20 mm long and placed directly adjacent to the lateral canthus and perpendicular to the lid margin. The medial incision is run obliquely to meet the end of the lateral incision, resulting in a rectangular triangle. Using scissors, the crescent of skin (at the widest point 3–7 mm wide) and the underlying orbicularis muscle of the partial Celsus–Hotz procedure are removed from the tarsus. C. Finally, the full‐thickness wedge is removed. The partial Celsus–Hotz wound is closed using simple interrupted, rapidly absorbable sutures. The wedge is closed double‐layered, with a figure‐of‐eight suture at the margin. Advantage: lid shortening in oversized lid fissures. Disadvantage: entropion recurrences in breeds with short to average‐sized stretched palpebral fissure length, more time‐consuming, and possible leakage of the full‐thickness wedge wound. Copyright Frans C. Stades.

in the direct interest of the dog, but will affect the dog’s appearance (see “Upper Eyelid Trichiasis” and “Redundant Skin Folds around the Eye”). Prognosis and Prevention

The prognosis for entropion correction is good when the surgical procedure is performed correctly. In cases of deep corneal damage, corneal scarring may remain. Parents and siblings should also be examined. Affected animals should not be used for breeding. Breeding schemes should aim for dogs with lids with fissures of normal length. It would be advantageous to have the breed, name, tattoo or microchip, and pedigree number of affected animals registered centrally, and to persuade owners to report such information to the breed association. Other Methods

Excision using CO2 laser including a superficial part of the orbicularis oculi muscle without bleeding and without suturing has been described. The wounds were left to heal by secondary

intention (Serrano & Rodríguez, 2014). Electrocautery of the skin and superficial aspects of the orbicularis oculi muscle have been used to stimulate the formation of scar tissue and thus correction of the entropion. The predictability of the ectropionizing effect is low. Several nonsurgical methods to treat entropion in small animals have been used. Subcutaneous injections of antibiotics, paraffin, mineral oil, hyaluronic acid (McDonald & Knollinger, 2019), and silicones have been used to provide temporary or permanent eyelid margin eversion and relief from the trichiasis and blepharospasm. The larger the volume of the injection, the greater the extent of the eversion of the eyelid margin. These methods have been generally replaced by the different lid surgeries because of the low predictability of the correction, and, more important, the injected agents such as silicones may cause severe necrosis, granuloma formation, and scarring. Hyaluronic acid is well tolerated and can be of use in elderly animals or poor anesthetic candidates, but long‐term tolerance has not been documented.

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m 2–3 m

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d

d 2–6 mm

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b

a

Figure 15.31  Lateral canthoplasty, Gutbrod and Tietz procedure. In this procedure, the lower lid is shortened over 2–6 mm and removed full‐thickness, including the lateral canthus over an area, with the appearance of an orange piece (A). The lateral canthus (d) is apposed to the lower lid margin (a) and closed, using 4‐0 absorbable material (B). The conjunctiva, the orbicularis muscle plus subcutis layers, and the skin wound are separately apposed by simple interrupted sutures of the same material (C, D). The method appeared to have good results in the correction of mainly entropion in a variety of breeds (see text). The type of entropion was not specified. The procedure has also been used for the correction of ectropion‐macroblepharon. Disadvantage: unpredictable results. Copyright Frans C. Stades.

Ectropion and Oversized Palpebral Fissure (Macro‐ or Euryblepharon) Ectropion is an eversion of the lid margin, usually of the lower eyelid (Fig. 15.32A and later Fig. 15.35A), but cicatricial eversion of the upper lid may occur. It is readily recognized because the orifices of the Meibomian glands are visible in the everted margin. In the dog, it is usually accompanied by an oversized palpebral fissure, and the lower lid is not adjacent to the globe. It is not always easy to differentiate between the two entities. In an oversized fissure, the lid margin is distinctly longer (stretched 5–15 mm) than the normal 33–35 mm necessary to cover the sclera in the opened eye. When the lower eyelid is not appropriately apposed to the globe over a distance of 1–10 mm or more, a funnel or sac is formed in the lower eyelid. The lids, blink reflex, and tears cannot perform their normal function of cleaning, shielding, and lubricating the eye. The conjunctival sac becomes chronically inflamed as a result of its permanent exposure to air, dust, bacteria, and stagnant tears. In more severe cases (e.g., Bloodhound, St. Bernard, Leonberger, Corso dog, Clumber Spaniel, or Pug; Krecny et al., 2015), when the middle portion of the lid is everted, there is often some inversion near both canthi (Fig. 15.32B and later Fig. 15.44A), or laterally there is distinct entropion, which may result in a chronic purulent conjunctivitis and corneal irritation.

Most forms of ectropion and oversized palpebral fissure are primary or congenital and breed related or presumed hereditary. The genetic transmission is most likely polygenic. The breeds of dogs frequently affected with lower lid ectropion/macroblepharon include the Bloodhound, St. Bernard, Great Dane, Newfoundland, Mastiff, and several spaniel and French hunting breeds. Some owners, dog fanciers, and breeders believe ectropion and oversized palpebral fissure to be normal, and some even encourage the “diamond”‐appearing palpebral fissures and the everted lower eyelids (which give the dog a “devoted and sad expression”). Moreover, some breed standards tolerate or even promote these conditions. Breed prescriptions vary from “showing little, if any, haw,” to “Acceptable to have some haw showing but without excess,” “the haw may sometimes show without excess,” “appear slightly sunken beneath thick eyelid, the lower lid shows a certain looseness,” “lower lids a little slack so that a little haw is visible are nevertheless tolerated,” and “a small angular fold on the lower lids with the haws only slightly visible as well as a small fold on the upper lids are permitted.” The country of origin prescribes the text of the breed standards. The UK has made a start, adding “Free from obvious eye problems” for all descriptions, and “Never protruding, exaggerated or showing white when looking straight ahead.” The additions of “normally fitting around the eye‐ball” and “at no time should the eye‐lashes touch or interfere with the eyes” are not yet optimal, but hopeful. It is important to influence Kennel Clubs to revise the breed descriptions and recommend adding a general line, such as “exaggerated facial conformation is undesired.” Strangely enough, many Kennel Clubs do not accept breeding from entropion‐ or ectropion‐affected dogs in their breed standards. Excessive facial skin folds, heavy ears, long eyelids (especially the lower lid), and unstable lateral canthus result in a sagging lower lid and an inverted upper and lower lateral canthus. Weakness of the lateral retractor muscle may lead to further instability of the lateral canthus. A poorly developed lateral canthal ligament or excessive tension from this structure and variable enophthalmos are other complicating disorders. The acquired or secondary forms of ectropion are fortunately rare. They may be associated with cicatrix formation, trauma, neurologic, and postoperative causes, such as overcorrection of an entropion. Ectropion and oversized palpebral fissure are rare in other species. Clinical Signs

Signs of ectropion or oversized palpebral fissure are as follows: the lower lid margin is rotated outward (the openings of the Meibomian glands are visible in the free margin); the fissure is often diamond or pagoda shaped; and the conjunctiva is red, swollen, and folded, resulting in increased tear and mucus production and purulent exudate. There is a

slight enophthalmos, which increases the distance between the lid margin and the globe. When the animal is more active than usual, as at dog shows or on the veterinarian’s examination table, and whenever it is held tightly by the nape of the neck, the ectropion or oversized palpebral fissure may almost disappear, but then too much sclera will be visible on the lateral side. Diseases associated with microphthalmos, phthisis, or enophthalmos (Horner’s syndrome, uveitis) must be considered in the differential diagnosis. Therapy

If the defect is slight, no treatment is required apart from irrigating the eyes upon returning from walks and applying a neutral, lubricating ophthalmic ointment or solution, particularly in young dogs whose heads have not yet reached adult size. Surgical correction of ectropion is recommended when chronic or severe secondary ophthalmic disease results. In more severe lesions, corrective measures may be taken, but usually not before age 2–2.5 years, when the skull is full sized and orbital fat is present. Surgery should attempt to provide a relatively normal lower eyelid length and an adequate apposition to the cornea. Overcorrection should be avoided, because entropion may result and can cause potentially more damage to the cornea and conjunctiva than the ectropion might cause. Also, excessive scar formation should be avoided because it may result in focal contractions and be unsightly to the owner. The methods vary from influencing the lower lid position to shortening the lid fissure, restoring it to the actual size of the globe and repositioning lateral canthus laterally. Because in most dogs there is a combination of ectropion and an oversized lid fissure, the different ectropion surgical procedures primarily shorten and strengthen the lid. Because the medial canthus is relatively fixed and more complicated by the presence of the lacrimal ducts and the nictitating membrane, most surgical procedures for ectropion and macroblepharon involve the lateral lower eyelid and canthus. Moreover, the lid excision is better performed at the lateral canthus to avoid the possible development of an irritating notch in the middle of the visual axis, or an unsightly postoperative eyelid margin defect or notch. In general, it is the authors’ preference to use the Blaskovics or similar procedures for moderate to severe ectropion of the lower lid only, and the simple lid fissure reduction permanent tarsorrhaphy procedures for distinct, oversized palpebral fissures. Evolution of Ectropion Surgery

Like the surgical correction of entropion in humans and animals, reports of different surgical procedures for the treatment of the various types of ectropion have spanned nearly 150 years. Often, these surgical procedures were refined by other surgeons, whose names were added to the basic surgical procedure. In veterinary ophthalmology, several of these procedures have been adapted for use in

animals. Of all of these techniques, the Kuhnt– Szymanowski (K‐S) procedure forms the basis for the surgical procedure for ectropion in humans (Bedford, 1999a, 1999b; Fox, 1976; Stades et al., 1998). In 1883, Kuhnt reported the lid‐splitting technique revived from Antyllus’ (Greek surgeon, ca. 150 ad) lid‐splitting surgery and added a tarsoconjunctival triangular resection (or wedge). He revised this procedure a few years later to include an additional resection of the outer skin and muscle of the eyelids (Fox, 1976). Szymanowski, in 1870, reported his initial technique, which was improved further by Kuhnt. It is now utilized as the K‐S procedure (Kuhnt & Szymanowski, 1976). Blaskovics, in 1938 and later, reported modifications of the K‐S procedure, avoiding splitting of the lid margin, for both medial and lateral ectropion (Blaskovics, 1959, 1976). Fox and Smith modified the K‐S–Blaskovics procedure further by placing the skin incision closer to the lid margin and preserved the lid margin with a full‐thickness eyelid resection laterally (Fox, 1976; Stades et al., 1998). This procedure was reported by Munger and Carter (1984) in the dog. Influencing the Lower Lid Position in Primary Ectropion, Not Shortening the Fissure

Shortening the lower palpebral conjunctiva is one method to treat pure ectropion but not lid length. Where there is normal fissure length, only slight correction could be achieved by removing an elliptical part of the conjunctiva and suturing together (basting) the ventral palpebral conjunctiva with a continuous, subconjunctival absorbable suture. In the dog, the procedure is rarely used and easily leads to unwanted conjunctival traction bands. The V to Y or Wharton–Jones procedure (Fig. 15.33) offers another approach. This method induces scar tissue below the margin of the eyelid, which supports and pushes up the lower margin. It may be indicated to treat mild (e.g., cicatricial) ectropion (Bedford, 1999a, 1999b). The method, however, is only reliable when ectropion is not combined with an overlong palpebral fissure, and therefore it is useful solely in exceptional cases. It has been shown to be advantageous in cases of scarring dermatopathies resulting in extensive cicatricial upper and lower lid–lateral canthus ectropion (Donaldson et al., 2005). Homologous and Prosthetic Lateral Canthal Ligament Construction

In these procedures, the lateral canthus is adjusted laterally, stretching the palpebral fissure, and resulting in lifting the lower lid. It does not influence the length of the fissure, which limits the indications. The lateral canthoplasty and construction of a lateral canthal ligament by Wyman (Fig.  15.29) can be useful for large and giant breeds with minor central ectropion and lateral entropion of the lower and upper lids and the lateral canthus. In this method, two strips of canthal orbicular muscle are sutured

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B

Figure 15.32  A. Pronounced lower lid macroblepharon‐ectropion in a Clumber Spaniel. The stretched fissure length was 51 mm. There is additional upper eyelid trichiasis. The lower lid ectropion results in chronic exposure and secondary conjunctivitis. B. Pronounced macroblepharon‐ ectropion (diamond‐shaped fissure) in a Bloodhound. The stretched fissure length was 48 mm. There is also some medial and lateral entropion and a notch or kink in the lower lid margin. Note that the lower lid hangs in the middle about 15 mm away from the third eyelid–cornea and is not really everted in an ectropion position. This all results in chronic exposure and secondary conjunctivitis. Courtesy of Frans C. Stades.

and returns to the incision subcutaneously. There it is tied inverted, adjusting the position of the canthus by tension on the suture (Peiffer et al., 1978a, 1978b). This method may be combined with lid fissure shortening, as is done in the Grussendorf procedure (Grussendorf, 2004). Pedicle Grafts, Z‐Plasties, and Free Transplants for Severe (Cicatricial) Pure Ectropion

A

B

C

D

Figure 15.33  The V to Y plasty may be used to treat mild (e.g., cicatricial) ectropion. A. Converging skin incisions are made by the scalpel blade starting 1–2 mm from the eyelid margin. B. The V‐shaped skin flap is separated from the underlying tissues, and present scar tissue is excised. C, D. The skin flap is apposed by simple interrupted, 5‐0 to 6‐0 sutures as a Y‐shaped closure, lifting the lid margin upward. Disadvantage: unpredictable results. Copyright Frans C. Stades.

to the zygomatic arch periosteum to retract the lateral canthus outward (Wyman, 1971, 1979). In the prosthetic lateral canthal ligament construction, an access incision is made 10–20 mm lateral to the lateral canthus. A 4‐0 nonresorbable suture is placed through the incision, penetrating the dermis (not epidermal) at the canthus,

Cicatricial pure ectropion is fortunately rare. It is usually caused by the overcorrection of entropion. When the entropion correction is made too far away from the lid margin, the wound is made too deep, or suture material is too heavy, irregular scar formation can retract the lower lid downward and away from the globe as far as 10–15 mm. After the lower lid margin has been freed and the undesired scar tissue removed, the missing tissue to bring the lid margin back to its normal position can be estimated. Similar tissue from elsewhere has to be found to fill the defect (e.g., by a pedicle graft or Z‐plasty; Fig.  15.34). Preferably, upper lid skin is used. If upper lid skin is unavailable, other adjacent skin or skin from elsewhere (free transplant), with the same hair growth and flexibility, must be found (Fig. 15.35). A temporary tarsorrhaphy is made to prevent distortion of the lid margin caused by postoperative conjunctival swelling and scarring. Ectropion‐Macroblepharon Correction Procedures to Shorten the Lower Lid Margin

In most instances of ectropion, the lower eyelid margin or both the upper and lower eyelid margins are oversized. Methods aimed at reduction either around the defect in the margin or at the lateral canthus yield the best results. These methods require critical judgment on the part of the surgeon. Scars from previous faulty operations may

15: Diseases and Surgery of the Canine Eyelid

Lateral Eyelid Wedge Excision

A full‐thickness triangular lower lid section, immediately next to the lateral canthus, is excised (Fig. 15.36). The surgical defect is apposed by one or two layers of sutures. The method is the most simple, but it does not have the benefit of the double‐layered staggered wound preventing leakage, and it has a greater chance of eventual wound dehiscence and atrophy of the eyelid margin. General Considerations for Double‐Layered, Staggered Wound Creation in Shortening the Lid Margin (Nonsplitting vs. Lid Margin Splitting)

A

B

1

C

1

D

Figure 15.34  Pedicle graft from the upper to lower lid may be used to correct, for example, severe cicatricial ectropion (Z‐plasty principle). A. The skin is incised 2.5 mm from the lid margin. The wound is bluntly dissected by tenotomy scissors, and the scar tissue is removed. B. The remaining defect can be filled by either a large skin pedicle from the upper lid or a free transplant of thin skin grafted from elsewhere in the body, preferably with the same type of hair and placed in the same direction (see also Fig. 15.35). C. The pedicle is transposed to the lower wound. D. The wounds are closed by simple interrupted, 6‐0 monofilament sutures. A temporary tarsorrhaphy (1) is placed for 10–14 days. Copyright Frans C. Stades.

A

When the lower lid overlength is not excessive, procedures for shortening only the lower lid may be sufficient. These procedures effectively shorten the lower eyelid, give some support of the lateral lower lid by the scar tissue between the double layers, and cause moderate traction laterally (Fig. 15.37, Fig. 15.38, Fig. 15.39, Fig. 15.40, and Fig. 15.41). In the Kuhnt–Szymanowski–Helmbold procedure, the lid margin (and deeper parts) are split. The lid margin is incised in the line of the Meibomian gland openings or “gray line” over the desired length plus 1–2 mm. The skin plus muscle is separated from the tarsoconjunctival tissues by blunt dissection to a depth of 10–15 mm. The Meibomian glands are damaged over the operated distance. Although there is no direct proof of problems caused by the missing glands, it is preferable to leave the lid margin intact as much as possible. Moreover, the suturing and healing of the two layers of free lid margin easily lead to notches and other deformities in the “new” lid margin. Neither procedure addresses overlength of the upper eyelid (Bedford, 1999a, 1999b; Kuhnt & Szymanowski, 1976; Patel & Anderson, 1996). In the K‐S modified by Blaskovics lateral canthoplasty and ectropion procedure (Fig. 15.40), reported in 1938, the lower lid is shortened, and splitting of the lid margin is avoided.

B

Figure 15.35  A. Severe cicatricial lower lid ectropion caused by massive overcorrection of an entropion in a young Dutch hunting dog. The lower lid margin is retracted by scar tissue to the zygomatic arch. B. The postoperative result in the same dog. The skin was incised 2.5 mm from the lid margin and all scar tissue removed, resulting in an approximately 10 mm broad defect. This remaining defect was filled using a free transplant of thin skin from the abdomen of the same dog (note that there is less hair on the transplanted skin). Courtesy of Frans C. Stades.

SECTION IIIA

complicate future surgeries. Before surgery, the lid fissure is stretched and measured by calipers. The fissure should be shortened to approximately 33–35 mm (Stades et al., 1992).

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A

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C Figure 15.36  The lateral wedge excision procedure for shortening the lower eyelid in ectropion‐macroblepharon. Before surgery, the lid fissure is stretched and measured by calipers. The fissure should be shortened to approximately 33–35 mm in medium and large breeds of dogs. A, B. A full‐thickness triangular section of lower lid is excised by scalpel and scissors. The surgical defect is apposed by one or two layers of sutures. C. The tarsoconjunctival layers can be apposed with a simple continuous, 8‐0 absorbable suture. The skin–muscle layers are apposed with 5‐0 to 6‐0, figure‐of‐eight suture at the margin and further with simple interrupted sutures. Advantage: simple. Disadvantage: no staggering closure preventing leakage and wound dehiscence. Copyright Frans C. Stades.

The lid margin and tarsal “plate” stay intact. The double‐­ layered, staggered wound, preventing leakage and wound dehiscence, starts below the lid margin (Blaskovics, 1959, 1976). Smith modified further the Blaskovics procedure by placing the upper skin incision closer to the lid margin (Fox, 1976). This procedure was described in the veterinary literature by Munger and Carter (1984). Removal of a Deformed Notch and Shortening of the Lid Margin

In breeds such as the St. Bernard, the ectropion notch, approximately in the middle of the oversized upper and

Figure 15.37  Principle of shortening of the lower lid margin using lid splitting according to Kuhnt–Szymanowski. A. The lid margin is incised in the line of the Meibomian gland openings or “gray line” over the desired length plus 1–2 mm. B. The skin plus muscle is split from the tarsoconjunctival tissues by blunt dissection to a depth of 10–15 mm. A desired part of the tarsoconjunctiva is removed. The oversized skin–muscle outside the lid rim is shortened over the same distance. Advantage: the resulting wound is in two different levels (staggering wound), preventing leakage and wound dehiscence. Disadvantage: the lid margin, including the Meibomian glands, is damaged over the operated distance. Copyright Frans C. Stades.

lower lid, is usually so deformed that even after shortening, or shortening and lateral traction, these notches will not totally disappear. In these cases, the removal of that area itself and shortening of the lid margin may be advantageous (Fig. 15.39). The disadvantages are that the procedure has to be done in both upper and lower lids, it is time‐consuming, and there is no further traction laterally toward the lateral canthus. Kuhnt–Szymanowski Blaskovic’s Modification (Further Modified by Fox and Smith): Procedure for Oversized Lower Lid Margin and Ectropion

This procedure was first described in dogs by Munger and Carter (1984). The skin incision is made 2–2.5 mm from and parallel to the margin of the lid, starting a few millimeters medial of the worst area of ectropion and ending 5–10 mm lateral to the lateral canthus and from there downward (Fig. 14.40). The entire skin–orbicular oculi flap is loosened. A wedge‐shaped part of the tarsoconjunctiva is excised in

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B SECTION IIIA

A

D C B Figure 15.38  Principle of shortening of the lower lid margin according to Kuhnt–Szymanowski, modified by Blaskovics to avoid splitting the lid margin. A. The skin is incised 2.5 mm (as near as possible to the margin for better prediction of the area of ectropion or deformity to be corrected, but leaving enough space for lid margin suturing) from and parallel to the lid margin. The skin is divided from the muscle–conjunctiva by blunt dissection to a depth of 10–12 mm. A desired part of the lid edge plus a wedge of muscle–conjunctiva is removed. The oversized skin flap is shortened over the same distance. B. Advantage: the resulting wounds are in two different levels (staggering wound), preventing leakage and wound dehiscence. Copyright Frans C. Stades.

the worst area of ectropion. A similarly sized wedge of skin– orbicular oculi is excised laterally, thus shortening the flap. This method shortens the eyelid margin to the desired length and draws it upward and laterally. The double‐layered, staggered wound prevents leakage and wound dehiscence. Kuhnt–Szymanowski and Helmbold Procedures for Oversized Lower Lid Margin and Ectropion

These procedures predate the newer and improved procedures in use. The K‐S procedure differs from Blaskovic’s method in that the incision is not below the margin of the eyelid but in the margin itself (lid splitting), in the line of the orifices of the Meibomian glands or gray line (Fox, 1976). The Meibomian glands are damaged and/or destroyed in the whole lid margin wound, and the procedure is more time‐ consuming than the Blaskovics method. The Kuhnt–Szymanowski–Helmbold procedure (Fig. 15.41) shortens the lower lid by removing two wedge sections from the outer and inner layers at different areas of the lid, thereby

951

E Figure 15.39  A. Removal of a deformed notch and thereby shortening the lower lid in, for example, a St. Bernard can be done by a Blaskovics plasty. B. The skin is incised 2.5 mm from and parallel to the lid margin. The skin is separated from the muscle– conjunctiva by blunt dissection to a depth of 10–12 mm. The deformed part of the lid margin plus a wedge of muscle– conjunctiva is removed. C. The oversized skin flap is shortened over the same distance. D. The lid margin wound is apposed by a figure‐of‐eight, 6‐0 monofilament nylon suture. E. The skin flap is sutured by simple interrupted sutures. Advantages: staggering wound and removal of the deformed notch. Disadvantage: more time‐consuming. Copyright Frans C. Stades.

avoiding a full‐thickness lid wound (Bedford, 1999a, 1999b; Fox, 1976). Like the K‐S method, the eyelid margin incision for the Kuhnt–Helmbold procedure is along the Meibomian gland ducts and causes damage to these vital structures. Macroblepharon‐Ectropion Correction, Reducing Lower and Upper Lid Length

Because the medial canthus is relatively fixed and more complicated by the presence of the lacrimal ducts and the nictitating membrane, surgical procedures just to change the size of the palpebral fissure usually involve the lateral ­canthus. Surgical reduction of the medial canthus is usually restricted to the smaller breeds, such as Pekingese and

952

Section IIIA: Canine Ophthalmology

SECTION IIIA

A

C

A B

D

Figure 15.40  Kuhnt–Szymanowski procedure, modified by Blaskovics and further by Fox and Smith for ectropion‐ macroblepharon to avoid splitting the lid margin. Use in the dog was first described by Munger and Carter. A. The skin incision is 2–2.5 mm below the eyelid margin and extends 5–10 mm beyond the lateral canthus. The skin flap is dissected from its deeper muscle layers. All bleeding has to be arrested. B. Equal‐sized wedges, one of lid margin conjunctiva and one of skin, are excised by scissors. C. The lid margin is apposed by a figure‐of‐eight or U‐figure 5‐0 to 6‐0 suture. If desired, the conjunctival wound can be sutured by a subconjunctival, simple continuous, 8‐0 absorbable suture. D. The skin defect is apposed by simple interrupted, 5‐0 to 6‐0 sutures. Advantages: staggering wound, less damaging to the lid margin. Disadvantage: shortens only the lower lid. Copyright Frans C. Stades.

Shih Tzu, with medial entropion, nasal folds, and caruncle trichiasis. In these breeds, the palpebral fissure measures some millimeters longer than the average 33 mm, thus easily allowing the globe to luxate but preventing spontaneous repositioning. Therefore, moderate lid shortening combined with a canthoplasty in the medial canthus is indicated (see also trichiasis of the medial canthus). The lateral canthus is most accessible, but surgical sites in this area are more apt to atrophy with time. The lack of stability and the increased movements of the lateral canthal region may also complicate these surgical procedures by causing greater short‐term stress on the suture line and long‐ term tension of the apposed eyelid tissues. For both the medial and lateral canthoplasty procedures, the goals are to reduce the stretched palpebral fissure to 33–35 mm and to provide some overlap of the tissues of the eyelids, thereby enhancing its strength. Simple, Permanent Lateral Palpebral Fissure Reduction Tarsorrhaphy

In general, the stretched lid fissure in macroblepharon‐­ ectropion measures over 40 mm. An average lid fissure measures 33–35 mm. The fissure can be shortened over the

B

C Figure 15.41  Kuhnt–Szymanowski–Helmbold procedure for ectropion. A. The lower eyelid is split at the gray line into tarsoconjunctival and skin–orbicularis oculi muscle layers to a depth of 10–15 mm. B. Identical wedges of tarsoconjunctiva and of skin–muscle are excised. C. The tarsoconjunctival defect is apposed with simple interrupted, 5‐0 to 6‐0 absorbable sutures. The skin– muscle layer is apposed with simple interrupted, 5‐0 to 6‐0 sutures. The lid margin wound is apposed with through‐and‐through interrupted, 6‐0 mattress sutures. Advantage: staggering wound. Disadvantages: the lid margin, including the Meibomian glands, is damaged over the operated distance; procedure shortens only the lower lid and therefore is rarely used. Copyright Frans C. Stades.

surplus distance. The free outer lid margin and the tarsal “plate,” including the Meibomian glands, are removed over the measured distance (Fig. 15.42 and Fig. 15.43). Closure is more secure if the conjunctiva is sutured separately (Fig. 15.33D). The method is the most simple, but it lacks the

15: Diseases and Surgery of the Canine Eyelid

953

x ≥40

33+x 1

2

B A

B

C

D

SECTION IIIA

A

3

C

D

Figure 15.42  Simple lateral (or medial) permanent tarsorrhaphy for macroblepharon-ectropion correction. A. In general, the stretched lid fissure in macroblepharon measures more than 40 mm. B. An average lid fissure measures 33–35 mm. The fissure can be shortened over the surplus distance (X). The lid margin is split by scalpel, and a pocket is made by tenotomy scissors to a depth of 3–5 mm. If the procedure is performed in the medial canthus, the lacrimal canaliculi and punctae must be avoided. C. The pigmented outside of the upper and lower lid margins is excised. D. Thereafter, the inside upper and lower margins with their Meibomian glands are excised. Advantage: removal of Meibomian glands and outer free rim of the lid margin. Copyright Frans C. Stades.

double‐­layered, staggered wound, which prevents leakage and wound dehiscence. The procedure is possible, but less desirable in the medial canthus. Permanent Lateral Palpebral Fissure Reduction Plasty (Modified Roberts–Jensen Pocket Procedure)

The original procedure by Jensen (1979) was described for the medial canthus; however, it may also be employed for the lateral canthus. The procedure starts with the removal of the medial or lateral upper lid margin and the inside margin plus Meibomian glands, as described in the simple palpebral fissure reduction tarsorrhaphy (Fig. 15.45). If performed in the medial canthus, the upper punctum is lost during the procedure. A flap of upper conjunctiva is pulled downward into the pocket in the lower lid between the conjunctiva and muscle–skin layers and anchored. The method is simple, provides a double‐layered, staggered wound, and prevents leakage and wound dehiscence. The procedure, as described by Jensen, is used in the medial canthus and also results in loss of the upper lacrimal punctum. It has the advantage of concurrent correction of medial lower entropion and protection from nasal folds in Pekingese, Shih Tzu, Pug, and similar breeds. It has the disadvantages of being more complicated and of the loss of the

33–35 mm

E

F

Figure 15.43  Simple lateral or (medial) lower plus upper lid fissure length reduction or permanent tarsorrhaphy for macroblepharon‐ectropion correction. Suturing methods. A. Wounds after removal of the outside lid margin and the inside margin plus Meibomian glands. B. Apposition of the new lateral canthus by a (1) figure‐of‐eight, 5‐0 to 6‐0 suture and further closure by simple interrupted sutures (2, 3). The ends of the sutures can be linked or gathered together in the outer‐placed suture to prevent irritation of the cornea (see also Fig. 15.8). C. The conjunctiva can be apposed by a simple continuous, 6‐0 to 8‐0 absorbable suture. C, D. The new lateral canthus and the remaining skin wound can be closed as shown in B or D. If the lid fissure length is shortened over X mm, the lid fissure after suturing should measure approximately 33–35 mm. E, F. Advantages: simple and effective; shortens both upper and lower lid margins. Disadvantages: no staggering wound, no extra lateral traction/anchoring. Copyright Frans C. Stades.

upper punctum. However, as the functioning of the tear ducts in these short‐nosed breeds is questionable, the loss generally does not result in (more) epiphora. Permanent Lateral Palpebral Fissure Reduction Plasty, Fuchs Procedure

The lateral canthoplasty, modified from Fuchs, provides a strong, permanent union at the lateral canthus by rotating a section of lower eyelid skin and orbicularis oculi muscle into a lateral upper lid defect (Kuhnt & Szymanowski, 1976;

Section IIIA: Canine Ophthalmology

SECTION IIIA

954

A

B

Figure 15.44  A. Pronounced lower lid macroblepharon‐ectropion (diamond‐shaped fissure) in a German Dog (Great Dane). The stretched fissure length was 49 mm. There is also severe medial and lateral entropion and a notch or kink in the lower lid margin. B. The postoperative result in the same dog. The stretched fissure length was shortened over 16 mm to 33 mm. There is some swelling of the lower lid conjunctiva, and the “notch” appeared to be a kink and did stretch nicely. Courtesy of Frans C. Stades.

Fig.  15.46). The larger surgical surface area provides a stronger union for the permanent lateral canthoplasty. The procedure starts with the removal of the outside lid margin and the inside margin plus Meibomian glands, as described in the simple palpebral fissure reduction tarsorrhaphy. The procedure is possible but less desirable in the medial canthus. Permanent Lateral Palpebral Fissure Reduction Plasty, Wyman and Kaswan Procedure

The procedure starts with the removal of the outside lid margin and the inside margin plus Meibomian glands, as described by Kaswan et al. (1988) in the simple palpebral fissure reduction tarsorrhaphy (Fig. 15.47). A double‐­layered, staggered wound is made. In contrast to the Fuchs method, the inner conjunctiva layers, in the modified Wyman and Kaswan method, are closed by a simple, continuous, absorbable suture. This method creates a double‐layered, staggered wound, preventing leakage and wound dehiscence. The procedure is possible but less desirable in the medial canthus. Permanent Lateral Palpebral Fissure Reduction Plasty, Kuhnt–Szymanowski Procedure

In this procedure, modified by Bedford (1998), the desired length of reduction is removed in the lateral lower and upper lid instead of reducing the lower lid length in the area of the most extensive ectropion in the middle (Fig. 15.48). The lateral lower skin flap provides further lifting and lateral fixation. Results from a series of 22 dogs collected over a period of 6 years demonstrated an overall improvement, but 5 of the dogs required further resection of redundant forehead skin.

Permanent Lateral Palpebral Fissure Reduction Plasty and Stabilizing the Lateral Canthus Procedure

This procedure, in which the lower lid is shortened over 2–6 mm and the lateral canthus area is removed full‐­ thickness, has been described mainly for the correction of entropion, but it has also been advocated for the correction of ectropion‐macroblepharon. For more details, see “Surgery for Entropion Combined with Shortening of the Lower Lid” (Gutbrod & Tietz, 1993; see Fig. 15.31). Macroblepharon‐Ectropion and Entropion Correction, Reducing Lower and Upper Lid Length plus Repositioning and Fixation of the Lateral Canthus Laterally

In combined macroblepharon‐ectropion‐entropion, the procedures for correction of lateral entropion may be insufficient, because they stabilize the lateral canthus but do not reduce the palpebral fissure and/or do not fixate the lateral canthus laterally, as required, for example, in the diamond‐ shaped lid fissures of the giant breeds of dogs. These more recently developed surgeries shorten the lid fissure and attempt to stabilize the lateral canthus laterally, thereby correcting the lateral entropion. In the Bigelbach (1996) procedure, the lower and upper eyelids can be shortened 20%–25% and attempts made to correct entropion and stabilize the lateral or medial canthus (Fig. 15.49). A trapezoid‐shaped section of skin and orbicularis oculi muscle is excised from the lateral canthus. Interrupted sutures anchor to the deep fascia–­lateral ligament, thus fixing the lateral canthus. The procedure has been recommended in large and giant breeds of dogs and in principle is possible in the medial canthus.

A

A

B

C B

C Figure 15.45  The Roberts–Jensen pocket method for lid fissure length reduction by permanent medial or lateral tarsorrhaphy. A. The procedure starts with the removal of the outside lid margin and the inside margin plus Meibomian glands. If performed in the medial canthus, the upper lacrimal punctum is incised in the procedure. B. A flap of upper conjunctiva is pulled downward into the pocket in the lower lid between the conjunctiva and muscle– skin layers and anchored through the muscle–skin by a simple interrupted, 5‐0 suture. C. Apposition of the new lateral or medial canthus by a figure‐of‐eight, 5‐0 to 6‐0 suture, and further closure by simple interrupted sutures. Advantage: effective, especially in Pekingese, Shih Tzu, Pug, and similar breeds. Disadvantages: more complicated; loss of upper punctum if performed medially, although the functioning of the tear ducts in these short‐nosed breeds is questionable. Copyright Frans C. Stades.

Figure 15.46  Lateral canthoplasty (Fuchs modification) method for lid fissure length reduction by permanent lateral tarsorrhaphy. The procedure starts with the removal of the outside lid margin and the inside margin plus Meibomian glands, as described in Fig. 15.42. A. A triangular flap of muscle–skin of 5–7 mm wide is removed. The lower lid skin–muscle is incised over 5–7 mm. B. The lower flap is sutured to the upper conjunctiva by a simple interrupted, 6‐0 suture. C. Apposition of the new lateral canthus by a figure‐of‐eight, 5‐0 to 6‐0 suture and further closure by simple interrupted sutures. Advantage: shortens both upper and lower lid margins. Disadvantages: no extra lateral traction/anchoring; less effective and more complicated. Copyright Frans C. Stades.

Reduction of Lower and Upper Lid Length plus Repositioning and Fixation of the Lateral Canthus Laterally: Stades Procedure

In this technique, two full‐thickness wedges (approximating the length of the required lid fissure shortening) are excised, and the new lateral canthus is apposed by a figure‐of‐eight, 5‐0 to 6‐0 absorbable suture anchored laterally in the lateral ligament and skin (Fig. 15.50). Reduction of Lower and Upper Lid Length plus Repositioning and Fixation, by Traction Suture of the Lateral Canthus Laterally

This procedure is especially suitable for palpebral fissure length reduction and lateral canthus replacement in giant breeds (Grussendorf, 2004). The redundant length of lid margin is removed, up to a third of the lid length (as shown in Fig.  15.51). An additional lateral skin incision is made

955

SECTION IIIA

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956

Section IIIA: Canine Ophthalmology

Prognosis and Prevention

The prognosis for correction of ectropion‐oversized palpebral fissure, although dependent on the cause, is usually good. Parents and siblings should also be examined, and affected animals should not be used for breeding. Breeding should aim for closed lids with fissures of normal length and also for ears of normal weight and placement. B

SECTION IIIA

A

C

D Figure 15.47  Lateral canthoplasty (Wyman and Kaswan modification) procedure for lid fissure length reduction by permanent lateral tarsorrhaphy. The procedure starts with the removal of the outside lid margin and the inside margin plus Meibomian glands. A. A triangle of skin–muscle 5–7 mm deep is removed. The opposite lid skin–muscle is incised over 5–7 mm. B. Below that area, the conjunctiva is excised. C. The lower and upper conjunctivae are apposed by a simple continuous, 6‐0 to 8‐0 absorbable suture (knot, subconjunctivally). D. The skin– muscle flap is apposed in the new lateral canthus by a figure‐of‐ eight, 5‐0 to 6‐0 suture and further closed by simple interrupted sutures. Advantage: shortens both upper and lower lid margin. Disadvantages: no extra lateral traction/anchoring; less effective and more complicated. Copyright Frans C. Stades.

some 2 mm behind the orbital ligament. The new canthus is created using a figure‐of‐eight suture. A nonabsorbable traction suture connected to the orbital ligament replaces the lateral canthus until the lid fissure reaches a normal appearance. The surplus skin triangles are then removed. Postoperative Treatment

Therapy after ectropion‐oversized lid fissure procedures consists of applying topical initial choice antibiotic ointment (more lubricating than drops) four times daily for 14 days. Systemic antibiotics may be indicated for extensive procedures. An Elizabethan collar is used routinely to prevent the patient from rubbing the surgical site and producing local irritation and even suture loss. The sutures are removed 12–16 days after surgery. The end result can be judged only after cicatrization, about 6–8 weeks after surgery.

Microblepharon, Blepharophimosis, or Blepharostenosis An abnormally small or narrowed palpebral fissure, which is referred to as microblepharon, blepharophimosis, or blepharostenosis, is not only seen particularly in miniature breeds like the Miniature Pinscher and Shetland Sheepdog, but also in larger breeds such as the English Bull Terrier, Chow Chow, Kerry Blue Terrier, and both Rough and Smooth Collies (Fig. 15.52). The entity should not be confused with a spasm of the orbicular muscle caused by entropion or other chronic corneal pain. Before enlarging the fissure in such patients, the stretched palpebral fissure should be measured using calipers after topical anesthesia, or for best results under general anesthesia. In microblepharon, the globe is usually of normal size, but it may accompany microphthalmos. The stretched palpebral fissure is usually 5–10 mm shorter than the normal fellow eye or the normal eye of a sibling. Microblepharon is often accompanied by upper lid entropion. However, if the lid fissure is surgically lengthened in these patients, the entropion disappears without further specific correction. The condition has no direct significance to the patient unless it predisposes to entropion and associated ocular surface disease. Patients with microblepharon and related dogs should not be used for breeding. Therapy

Correction is achieved by a lateral augmentation canthoplasty that increases the functional length of the palpebral fissure (Fig. 15.53). The stretched palpebral fissure is measured by calipers. A 5 to 10 mm long lateral canthotomy is created using tenotomy scissors. Two small arrowhead skin resections will achieve a more gradual transition to the newly ­created lid “margin.”

Trichiasis Trichiasis is the presence of normally located but abnormally directed hairs that irritate the opposite lid margin, the globe, conjunctiva, or both. The chronic corneal irritation results in extra lacrimation, blepharospasm, and mucopurulent conjunctival discharge. When hairs contact the cornea, corneal disease is common. The lesions are often healed by granulation tissue, but they may also deepen until

15: Diseases and Surgery of the Canine Eyelid

d

957

d b

b

f a

e

a

e f

B

c

SECTION IIIA

A d

d

b

c

f b

e

a

e

a f c

C

D

Figure 15.48  Lateral canthoplasty (Kuhnt–Szymanowski modified by Bedford) procedure for lid fissure length reduction by permanent lateral tarsorrhaphy. A. A lid split (a–f) is made, and following the curvature of the lower eyelid, a skin incision is constructed to (d) and downward to (e). This outer lid margin skin–muscle flap is bluntly dissected by tenotomy scissors from its underlying tarsoconjunctival– subcutaneous tissues. B. A triangle of lower eyelid margin–tarsoconjunctiva is excised for a distance that approximates the length of the desired lid shortening. The outer lid margin (a–f) is not removed. C. The skin flap is shortened (c–e), using scissors, over the same length. D. Apposition of the new lateral canthus by a figure‐of‐eight, 5‐0 to 6‐0 suture and further closure by simple interrupted sutures. Advantages: shortens both upper and lower lid margin; provides lateral anchoring. Disadvantages: no extra lateral traction; more complicated. Copyright Frans C. Stades.

­ erforation occurs. The final stage is the formation of scar p tissue and pigmentation, or sometimes even the loss of the eye (Stades et al., 1993). Trichiasis is usually corrected surgically. Trichiasis occurs mainly in (1) nasal folds; (2) the upper eyelid, usually dorsolaterally; and (3) in combination with entropion in the same area (Fig. 15.54). In brachycephalic breeds with exophthalmia, such as the Pekingese, Shih Tzu, and Lhasa Apso with exophthalmic eyes, the caruncle hairs may also irritate the globe and contribute to epiphora. Less frequent hairs in nonpredilection locations around the lid fissure (e.g., in dysplasia or lid colobomata) are misdirected and irritate the globe. Also, poorly healed lid lacerations or blepharoplasties may result in trichiasis. Trichiasis occurs in several dog breeds as a hereditary, most likely polygenic entity and is a desired characteristic in some breed standards.

Nasal Fold Trichiasis Because of breed standards and fashions that disregard the animals’ health but are nevertheless supported by breeders,

judges, and buyers alike, almost all eyes of prominent‐eyed breeds (e.g., Pekingese, Shih Tzu, and Lhasa Apso) are chronically irritated, have corneal disease, and are predisposed to proptosis or luxation. For example, breed standards, which most veterinarians do not agree with, require that the Pekingese should have a short muzzle with a marked stop and heavily wrinkled skin with long and straight hairs, and also that it should have large and protruding eyes. In most patients, it is found in combination with medial entropion, caruncle trichiasis, a slightly oversized lid fissure, and lagophthalmos. Dogs with nasal folds were nearly 5 times more likely to be affected by corneal ulcers than those without, and brachycephalic dogs (craniofacial ratio < 0.5) were 20 times more likely to be affected than nonbrachycephalic dogs. A 10% increase in relative eyelid aperture width more than tripled the ulcer risk. Exposed eye‐white was associated with a nearly three times increased risk (Packer et al., 2015). These breeds often develop recurrent mediocentral corneal ulcerations that have the potential to progress and even perforate. The blink reflex may be weak and incomplete, resulting in a thin precorneal tear film on the center of the cornea and increased risk of epithelial loss.

958

Section IIIA: Canine Ophthalmology d 2 mm

a

c

b

SECTION IIIA

A

B

e

A

d a

a

c

c

f

f

b

b e

C

B

D

a a f

f

b

b

E

F

Figure 15.49  Lateral canthoplasty, Bigelbach procedure, for lid fissure length reduction and lateral entropion correction by permanent lateral tarsorrhaphy. In this lateral tarsorrhaphy‐ canthoplasty method, a trapezoid‐shaped section of skin and orbicularis muscle is excised from the lateral canthus. A. Two 2 mm scalpel incisions (a, b) are made perpendicular to the upper and lower eyelid margins. They mark the extent of the lid shortening. B. A curved skin incision is extended from the lateral canthus following the curvature of the lower eyelid to (d). Similarly, a skin incision is performed from the lateral canthus following the curvature of the upper eyelid to (e). An additional skin incision is made between (d) and (e). This skin triangle is excised. C. Two upper and a lower lid, full‐thickness triangles of adc and bec are excised. D. A trapezoid area remains. E. The new lateral canthus is apposed by a figure‐of‐eight, 5‐0 to 6‐0 nonabsorbable suture. F. Further closure is by interrupted sutures anchored in the deep fascia–lateral ligament. Advantages: shortens both upper and lower lid margin; provides lateral anchoring. Disadvantages: no extra lateral traction; more complicated. Copyright Frans C. Stades.

The hairs on the nasal fold, the caruncles, and the medial entropion are potential sources of irritation to the conjunctiva, including the nictitating membrane and the medial quadrant of the cornea, resulting in excessive lacrimation, slight blepharospasm, corneal edema, vascularization, pigmentation, and other corneal defects. The final stage is

C Figure 15.50  Lateral canthoplasty (Stades Diabolo) method for lid fissure length reduction by permanent lateral tarsorrhaphy. A. Two full‐thickness lid wedges (approximating the length of the required lid fissure shortening) are excised. B. The new lateral canthus is apposed by a figure‐of‐eight, 5‐0 to 6‐0 absorbable suture anchored in the lateral ligament–skin. C. Further closure of the wound by simple interrupted sutures. Advantages: shortens both upper and lower lid margin; provides lateral anchoring. Disadvantages: no extra lateral traction; more complicated. Copyright Frans C. Stades.

medial pannus formation with accompanying pigmentation, which may ultimately cover the entire cornea. Additionally, the prominent eyes and associated lagophthalmos result in drying of the axial cornea and erosion of the epithelium. Some of these dogs sleep with the central cornea exposed. Ulcers (rounded, craterlike) in these breeds resulting from this insult (without being noticed by the owner) often become lytic and progress to descemetocele within 24 hours. They may rupture during excitation, which results in pain reactions like whining and moaning and is often interpreted by the owner as trauma caused by a cat or dog fight. Traumatic defects, however, are usually scratch shaped. Finally, they may end in severe central corneal scarring, often with anterior synechia or even the loss of the eye. The retention of topical rose Bengal by the central cornea suggests this region is at risk for ulceration and confirms the lagophthalmos.

15: Diseases and Surgery of the Canine Eyelid

c LIG. ORB

OR BIT AL L

a d f

b e

b

A

B

C

D

c a

f

b e

Figure 15.51  Lateral canthoplasty, Grussendorf procedure for lid fissure length reduction including lateral entropion, mainly in giant breeds, by permanent lateral tarsorrhaphy and lateral canthus repositioning by a traction suture. The redundant length of lid margin, up to one‐third of the lid length, is removed. A. A further lateral skin incision is made some 2 mm behind the orbital ligament. B. The new canthus is created, using a figure‐of‐eight suture. A nonabsorbable traction suture connects the lateral canthus to the orbital ligament until the lid fissure reaches a normal appearance. The surplus triangles of skin (acd and bef) are removed. C. The four wound angles are sutured together using a U‐figure suture. D. Further closure of wounds by simple interrupted sutures. Advantages: effective in diamond‐ shaped eyes; shortens both upper and lower lid margins; provides lateral anchoring and extra lateral traction as required. Disadvantages: more complicated; stretches but does not remove lid notches in breeds like the St. Bernard. Copyright Frans C. Stades.

Therapy

In cases of minor corneal disease, therapy can be started with an initial choice antibiotic and lubricating ointments, every 6 hours. If the corneal defects have healed after 10 days, the cornea may be protected by oil or a neutral ointment 2–4 times daily, adhering the hairs together, but this alone seldom resolves the problem. Removal of part or all of the nasal folds is possible, but usually is not sufficient to deal with the other deformities in these breeds. Removing the medial canthus and caruncle hairs, repositioning the medial canthus more laterally, and reducing the normal or sub‐oversized palpebral fissures may be indicated in the brachycephalic breeds with nasal fold trichiasis and exophthalmia, such as the Pekingese, Shih Tzu, and Lhaso Apso. The surgical reduction in the size of the palpebral fissure will decrease corneal exposure, the possibility for recurrent corneal ulcerations, and the risk for proptosis or luxation of the globe. Removal of Nasal Folds Figure 15.52  Microblepharon or blepharophimosis in a Miniature Pinscher puppy. The upper lid shows a high degree of entropion. Courtesy of Frans C. Stades.

Nasal folds (partial upper or complete) can simply be removed. In this operation, the fold is lifted and excised with large scissors, and the wound is closed with 5‐0 absorbable sutures (Fig. 15.55). However, this operation does not correct

SECTION IIIA

IG.

a

d

959

Section IIIA: Canine Ophthalmology

SECTION IIIA

960

A A

B Figure 15.53  Microblepharon or blepharophimosis correction. A. Often a microblepharon is combined with entropion of the upper lid. A full‐thickness lateral canthotomy is performed. The entropion will then usually correct spontaneously. Two triangles of skin, 2 mm lateral to the lateral canthus, are removed. B. The lateral canthus skin is sutured to the middle of the opposite skin wound edge, and the rest of the wounds are closed by simple interrupted, 5‐0 to 6‐0 sutures. The remaining canthotomy wounds of skin and conjunctiva are left to heal by secondary healing. Advantage: simple and effective. Copyright Frans C. Stades.

1

1 2

Figure 15.54  An eye with the two main locations of trichiasis. A. Dorsolateral eyelash hairs drooping into the lower conjunctival sac and on the cornea. B. Nasal fold hairs irritating the ventromedial quadrant of the cornea. Copyright Frans C. Stades.

the associated medial entropion or the caruncle trichiasis, and does not reduce the palpebral fissure length. Medial Canthoplasties

Many of the surgical techniques that address ectropion‐­ oversized palpebral fissure as well as the combination of entropion and ectropion also decrease the size of the

B Figure 15.55  For the treatment of nasal fold trichiasis, the nasal folds can be excised. A. The nasal folds are clamped and carefully excised by curved Mayo scissors. B. The wound edges are apposed with simple interrupted, 5‐0 to 6‐0 sutures. The first sutures are placed at the upper and lower ends and at the medial canthus, then the rest of the wounds are closed by halving the intervals. Advantage: simple. Disadvantage: ineffective. Copyright Frans C. Stades.

­ alpebral fissure and can be used in nasal fold trichiasis. p However, these procedures do not specifically remove the caruncle hairs and may be more complicated to perform in the medial canthus, with its deep “stop” of the muzzle of these breeds. Medial Canthoplasties for Brachycephalic Dog Breeds and Dogs with Medial Canthus Hair Irritation

Medial canthoplasty procedures reduce the size of the palpebral fissure, remove the caruncle hairs, and replace the medial canthus laterally, away from the nasal folds (Fig. 15.56; Stades & Boevé, 1986) and prevent medial canthal hair irritation of the conjunctiva and globe. The lacrimal puncta and canaliculi should be identified and protected during surgery. A diamond‐shaped area of skin, upper and lower lid margin, and outer conjunctiva of the nictitating membrane, including the caruncle hairs, are removed. A slightly more simplified technique has been described by

15: Diseases and Surgery of the Canine Eyelid

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SECTION IIIA

B

A

1 3 C

2 D

E

Figure 15.56  Medial canthoplasty procedure for the correction of nasal fold trichiasis. A. This technique turns the medial lid margin outward and, replacing it approximately 7 mm laterally, eradicates caruncle trichiasis and reduces the size of the palpebral fissure, which practically precludes luxation of the globe and lagophthalmic complications. B. To prevent surgical damage to the lacrimal apparatus, a well‐recognizable, 00 to 2‐0 monofilament blue Prolene suture with heat‐rounded tips may be positioned from the upper to the lower lacrimal punctum‐canaliculus via the cul‐de‐sac. C. An arrowhead‐shaped skin and medial caruncle conjunctiva area is circumcised with a scalpel. The lid margins are cleaved just before, at, or lateral to the punctae, depending on the estimated required shortening of the lid fissure. The skin and conjunctiva are bluntly dissected by tenotomy scissors. D. The remaining wound is either apposed by 1–2 single subconjunctival 6‐0 absorbable sutures (1) closing the palpebral conjunctiva, a figure‐of‐eight suture (2) closing the lid margins, and a continuous suture (3) closing the remaining skin wound; or is apposed by one continuous suture, starting deep, subconjunctivally. Special care should be taken that the suture ends do not enter the conjunctival sac and that the lid margin wounds appose perfectly. E. The sutures end medially in the skin. Advantage: simple and effective, especially in Pekingese, Shih Tzu, Pug, and similar breeds. Disadvantage: if more length is required, it is possible but more difficult to prevent damage to the puncta. However, the functioning of the tear ducts in these short‐nosed breeds is questionable. Copyright Frans C. Stades.

Yi et  al. (2006) primarily for the treatment of epiphora in dogs, in which the medial canthus upper and lower lid margins up to just 1 mm medial of the punctae, plus the haired mucosa of the caruncle, are removed (Fig. 15.57). The medial canthus is thereafter closed with a figure‐of‐eight suture and nasally an additional simple interrupted suture. Also skin cauterization and hair follicle destruction around the medial canthus in a figure of an arrowhead using a radiofrequency hyperthermia unit have been described by Lieberknecht et al. (2010), resulting in a hairless medial canthus and a lid position correction. Postoperative treatment after a medial canthoplasty consists of topical, initial choice, antibiotic ointment 4 times daily for 14 days. As a result of this operation, the medial canthus is turned outward, emerges from behind the nasal folds, and is replaced 6–10 mm laterally. Additional benefits are the removal of the caruncle hairs and the shortening of the palpebral fissure by 6–8 mm, which practically precludes luxation of the globe and diminishes lagophthalmic complications.

Upper Eyelid Trichiasis In this condition, the eyelash hairs of the lateral upper eyelid or hairs on skin folds above the eyes, in combination with

upper eye lid entropion, irritate the eye. These hairs droop over the eyes, irritating the lower conjunctiva and the cornea. Particularly in breeds such as the Bloodhound, Chow Chow, and Shar Pei (and less severely in the elderly English Cocker Spaniel and Basset Hounds), these hairs may cause serious lesions of the cornea. In these breeds, the excessive masses of frontal wrinkles press the margin of the upper eyelid inwardly onto the globe. In the Bloodhound, Basset Hound, and English Cocker Spaniel, this pressure is increased by the heavy weight of the ears when the head is turned toward the ground. The irritation results in extra lacrimation and blepharospasm, which may worsen the condition. The hairs on the upper eyelid are dark and moist, and the upper lid margin is entropic. The conjunctiva is red and swollen, and the corneal epithelium is damaged, resulting in ulceration, mainly of the upper lateral part of the cornea, and, in rare cases, the condition also leads to perforation. Finally, it often results in scarring and pigmentation. Therapy

In cases of minor irritation, the cornea may be protected by an indifferent topical ointment, oil, artificial tears, or petrolatum 2–4 times daily, but this measure alone seldom

Section IIIA: Canine Ophthalmology

with scar tissue, preventing redundant folds from reaching the globe (Fig. 15.59). Infection in the open wound has not been reported. The brow‐sling procedures (see “Redundant Skin Folds around the Eye”) can be successful in those breeds in which excessive skin folds are distorting the eyelid function (Bedford, 1990; Blogg, 1980; Kása & Kása, 1979; Kirschner, 1995; Krahwinkel & Merkley, 1976; McCallum & Welser, 2004; Stuhr et al., 1997). The removal of upper and dorsolateral folds or frontal skin or a brow‐sling procedure takes away the pressure on the lids and canthi, but has less effect on the lid margin entropion itself. It usually produces less satisfactory long‐term results because it does not eliminate the lash‐type hairs that cause the direct trichiasis irritation. The degree of correction requires a skilled hand. Recurrences, infections around the sutures and implants, and undesired scarring may cause complications.

SECTION IIIA

962

A

Prognosis and Prevention

B

C

Figure 15.57  Medial canthoplasty procedure for the prevention of medial canthal hair irritation of the conjunctiva and globe by Yi et al. (2006). A. The lacrimal puncta and canaliculi are identified and protected during surgery. B. The medial canthus upper and lower lid margins up to just 1 mm medial of the punctae, plus the haired mucosa of the caruncle, are removed. C. The medial canthus is thereafter closed with a figure‐of‐eight suture and nasally an additional simple interrupted suture. Copyright Frans C. Stades.

resolves the problem. A simple Celsus–Hotz entropion correction, as described previously, is possible although rarely sufficient. Radical excision of the upper lid skin, including the irritating, eyelash‐like hairs, and forced healing by secondary granulation (Stades method) is most useful in these cases (Fig. 15.58; Allgoewer, 2011; Stades, 1987a, 1987b; Stades & Boevé, 1987). Skin directly above the free rim of the upper eyelid margin (removing all hair follicles), up to 25 mm in width, is circumcised in the form of a “clown’s eyebrow” and superficially removed. Up to 5 interrupted 6‐0 absorbable presutures are used to divide and appose the much longer dorsal wound edge to the base of the Meibomian glands–tarsal “plate.” A continuous suture over it apposes the outer wound edge completely at that line. The remaining open part of the wound is forced to heal by secondary granulation (the owner must be warned of this before surgery). This results in an upper lid covered over approximately 5 mm

The prognosis is usually favorable. Affected animals should not be used for breeding. Parents and siblings should also be examined. The desire of breeders and judges, supported by buyers, for very short noses, a marked stop, and heavily wrinkled and abundant skin should be discouraged. Breed standards should be corrected.

Caruncle Trichiasis The caruncle normally has some short, soft hairs directed outward nasally. In brachycephalic breeds with exophthalmia, such as the Pekingese, Shih Tzu, and Lhasa Apso, the caruncle hairs may irritate the globe, resulting in medial, limbal pigmentation of the cornea and even epiphora. In rare cases, some of the caruncle hairs grow up to 10–15 mm long and irritate the cornea (Fig. 15.60). For therapy in the brachycephalic breeds, see “Nasal Fold Trichiasis.” In the other cases, the hairs can be epilated first to be sure they are the cause of the irritation. They can be removed permanently by destroying the hair follicles using electro‐, laser‐, or cryodestruction. See the therapy section under “Distichiasis and Conjunctival Ectopic Cilia.”

Trichiasis in Other Locations Infrequently, hairs in nonpredilection locations around the lid fissure or in dysplastic areas are misdirected and irritate the conjunctiva, globe, or both. For therapy, the hairs can be epilated first to make certain they are the cause of the irritation. If the area is more than 2–3 mm away from the lid margin, the area can be circumcised and removed, and the wound closed by one or two sutures. If the hair follicles are located within 2 mm of the free rim of the lid margin, the Celsus–Hotz principle will usually result in recurrent

15: Diseases and Surgery of the Canine Eyelid

B

C

D

SECTION IIIA

A

963

Figure 15.58  A. Upper eyelid trichiasis‐entropion and redundant skin folds: Stades forced granulation procedure. B. The first incision is located 0.5 mm from and parallel to the margin of the eyelid, care being taken not to injure the Meibomian glands. A piece of skin up to 25 mm (usually where the first fold above the eye ends in a sulcus) in width is circumcised in the form of a “clown’s eyebrow” and superficially removed by blunt dissection. If the trichiasis is combined with distichiasis, the now visible follicles should be scraped away or destroyed by cautery. C. The dorsal edge of the wound is reattached at a distance of 4–5 mm from the margin of the eyelid by three to five simple interrupted sutures (absorbable 6‐0, round‐body needle), at the base of the Meibomian glands–tarsal “plate” (and not closer to the lid margin). D. A continuous suture apposes the outer wound edge completely at that line, forces the remaining open wound to heal by secondary granulation (the owner must be warned of this before surgery), and rotates the lid margin upward. After further scarring, the upper lid is covered by hairless scar tissue, which becomes pigmented after a few months. Advantages: simple and very effective. Disadvantages: no effect on the medial canthus; open wound directly after surgery; visible scar. Copyright Frans C. Stades.

A

B

Figure 15.59  A. Preoperative appearance of a 6‐week‐old Chow Chow puppy with upper eyelid trichiasis‐entropion and redundant skin folds. B. Postoperative appearance of the same Chow Chow puppy, 3 weeks after a Stades forced granulation procedure. The wound has healed by secondary granulation. The upper lid skin can no longer reach the conjunctiva or globe. Courtesy of Frans C. Stades.

Section IIIA: Canine Ophthalmology

SECTION IIIA

964

A

Figure 15.60  Elongated caruncle hairs in the medial canthus of a dog. Courtesy of Frans C. Stades.

trichiasis. In this case, the Stades (1987a, 1987b) forced granulation procedure (Fig. 15.61 and Fig. 15.62), electro‐, laser‐, or cryodestruction, is indicated for therapy. See also the therapy section under “Distichiasis and Conjunctival Ectopic Cilia.”

Secondary Trichiasis Poorly healed lid lacerations and blepharoplasties that involve reconstruction of the lid margin may result in trichiasis. Usually, one or more hair follicles are misdirected because of scarring. In blepharoplasties, the leading edge of pedicles can easily be inverted by traction of the faster‐­ healing conjunctiva on the inside and on the nonprecise apposed and sutured transition of the graft to the normal lid margin. This should be prevented by cutting the free edge in a nonundermining way, preventing any traction on the leading edge, the use of relaxation sutures, and having the leading edge of the graft bulge slightly within the lid margin contour. The hair follicles can be destroyed (e.g., by cryodestruction), or the scarring notch with the hair follicles must be removed and the wound closed with great care. In severe cases, more extensive blepharoplasty has to be performed.

Trichomegaly Trichomegaly refers to abnormally elongated eyelid cilia and is most commonly observed in American Cocker Spaniels. It has no clinical significance as long as the hairs do not touch the conjunctiva or cornea.

B Figure 15.61  Medial canthus or any other displaced trichiasis hairs very near the lid margin (no space for Celsus–Hotz procedure) can also be removed or repositioned by the Stades forced granulation procedure. A. The trichiasis area is circumcised and removed. B. The outer wound edge is dissected over 3–5 mm and anchored to the subdermal muscular layers by a simple continuous, 6‐0 absorbable suture. Advantages: simple and very effective. Disadvantages: open wound directly after surgery; visible scar. Copyright Frans C. Stades.

Redundant Skin Folds around the Eye Redundant skin folds around the eye, complicated by heavy ears, usually do not directly irritate the eye, but cause pressure on the lid margins and canthi, resulting in medial and upper lid entropion and trichiasis. In breeds such as the Bloodhound, Chow Chow, and Shar Pei, the elderly English Cocker Spaniel, Basset Hound, English Bulldog, and Pug, the wrinkles may cause serious eye problems. In the Bloodhound, Basset Hound, and English Cocker Spaniel, the problem is worsened by the heavy weight of the ear pinnae when the head is turned toward the ground. The palpebral fissure droops and masks the globe, affecting sight. There is usually entropion of both the upper and lower eyelids at the lateral canthus as well as ectropion of the central part of the lower eyelid. The nictitating membrane and the lower

965

SECTION IIIA

15: Diseases and Surgery of the Canine Eyelid

A

B

Figure 15.62  A. Operative appearance of an English Springer Spaniel with trichiasis near the medial canthus. B. Postoperative appearance (about 3 weeks) of the same dog after a Stades forced granulation procedure. Courtesy of Frans C. Stades.

­ alpebral conjunctiva are exposed, and there is impaired tear p film drainage and ocular surface disease. The irritation results in extra lacrimation and blepharospasm, which may worsen the situation. The hairs on the upper eyelid are dark and moist, and the upper lid margin is entropic. The conjunctiva is red and swollen, and the corneal epithelium is damaged, resulting in ulceration, mainly of the upper lateral part of the cornea, and in rare cases the condition also leads to perforation. Finally, it often results in scarring and pigmentation. In cases of minor irritation, the cornea may be protected from the trichiasis by an indifferent topical ointment, artificial tears, oil, or petrolatum 2–4 times daily, but this measure alone seldom Courtesy of Frans C. Stades. resolves the problem. A simple Celsus–Hotz entropion correction is rarely sufficient. In breeds such as the Pekingese, Shih Tzu, English Bulldog, and Pug, the removal of the nasal folds will relieve pressure on the medial canthus, but in most patients surgical correction by medial canthoplasty of the medial canthus is much more likely to produce an effective and durable result, and such correction should be attempted as the first option. Surgical correction of trichiasis prevents further direct irritation (Stades procedure and medial canthoplasty). However, in some cases the pressure on the direct eye adnexa still has to be relieved. The brow‐sling procedure (Fig.  15.63) in breeds like the Shar Pei can be successful (Cairó et al., 2018; McCallum & Welser, 2004; Stuhr et al., 1997; Willis et al, 1999). Recurrences, infections around the sutures, and undesired scarring may cause complications. Furthermore, entropion‐trichiasis of the lid margins superior and or inferior generally still have to

be corrected additionally. The removal of the upper lateral folds is simple, relieves direct pressure on the dorsolateral part of the eye, and “opens” the face of the patient (Fig. 15.64 and Fig. 15.65). Removal of 15–20 cm frontal skin, as in Bloodhounds and as advocated by Blogg (1980), can prevent the major wrinkles disturbing the eye. The removal of an elliptical area of skin on the forehead (rhytidectomy) running from the medial canthi to the nuchal crest, as in the elderly English Cocker Spaniel and as described by Bedford (1990), or dorsolaterally of the eye in the Neapolitan Mastiff as described by Steinmetz (2015), does “open” the face (see Fig.  15.65A). Attempts to anchor facial skin to the nuchal crest do not enjoy long‐term success. Major “facelifts” can be performed in severe cases, as described by Kása and Kása (1979), although the trichiasis‐entropion of the upper lid margin itself still has to be corrected. The latter four methods do not stop further drooping during the remaining life and do not eliminate the direct trichiasis significantly. Thus, in most patients, surgical procedures directly influencing the palpebral fissure are more likely to produce an effective and durable result, and such correction should be attempted as the first option.

Lid Trauma Trauma to the lids can be caused by materials contacting or penetrating the lid skin or directly disrupting the lids. Contact trauma to the lids (and deeper structures) may be caused by chemicals such as alkaline and acids such as

966

Section IIIA: Canine Ophthalmology

1

5 2

SECTION IIIA

3

4

B

C

A Figure 15.63  A. Redundant folds can be lifted utilizing two mersilene strip slings fixed to the temporal bone periosteum (procedure developed by Willis, Martin, Stiles, and Kirschner). Five stab incisions are made above the eye (more or less in the interfold sulci). B, C. A strip of mersilene on a straight needle is passed from incision 1, via incision 2, to the upper lid stab (3) and parallel to the lid margin to stab (4) back upward via 5, and finally is anchored in the temporal bone periosteum. Advantages: simple and effective. Disadvantages: no effect on the medial canthus; contamination may cause infection around the sling, and overcorrection may cause lagophthalmos; introduction of foreign material. Copyright Frans C. Stades.

A

B

Figure 15.64  Redundant fold correction by removal of (A) an elliptic area of the dorsum (Stellate rhytidectomy procedures; Bedford procedure; approximately 5 × 10 cm, dotted line, e.g., in English Cocker Spaniel) of the frontal skin (Blogg procedure; 15 × 20 cm, in Bloodhounds, dot‐stripe line), or (B) the primary folds dorsolateral of the eye (dot‐dot‐stripe line), stops the drooping of the skin folds above the eyes. Advantage: simple. Disadvantages: does not prevent direct trichiasis‐entropion of the upper lid margin itself; disastrous wound appearance in cases of wound dehiscence. Copyright Frans C. Stades.

­ attery acid, detergents, and quicklime, caterpillar hairs, b and snake bite poison. Alkaline and acids can cause very severe defects. Acids are slightly less dangerous because they cause precipitation of protein, which hinders a deeper penetration. Alkalis penetrate quickly and cause more severe damage. There is profuse, diffuse edema and there may be hemorrhagic defects and depigmentation (Busse et al., 2015).

The owner must irrigate the eye immediately, preferably with liberal amounts of lukewarm tap water, or any other water available. The first seconds/minutes are by far the most important. In the case of a distinct alkali burn, vinegar or boric acid solutions may be useful. After local anesthesia, the veterinarian can then irrigate the eye for 5–10 minutes with lukewarm 0.9% sodium chloride solution (1–2 L). The conjunctival sac should be examined for possible residues of the injurious material. Aftercare consists of initial choice antibiotics and topical anti‐inflammatory agents. Parenteral antiprostaglandins and corticosteroids may be necessary. In caterpillar trauma, the removal of the hairs by saline hydropulsion and medical treatment by anti‐inflammatory drugs was successful in almost all cases (Costa et al., 2016). In snake bite trauma, blepharoedema, blepharospasm, chemosis, and conjunctival hyperemia occurred in all cases, regardless of the bite location (periocular or ocular). In most cases the clinical signs resolved quickly with symptomatic topical medications and antivenin therapy. However, severe complications such as blindness did occur (Martins et al., 2016). Disrupting eyelid lacerations caused by dog bites, cat claws, barbed wire, and so on are frequent in young smaller dogs and require surgical repair. Eyelid lacerations may be divided into partial and full‐thickness, marginal and ­nonmarginal, and may include the lacrimal canaliculi. Eyelid and conjunctival sac wounds are often right‐angled. Because eyelids are highly vascular, they will usually bleed  heavily. The extensive vascularity also protects

967

SECTION IIIA

15: Diseases and Surgery of the Canine Eyelid

A

B

Figure 15.65  A. Preoperative appearance of a Chow Chow with a redundant lateral facial fold. B. Postoperative appearance of the same Chow Chow after removal of these folds. Courtesy of Frans C. Stades.

against ­tissue ischemia and necrosis. If the lid edge is transected, the defect will enlarge spontaneously in the lid via contraction of the orbicularis oculi muscle. Lid healing by secondary intention may result in considerable fibrosis and distortion of the eyelids and lid margin, which may eventually require surgical correction. Injuries at a 90° angle to the eyelid margin have a greater potential to affect eyelid function and cosmesis than do injuries parallel to the lid margin. Wounds in the eyelid should therefore always be sutured directly, even if they are more than 8 hours old. Hair along the wound edges can be clipped. Both the wound in the lid and the wound in the conjunctival sac must be very thoroughly irrigated. A water pick is an excellent method of providing irrigation and wound debridement. Mechanical wound debridement should be kept to a minimum. Loose parts (over 1 mm), especially of the lid margin, should not be excised but used to fill the defect. Reapposition of severely traumatized eyelids usually yields better postoperative results than the excision of still attached but lacerated lid tissues and subsequent reconstructive blepharoplastic surgical procedures. Sutures at the eyelid margin should have their knots external to the free rim of the lid margin to avoid contact with the cornea. Two layers of sutures may be used in sterile wounds. In contaminated wounds, conjunctival drainage is desirable. The deeper palpebral conjunctiva and tarsus can be closed by simple continuous, 6‐0 to 8‐0 absorbable suture. Knots should be avoided or placed beneath the conjunctiva. The skin, together with the orbicularis oculi muscle, is

closed using simple interrupted, 5‐0 to 6‐0 nonabsorbable monofilament sutures. Absorbable material may be used in aggressive or anesthesia‐risk patients. The wound in the eyelid margin must be apposed very precisely with a figure‐of‐eight or mattress (only in thick lid margins) suture. The Meibomian gland openings or gray line are used as a guideline for precise realignment. Horizontal or vertical mismatching (see Fig. 15.9 and Fig. 15.10) of the two parts of the lid margin is unacceptable. Small defects in the conjunctiva rarely have to be sutured. After the lid margin has been closed, the most conspicuous points of the wound (e.g., angles) are brought together with simple interrupted sutures. The remaining parts of the wound are then closed by dividing into halves. The maximal distance between sutures should not be more than 2 mm.

Lacerations of the Medial Canthus, Including the Lacrimal Canaliculus Lacerations of the medial canthus are rare. They are usually in the lower lid and are accompanied by laceration of the lower lacrimal duct. The canaliculi are located in the swollen wound by intubation and injecting sterile saline and/or air. An S‐shaped 000 probe or Worst pigtail probe, preferably with an eye in the tip, is introduced via the upper punctum into the wound (see Chapter  16). A 0.7–1.3 mm diameter circular silicone tubing is used to appose the edges of the canaliculus wounds. The skin wound is closed as described previously. The tubing is left in place for at least 2–4 weeks.

SECTION IIIA

968

Section IIIA: Canine Ophthalmology

Lacerations with Loss of Tissue

Inflammation

When there is loss of tissue at the margin of the lid, retraction will enlarge the defect even more. If reconstructive blepharoplasty cannot be performed directly, one or two relaxation sutures should be inserted. Cutting into the tissue by the sutures should be prevented by the use of pieces of silicone or infusion tube. If possible, a blepharoplasty should be performed directly. The house‐inverted triangle method is appropriate for closure of a small but deeper defect. Broad, shallow defects should be corrected by an H‐plasty. Even larger defects can be closed by rotating, sliding, Z‐, or other blepharoplasties.

Inflammation of the eyelids may be restricted to one eye or both or may be associated with a generalized dermatologic disease. They may involve only certain glands of the eyelids or involve the entire lid surfaces. Eyelid margins without macroscopic evidence of ocular disease may frequently show histopathologic signs of inflammation, for example blepharitis, meibomitis, or perifolliculitis (64.6%), or even of developing adenomas and melanocytomas (6.4%). The clinical relevance of these changes is not yet understood (Eule et al., 2010).

Generalized Blepharitis Aftercare

After surgical repair, the aftercare consists of topical initial choice antibiotic ointment onto the eye and the wound. Some clinicians avoid topical therapy and administer antibiotics only parenterally, and some do both. If contamination is evident and concern about bacterial infection is present, culture and sensitivity tests are indicated. The progression of healing should be evaluated and treatment modified as necessary.

Ptosis Ptosis is the drooping of the upper eyelid. It may be a consequence of disorders of the third nerve or sympathetic innervation, as in, for example, Horner’s syndrome. The cause of the lagophthalmos should be determined and, if possible, treated.

Lagophthalmos Lagophthalmos is an inability to close the eyelids completely. It may be a consequence of disorders of the facial nerve that lead to paralysis of the orbicularis oculi muscle, or it may be congenital in the prominent‐eyed breeds (Pekingese, Shih Tzu, Lhasa Apso, Pug, French Bulldog, and other breeds), as previously described. If lagophthalmos persists, it predisposes to exposure corneal desiccation, resulting in vascularization, granulation, pigmentation, and recurrent ulcerations. Lagophthalmos should be treated medically as a keratoconjunctivitis sicca or by temporary tarsorrhaphy (see “Miscellaneous Eyelid Procedures”) until the cause of the lagophthalmos is found and, if possible, cured. If it is evident that temporary therapy is not sufficient, the lid fissure can be shortened permanently (see “Trichiasis,” “Medial Canthoplasties”). Medical stimulation of tear formation may also be helpful.

Blepharitis covers a number of inflammatory conditions of the eyelid, often the primary cause being masked to some extent by possible secondary complications. The inflammation may be focal or diffuse with variable involvement of all four eyelids or one or both eyes. Because the eyelids are highly vascular structures, hyperemia and edema are usually marked. Pain is indicated by blepharospasm and excessive lacrimation with epiphora, which may be worsened by self‐ induced trauma. In addition, there may be exudate, evidence of self‐trauma, alopecia, erosion, and scaliness. Chronic inflammation can lead to eyelid distortion, with both entropion and ectropion resulting from cicatrix formation and secondary corneal and conjunctival diseases. The causes of generalized blepharitis include sebaceous overproduction, bacteria, parasites (especially demodex and scabies), leishmania, fungi, flies, and ticks. Bacterial Blepharitis

In puppies, a purulent blepharitis occurs as part of juvenile pyoderma or puppy “strangles.” The entire skin of the head may be involved with multiple abscesses, usually caused by Staphylococci spp. Pain and complicating self‐trauma to the face may require an Elizabethan collar. High levels of systemic antibiotics (based on culture and sensitivity) and corticosteroids usually resolve the condition. Topical initial choice or sensitivity test–based specific antibiotics are used to help lubricate and protect the cornea. Staphylococci and Streptococci spp. are most commonly involved in bacterial blepharitis in adult patients (Fig. 15.66). Bacterial blepharitis may be presented as a diffuse superficial lid inflammation, pyogranulomas of the lid subcutaneous tissues, and meibomianitis (discussed later in this section). Acute diffuse blepharitis is characterized by hyperemia, lid swelling, and crusting. Over several weeks, ulceration of the eyelid skin and margins, alopecia, and fibrosis with the development of entropion, ectropion, or a combination of both develop. Abscessation and impaction of the Meibomian glands may also occur. Systemic and topical

Figure 15.66  Chronic staphylococcal blepharitis in an adult dog. Courtesy of Kirk N. Gelatt.

Figure 15.67  Eyelid pyogranulomas of the upper lid and lateral canthus in a Miniature Poodle. Courtesy of Kirk N. Gelatt.

­ phthalmic antibiotics (applied directly to the eyelid skin) o based on culture and sensitivity are indicated. Staphylococcal infections may also involve the deeper parts of the lids and present as single or multiple pyogranulomas (Fig. 15.67; Barrie & Parshall, 1979; Chambers & Severin, 1984; Sansom et al., 2000). Diagnosis is established by histopathologic examination, which reveals microabscesses. Pyogranulomatous blepharitis is treated with systemic and intralesional antibiotics. Because staphylococcal toxins may have a necrotizing effect, topical corticosteroids may be beneficial. Autogenous vaccine can be effective in chronic and seemingly resistant staphylococcal infections (Chambers & Severin, 1984).

and pruritus, and often complicated by secondary bacterial infection and self‐trauma (Mueller, 2004; Shipstone, 2000). Demodex canis is considered to be a normal inhabitant of hair follicles, sebaceous glands, and sweat glands, and disease may develop only when large numbers of the parasite are present in the presence of immunosuppression or possible inherited T‐cell deficiency. In young dogs, the disease tends to be restricted to the face, and eyelid involvement is common (Fig.  15.68). Spontaneous regression is expected, but topical rotenone ointment or isofluorophate ophthalmic ointment can be used to good effect. In older dogs, a more generalized disease is seen, which often proves resistant to treatment. Sarcoptes scabiei var. canis infection causes intense pruritus, several parts of the body being classically involved in addition to the eyelids. Oral treatment with fluralaner or spot‐on treatment with imidacloprid/moxidectin is currently considered as a highly effective initial choice therapy. Cuterebra infestation has been reported in the conjunctiva of a puppy (Rosenthal, 1975). Cuterebra spp., order Diptera, family Cuterebridae, is a larva of the rabbit or rodent bot fly. Larva involving the lid probably enters the conjunctiva or lid surface; wounds can facilitate penetration. Larva requires about 4 weeks to develop with black cuticular spines, often within a thick‐walled abscess and an identifying entry hole. Eventually, the larva pupates and exits the host. Presence of a drainage tract should alert the client to the possibility of Cuterebra infestation. Therapy is larva removal, and topical and systemic antibiotics.

Mycotic Blepharitis

Blepharomycosis is uncommon, but infection with Microsporum and Trichophyton spp. is seen as part of a generalized problem in young dogs. Expanding alopecia, scaling, and hyperemia are the clinical features, and diagnosis is confirmed by staining skin scrapings with either Gram’s or Giemsa stain or culturing the organisms on Sabouraud’s agar. Effective antifungal therapy may include povidone‐ iodine scrubs together with topical miconazole nitrate (preferably combined with chlorhexidine). Clotrimazole creams are effective for superficial infection, but care should be taken to avoid corneal contact. Persistent and deep‐seated infection may be treated by additionally using itraconazole or terbinafine (Moriello et al., 2017). Malassezia spp. found on the skin of dogs have been associated with blepharitis, mucoid or mucopurulent ocular discharge, or dogs that were administered topical aqueous‐based ophthalmic medications (Newbold et al., 2014). Parasitic Blepharitis

Both demodectic and sarcoptic mange can include the eyelids, the lesions being characterized by hyperemia, alopecia,

Leishmania Blepharitis

Systemic leishmaniasis, a chronic and potentially fatal disease, is endemic in countries around the Mediterranean Sea as well in India and Central and South America. In the Mediterranean region, the protozoan Leishmania infantum

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Section IIIA: Canine Ophthalmology

Figure 15.68  Superficial blepharitis associated with demodex infestation in a young dog. Courtesy of Kirk N. Gelatt.

is carried by sand flies (Phlebotomus spp.). The clinical signs of leishmaniasis are quite variable, but the eyelids are frequently involved (Di Pietro et al., 2016; Koutinas et al., 1999; Pena et al., 2000; Slappendel & Ferrer, 1998). In one report, one‐fourth of all leishmania cases had ocular or periocular disease. The eyelid lesions may vary from a dry dermatitis with alopecia, diffuse edema, and cutaneous ulcerations, to discrete nodular granuloma formations. Diagnosis is by cytologic or histopathologic examination, serology, or polymerase chain reaction testing. Antileishmania therapy includes subcutaneous N‐methylglucamine antimoniate (80 mg/kg daily for a minimum of 30 days) and allopurinol orally (10 mg/kg every 12 hours for 6–12 months). Local treatment often includes antibiotics and corticosteroids. Immune‐Mediated Blepharitis

Several autoimmune and immune‐mediated phenomena can involve the canine eyelid, either in isolation or in association with systemic clinical features, but are fortunately rare diseases (Ackerman, 1985; Halliwell, 1980; Ihrke et al., 1985; Manning et al., 1980; Marsella, 2000; Olivry & Chan, 2001; Scott et  al., 1980, 1982; Walton et  al., 1981; White et al., 1992). The pemphigus group of vesiculobullous epidermal diseases can involve mucocutaneous junctions, with inflammation and ulceration of eyelid tissue being commonly seen. In both pemphigus foliaceus, which is more common, and pemphigus erythematosus, the facial lesions usually involve the eyelids. Pemphigus vulgaris and bullous pemphigoid are more severe but uncommon types of autoimmune dermatoses, and may involve the oral cavity, nail beds, and skin in addition to ulcerative lesions of the eyelids, lips, external nares, and ears. Whereas in pemphigus the lesions are the result of autoantibody production against the intercellular matrix of the epidermis, in bullous pemphigoid these ­antibodies are directed against the epidermal basement

membrane. Hence, the resultant blister formation is observed intradermally or subepidermally, respectively, which can be confirmed by means of dermatohistopathology of skin biopsies or the finding of so‐called acantholytic cells at cytology (pemphigus only). The treatment of this disease complex requires long‐term systemic and topical corticosteroid therapy. Occasionally, the cicatricial entropion from these diseases may require corrective blepharoplasty. It is also recommended to refer such cases to a dermatologist. Medial canthal ulcerative blepharitis represents a juxtapalpebral disorder, usually affecting the medial canthus (Fig. 15.69). Breeds most often affected include the German Shepherd, Long‐Haired Dachshund, and Toy and Miniature Poodle. In the German Shepherd, the medial canthal blepharitis may be concurrent with pannus (chronic superficial keratitis) and the immune‐mediated plasma cell infiltration (plasmocytoma) of the nictitating membrane. In the Long‐Haired Dachshund, medial canthal blepharitis may occur concurrent with superficial punctate keratitis. The condition is usually bilateral. Biopsy reveals both lymphocytic and plasma cell infiltration; sebaceous glandular hyperplasia may also be present. Epithelial cell antibodies have been demonstrated in selected cases and may suggest a relation to pemphigus. The condition usually responds to topical ophthalmic antibiotics and corticosteroids. Vogt–Koyanagi–Harada (VKH), or uveodermatologic syndrome, is another immune‐mediated disease that can affect the eyelids and can be presented to veterinary ophthalmologists (Herrera & Duchene, 1998; Morgan, 1989). Often, the loss of pigmentation of the nose and eyelids is the primary clinical sign recognized by the owner and is the basis for the initial examination. Breed predisposition may be important; affected breeds include Akita, Siberian Husky, Golden Retriever, Samoyed, Rottweiler, Chow Chow, Shetland

Figure 15.69  Immune‐mediated medial canthal blepharitis in an adult mongrel German hunting dog. The dog also has bilateral chronic superficial keratitis. Courtesy of Frans C. Stades.

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971

Sheepdog, and others. Because the uveal component of VKH dominates the ophthalmic disease clinically, and the eyelid signs are a minor aspect, the reader should consult Chapter 21 for additional details. Chalazion

Hordeolum or Stye

An external hordeolum or stye is caused by suppurative infection of the Zeis or Moll glands and manifests itself as either single or multiple abscess formation along the anterior aspect of the eyelid. External hordeolum affects mainly young dogs; an individual dog may exhibit these lesions over several weeks. Affected lids are usually swollen and painful; focal abscesses occur on the eyelid surface. Treatment consists of hot compresses and topical and systemic antibiotics. During therapy, these abscesses usually rupture. Focal abscesses can be opened by scalpel or cannula incision along the swelling with curettage. In the hordeolum internum, the eyelid is also swollen and painful. The localized infection can be directly observed within the tarsal “plate,” distending the palpebral conjunctiva when the eyelid is everted. Treatment is by scalpel or cannula incision along the swelling, parallel to the margin of the lid, with curettage. The incision is allowed to heal by secondary intention. Topical initial choice antibiotic ointment is administered for 7–10 days. Focal Blepharitis, Blepharitis Adenomatosa, Meibomianitis, and External Hordeolum

Meibomianitis is inflammation of the Meibomian glands; either or both eyelids can be involved, and the condition may be unilateral or bilateral. The lid is usually swollen and somewhat painful with blepharospasm (Fig. 15.70). Eversion of the affected eyelid permits direct observation of the swollen and often enlarged Meibomian glands. Pressure on the inflamed glands frequently causes expression of exudate from the gland’s ducts along the eyelid margin. With persistent meibomianitis, bacterial culture followed by sensitivity tests and cytologic examination may guide the optimal choice of topical and systemic antibiotics. Chronic meibomianitis may result in thickened and fibrotic eyelids with either entropion or ectropion that may require later surgical correction. Chronic meibomianitis can also result in reduction or loss of the lipid layer of the precorneal tear film and a

SECTION IIIA

Chalazion is a firm, nonpainful swelling of the Meibomian gland caused by accumulation of secretion that results in chronic inflammation and a granulomatous reaction. The inflammation may predispose to a staphylococcal infection and thus hordeolum formation. Treatment is by scalpel incision along the granuloma with curettage. The incision is allowed to heal by secondary intention. Topical initial choice antibiotic ointment is administered for 7–10 days after curettage. Figure 15.70  Diffuse meibomianitis of the eyelid in a Miniature Pinscher. Courtesy of Frans C. Stades.

qualitative tear deficiency with normal levels of aqueous tear formation (as measured by the Schirmer’s tear test), but an accelerated tear film breakup time with topical fluorescein application. Treatment includes application of hot compresses, possible manual expression of the lesions under topical analgesia, and the use of both topical and systemic antibiotics. Topical and sometimes systemic, sensitivity‐ tested antibiotics and corticosteroids are administered for 14–21 days.

OTHER EYELID DISEASES Marginal Meibomian cysts are single to multiple small cystic structures that may develop along the eyelid margin. These cysts may occur more frequently in older than in younger dogs and may or may not be associated with Meibomian tumor formation. They can cause local corneal irritation. Therapy consists of manual rupture and topical antibiotics and steroids for 5–7 days. An allergic blepharitis (Fig. 15.71) is usually characterized by an acute‐onset edema and hyperemia, and may be caused by local exposure to a contact allergen or occur as part of a generalized response. Swelling of the eyelids and muzzle will be seen following insect bites (ants, ticks, fleas) and as postvaccinal reaction. Topically applied drugs may be responsible for contact allergy, with neomycin being most commonly involved. Seasonal or nonseasonal reaction to environmental allergens is seen in atopy, in which there is an inherited predisposition to immunoglobin E antibody production (Bedford, 1999a, 1999b; Marsella, 2000; Olivry & Chan, 2001). Several breeds are involved, with the West Highland White Terrier demonstrating especially high incidence. Clinical signs are manifest in young dogs usually from the age of 1 year, and

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Figure 15.71  Allergic, likely parasitic, blepharitis in a Labrador Retriever. The lesions resolved after treatment with systemic corticosteroids for 1 month. Courtesy of Frans C. Stades.

periocular hyperemia, facial pruritus, and conjunctivitis are common. Identification of the specific allergen and desensitization are rarely possible, with treatment relying upon the use of topical and systemic corticosteroids and antihistamines. Food allergies and systemic drug reactions can cause periocular dermatitis and blepharitis, with the avoidance of the allergen or cessation of the drug therapy being the obvious lines of treatment.

Eyelid Masses and Neoplasia Inflammatory Masses Inflammatory masses or pseudotumors of the eyelids are infrequent in dogs and tend to occur in certain breeds. Eosinophilic granuloma is a more frequent condition in cats, but is also described in dogs (Vercelli et al., 2005). This may present as slow progressing granulomatous nodules or plaques, sometimes with yellow‐white detritus on them. It is mostly localized not only in the oral cavity but also at the lid margin, or in cats on the cornea. Complete remission usually can be achieved with topical glucocorticoid eye ointment or oral glucocorticoid treatment. Histocytosis of the Bernese Mountain Dog is a systemic and familial disorder that affects males more often than females (Collins et  al., 1992; Moore, 1984; Radgett et  al., 1995; Rosin & Moore, 1986; Scherlie et al., 1992). The condition has also occurred in the Rottweiler, Golden Retriever, Labrador Retriever, and Flat‐Coated Retriever. This disease manifests in two different forms: (1) a generally slow, cutaneous form; and (2) an aggressive or malignant cutaneous form with eventual multiorgan involvement of the lymph nodes, spleen, and bone marrow. The eyelids are often

involved and present as recurrent or persistent nodules, papules, or plaques of upper and lower eyelids. Their surface may be alopecic to ulcerated, and subsequent recurrences tend to be more severe. Biopsy of the masses is usually diagnostic. This disease is unfortunately progressive and fatal. Nodular fasciitis occurs rarely in the dog and may be most frequent in the Collie and similar breeds (Gwin et al., 1971). In the Collie, the condition affects the eyelids, conjunctiva, episclera, and peripheral cornea. Microscopically, the lesions are characterized as a subcutaneous mass with abundant fibroblasts, variable ground substance, and fiber formation. Inflammatory cells consist of lymphocytes and mononuclear cells, with occasional giant cells. Therapy consists of surgical excision, cryotherapy, and for dogs heavier than 10 kg, oral administration of niacinamide (500 mg every 8 hours) and tetracycline (500 mg every 8 hours), with therapy gradually tapered. Mesenchymal hamartoma may be found in the eyelid as a benign eyelid mass. A subcutaneous, firm, lobular soft tissue growth ranging in diameter from 0.6 to 3 cm can be found, which in some cases can be adherent to the underlying orbital rim, or be freely palpable between the skin and conjunctiva of the eyelid. The lateral canthus is predisposed. It should be included in the differential diagnoses of benign eyelid masses in dogs. Fine needle aspiration may easily be inconclusive. Therapeutically, it has to be bluntly dissected, which may lead to large defects, necessitating blepharoplasties (Kafarnik et al., 2010).

Lid Neoplasia In contrast to cats, horses, and cattle, the dog eyelids exhibit a large number of different neoplasms that are fortunately, for the most part, locally minimally invasive and respond to fairly conservative surgical procedures. Distinct metastasis from eyelid neoplasms in dogs has not been reported. Eyelid tumors must be distinguished from conjunctival neoplasms, which tend to be locally invasive, often recur after attempts at surgical excision, and may metastasize. At least two reports on canine eyelid neoplasms have been published and indicate similar results (Table  15.1; Krehbiel & Langham, 1975; Roberts et al., 1986). Benign neoplasms outnumber malignant tumors by a ratio of about 3 : 1. The epithelial tumors outnumber the mesenchymal tumors by a ratio of about 5 : 1. Most eyelid tumors occur primarily in dogs over 10 years old, and no gender predisposition has been reported. The upper lid is affected slightly more often than the lower lid. Breeds reported as having increased prevalence of lid tumors include the Beagle, Siberian Husky, and English Setter in one report, while Bedford in the UK reports the Toy and Miniature Poodle, Labrador Retriever, and Golden Retriever as overrepresented (Bedford, 1999a, 1999b). However, these numbers were not corrected for the frequencies of the

Table 15.1  Histologic classification and frequency of canine eyelid neoplasms. Tumor Classification

N = 202 (%)

N = 200 (%)

Sebaceous adenoma

28.7

60

Squamous papilloma

17.3

10.6

Sebaceous adenocarcinoma

15.3

2.0

Benign melanoma

12.9

17.6

Malignant melanoma

7.9

2.8

Histiocytoma

3.5

1.6

Mastocytoma

2.5

1

Basal cell carcinoma

2.5

1.2

Squamous cell carcinoma

2

1

Fibroma

2.1

–

Fibropapilloma

1

–

Lipoma

1

All others (less than 1% individually)

3

Undetermined

– 1

0.5

1.2

Benign

73.3

87.8

Malignant

26.7

8.2

Source: Data from Krehbiel & Langham (1975) and Roberts et al. (1986).

breed in the population. The largest group of neoplasia arising from the Meibomian glands are the adenomas and adenocarcinomas (Barron, 1962; Buyukmihci & Karpinski, 1975; Krehbiel & Langham, 1975; Roberts et  al., 1986). These tumors are first noticed erupting through the eyelid margin or the palpebral conjunctiva just behind the eyelid margin (Fig. 15.72A). They may be pink or have varying degrees of pigmentation and may appear as multiple lobes. With exposure, advanced Meibomian adenomas or adenocarcinomas may ulcerate and even hemorrhage. They can cause local irritation resulting in blepharospasm, epiphora, conjunctival hyperemia, corneal vascularization, and pigmentation. Melanocytic neoplasias of the eyelid are the second‐largest group of tumors and appear as two distinct types (Gwin et al., 1976a, 1976b, 1982; Wang & Kern, 2015). One type arises from the eyelid skin and is usually a single or multiple pigmented mass, which can generally be excised with low recurrence rates. The second type arises from the pigmented eyelid margin and tends to expand to both directions (Fig.  15.73). These tumors are more aggressive locally, and their removal involves the eyelid margin, which must then be restored. Again, these melanomas behave more benignly than melanomas in the conjunctiva, mouth, or other sites and can be treated successfully by one or more attempts at surgical excision. The surgery site may also be treated by cryosurgery following excisional surgical biopsy.

Fibromas and fibrosarcomas are less prevalent but can be locally invasive. They appear as gradually enlarging subcutaneous masses. Other masses affecting the lid subcutaneous tissues are mastocytoma, or mast cell sarcoma, and lipomas. Squamous cell carcinoma rarely affects the canine eyelid; it appears as either a surface proliferative or ulcerative lesion (Barrie et al., 1982). Histiocytomas affect mainly young dogs, appearing often as rapidly proliferative masses. These tumors may spontaneously regress over a few weeks. Firm masses with swollen hyperemic lids and ulcerated skin overlying the mass, extending from the palpebral conjunctiva to the eyelid margin at the medial canthus, may be identified as granular cell tumors (Lu & Dubielzig, 2012). Papillomas represent about 10%–20% of lid tumors, and if combined with oral papillomatosis affect young dogs. These tumors may have a viral origin, but autogenous vaccines have been of limited value. These lid tumors often regress with time and are removed only when tumor‐ induced corneal contact and irritation result. In rare cases they may transform into malignant squama cell carcinomas (Wiggans et  al., 2013). Surgical excision followed by cryosurgery decreases recurrence (Barrie et al., 1982; Gwin et al., 1976a, 1976b). Therapy

Therapies for the canine lid tumors include surgical excision, debulking plus cryosurgery (Zibura et al., 2019), cryosurgery, or a combination of these. Most veterinary ophthalmologists prefer surgery. Recurrence rates after surgery (15%) and cryosurgery (11%) were not significantly different in one study, but the time for recurrence after surgery was 28.3 months compared to 7.4 months after cryosurgery (Collins & Collins, 1994; Holmberg, 1980). Surgical procedures depend on the size and site of the eyelid mass and the involvement of the lid margin (Aquino, 2007; Blogg & Turner, 1994; Bussieres et  al., 2005; Carter, 1970; Esson, 2001; Gelatt & Blogg, 1969; Gwin, 1980; Hamilton et al., 1999; Lewin, 2003; Munger & Gourley, 1981; Mustardé, 1981; Pavletic et al., 1982; Peiffer, 1979; Pellicane et  al., 1994; Poinsard et  al., 2019; Stades, 1987a, 1987b; Szentimrey, 1998). In general, eyelid neoplasia are best removed early, when the resultant surgical defect is small. Larger masses result in more extensive defects that require greater reconstruction. Lid masses removed at surgery should be submitted for histopathologic examination and the surgical margins closely examined for the possible tumor. Masses that involve the medial canthus, lacrimal puncta, or both can be excised, but with greater difficulty. In high risk cutaneous malignancies, such as on suspicion of a mast cell tumor, narrow removal and direct histopathology (Mow’s micrographic surgery) enable identification of the tumor type and the margins. This allows an optimal surgical margin assessment, blepharoplasty method, and provides the lowest recurrence rate (Bernstein et  al., 2013).

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A

B

Figure 15.72  A. Preoperative appearance of an adenoma in the lateral upper eyelid in a 9‐year‐old Dalmatian. B. Postoperative appearance in the same dog after a four‐sided wedge or “house‐shaped” removal of the tumor. Courtesy of Frans C. Stades.

with topical corticosteroids. The Elizabethan collar or other protective devices (e.g., Optivizor) are useful to prevent the patient from rubbing and possibly interrupting the surgical wound. The most frequent result after these procedures is the development of an obvious V notch at the eyelid margin. This can usually be avoided by use of the four‐sided procedure.

Reconstructive Blepharoplasty

Figure 15.73  Multiple melanomas of the lower lid margin in a mixed‐breed dog. Courtesy of Frans C. Stades.

Hyperthermia, cryotherapy, and carbon dioxide laser therapy have been reported for canine lid tumors. Cryosurgery is best monitored with thermal couples within and adjacent to the mass to measure the extent of freezing (Collins & Collins, 1994; Grier et al., 1980; Holmberg, 1980). Laser ablation can successfully treat Meibomian gland adenomas, but because lid margin loss occurs often, apposition of the wound post laser is recommended (Bussieres et  al., 2005; Swinger & Carastro, 2006). When the surgical defect approaches or exceeds 50% of the upper eyelid, a semicircular skin flap can be constructed to permit medial movement to increase the size of the resultant palpebral fissure. When 60%–90% of the eyelid is involved with neoplasia, more extensive blepharoplastic procedures are required for successful treatment (presented in the subsequent section). The usual postoperative treatment after the excision of small lid masses is topical antibiotics, eventually combined

Reconstructive blepharoplasty includes the different surgical procedures to restore the lids after extensive defects resulting from congenital defects or abnormalities, trauma, or the removal of scar tissues and neoplasia (Blogg & Turner, 1994; Carter, 1970; Esson, 2001; Gelatt & Blogg, 1969; Gwin, 1980; Hamilton et  al., 1999; Lewin, 2003; Munger & Gourley, 1981; Mustardé, 1981; Pavletic et  al., 1982; Pellicane et  al., 1994; Stades, 1987a, 1987b; Szentimrey, 1998). The limits of these surgical procedures depend on the skill and imagination of the surgeon. The basic blepharoplastic procedures include sliding skin and pedicle grafts, tarsoconjunctival grafts, pedicle skin or skin and muscle grafts, full‐thickness eyelid grafts – also called the bucket‐handle or Beard–Cutler technique (Cutler & Beard, 1955); see also “Tarsoconjunctival Grafts and Whole Lid Grafts”  –  and full‐thickness grafts from the upper to lower lid. All of these procedures, with occasional modifications, are applicable to all animal species. These procedures have several general principles. The upper lid is more mobile than the lower lid, is the most important lid to cover the cornea, and is essential for most of the blink reflex. The upper lid is also larger than the lower lid and a potential donor of autogenous tarsoconjunctiva, myocutaneous, or full‐thickness lid tissues. Only the lateral

15: Diseases and Surgery of the Canine Eyelid

sary when eyelid dressing and sutures are in place to prevent self‐damage to the surgical site. Most blepharoplastic procedures can restore adequate lid function following large congenital, traumatic, and surgery defects, but they may not completely restore the lid appearance to normalcy.

“House‐Inverted‐Triangle” or “Triangle‐Triangle” Blepharoplasty The most simple and effective procedure is the “triangle‐­ triangle,” or more precisely “house‐inverted‐triangle,” blepharoplasty for the correction of smaller but relatively deeper lid margin defects (e.g., after removal of an adenoma), leaving an intact lid margin in the center of the eye (besides the scar) and an artificial lid margin (A to B) laterally. When the stretched lid fissure reaches less than 33 mm after closing of the defect, this is the first‐choice method to add some lid margin length (Fig. 15.74). Depending on the lid laxity, eyelid masses involving up to 25% of the eyelid length may be excised by scalpel or scissors as a wedge of full‐thickness lid, shaped either as a V or as a four‐sided defect (Gelatt & Blogg, 1969; Gwin, 1980; Hamilton et al., 1999). The V (thus cutting some Meibomian glands obliquely) or four‐sided (house shape, cutting the lid margin in a rectangular‐shaped excision) wedge excision is performed by scissors and/or scalpel and should be at least one Meibomian gland or 1 mm beyond the tumor margins (Fig.  15.74). Closure is by one (or two) layers. The deeper tarsoconjunctival layer can be apposed by simple continuous, 6‐0 to 8‐0 absorbable sutures with the knots buried. The eyelid margin is apposed with a figure‐of‐eight or U‐figure suture (see Fig.  15.9), using 5‐0 or 6‐0 monofilament or

A C

C

A

B

D B

D

Figure 15.74  “Triangle‐triangle,” or more precisely “house‐inverted‐triangle,” blepharoplasty for the correction of smaller but relatively deeper lid margin defects (e.g., after removal of an adenoma), leaving an intact lid margin in the center of the eye (besides the scar) and an artificial lid margin (A-B) laterally. When the stretched lid fissure reaches less than 33 mm after closing of the defect, this is the first‐choice method to add some lid margin length. The “house”‐formed defect after the tumor removal is sutured by a figure‐of‐eight suture at the free rim and further by simple interrupted, 5‐0 to 6‐0 monofilament nylon sutures. If the defect is in the upper lid, the suture ends are tied together, thus preventing corneal irritation. After removal of the skin triangle CDB (always pointing in the opposite direction to the defect), B is apposed to C. Note that the canthotomy wound AB is full‐thickness, follows a continuous lid margin line, and is left open to become an artificial lid margin. Advantages: simple, effective, no scarred new lid margin at the tumor removal site. Disadvantage: small, open wound laterally directly after surgery. Copyright Frans C. Stades.

SECTION IIIA

upper lid margin of the dog contains eyelashes or cilia; transplantation of these cilia follicles from the same or fellow upper eyelid has not been described, but is technologically simple with insertion of a strip of cilia follicles into a V‐shaped furrow about 5 mm deep in the recipient upper lid. Lid surgeries involving the medial canthus must consider the upper and lower lacrimal puncta; if a punctum is to be sacrificed, the lower carries the majority of the tears into the nasolacrimal system and should be spared if possible. The lid margin is the most important in blepharoplasty and is sometimes the most difficult area to restore. Fibrotic eyelid margins can cause considerable corneal and conjunctival discomfort and damage. The posterior aspects of the skin graft may be lined by conjunctival cells spontaneously, possibly with more scarring, or can be lined with mucosa from adjacent palpebral conjunctiva, buccal mucosa, or an island graft from bulbar conjunctiva of the opposite eye. However, these methods are more time‐consuming and may result in traction bands (also in the area where the graft is harvested) and secondary leading‐edge entropion. The lower conjunctival fornix is critical to tear collection and movement to the lacrimal punctum. Adequate blunt dissection and tissue undermining are important to reduce tension on sutures, but should be minimized to reduce trauma and postoperative swelling, and possibly comprising blood supply to the lid. Lid flaps and grafts should be handled minimally during surgery because they rapidly swell. They tend to contract postoperatively, and should always be constructed slightly larger than the defect to allow for shrinkage. Immediate postoperative dressings can be used to apply limited pressure to fresh grafts and reduce the swelling, hemorrhage, and serum accumulation. An E‐collar is neces-

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­ olyfilament absorbable or nonabsorbable suture material, p sometimes including the upper eyelid for extra support. The lid margin is most important because the greatest tension occurs at this single suture. For this reason, the use of a round‐body needle, at the least in the lid margin, is preferred over a triangular or spatula cutting needle. The remaining muscle–skin lid is apposed with simple interrupted, 5‐0 to 6‐0 (non‐)absorbable mono‐ or polyfilament sutures. The four‐sided wedge technique offers the advantage of accommodating a larger surgical approach, and all of the muscle– skin sutures share equally in the wound tension and prevent an obvious notch postoperatively. As in the simple V‐wedge technique, closure is in one or two layers. Depending on the affected lid laxity after these wedge procedures, a permanent relief lateral canthotomy may be necessary.

Sliding Skin Graft or H‐Figure Plasty The sliding skin graft, consisting of the thin lid skin and limited depths of the orbicularis oculi muscle, is the most basic blepharoplastic procedure. The technique can be applied to the entire lower and upper lids and lateral canthus, and can restore the lid length to preoperative size. Pedicle rather than sliding grafts are used for medial canthal defects because tissues in this area are very firmly attached to the deeper tissues. Sliding skin grafts generally are used for full‐thickness lid defects, but can also be used to replace the outer lid tissue layers following extensive trauma or removal of a superficial neoplasm (Fig. 15.75). The adjacent deeper layers of the orbicularis oculi are separated from the sliding skin graft to permit movement of the graft into the surgical defect. If this tissue dissection is incomplete, contract of the graft may occur, resulting in postgraft ectropion, trichiasis, and distortion of the lid margin. The sliding skin incision should be larger than the surgical defect to accommodate tissue shrinkage; small triangles of skin (Burow’s triangles) are excised to prevent puckering of the graft’s base (Fig. 15.75B). The posterior aspects of the skin graft may be lined by conjunctival cells spontaneously, or can be lined with mucosa from adjacent palpebral conjunctiva. If the available local conjunctiva is inadequate, free‐hand conjunctival grafts from the fellow eye or mucosal grafts from the mouth may be used. The skin graft is positioned slightly higher than the adjacent lid margins to accommodate graft contraction (Fig. 15.75C and Fig. 15.76). Sutures attaching the conjunctiva to the sliding skin graft should not touch the cornea; interrupted mattress sutures are often used, especially at the lid margin. Counterpressure with a partial to complete temporary tarsorrhaphy is sometimes indicated to maintain the opposite lid sliding skin graft in position and ensure the best postoperative results.

Sliding Skin and Myocutaneous Grafts When an eyelid surgical defect approaches one‐third or more of the eyelid length, a rotation skin graft, rotation skin graft

2

1

A

1

1

1

C

B Figure 15.75  H‐figure sliding graft for broader defects: after full‐thickness excision of the eyelid neoplasm. A. Two slightly diverging skin incisions are continued from the base of the wound. These skin incisions should be 1.5–2 times the length of the defect’s height. B. Two equal‐sized triangles (Burow’s triangles) of skin are excised to facilitate shifting the graft into the surgical wound. C. After careful subcutaneous dissection under the skin graft, the flap is moved into the wound. The leading edge of the skin graft should be 0.5–1.0 mm bulging into the contour of the adjacent eyelid margin. The skin graft is secured by simple interrupted, 5‐0 to 6‐0 nonabsorbable monofilament sutures starting at the angled area. The sutures should pull the flap forward to the lid margin (1–2). Advantages: simple and effective. Disadvantages: small, open wound directly after surgery; scarred new lid margin. The posterior aspects of the skin graft can be overgrown by conjunctival cells spontaneously or can be lined with mucosa from adjacent palpebral conjunctiva, buccal mucosa, or an island graft from bulbar conjunctiva of the opposite eye. However, these methods are more time‐consuming and may result in traction bands (also in the area where the graft is harvested) and secondary leading‐edge entropion. Copyright Frans C. Stades.

(Mustardé procedure), sliding outer lid margin (Landolt) graft, or caudal auricular axial pattern flap may be used to close the defect (Fig. 15.76, Fig. 15.77, Fig. 15.78, Fig. 15.79, Fig.  15.80, Fig.  15.81, and Fig.  15.82; Degner, 2007; Esson, 2001; Jacobi et  al., 2008a, 2008b; Munger & Gourley, 1981; Mustardé, 1981; Pavletic et  al., 1982; Pellicane et  al., 1994; Stades, 1987a, 1987b; Stanley et al., 2010; Stiles et al., 2003). In the semicircular flap procedure, a curved skin–orbicular oculi incision is extended laterally, and the flap is separated from its deeper tissues. The flap is then shifted medially to appose the lid defect. Conjunctival mucosa may be used to line the deeper flap’s surface. Surgery results appear promising.

Sliding Z‐Plasty A modified sliding myocutaneous graft for the upper eyelid at the lateral canthus is the sliding Z‐plasty (Gelatt & Blogg, 1969; Gwin, 1980). In this procedure, after en bloc excision of the neoplasm involving the lateral aspects of the upper eyelid, incisions including skin and some orbicularis oculi muscles are made in the form of triangles, which are then excised (Fig. 15.83). The Z‐graft is then advanced to replace the missing eyelid margin. The posterior aspects of the skin

15: Diseases and Surgery of the Canine Eyelid B D

977

C

A H

E

G F C

H

A

B

C Figure 15.76  A sliding skin graft involving one eyelid may be combined with tarsoconjunctival grafts from the upper eyelid or vice versa. A. The lower eyelid neoplasm has been excised full‐thickness. The upper tarsoconjunctival graft is constructed to be slightly larger than the lower lid defect. About 2 mm above the eyelid margin, a palpebral conjunctiva and tarsus pedicle graft is prepared by tenotomy scissors. B. The tarsoconjunctival graft is secured in the lower lid defect by simple continuous, or interrupted, 5‐0 to 6‐0 absorbable suture(s). C. The lower lid sliding skin graft is prepared. A temporary complete tarsorrhaphy is performed to immobilize the graft sites. The skin sutures are removed in 10–14 days. The tarsorrhaphy sutures are removed in 3–4 weeks, and the base of the tarsoconjunctival graft is transected by tenotomy scissors. The upper tarsoconjunctival defect is allowed to heal by secondary intention. Disadvantages: much more time‐consuming and complicated, two‐step procedure than alternative methods; open wound directly after surgery; scarred new lid margin. Copyright Frans C. Stades.

graft may be lined by conjunctival cells spontaneously or can be lined with adjacent conjunctival mucosa.

Tarsoconjunctival Grafts and Whole Lid Grafts Tarsoconjunctival grafts are similar to sliding skin grafts, but are the deep aspects of the lid. Combinations of the sliding

F

Figure 15.77  Rotation skin graft for larger defects in the lid margin. The radius of the circle must be twice the length of the lid margin defect. After careful subcutaneous dissection under the skin graft, the flap is moved into the wound. The leading edge of the skin graft should be 0.5–1.0 mm bulging into the contour of the adjacent eyelid margin. The skin graft is secured by simple interrupted, 5‐0 to 6‐0 nonabsorbable monofilament sutures starting at F–H, thus relieving tension on the flap. Further interval sutures should pull the flap into the direction of the lid margin. The posterior aspects of the skin graft may be lined by conjunctival cells spontaneously, or can be lined with mucosa from adjacent palpebral conjunctiva, buccal mucosa, or an island graft from bulbar conjunctiva of the opposite eye. However, these methods are more time‐consuming and may result in traction bands (also in the area where the graft is harvested) and secondary leading‐edge entropion. Advantage: effective. Disadvantages: more time‐consuming; open wound directly after surgery; scarred new lid margin. Copyright Frans C. Stades.

skin and tarsoconjunctival grafts include the entire lid thickness and most often involve transplantation of part of the upper lid to lower lid defects (Fig. 15.84). A 5–7 mm strip of the upper lid margin is avoided during upper to lower lid transplantation to ensure upper lid function and cosmesis. This procedure is referred to as the bucket‐handle or Beard– Cutler technique. Recently, a human Hübner’s tarso‐conjunctivo‐marginal graft technique has been described in dogs for repairing eyelid margin defects after tumor resection involving between one‐ quarter and two‐thirds of the length of the eyelid (Poinsard et al., 2019). Harvesting of the graft with a length of half the length of the tumor, including its free margins, was performed via a full‐thickness incision on the ipsilateral healthy eyelid. The cutaneous layer and all of the muscle fibers of the transplant were meticulously removed except for a 3 mm strip along the free lid margin. A full‐thickness tumor excision was then performed. The graft was sutured at the level of the defect to be reconstructed. A sliding H flap was generated. The resulting nourishing myocutaneous flap was then sutured along the free margin of the tarso‐conjunctivo‐marginal graft. The lateral edges of the advancement flap were sutured to the edges of the receiving sites, resulting in a stretched lid fissure length that was shortened by 7–11 mm. This tarsomarginal

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grafting technique has yielded encouraging results in dogs. The few complications that were encountered were mainly the development of keratitis or suture dehiscence.

SECTION IIIA

Miscellaneous Eyelid Procedures

A

B Figure 15.78  Sliding skin–outer lid margin flap (Landolt) for larger, deeper defects. A. After lid splitting, a large flap of 10 to 15 mm depth is dissected, and a relaxation triangle is removed at the end of the wound. B. The sliding skin–outer lid margin flap is secured by simple interrupted, 5‐0 to 6‐0 nonabsorbable monofilament sutures. Advantage: effective. Disadvantages: more time‐consuming; open wound directly after surgery; scarred new lid margin. Copyright Frans C. Stades.

A

B

C Figure 15.79  Rotation skin graft, Mustardé procedure in a central defect. A. Outline of the area to be used as donor tissue. B. Creation of a flap to fill the defect in the upper eyelid. C. Lower eyelid tissue sutured into upper eyelid defect. This procedure shortens the lid fissure, which later should be corrected by a canthoplasty procedure. A temporary tarsorrhaphy will prevent wound dehiscence. Disadvantages: time‐ consuming, two‐step procedure; shortens lid fissure after enlargement; scarred new lid margin. Copyright Frans C. Stades.

In tarsorrhaphy procedures, portions of or the entire eyelids are apposed, either temporarily or permanently. In the partial procedures, only part (medial, central, or lateral) of the palpebral fissure is closed, thereby permitting vision by the patient, daily inspections by the veterinarian, and topical medication of the eye as well as keeping the eye in its orbit. If the indication was luxation or proptosis of the globe in brachycephalic breeds such as the Pekingese, after opening, a medial canthoplasty (tarsorrhaphy) must be considered as a preventive measure against recurrence. In permanent tarsorrhaphy procedures, all or parts of the eyelid margins of the upper and lower eyelids are excised; they grow together and remain sealed for extended periods of time or indefinitely. Partial permanent tarsorrhaphies are indicated to treat long‐term ocular disorders, such as neuroparalytic keratitis, neurotropic keratitis, lagophthalmos, and chronic proptosis and exposure keratitis. Complete permanent tarsorrhaphies are part of the enucleation and exenteration procedures after removal of the eye and the orbital contents.

Temporary Tarsorrhaphy The partial temporary tarsorrhaphy is used frequently after conjunctival and corneal surgery to reduce the eyelid trauma to the surgical site and provide some contact and pressure to fresh grafts or to keep contact lenses in place. The complete temporary tarsorrhaphy is indicated for the treatment of traumatic proptosis, after most orbitotomies, after many extensive eyelid procedures, after nictitating membrane flaps, after extensive conjunctival surgery, to treat premature opening of the eyelids, to help maintain collagen shields or soft contact lenses, and for the treatment of recurrent corneal erosions and other selected superficial corneal disorders. Complete temporary tarsorrhaphies are also indicated when upper eyelid function is impaired and the development of exposure keratitis is anticipated. A temporary tarsorrhaphy is performed by placing 1–3 horizontal mattress sutures (5‐0 or 6‐0, cutting, micropoint, or round‐body needle) on the required area, using, for example, silicone or infusion tubing to prevent the suture from cutting into the skin (Fig. 15.85). Mattress sutures are used to close the lid fissure. Sutures placed too far from the lid margin can cause entropion. Sutures placed through the conjunctiva may result in an “egg‐slicing” effect of the suture to the cornea. After days or weeks, the sutures are removed (the medial first, if proptosis was the indication; if

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B

A

Figure 15.80  A. Rotational graft using the dog’s upper lip for large defects of the lower eyelid. Note that the pedicle has to be rotated 180° into the lower lid defect. B. Rotational graft using the dog’s lip commissure for large defects of the lower eyelid and the lateral canthus, as described for the correction of aplasia or coloboma of the upper lid by Whittaker et al. (2010). Copyright Frans C. Stades.

A

B

Figure 15.81  Caudal axial pattern flap for the reconstruction of medial eyelid defects, as described by Jacobi et al. (2008). A. A superficial axial pattern or transposition flap based on the opposite vascular pedicle is created and transposed into the defect. B. The subcutaneous tissues are apposed with several interrupted absorbable sutures, followed by a simple continuous pattern suture, and a drain is placed. Thereafter, the skin is closed. Copyright Frans C. Stades.

there is still an apparent tendency to luxation, the remaining suture is left in place for a longer period). The suture ends in the temporary tarsorrhaphies may be left long to facilitate occasional adjustment of the suture pressure as well as occasional loosening to open the tarsorrhaphy and inspect the eye.

Permanent Tarsorrhaphy In permanent tarsorrhaphy procedures, all or parts of the eyelid margins of the upper and lower eyelids are excised and, after apposition by sutures, the “eyelids” grow together

and remain sealed for extended periods of time or indefinitely. Medial or lateral partial, permanent tarsorrhaphies are indicated for diseases such as trichiasis, chronic exposure keratitis, and recurrent central corneal ulceration in the brachycephalic breeds (Fig. 15.86). Aftercare consists of administration of an appropriate antibiotic ointment for 10 days. If the indication for the procedure has been healed, the tissue bridge can be transected. The wounds close spontaneously. Complete, temporary tarsorrhaphy constitutes a barrier to topical medication of an eye, but subpalpebral systems can be inserted in the dorsolateral or lateral conjunctival fornix at the conclusion of

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SECTION IIIA

Figure 15.82  Caudal auricular axial pattern flap, as described for the closure of large defects, for example, after orbital exenteration by Stiles et al. (2003). A. The base of the flap was centered over the lateral aspect of the wing of the atlas. A flap of about 7 cm by 16 cm, including skin and the platysma muscle, is rotated ventrally into a bridging incision ventral to the ear, between the flap and the orbit, and sutured in place (B). As the exact course of the arterial supply varies, the distal portion of the flap is more vulnerable to avascular necrosis. Copyright Frans C. Stades.

A

B

a

b c d

A

a a b b

c d

B

C

c

d

Figure 15.83  The Z‐plasty procedure is a modified sliding skin graft for lateral canthal defects. A. After removal (full‐thickness) of the mass by tenotomy scissors from the lateral portion of the upper eyelid, the subcutaneous tissues in the lateral canthus are dissected bluntly and two equal‐size triangles of skin are excised. B. The skin flaps are slid into position. Note that both ab and cd can be used as the leading edge of the graft, depending on the availability of skin dorsally or laterally. C. The flaps are secured by simple interrupted, 5‐0 to 6‐0 nonabsorbable monofilament sutures. Advantage: effective. Disadvantages: time‐consuming; open wound directly after surgery; scarred new lid margin. The posterior aspects of the skin graft may be overgrown by conjunctival cells spontaneously or can be lined with mucosa from adjacent palpebral conjunctiva, buccal mucosa, or an island graft from bulbar conjunctiva of the opposite eye. These latter methods may result in traction bands (also in the area where the graft is harvested) and secondary leading‐edge entropion. Copyright Frans C. Stades.

Figure 15.84  For full‐thickness eyelid (bucket‐handle or Cutler– Beard technique) grafts, either the lower or upper eyelid may be used as the donor. A. The full‐thickness lid graft is constructed about 4 mm from the eyelid margin and should be 0.5–1 mm larger than the surgical wound. B. The lower lid graft is positioned under (deep to) the strip of remaining lower lid margin and secured in the upper lid defect by two layers of sutures. The tarsoconjunctival layers are apposed by a simple continuous, 5‐0 to 6‐0 absorbable suture. The skin–orbicularis oculi layer is apposed by simple interrupted, 5‐0 to 6‐0 nonabsorbable sutures. A complete temporary tarsorrhaphy is performed to stabilize the graft site. After 3–4 weeks, all the skin and tarsorrhaphy sutures are removed, and the base of the full‐thickness lid graft is transected (1). C. The upper lid edges are reapposed by simple interrupted, nonabsorbable 4‐0 to 6‐0 sutures. Advantage: effective. Disadvantages: very time‐consuming, complicated, two‐step procedure; open wound directly after surgery. Copyright Frans C. Stades.

C A

1

B

Figure 15.85  Temporary tarsorrhaphy. After, for example, a canthotomy and repositioning of a luxated or proptosed globe, a temporary tarsorrhaphy can be performed, seen from the front (A) and in section (B). The lid fissure is closed by two or three U‐figure sutures, prevented from cutting into the skin by, for example, infusion tubing. Copyright Frans C. Stades.

A

surgery to ensure delivery of ophthalmic solutions. The apposed eyelids may also retain the topical solutions in contact with the cornea for longer periods of time, thereby increasing their effectiveness.

Postoperative Care and Complications after Tarsorrhaphy The most frequent complications immediately after temporary tarsorrhaphy techniques are variable swelling of the eyelids and suture contact with the cornea. Thus, patients should be examined daily or every other day. If the sutures

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B

become too tight, local eyelid necrosis and irritation result. If the sutures become too loose, “egg‐slicing” suture contact to the cornea may occur. Routine use of a protective E‐collar postoperatively in small animals is important and effectively prevents self‐trauma to the surgical site. The most frequent postoperative complications after permanent tarsorrhaphy are related to excessive tension on the lid sutures for the short term and wound failure for the long term. Chronic tension may result in gradual weakening and atrophy of the surgical apposition site. Dehiscence within the first few weeks postoperatively is usually repaired by debriding the wound edges and apposition with additional sutures.

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Figure 15.86  Permanent central tarsorrhaphy, seen from the front and in section, for long‐term closure of the lid fissure. In the center of the lid, over 10–15 mm, the outer free rim of the margin of upper and lower lids is incised by scalpel and removed by tenotomy scissors (A). The opposite skin wounds are apposed by simple interrupted, 5‐0 to 6‐0 sutures (B), forming a bridge of skin over the intact free inner rims of the upper and lower lids (C). Copyright Frans C. Stades.

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A

B

C

References Ackerman, L.J. (1985) Canine and feline pemphigus and pemphigoid: Part I. Pemphigus. Compendium of Continuing Education for the Practicing Veterinarian, 7, 89. Allgoewer, I. (2011) Evaluation of a slightly modified Stades technique for the correction of upper lid entropion in the Shar Pei. Conference Proceedings, European College of Veterinary Ophthalmologists, p. 64. Aquino, S.M. (2007) Management of eyelid neoplasms in the dog and cat. Clinical Techniques in Small Animal Practice, 22, 46–54. Aquino, S.M. (2008) Surgery of the eyelids. Topics in Companion Animal Medicine, 23, 10–22. Badanes, Z. & Ledbetter, E.C. (2019) Ocular dermoids in dogs: A retrospective study. Veterinary Ophthalmology, 22, 760–766. Barrie, K.P. & Parshall, C. (1979) Eyelid pyogranulomas in four dogs. Journal of the American Animal Hospital Association, 14, 433–437. Barrie, K.P., Gelatt, K.N., & Parshall, C.P. (1982) Eyelid squamous cell carcinoma in four dogs. Journal of the American Animal Hospital Association, 18, 123–127. Barron, C.W. (1962) The comparative pathology of neoplasms of the eyelids and conjunctiva with special reference to those of epithelial origin. Acta Dermato‐Venereologica, 42(Suppl. 51), 1–100.

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Fröhner, B. (1900) In: Handbuch der Tierärztlichen Chirurgie und Geburtshilfe, V. Augenheilkunde (eds. Bayer, J.J. & Fröhner, F.), p. 185. Vienna: W. Braumüller. Gelatt, K.N. (1969) Resection of cilia‐bearing tarsoconjunctiva for correction of canine distichia. Journal of the American Veterinary Medical Association, 155, 892–897. Gelatt, K.N. & Blogg, J.R. (1969) Blepharoplastic procedures in small animals. Journal of the American Animal Hospital Association, 5, 67–78. Gelatt, K.N. & Gelatt, J.P. (2011) Veterinary Ophthalmic Surgery. Edinburgh: Elsevier‐Saunders. Giuliano, E.A. (2008) Regional anesthesia as an adjunct for eyelid surgery in dogs. Topics in Companion Animal Medicine, 23, 51–56. Gómez, A.P., Mazzucchelli, S., Scurrell, E., et al. (2020) Evaluation of partial tarsal plate excision using a transconjunctival approach for the treatment of distichiasis in dogs. Veterinary Ophthalmology, 21 Feb. https://doi.org/10.1111/vop.12748. Grier, R., Brewer, W.J., & Theilen, G. (1980) Hyperthermic treatment of superficial tumors in cats and dogs. Journal of the American Veterinary Medical Association, 177, 227–232. Grussendorf, H. (2004) Outcome of a surgical technique for dogs suffering from macroblepharon. Transactions of the ECVO‐ESVO‐DOK Meeting, Munich, p. 41. Guandalini, A., Girolamo, N., di, Santillo, D., et al. (2016). Entropion/ectropion epidemiology of ocular disorders presumed to be inherited in three large Italian dog breeds in Italy. Veterinary Ophthalmology, 19, 1–7. Gutbrod, F. & Tietz, B. (1993) Entropion‐operation mit Lidrand‐verkürzung. Veterinäre Spiegel, 4, 14. Gwin, R.M. (1980) Selected blepharoplastic procedures of the canine eyelid. Compendium on Continuing Education, 2, 267–272. Gwin, R.M., Alsacker, R.D., & Gelatt, K.N. (1976a) Melanoma of the lower eyelid of a dog. Veterinary Medicine, Small Animal Clinician, 22, 929–931. Gwin, R.M., Gelatt, K.N., & Peiffer, R.L. (1971) Ophthalmic nodular fasciitis in the dog. Journal of the American Veterinary Medical Association, 170, 611–614. Gwin, R.M., Gelatt, K.N., & Peiffer, R.L. (1976b) Enophthalmia and entropion associated with an ectopic cilium of the upper lid in a dog. Veterinary Medicine, Small Animal Clinician, 71, 1098–1099. Gwin, R.M., Gelatt, K.N., & Williams, L.W. (1982) Ophthalmic neoplasms in the dog. Journal of the American Animal Hospital Association, 18, 853–866. Halliwell, R.E.W. (1980) Skin diseases associated with autoimmunity: Part I. The bullous autoimmune skin diseases. Compendium on Continuing Education for the Practicing Veterinarian, 2, 911. Halliwell, W. (1965) Undermined skin flaps as a method of entropion correction. Veterinary Medicine, Small Animal Clinician, 60, 915–919. Halliwell, W. (1967) Surgical management of canine distichia. Journal of the American Veterinary Medical Association, 50, 874–879.

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16 Diseases and Surgery of the Canine Nasolacrimal System Lynne S. Sandmeyer1 and Bruce H. Grahn2 1

  Department of Small Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada   Western College of Veterinary Medicine and Prairie Ocular Pathology of Prairie Diagnostic Laboratories, University of Saskatchewan, Saskatoon, SK, Canada

2

Introduction The nasolacrimal duct system of the dog is similar to that of most domestic animals. It is a thin‐walled conduit that drains the tear film from the eye into the nasal passages. This chapter reviews the embryology, anatomy, physiology, and diagnostic procedures of the canine nasolacrimal system. The clinical manifestations for both congenital, develop­ mental, and acquired diseases and the appropriate medical and surgical management of each disorder are described.

Embryology The nasolacrimal duct system develops from surface ecto­ derm within the nasolacrimal groove (i.e., furrow), which separates the lateral nasal fold and the maxillary process (Fig. 16.1A) (Arey, 1974). Ectodermal cells grow along this groove, sink into mesenchyme, and become buried. These cells form a cord as the maxillary process fuses with the lat­ eral nasal fold between days 22 and 26 of gestation in the dog (Fig.  16.1B) (Noden & de Lahunta, 1985). The ectodermal cords grow toward the nasal cavity and the eye, and eventu­ ally, they extend from the eyelid to the inferior nasal passage (Noden & de Lahunta, 1985). The upper end of this cord develops two buds, which grow into the upper and lower eyelid near the medial canthus (Fig. 16.1C) and develop into the superior and inferior canaliculi and puncta. The cord becomes a duct through a process of canalization and nor­ mally is patent at birth (Noden & de Lahunta, 1985).

Anatomy The superior and inferior puncta are oval to slit‐like openings that measure approximately 1 mm by 0.3 mm, with their long axis parallel to the lid margin (Evans, 1993; Getty, 1975). They

are located on the palpebral conjunctiva at the edge of the upper and lower eyelids 2–5 mm from the medial canthus, approximately where the tarsal glands end (Fig. 16.2A). The puncta are the openings to the superior and inferior canali­ culi. The canaliculi are approximately 4–7 mm in length and 0.5–1.0 mm in diameter (Getty, 1975). They extend through the orbicularis oculi muscle, and they join together ventral to the medial canthus to form the lacrimal sac, which lies within a slight depression (i.e., the lacrimal fossa) in the lacrimal bone. The lacrimal sac is poorly developed in the dog; it is simply a slight dilation at the beginning of the nasolacrimal duct (Evans, 1993). The nasolacrimal duct itself is constricted as it traverses the lacrimal bone (Lavach, 1993), and the con­ stricted region is important in retention of foreign bodies and development of dacryocystitis in the dog. The duct then passes through a canal on the medial surface of the maxillary bone and ends in a nasal punctum. The nasal puncta are usually located in the ventral lateral nasal meatus, opening approximately 1 cm inside the external nares (Fig. 16.2B). In approximately 50% of dogs, the nasolacrimal duct has a sec­ ond opening in the oral mucosa of the central hard palate, behind the incisors at the level of the canine teeth (Severin, 1995). The nasolacrimal duct is approximately 1 mm in diam­ eter, and the length varies considerably between brachyce­ phalic, mesocephalic, and dolichocephalic dogs (Gelatt & Gelatt, 2011). Brachycephalic breeds often have short nasol­ acrimal ducts and they often drain the tears into the pharynx. The nasolacrimal ducts are lined with tall, pseudostratified columnar epithelium (Fawcett, 1994).

Physiology The sole purpose of the nasolacrimal duct system is to drain tears from the surface of the eye to the nasal passages. Evaporation, which varies with environmental conditions, removes a significant portion (approximately 25%) of tears

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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Canaliculi Puncta Lateral nasal fold Lacrimal sac A

A Nasolacrimal duct Nasal puncta

Nasolacrimal groove

B

B

Figure 16.2  A, B. Gross anatomy of the canine nasolacrimal duct system. Note the relationship of the eyelids, puncta, canaliculi, lacrimal sac, nasolacrimal duct, and nasal puncta.

Nasolacrimal duct

C Figure 16.1  Embryologic development of the canine nasolacrimal system. A. Note the nasolacrimal groove between the lateral nasal fold and the maxillary process at approximately day 21 of development in the dog. B. The lateral nasal fold fuses with the maxillary process between days 22 and 26. This fusion buries the surface ectoderm cells, which will grow and form the nasolacrimal duct system. C. The ectodermal cells form a cord with two proximal processes that extend toward the medial upper and lower eyelid, whereas the distal end grows toward the nostril. This ectodermal cord canalizes and becomes a duct and canaliculi shortly after birth.

from the ocular surface before drainage can occur (Lemp & Wolfley, 1992). Drainage through the nasolacrimal system occurs as a result of multiple forces. Most (at least 60%) of the tear volume is normally drained through the inferior puncta

and canaliculi (Lemp & Wolfley, 1992). Tears flow ventrally in response to gravity and they are pulled into the canaliculi during eyelid closure because of reduced intracanalicular pressure (Doane, 1981). This reduced pressure develops as these thin‐walled ducts are compressed by contraction of the orbicularis oculi muscle. In addition, capillary action and siphon effect from the lacrimal sac pull tears through the canaliculi and duct (Doane, 1981; Gelatt, 1991b; Gelatt & Gwin, 1981; Hill et al., 1974a, 1974b; Lemp & Wolfley, 1992). Mucosa‐associated lymphoid tissue has been reported in human nasolacrimal drainage systems (Knop & Knop, 2001). This lacrimal drainage‐associated lymphoid tissue is part of the common mucosal immune system, and T cells, B cells, and plasma cells were confirmed with immunohistochemis­ try within the walls of the nasolacrimal ducts and canaliculi (Knop & Knop, 2001). In addition, basal mucous glands were associated with the lacrimal canaliculi (Knop & Knop, 2001). It is hypothesized that the main and accessory lacrimal glands, conjunctiva, and lacrimal drainage system are an integrated system and that the mucosal‐associated lymphoid tissues in these are connected, and recirculation of lympho­ cytes within this system is likely (Knop & Knop, 2001). In addition, the lacrimal drainage mucosal‐associated lym­ phoid tissue may be connected to the ocular surface and lac­ rimal glands via a neural reflex arc that may influence ocular surface integrity (Knop & Knop, 2001). The nasolacrimal

SECTION IIIA

Maxillary process

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Section IIIA: Canine Ophthalmology

SECTION IIIA

ducts have also been reported to produce natural peptide antibiotics, which may have a therapeutic benefit in dacryo­ cystitis; however, they may also be detrimental because they induce scarring and dacryostenosis (Paulsen et  al., 2001). Mucosa‐associated lymphoid tissue and production of natu­ ral peptide antibiotics has not been reported in the dog, but they are likely present in animals.

Clinical Manifestations of Nasolacrimal Disease Disorders of the nasolacrimal duct system in the dog may be congenital, developmental, or acquired, and they are limited to a lack of patency or inflammation. The clinical manifesta­ tions of nasolacrimal system disease include: epiphora; mucopurulent punctal, conjunctival, and nasal discharge; swelling of the ventral medial canthal region; punctal for­ eign bodies; and draining fistula in the medial canthal region (Fig. 16.3, Fig. 16.4, and Fig. 16.5). Epiphora is the most common clinical manifestation. Epiphora develops secondary to obstructions of tear flow through the nasolacrimal duct system (see Fig.  16.3 and Fig. 16.4) or to an overproduction of tears (i.e., lacrimation), in which the tear volume overwhelms the normal drainage system. Mucopurulent punctal and ocular discharge (Fig.  16.5), conjunctivitis, and draining fistulas from the duct system may develop secondary to nasolacrimal sac inflammation (i.e., dacryocystitis).

Figure 16.4  Tear‐staining syndrome in a 10‐month‐old American Eskimo dog. The clinical manifestation was bilateral tear staining and epiphora. Abnormalities noted on biomicroscopic examination included medial caruncular trichiasis, subtle medial ventral entropion, tight medial canthal ligaments, and mild eyelid trichiasis.

Diagnostic Procedures Several diagnostic procedures allow clinicians to establish an accurate diagnosis of obstruction or inflammation of the  nasolacrimal duct system or epiphora secondary to increased  lacrimation. These include: the Schirmer tear

Figure 16.5  A superior punctal and canalicular foreign body that was causing dacryocystitis in a 2‐year‐old Lhasa Apso. Note the mucopurulent ocular discharge and conjunctivitis.

Figure 16.3  A 12‐week‐old Papillon puppy with bilateral inferior punctal atresia, resulting in marked epiphora.

test (Gelatt et al., 1975); slit‐lamp biomicroscopy; cytology and microbial culture of punctal discharge (Lavach et al., 1977; Murphy, 1988); fluorescein dye passage test (Jones, 1961); normograde punctal and canalicular cannula­ tion, and lavage (Gelatt, 1981, 1991a; Severin, 1972); nasal punctal cannulation and retrograde flushing (Gelatt, 1981, 1991b; Severin, 1972); endoscopy (Strom et  al., 2018), dacryocystorhinography (DCG) (Gelatt et al., 1972;

16: Diseases and Surgery of the Canine Nasolacrimal System

Schirmer Tear Test The Schirmer tear test should be the first diagnostic test com­ pleted during examination of a dog with epiphora. It estimates total reflex aqueous tear production; volumes from dogs in excess of 25 mm/min are consistent with the diagnosis of stimulated lacrimation. Lacrimation may overwhelm a func­ tional nasolacrimal duct and result in epiphora. The causes of increased lacrimation vary, and they relate to diseases that cause red eye (e.g., conjunctivitis, keratitis, scleritis, uveitis, glaucoma, orbital cellulitis); the diagnoses of and therapy for those diseases are discussed elsewhere in this book.

during surgery (Blicker  & Buffam, 1993; MacEwen et  al., 1994). Fungal dacryocystitis has been reported in humans (Arstenstein et al., 1993; Bessler et al., 1994; Purgason et al., 1992), but not in the dog.

Fluorescein Dye Passage Fluorescein dye passage (i.e. Jones test) is the primary test of patency. It involves placing liquid fluorescein dye on the cor­ nea and conjunctiva, and after several minutes have elapsed, both the nasal area (Fig. 16.6) and pharynx are examined with cobalt‐filtered or ultraviolet light to confirm dye passage and duct patency. In a study evaluating fluorescein nasolacrimal transit times in normal dogs, transit times were highly varia­ ble, ranging from 2 to 840 seconds, with cephalic conforma­ tion, snout length, and reproductive status affecting the result. The test was found not to be of clinical use in brachycephalic dogs because most of these dogs did not show dye passage at the 30‐minute test cut‐off (Binder & Herring, 2010). Failure of passage to the nares may be an indication of physiologic or functional inadequacy of the nasolacrimal duct system. However, false negatives occur and a normograde nasolacri­ mal duct flush is frequently required to confirm patency.

Slit Lamp Biomicroscopy Biomicroscopic examination of the superior and inferior puncta for patency, size, and location of the punctal open­ ings is an essential component of the ocular examination. The puncta are normally oval to slit‐like openings of 1 mm by 0.3 mm, with their long axis parallel to the lid margin (Evans, 1993; Getty, 1975). They are located on the palpebral conjunctiva at the edge of the upper and lower eyelids 2–5 mm from the medial canthus. Punctal atresia and micro­ punctum of the ventral punctum commonly cause epiphora in dogs. Misplacement of the ventral puncta and displace­ ment caused by medial ventral entropion may also be associ­ ated with epiphora.

Nasolacrimal Flushing A 24‐gauge intravenous catheter or nasolacrimal cannula (Fig.  16.7 and Fig.  16.8) is preplaced on a 3 mL syringe

Cytology and Microbial Cultures Cytology as well as both aerobic and anaerobic bacterial and fungal culture reveals inflammatory cells, foreign bodies, and microbial content of mucopurulent ocular discharge. These laboratory evaluations may be completed on the dis­ charge expressed from puncta, canaliculi, and skin fistulae, or on that flushed from the nasolacrimal duct system of dogs with dacryocystitis, before application of topical anes­ thetics or stains. Bacterial opportunists, including Staphylococcus sp., Streptococcus sp., Proteus sp., and Escherichia sp., are often cultured from the nasolacrimal duct system of dogs with dacryocystitis (Lavach et al., 1984). Bacterial cultures from within the diseased nasolacrimal system often differ significantly from those taken from the conjunctiva around the punctum, thus prompting culture

Figure 16.6  A positive left‐ and negative right‐nasal fluorescein dye passage test in a 1‐year‐old mixed‐breed dog with right inferior punctal aplasia.

SECTION IIIA

Yakely & Alexandra, 1971); ultrasonography (Alper et al., 1994; Barsotti et  al., 2019; Jedrzynski  & Bullock, 1994; Pavlidis et  al., 2005); computed tomography (CT) (Divaris, 1995; Loftus et  al., 1996; Massauld et  al., 1993; Nykamp et al., 2004; Rached et al., 2011); magnetic resonance imag­ ing (MRI) (Amrith et  al., 2005; Goldberg et  al., 1993; Hoffman et al., 1999; Kirchof et al., 2000; Manfre et al., 2000; Rahangdale et al., 1995; Rubin et al., 1994; Takehara et al., 2000); and lacrimal scintigraphy (Wearne et al., 1999).

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Section IIIA: Canine Ophthalmology

nare. Similar to anterograde flushing, a 24‐gauge intrave­ nous catheter preplaced on a 3 mL syringe is inserted and a small volume of eye wash is injected.

SECTION IIIA

Radiographic and Other Imaging Examinations

Figure 16.7  A 24‐gauge intravenous catheter inserted in the ventral punctum of a 1‐year‐old King Charles Cavalier Spaniel.

Lateral and ventrodorsal open‐mouth nasal radiographs are useful in evaluation of the nasal bones along which the nasolacrimal duct passes. The nasolacrimal ducts are vulner­ able to traumatic laceration, erosion, or compression by infectious and neoplastic processes (Fig. 16.9). Results of DCG will confirm nasolacrimal duct patency (Gelatt et al., 1972; Yakely & Alexandra, 1971). To perform DCG, the superior and inferior lacrimal canaliculi are can­ nulated using a 22‐gauge catheter for large breed dogs and a 24‐gauge catheter for small breed dogs. The catheters are sutured in place to ensure a tight seal in order to prevent leakage of the irritating contrast agent on the cornea. To pro­ tect the cornea further, lubricating corneal gels are applied at this time. Next, 2–4 mL of iodinated contrast media is injected. Radiographs are obtained as the dye passes through the nasolacrimal duct system (Fig.  16.10). Perforations or blockages of the nasolacrimal duct are readily detected on these images (Fig. 16.11).

Figure 16.8  A 24‐gauge nasolacrimal cannula, which may be used for punctal and canalicular cannulation in the dog. The soft, flexible nature of the intravenous catheter makes it ideal for punctal cannulation; however, small puncta in toy breeds may require the smaller diameter nasolacrimal cannula.

c­ ontaining a commercial eye wash, and a drop of topical anesthetic is applied to the conjunctiva. The punctum and canaliculus are cannulated and a small volume of eye wash is injected while observing the contralateral punctum. When fluid passes through the opposite punctum, it is gen­ tly occluded with finger pressure, and continued injection into a normal nasolacrimal duct system will produce eye wash at the nostrils or induce swallowing as the solution flows into the pharynx. Retrograde nasolacrimal duct flushing is performed when a normograde flush is not suc­ cessful. In most dogs, general anesthesia is required before cannulation of the nasal punctum and retrograde flushing can be completed. After anesthesia is induced, a nasal spec­ ulum is inserted into the nostril and is directed ventrally. Rhinoscopy may also be useful in locating the nasal pun­ tum (Strom et al., 2018). The nasolacrimal duct punctum is located at the junction of the floor and lateral wall of the

Figure 16.9  Ventrodorsal, open‐mouth radiograph of a dog showing increased density of the left nasal cavity and deviation of the nasal septum into the right nasal cavity. These radiographic signs are consistent with a diagnosis of a left nasal neoplasm. Results of endoscopic biopsies, light microscopy, and CT scan confirmed the diagnosis of nasal carcinoma with compression of the left nasolacrimal duct. Blockage of the duct resulted in left epiphora, which was the presenting clinical sign.

Figure 16.10  Dacryocystorhinogram of a normal dog. Note contrast media is visible throughout the nasolacrimal apparatus.

Figure 16.11  Dacryocystorhinograph of an obstructed nasolacrimal duct in a dog. Note the distended nasal lacrimal duct is filled with contrast media.

Advanced imaging studies (i.e., ultrasonography, CT, MRI, and scintigraphy) (Alper et  al., 1994; Amrith et  al., 2005; Barsotti et  al., 2019; Divaris, 1995; Goldberg et  al., 1993; Hoffman et  al., 1999; Jedrzynski & Bullock, 1994; Kirchof et al., 2000; Loftus et al., 1996; Manfre et al., 2000; Massauld et  al., 1993; Nykamp et  al., 2004; Pavlidis et  al., 2005; Rached et  al., 2011; Rahangdale et  al., 1995; Rubin et  al., 1994; Takehara et al., 2000; Wearne et al., 1999) are also use­ ful to confirm compression and occlusion of the nasolacri­ mal duct system. In addition, they are useful to determine the extent of primary disease in the nose and orbit (Fig.  16.12). Ultrasonography is not commonly utilized in evaluation of the nasolacrimal system but has been reported as a diagnostic modality in humans (Alper et  al., 1994; Jedrzynski & Bullock, 1994; Pavlidis et al., 2005, Rached et al 2011). Ultrasonography of the medial canthus utilizing a multifrequency linear probe (8–14 MHz) was recently reported as useful for identification of foreign bodies in the lacrimal sac of dogs (Barsotti et al., 2019). CT‐DCG is reported in humans and dogs and is a superior imaging modality compared with conventional radiography (Divaris, 1995; Loftus et  al., 1996; Massauld et  al., 1993; Nykamp et al., 2004, Rached et al., 2011). CT‐DCG provides information about bony tissue around the lacrimal sac and nasolacrimal duct. Smaller drainage structures, such as ­lacrimal canaliculi, are more consistently visualized com­

Figure 16.12  CT scan of a nasal carcinoma invading the anterior orbit through the maxillary bones.

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16: Diseases and Surgery of the Canine Nasolacrimal System

SECTION IIIA

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Section IIIA: Canine Ophthalmology

pared with conventional radiographic DCG. When com­ bined with 3D reconstruction techniques CT‐DCG provides detailed information regarding the anatomy of the nasolac­ rimal system and surrounding structures that is useful in diagnosis and in facilitation of preoperative planning. To perform CT‐DCG, the superior lacrimal canaliculi are can­ nulated and iodinated contrast media is injected as for radi­ ographic DCG. When detected at the nares, the injection is stopped and CT scans performed (Nykamp et  al., 2004; Rached et al., 2011). Transverse beam projection orientation is reported to be superior to the oblique orientation for eval­ uation of inferior and superior canaliculi and the lacrimal sac (Rached et al., 2011). Disadvantages of radiographic and CT‐DCG include exposure of the eye to ionizing radiation, lack of detailed soft tissue imaging, and the required cannulation of the lac­ rimal canaliculi, which precludes functional evaluation of lacrimal drainage. Conventional and CT‐DCG also require the use of iodinated contrast medium which may be irritat­ ing to the eye (Manfre et  al., 2000; Rached et  al., 2011). Magnetic resonance dacryocystography (MR‐DCG) does not result in ocular exposure to ionizing radiation and has therefore been utilized with increasing frequency in humans but has not been reported in dogs. (Amrith et  al., 2005; Goldberg et  al., 1993; Hoffman et  al., 1999; Kirchof et  al., 2000; Manfre et  al., 2000; Rahangdale et  al., 1995; Rubin et al., 1994; Takehara et al., 2000). The technique is similar to CT‐DCG, utilizing gadolinium as a contrast agent. Signal loss in the bony canal is a major disadvantage of MRI (Manfre et al., 2000). Although MRI is considered to be the technique of choice for evaluating periorbital soft tissues, CT‐DCG depicts surrounding soft tissues reliably despite the limited contrast resolution (Nykamp et al., 2004; Rached et al., 2011). Nasolacrimal scintigraphy (dacryoscintigraphy) invol­ ves the application of a radionucleotide (e.g. techne­ tium‐99) to the ocular surface, followed by imaging with a gamma camera (Lefebvre & Freitag, 2012). Images are obtained as the tracer passes through the lacrimal drain­ age system. This does not require forced injection of con­ trast into the nasolacrimal system thus allowing evaluation of physiological lacrimal outflow and is therefore more suitable for the study of physiologic or functional tear drainage than previously mentioned DCG techniques (Detorakis et al., 2014). Dacryoscintigraphy has been uti­ lized to assess lacrimal drainage in humans but is not reported in dogs. Endoscopy of the lacrimal drainage system (lacrimos­ copy or dacryoendoscopy) is performed in humans using a small‐diameter (0.9 mm) endoscope that can be passed through the punctum into the canaliculus for internal visu­ alization of the drainage system. The technique is reported in humans and horses (Cassotis et  al., 2000; Emmerich et  al., 2000) and  recently in dogs utilizing a miniature

straightforward ­flexible telescope with a 0.5 mm outer diameter (Strom et  al., 2018). Dacryoendoscopy has been utilized in humans to diagnose and surgically correct nasolacrimal duct obstruction (Sasaki, et al. 2005a, 2005b). In dogs, passage of the miniature endoscope was possible through the canaliculus and into, but not beyond, the lacri­ mal sac due to the high degree of flexibility which limited manual passage beyond this region (Strom et  al., 2018). However, by passing an endoscope anterograde or retro­ grade through the lumen of a previously placed stent, observation of the entire nasolacrimal system was possible with gradual and simultaneous withdrawal of the stent and endoscope from the nasolacrimal system (Strom et  al., 2018). There are several limitations to this modality in dogs, including the inability to provide insufflation or ­irrigation through an auxiliary channel due to the small diameter, as well as the high degree of flexibility which complicates manual passage (Strom et  al., 2018). Further refinement of equipment and technique may improve the diagnostic practicality of endoscopy of the canine nasolac­ rimal system.

Congenital Diseases Reported congenital anomalies of the nasolacrimal duct sys­ tem include punctal atresia and micropuncta (Barnett, 1979); canalicular and nasal lacrimal duct atresia (Lavach, 1993; Severin, 1995); misplacement of the punctum and can­ aliculus (Gelatt & Gelatt, 2011; Gelatt & Gwin, 1981; Gelatt, 1991b); displacement of the punctum secondary to medial ventral entropion (Gelatt, 1991b; Gelatt & Gelatt, 2011; Gelatt & Gwin, 1981); dacryops (Grahn & Mason, 1995); and canaliculops (Gerding, 1991). Both the etiologies and inci­ dence of these anomalies are unknown.

Lacrimal Punctal Atresia Punctal atresia is the most frequently diagnosed congenital anomaly. It may affect the superior, inferior, or both puncta, and it may be either unilateral or bilateral. It occurs in numerous breeds and is commonly seen in American Cocker Spaniels, Bedlington Terriers, Golden Retrievers, Miniature and Toy Poodles, and Samoyeds (Genetics Committee of the American College of Veterinary Ophthalmologists, 1996; Grahn, 1999; Rubin, 1989). The diagnosis is confirmed by biomicroscopic examina­ tion and normograde or retrograde nasolacrimal duct flush­ ing. Superior punctal atresia is asymptomatic and is diagnosed incidentally during routine biomicroscopic exam­ inations. Further diagnostic examinations are usually not completed with this condition; therefore, the presence of a superior canaliculus is not determined. When inferior punc­ tal atresia is present, epiphora is usually present in puppies

16: Diseases and Surgery of the Canine Nasolacrimal System

nasolacrimal duct may then be cannulated with an indwell­ ing silastic tube and then treated with an antibiotic–steroid solution for approximately 21 days to ensure patency. The silastic tube may be removed and the patency of the nasolac­ rimal duct should be reassessed after an additional 7 days of topical antibiotic–steroid therapy.

Micropunctum Incomplete development (i.e., micropunctum) or strictures of the ventral punctum causing epiphora may be enlarged with a punctal dilator (see Fig. 16.14E, F) or the 1–2–3 snip technique (see Fig. 16.14A–D) and catheterization (Barnett, 1979; Grahn, 1999). Punctal strictures in humans have also been treated successfully with cauterization (Fein, 1977) and the punctal pucker technique (Dolin & Hecht, 1986). These techniques are not reported in dogs; however, they may be useful. The punctal pucker technique involves a palpebral conjunctival incision through the ventral punctum and can­ aliculus (Fig.  16.15). Next, a horizontal mattress suture is placed from the edge of the incised ventral punctum and onto the medial canthus, and the suture is gently tightened; the tension puckers the skin and opens the punctum. The suture is left in place until the punctum heals. Punctal cau­ terization involves discrete placement of cautery burns around the ventral punctum and the cicatrization opens the ventral punctum (Fein, 1977).

Atresia of the Canaliculus, Nasolacrimal Sac, and Nasolacrimal Duct A

B

C Figure 16.13  Ventral punctal aplasia. Note the ballooning of the conjunctiva over an aplastic puncta (A) during a normograde nasolacrimal flush through the superior puncta. The ballooning conjunctiva is excised with scissors (B) to create a new punctum (C).

Atresia of the canaliculus, nasolacrimal sac, or duct are rare (Lavach, 1993; Severin, 1995). Congenital anomalies of the nasolacrimal duct have been reported in cattle (Heider et al., 1975; van der Woerdt et al., 1996; Wilkie & Rings, 1990) and the horse (Latimer & Wyman, 1984; Lundvall & Carter, 1971), but not in the dog. When the ventral canaliculus, nasolacrimal sac, or nasolacrimal duct are missing, epiphora will be present, and the diagnosis is confirmed with a dacryocystorhinograph. Therapeutic options are limited to surgery, and they include conjunctival rhinostomy (Blicker & Buffam, 1993; Covitz et al., 1977; Gelatt & Gelatt, 2011; Long, 1975), con­ junctival maxillary sinusotomy (Gelatt & Gelatt, 2011), or conjunctival buccostomy (Fig. 16.16) (Gelatt & Gelatt, 2011). These procedures attempt to create a permanent fistula from the conjunctiva to the nasal turbinates, maxillary sinus, or mouth, respectively. The conjunctival rhinostomy is com­ pleted most commonly. A custom‐made, 6‐French polyethyl­ ene cannula is constructed either by estimating the total length from a preoperative radiograph for the conjunctival rhinostomy and conjunctival maxillary sinusotomy or by direct measurement on the patient for the conjunctival buc­ costomy. The distal end of the cannula is cut on an oblique

SECTION IIIA

(see Fig. 16.3) and nasolacrimal flushing is warranted. The conjunctiva over the canaliculus will bulge during flushing. Ventral punctal atresia is treated by surgical excision of the ballooning conjunctiva (Fig. 16.13). The affected eye is then treated with topical antibiotic and corticosteroid solutions four times a day until reexamination in approximately 7 days; if the punctum is patent and epiphora no longer pre­ sent, further therapy is not required. If the punctum has closed or significantly narrowed, it should be enlarged by the 1–2–3 snip technique (Fig.  16.14A–D) (Grahn & Mason, 1995; Lavach, 1993) or with a punctal dilator (Fig. 16.14E, F). The punctal dilator is inserted through the ballooning con­ junctiva and down the canaliculus as the dilator is twisted (Fig. 16.14E, F). The enlarged punctum and canaliculus and

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Section IIIA: Canine Ophthalmology

A

B

C

D

E

F

Figure 16.14  The 1–2–3 snip technique (A–D) using scissors for enlarging a micropunctum or stenotic punctum. The punctum and canaliculus are cannulated for approximately 3 weeks postsurgery. E. A photograph of a punctal dilator; note the two varied sized taper ends. F. The punctal dilator is inserted into the ventral micropuncta and twisted to enlarge the puncta and canaliculus.

taper, and the proximal end is cut so that two suture tabs are present, thus allowing it to be anchored to the medial can­ thus. Both ends are open flamed until they are smooth, and the cannula is autoclaved. The conjunctiva is surgically pre­ pared with three lavages of dilute (1:25–1:50) aqueous iodine, and a 0.25‐inch Steinmann pin is inserted in a Jacob’s

chuck. The pin is then drilled through the conjunctiva at the medial canthus and into the dorsal nares, maxillary sinus, or buccal cavity (Fig.  16.16A). The custom‐made cannula is inserted through the tract, and the tabs are sutured into the medial canthus with simple, interrupted, 5‐0 nonabsorbable monofilament suture (Fig. 16.16B, C). The cannula is left in

16: Diseases and Surgery of the Canine Nasolacrimal System

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SECTION IIIA

A

B Figure 16.15  An illustration of the punctal pucker technique. The ventral puncta and canaliculus and overlying palpebral conjunctiva are cut with small Vanna’s scissors (A). A horizontal mattress suture is placed with enough tension to cause the punctum and canaliculus to gape (B). The suture is left in place until the punctum and canaliculus are epithelialized and the wound has healed.

place for as long as possible provided that it is secure. To ensure a permanent fistula, the cannula should be left in place for a minimum of 12–20 weeks. The affected eye is treated with topical antibiotic steroid drops to decrease scar­ ring and bacterial growth while the epithelium is growing over the exposed tissues around the tube. Complications related to these procedures include cor­ neal ulceration secondary to cannula or suture contact, dis­ lodgement of the cannula, and strictures of the fistula after the cannula has been removed. Surgeons must take care to avoid iatrogenic damage to neighboring tissues (e.g., the facial and infraorbital veins, arteries, and nerves). The longer the cannula is left in situ, the less likely strictures will develop. A surgical technique based on the transposition of the parotid duct to the medioventral conjunctival fornix to allow tear drainage into the mouth was successful for treat­ ment of a nonpatent nasolacrimal drainage system in a dog (Scotti et  al., 2007). In this procedure, the parotid duct is cannulated with 2/0 nylon from the oral papilla. A 3 cm skin incision centered on the cranial border of the masseter mus­ cle is made over the lateral aspect of the cheek. The parotid duct is identified between the buccal branches of the facial nerve and carefully dissected from surrounding tissues. The proximal duct is ligated and sectioned near the parotid gland and transposed to the medioventral conjunctival for­ nix, between the lower eyelid and nictitating membrane through a subcutaneous tunnel. The transected end is then

spatuled and sutured to the conjunctiva with simple inter­ rupted sutures (Scotti et  al., 2007). Parotid gland atrophy was reported following the procedure. This technique may avoid some of the complications of conjunctival rhinos­ tomy, conjunctival buccostomy, and conjunctival maxillary sinusotomy.

Congenital Puncta and Canaliculi Misplacement Congenital puncta and canaliculi misplacement is often asymptomatic in dogs. When chronic epiphora is present and relates to the position of the ventral punctum, surgical repositioning is indicated. This procedure should be com­ pleted with the aid of an operating microscope. After rou­ tine presurgical preparation and positioning, the affected punctum and canaliculus are cannulated with a sterile, 24‐gauge intravenous catheter or monofilament suture. This allows the ophthalmic surgeon to microdissect the punctum and thin‐walled canaliculus accurately and to move them through a conjunctival incision to the eyelid margin approximately 3 mm from the medial canthus. The conjunctival rim around the punctum is sutured to the medial canthal region with 9‐0 absorbable sutures (Fig. 16.17), and the catheter is removed. Specific care and attention to detail are required during dissection, transloca­ tion, and suturing to prevent strictures or corneal contact. Topical ophthalmic antibiotics are applied until the inci­ sions have healed (in approximately 1 week).

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Section IIIA: Canine Ophthalmology

Maxillary sinus

SECTION IIIA

Nasal cavity

Buccal cavity

A

C

B Figure 16.16  Conjunctival rhinostomy. A. Conjunctival rhinostomy is completed by drilling a hole into the nasal cavity with a Steinmann pin and Jacob’s chuck. B. Conjunctival maxillary sinusotomy is completed by drilling a hole into the maxillary sinus from the medial canthus. Conjunctival buccostomy is completed by blunt dissection from the medial canthus to the oral cavity. C. A custom‐made cannula is then inserted into the tract and sutured to the medial canthus.

Congenital Canaliculi Obstruction Epiphora secondary to compression of the canaliculi by a congenital cyst of canalicular origin (i.e., canaliculops) has been reported in the dog (Gerding, 1991). In this report, can­ alicular patency was restored by surgical removal of the cyst.

Congenital Nasolacrimal Duct Obstructions The nasolacrimal duct in the dog has been reported to be occluded by dacryops (Grahn & Mason, 1995). These cystic obstructions were assumed to be congenital and similar to those reported to affect the canaliculi (Gerding, 1991). They were diagnosed through the use of DCG and rhinoscopy, and they were confirmed with biopsy and light microscopic examination. They were treated by surgical exploration of the

nasal cavity, curettage, and cyst drainage (Grahn & Mason, 1995), cyst removal (Lussier & Carrier, 2004; Ota et al., 2009), and by nasal endoscopic cyst perforation (White et  al., 1984), which relieved the nasolacrimal duct obstructions. Laser dacryocystorhinostomy has been reported as a suc­ cessful therapy for congenital obstructions of the nasolacri­ mal duct system in humans (Bartley, 1994; Dutton & Holck, 1996; Javate et al., 1995; Schauss et al., 1996; Seppa et al., 1994; Tutton & O’Donnell, 1995). As this technology becomes more readily available, these techniques may be applied to the dog.

Developmental Disorders Reported inherited nasolacrimal duct anomalies are limited to puncta atresia in Bedlington Terriers; these are ­congenital

A

B

C

D Figure 16.17  Microsurgical repositioning of a misplaced lower puncta and canaliculi. A. The lower lacrimal punctum is identified. B. The punctum is cannulated by monofilament suture and the punctum microdissected with the canaliculus. C and D. Both lower punctum and canaliculus are moved through the conjunctival incision to the medial canthal eyelid margin.

disorders, discussed previously in this chapter. However, many brachycephalic and toy dogs have epiphora related to multiple anomalies of the medial canthal region and infe­ rior puncta (Fig.  16.18). These anomalies are inherited as part of the facial development in these breeds of dogs, and

epiphora usually manifests in the first year of life. Therefore, it is appropriate to categorize this nasolacrimal dysfunction as developmental. The inferior puncta and canaliculi are commonly displaced inward and ventrally by a subtle, medioventral entropion, which rolls the medial eyelid mar­ gin into the cornea and partially obstructs the puncta and narrows the canalicular lumen (see Fig.  16.18). This dis­ placement is integral to the tear‐staining syndrome com­ monly seen in the toy and brachycephalic breeds. This tear‐staining syndrome has been examined by comparison of tear production and excretion and of the angle of bend between the vertical and horizontal bony lacrimal duct in tear‐stained Poodles and German Shepherds without epi­ phora (Seo & Nam, 1995). The results of that study revealed that tear staining in the Poodle was related to a prolonged rate of tear drainage. Tear production in these two popula­ tions were similar, and the angle of the bony nasolacrimal duct was more obtuse in the German Shepherd. Epiphora and unsightly tear staining in the Poodle and other small breeds (see Fig. 16.3 and Fig. 16.4) develop during the post­ weaning period. The puncta are usually normal in these dogs, and the clinical signs relate to multiple factors, includ­ ing displacement of the ventral puncta and compression of the canaliculi by the medioventral entropion. In addition, tight medial canthal ligaments displace the medial canthus ventrally and, in combination with medial canthal trichiasis and eyelid trichiasis, exacerbate tear spillage in these dogs. Oral tetracycline (Thun et  al., 1975) and metronidazole (Filipek & Rubin, 1977; Gale, 1976) have been reported as a therapy for tear staining, but neither has any appreciable effect on tear production or excretion. Their success relates to reduced staining of the medial canthal region rather than to control of the epiphora. Therefore, they are used infre­ quently as therapy today. Removal of the gland of the third eyelid has also been recommended as a surgical therapy for epiphora (Kerpsack & Kerpsack, 1966), but this is not justi­ fiable when tear production is normal. The treatment of choice for this condition is a Hotz–Celsus repair of the medial ventral entropion in which a triangular piece of skin is excised with the apex of the triangle opposite the lower lacrimal punctum (Peiffer et al., 1978) or, preferably, a bilat­ eral medial canthoplasty to correct the caruncular trichiasis and tight medial canthal ligaments (Fig.  16.19) (Jensen, 1979; Ny et al., 2006). Medial canthoplasty can also be used to reduce the palpebral fissure size in brachycephalic dogs. In this procedure, the superior and inferior lacrimal puncta are identified and perpendicular incisions are made in the eyelid margin medial to these structures. The medial palpe­ bral ligament may be cut, taking care to preserve the canali­ culi, and the skin is undermined to free it from its orbital attachments. An arrow‐shaped wedge of skin near the medial canthus is removed, as well as the caruncle. The resulting skin wound is closed in two layers using 6‐0 to 9‐0 absorbable suture to appose the palpebral conjunctiva and

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Figure 16.18  The anomalies of the medial canthus of small‐breed dogs that predispose to epiphora and pigmentary keratitis. Note the caruncular trichiasis, the tight medial canthal ligaments that create a medial canthal trough, and the medial ventral entropion that compress the ventral punctum and canaliculus.

A

B

D

C

E

Figure 16.19  A medial canthal plasty to repair the anomalies shown in Figure 16.18. A. Note the medial palpebral ligament is cut. B. The caruncular trichiasis and medial canthal trough are excised to the level of the dorsal and ventral puncta. C. The palpebral conjunctival is apposed with 9‐0 absorbable suture. D and E. The medial canthal skin is apposed with 5‐0 nylon sutures. The medial ventral entropion is corrected with a Hotz–Celsus repair.

5‐0 nylon sutures to close the skin, ­employing a figure‐of‐ eight suture at the lid margin (Ny et al., 2006). The medial ventral entropion may then be corrected with a Hotz–Celsus repair if necessary (see Fig. 16.19D, E).

et al., 1974a, 1974b; Laing et al., 1988; Lavach, 1993; Nykamp et al., 2004; Severin, 1995), and invasion or compression by neoplasms (Carter, 1970; Gelatt & Gelatt, 2011; Hill et  al., 1974a, 1974b; Lavach, 1993).

Acquired Diseases

Lacerations

Acquired nasolacrimal disorders of the dog include trau­ matic lacerations (Gelatt & Gelatt, 2011; Hill et  al., 1974a, 1974b; Lavach, 1993; Peiffer et al., 1987), dacryocystitis and obstruction with foreign bodies (Gelatt & Gelatt, 2011; Hill

Facial trauma may result in lacerations of the puncta, cana­ liculi, medial canthus, and eyelids. Lacerations of the canali­ culi are diagnosed with use of biomicroscopic examination and the bubble test (Loff et al., 1996), which involves can­ nulation of both puncta and injection of air. The resultant

16: Diseases and Surgery of the Canine Nasolacrimal System

A

B

C

D

E

Figure 16.20  Microsurgical repair of a lacerated canaliculus. Note the distal lacerated end of the duct is identified by injection of viscous fluid and air bubbles (A), is cannulated (B), and is then repaired by meticulous apposition of the tissue around the canaliculus (C and D). The cannula is sutured to the ventral eyelid (E) and left in situ for approximately 3 weeks.

­ owever, should be treated with conjunctival rhinostomy, h conjunctival–maxillary sinusotomy, or conjunctival buccos­ tomy (Gelatt & Gelatt, 2011; Latimer & Wyman, 1984). Balloon dilatations of recurrent obstructions in the human nasolacrimal duct have been reported (Iigit et  al., 1996; Janssen et al., 1994; Liermann et al., 1996; Örge & Dar, 2015).

Dacryocystitis and Foreign Bodies Clinical manifestations of dacryocystitis and nasolacrimal duct foreign bodies include epiphora, purulent conjunctival discharge, punctal foreign bodies (see Fig. 16.5), and drain­ ing skin fistulas ventral to the medial canthus (Bessler et al., 1994; Gelatt, 1991b; Gelatt & Gwin, 1981; Laing et al., 1988; Severin, 1995). Dacryocystitis in the dog usually develops secondary to nasolacrimal duct obstruction. This is most commonly caused by foreign bodies that lodge in the nasol­ acrimal sac (Pope et al., 2001). These foreign bodies must be removed for effective therapy. Dacryocystitis has also been reported in a dog secondary to nasolacrimal duct obstruction caused by an ectopic, unerupted, intranasal tooth (Voelter‐ Ratson et al., 2015), and in humans secondary to obstruction with congenital cysts (Choi et  al., 1995), tuberculosis (Arstenstein et  al., 1993; Bessler et  al., 1994; Cotton et  al., 1995), and dacryoliths (Dhillon et al., 2014). Dacryocystitis has been reported in dogs to induce nasal cysts (Lussier & Carrier, 2004; van der Woerdt et  al., 1997; Voelter‐Ratson et al., 2015). The diagnosis of dacryocystitis is confirmed through use of imaging modalities and cytological examination of the contents from a nasolacrimal lavage or from biopsies from tissues excised during surgical exploration (i.e., dacryocyst­ otomy). Foreign bodies may be flushed from the nasolacri­ mal duct system by retrograde or normograde lavages. Depending on the location, foreign bodies may be removed manually using alligator forceps guided by ultrasound, endoscopy, rhinoscopy, or fluoroscopy (Barsotti et al., 2019; Strom et al., 2018). They may also be removed via a dacryo­ cystotomy (Fig. 16.21). The skin incision for a dacryocysto­ tomy is ventral to the medial canthus over the lacrimal fossa. The maxillary and lacrimal bones are commonly burred or removed with rongeurs until the lacrimal sac is exposed and incised (Fig.  16.21). The foreign material is removed and submitted for aerobic and anaerobic cultures and cytological examination. The nasolacrimal duct system is then cannulated with a silastic tube and treated with topi­ cal broad‐spectrum antibiotics for approximately 3 weeks postoperatively (Dhillon et al., 2014; Gelatt, 1991b; Gelatt & Gwin, 1981; Getty, 1975; Laing et  al., 1988; Lavach et  al., 1984; Murphy et  al., 1977; Severin, 1995). Cannulation of the nasolacrimal duct system may be anterograde or retro­ grade. For retrograde cannulation, the nasal punctum is located using rhinoscopy or using a nasal speculum inserted into the nostril and directed ventrally (Fig. 16.21B). A pair

SECTION IIIA

bubbling allows the surgeon to detect and cannulate the lac­ erated canalicular ends with a silastic tube (Fig.  16.20). Deploying viscoelastic superficially in the vicinity of the injured canaliculus and injecting it into the proximal torn end can also improve visualization of the operative field because it promotes retraction of the surrounding tissue and tamponades bleeding. This also dilates and lubricates the torn canaliculus allowing for easier intubation (Örge & Dar, 2015). The lacerated eyelid surfaces are then repaired by microsurgical apposition of the tissues around the cannu­ lated duct (Fig. 16.20). The eye is treated with topical antibi­ otic solutions four times a day until the cannula is removed (at approximately 3 weeks). Fractures of the maxillary or lacrimal bones may compress or lacerate the nasolacrimal duct or canaliculi as well. Plain radiography and DCG are required to confirm the diagnosis. Lacerated nasolacrimal ducts often form permanent fistula intranasal at the point of laceration. Extensive trauma that results in epiphora and a nonpatent nasolacrimal duct,

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SECTION IIIA

(e) (a)

(a)

(b) (b)

(c)

(f)

(d)

(c)

(e) (g)

A

(d)

B

Figure 16.21  A. Dacryostomy in the dog. (a) An incision is completed ventral to the medial canthus into the lacrimal sac. (b) and (c) The foreign material is removed and submitted for laboratory evaluation. (d) The nasolacrimal duct system is cannulated with a silastic tube, and (e) the incision is closed routinely. B. Retrograde cannulation of the nasolacrimal duct. (a) The nasal punctum is identified by gently spreading the external nares with a small curved hemostat. (b) A flame‐rounded end of 5‐0 nylon suture is introduced into the punctum with the aid of a second small hemostat. The suture is advanced up the duct (c and d) and through the canaliculus and (e) exits the ventral punctum. (f) A small silastic tube is threaded over the indwelling suture and through the nasolacrimal duct system, and (g) both ends are secured with sutures to the ventral eyelid and nares skin after the indwelling suture is removed.

of curved mosquito forceps introduced through the nasal speculum and into the nasal puncta and slight opening of the jaws will facilitate passage of a flamed, rounded 5‐0  nylon suture tip held with a second pair of mosquito forceps, which directs the suture up through the nasolacri­ mal duct and out through the ventral canaliculus and puncta. A small silastic tube is threaded over the suture and up the nasolacrimal duct and out of the puncta. The tube is then secured with a suture to the ventral eyelid and nasal skin, and the indwelling suture is removed. Fluoroscopy‐ guided stent placement has recently been described (Strom et  al., 2018). This technique utilized a hydrophilic guide­ wire  introduced anterograde through the superior or ­inferior puncta or retrograde through the nasal punc­ tum under fluoroscopic guidance, followed by passage of an

a­ ppropriately sized stent retrograde over the guidewire into the nasal punctum. The guidewire was then removed and the stent secured to the adjacent skin (Strom et al., 2018). Fluoroscopy was useful in identifying appropriate passage of the guidewire and facilitated stent placement in a mini­ mally invasive manner (Strom et al., 2018).

Dacryolithiasis Dacryoliths are concretions of debris and protein which form in the nasolacrimal sac. They may calcify and contrib­ ute to nasolacrimal duct obstruction. They are reported in humans to form in any part of the lacrimal system (Lew et  al., 2004). Dacryolithiasis may be asymptomatic. However, the most common clinical manifestations are

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epiphora, acute or recurrent dacryocystitis, punctal dis­ charge, and medial canthal swelling (Mishra et al., 2017). Dacryoliths have been found in up to 17% of people under­ going dacryocystorhinostomy (Iliadelis et al., 1999; Iliadelis et al., 2006; Lew et al., 2004; Mishra et al 2017; Repp et al., 2009; Wilkins & Pressly, 1980,). There is one report of dacryolithiasis in a Labrador Retriever (Malho et al., 2013). Dacryoliths were located within a canalicular cyst which was presumed to have developed from a canalicular diver­ ticulum. Mineral analysis of the dacryoliths revealed them to be composed of calcium carbonate (Malho et al., 2013). The mechanism of dacryolith formation is poorly under­ stood. However, changes in tear flow are thought to play an important role (Lew et  al., 2004). In humans, removal of dacryoliths is the most effective treatment in symptomatic cases (Mishra et al. 2017).

Neoplasia of the Nasolacrimal Duct Primary neoplasia of the nasolacrimal duct is rare in all spe­ cies (Lavach, 1993; Pe’er et  al., 1996; Rahangdale et  al., 1995). Lymphoma is reported to have invaded the lacrimal sac and to have induced dacryocystitis (Karesh et al., 1993). Pseudotumors of the lacrimal canaliculus have been reported in a dog (Williams et  al., 1998). Tumors of nasal turbinates and the maxillary sinus, however, may compress or invade the nasolacrimal ducts and spread into the orbit via the nasolacrimal foramen and cause epiphora, mucopu­ rulent or serosanguineous ocular and nasal discharge, masses ventral to the medial canthus (Fig.  16.22), and orbital signs, including prolapse of the third eyelid, enoph­ thalmos, and conjunctival hyperemia (Gelatt et  al., 1970). The diagnosis of nasal neoplasia with involvement of the nasolacrimal duct system is established by clinical examina­ tion, plain and contrast radiography (see Fig.  16.11), or advanced multisectional imaging (see Fig. 16.12), and it is confirmed through light microscopic evaluation of nasal biopsies. Nasal neoplasia is a therapeutic challenge, and various surgical, medical, and radiation therapies have been

Figure 16.22  A medial canthal mass in an 8‐year‐old, neutered male Shetland Sheepdog. Nasal radiographs revealed signs consistent with a nasal tumor, which eroded through the maxillary and lacrimal bones into the medial canthal region. Results of nasal endoscopic biopsies confirmed the diagnosis of a nasal carcinoma.

reported (Gelatt et  al., 1970; Hahn et  al., 1992; Laing & Binnington, 1988; Theon et al., 1993).

ACKNOWLEDGMENT The illustrations in this chapter are by Juliana Deubner, Medical Illustrator, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

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Hill, J.C., Bethell, W. & Smirmaul, H.J. (1974a) Lacrimal drainage – a dynamic event. Part I: mechanics of tear transport. Ophthalmology, 9, 411–416. Hill, J.C., Bethell, W. & Smirmaul, H.J. (1974b) Lacrimal drainage – a dynamic evaluation. Part II: clinical aspects. Ophthalmology, 9, 417–424. Hoffman, K.T., Hosten, N., Anders, N., et al. (1999) High‐ resolution conjunctival contrast enhanced MRI dacryocystography. Neuroradiology, 41, 208–213. Iigit, E.T., Yüksel, D., Unal, M., et al. (1996) Treatment of recurrent nasolacrimal duct obstructions with balloon expandable metallic stents: results of early experience. American Journal of Neurologic Radiology, 17, 657–663. Iliadelis, E., Karabatakis, V. & Sofoniou, M. (1999) Dacryoliths in chronic dacryocystitis and their composition (spectrophotometric analysis). European Journal Ophthalmology, 9, 266–268. Iliadelis, E.D., Karabatakis, V.E. & Sofoniou, M.K. (2006) Dacryoliths in a series of dacryocystorhinostomies: histologic and chemical analysis. European Journal Ophthalmology, 16, 657–662. Janssen, A.G., Mansour, K., Krabbe, G.J., et al. (1994) Dacryoplasty: treatment of epiphora by means of balloon dilatation of the obstructed nasolacrimal duct system. Radiology, 193, 453–456. Javate, R.M., Mansour, K., Krabbe, G.J., et al. (1995) The endoscope and the radiofrequency unit in DCR surgery. Ophthalmic Plastic and Reconstructive Surgery, 11, 54–58. Jensen, H.E. (1979) Canthus closure. Compendium for Continuing Education for the Practicing Veterinarian, 10, 735–741. Jedrzynski, M.S. & Bullock, J.D. (1994) Lacrimal ultrasonography. Ophthalmic Plastic and Reconstructive Surgery, 10, 114–120. Jones, L.T. (1961) An anatomical approach to problems of the eyelids and lacrimal apparatus. Archives of Ophthalmology, 66, 137–150. Karesh, J.W., Perman, K.I. & Rodrigues, M.M. (1993) Dacryocystitis associated with malignant lymphoma of the lacrimal sac. Ophthalmology, 100, 669–673. Kerpsack, R.W. & Kerpsack, W.R. (1966) The orbital gland and tear staining in the dog. Veterinary Medical and Surgery Small Animal Clinic, 61, 121–124. Kirchof, K., Hähnel, S., Jansen, O., et al. (2000) Gadolinium‐ enhanced magnetic resonance dacryocystography in patients with epiphora. Neuroradiology, 24, 327–331. Knop, E. & Knop, N. (2001) Lacrimal drainage‐associated lymphoid tissue (LDALT): a part of the human mucosal immune system. Investigative Ophthalmology and Visual Science, 42, 566–574. Laing, E.J. & Binnington, A.G. (1988) Surgical therapy of canine nasal tumors: a retrospective study (1982–1986). Canadian Veterinary Journal, 29, 809–813. Laing, E.J., Speiss, B. & Binnington, A.G. (1988) Dacryocystotomy: a treatment for chronic dacryocystitis in

the dog. Journal of the American Animal Hospital Association, 24, 223–226. Latimer, C.A. & Wyman, M. (1984) Atresia of the nasolacrimal duct in three horses. Journal of the American Veterinary Medical Association, 84, 989–992. Lavach, J.D. (1993) The lacrimal system. In: Textbook of Small Animal Surgery (ed. Slatter, D.), 2nd ed., pp. 225–245. Toronto: WB Saunders. Lavach, J.D., Severin, G.A. & Roberts, S.M. (1984) Dacryocystitis in dogs: a review of twenty‐two cases. Journal of the American Animal Hospital Association, 20, 463–467. Lavach, J.D., Thrall, M.A., Benjamin, M.M. & Severin, G.A. (1977) Cytology of normal and inflamed conjunctivas in dogs and cats. Journal of the American Veterinary Medical Association, 170, 722–727. Lefebvre, D.R. & Freitag, S.K. (2012) Update on imaging of the lacrimal drainage system. Seminars in Ophthalmology, 27, 175–186. Lemp, M.A. & Wolfley, D.E. (1992) The lacrimal apparatus. In: Physiology of the Eye (ed. Hart, W.M.), 9th ed., pp. 24–27. Toronto: Mosby‐Year Book. Lew, H., Lee, S. & Yun, Y. (2004) Measurement of pH, electrolytes and electrophoretic studies of tear proteins in tears of patients with dacryoliths: a novel concept for dacryoliths. Ophthalmologica, 218, 130–135. Liermann, D., Berkefeld, J., Fries, U., et al. (1996) Balloon dacryocystoplasty: an alternative therapy for obstructed tear ducts. Ophthalmologica, 210, 319–324. Loff, H.J., Wobig, J.L., Dailey, R.A., et al. (1996) The bubble test: an atraumatic method for canalicular laceration repair. Ophthalmic Plastic and Reconstructive Surgery, 1, 61–64. Loftus, W.K., Kew, J. & Metreweli, C. (1996) Nasolacrimal duct opacity on CT. British Journal of Radiology, 69, 630–631. Long, R.D. (1975) The relief of epiphora by conjunctivorhinostomy. Journal of Small Animal Practice, 16, 381–386. Lundvall, R.L. & Carter, J.D. (1971) Atresia of the nasolacrimal meatus in the horse. Journal of the American Veterinary Medical Association, 159, 289–291. Lussier, B. & Carrier, M. (2004) Surgical treatment of recurrent dacryocystitis secondary to cystic dilation of the nasolacrimal duct in a dog. Journal of the American Animal Hospital Association, 40, 216–219. MacEwen, C.J., Phillips, M.G. & Young, J.D. (1994) Value of bacterial culturing in the course of congenital nasolacrimal duct (NLD) obstruction. Journal of Pediatric Ophthalmology and Strabismus, 31, 246–250. Malho, P., Sansom, J., Johnson, P. & Stewart, J. (2013) Canine dacryolithiasis: a case description and mineral analysis. Veterinary Ophthalmology, 16, 289–296. Manfre, L., de Maria, M., Todaro, E., et al. (2000) MR dacryocystography: comparison with dacryocystography and CR dacryocystography. American Journal of Neuroradiology, 21, 1145–1150. Massauld, T.F., Whittet, H.B. & Anslow, P. (1993) CT‐ dacryocystography for nasolacrimal duct obstruction

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following paranasal sinus surgery. British Journal of Radiology, 66, 223–227. Mishra, K., Hu, K.Y., Kamal, S., et al. (2017) Dacryolithasis: a review. Ophthalmic Plastic Reconstructive Surgery, 33, 83–89. Murphy, J.M. (1988) Exfoliative cytologic examination as an aid in diagnosing ocular diseases in the dog and cat. Seminars in Veterinary Medicine and Surgery in Small Animals, 3, 10–14. Murphy, J.M., Severin, G.A. & Lavach, J.D. (1977) Nasolacrimal catheterization for treating chronic dacryocystitis. Veterinary Medicine, Small Animal Clinician, 72, 883–887. Noden, D.M. & de Lahunta, A. (1985) The Embryology of Domestic Animals: Developmental Mechanisms and Malformations. London: Williams & Wilkins. Ny, Y., Park, S.A., Jeong, M.B., et al. (2006) Medial canthoplasty for epiphora in dogs: a retrospective study of 23 cases. Journal of the American Animal Hospital Association, 42, 435–439. Nykamp, S.G., Scrivani, P.V. & Pease, A.P. (2004) Computed tomography dacryocystography evaluation of the nasolacrimal apparatus. Veterinary Radiology & Ultrasound, 45, 23–28. Örge, F.H. & Dar, S.A. (2015) Canalicular laceration repair using viscoelastic injection to locate and dilate the proximal torn edge. Journal of the American Association of Pediatric Ophthalmology and Strabismus, 19, 217–219. Ota, J., Pearce, J.W. & Finn, M.J. (2009) Dacryops (lacrimal cyst) in three young Labrador Retrievers. Journal of the American Animal Hospital Association, 45, 191–196. Paulsen, F.P., Pufe, T., Schaudig, U., et al. (2001) Detection of natural peptide antibiotics in human nasolacrimal ducts. Investigative Ophthalmology and Visual Science, 42, 2157–2163. Pavlidis, M., Stupp, T., Grenzebach, U., et al. (2005) Ultrasonic visualization of the effect of blinking on the lacrimal pump mechanism. Graefe’s Archives for Clinical and Experimental Ophthalmology, 243, 228–234. Pe’er, J., Hidayat, A.A., Ilsar, M., et al. (1996) Glandular tumors of the lacrimal sac. Their histopathologic patterns and possible origins. Ophthalmology, 103, 1601–1605. Peiffer, R.L., Gelatt, K.N., Gwin, R.M., et al. (1978) Correction of inferior medial entropion as a cause of epiphora. Canine Practice, 5, 27–31. Peiffer, R.L., Nasisse, M.P., Cook, C.S. & Harling, D.E. (1987) Surgery of the canine and feline orbit, adnexa and globe. Part 4: the nasolacrimal system. Companion Animal Practice, 1, 5–11. Pope, E.R., Champagne, E.S. & Fox, D. (2001) Intraosseous approach to the nasolacrimal duct for removal of a foreign body in a dog. Journal of the American Veterinary Medical Association, 218, 541–542. Purgason, P.A., Hornblass, A. & Loeffler, M. (1992) Atypical presentation of fungal dacryocystitis. A report of two cases. Ophthalmology, 99, 1430–1432. Rached, P.A., Canola, J.C., Schluter, C., et al. (2011) Computedtomographic‐dacryocystography (CT‐DCG) of the

normal canine nasolacrimal drainage system with three‐ dimentional reconstruction. Veterinary Ophthalmology, 14, 174–179. Rahangdale, S.R.N., Castillo, M & Shockley, W. (1995) MR in squamous cell carcinoma of the lacrimal sac. American Journal of Neurologic Radiology, 16, 1262–1264. Repp, D., Burkat, C.N. & Lucarelli, M.J. (2009) Lacrimal excretory system conctretions: canalicular and lacrimal sac. Ophthalmology, 116, 2230–2235. Rubin, L.F. (1989) Inherited Eye Diseases in Purebred Dogs. Baltimore, MD: Williams & Wilkins. Rubin, P.A., Bilyk, J.R., Shore, J.W., et al. (1994) Magnetic resonance imaging of the lacrimal drainage system. Ophthalmology, 101, 235–243. Sasaki, T., Nagata, Y. & Sugiyama, K. (2005a) Nasolacrimal duct obstruction classified by dacryoendoscopy and treated with inferior meatal dacryorhinotomy. Part I: Positional diagnosis of primary nasolacrimal duct obstruction with dacryoendoscopy. American Journal Ophthalmolog, 140, 1065–1069. Sasaki, T., Nagata, Y. & Sugiyama, K. (2005b) Nasolacrimal duct obstruction classified by dacryoendoscopy and treated with inferior meatal dacryorhinotomy. Part II: Inferior meatal dacryorhinotomy. American Journal Ophthalmology, 140, 1070–1074. Schauss, F., Weber, R., Draf, W. & Keerl, R. (1996) Surgery of the lacrimal system. Acta oto‐rhino‐laryngologica Belgica, 50, 143–146. Scotti, S., Klein, A. & Vanore, M. (2007) A new surgical method for the control of epiphora in dogs: modified parotid duct transposition. Journal of Small Animal Practice, 48, 279–282. Seo, K.M. & Nam, T.C. (1995) Tear formation, the patency and angle of bend of nasolacrimal duct in poodle dogs with tear staining syndrome. Korean Journal of Veterinary Research, 35, 383–390. Seppa, H., Grenman, R. & Hartikainen, J. (1994) Endonasal CO2‐Nd: YAG laser dacryocystorhinostomy. Acta Ophthalmologica, 72, 703–706. Severin, G.A. (1972) Nasolacrimal duct catheterization in the dog. Journal of the American Animal Hospital Association, 8, 13–16. Severin, G.A. (1995) Severin’s Veterinary Ophthalmology Notes, 3rd ed. Fort Collins, CO: Design Pointe Communications. Strom, A.R., Culp, W.T.N., Leonard, B.C., et al. (2018). A multidisciplinary, minimally invasive approach combining lacrimoscopy and fluoroscopically guided stenting for management of nasolacrimal apparatus obstruction in dogs. Journal of the American Veterinary Medical Association, 252, 1527–1537. Takehara, Y., Isoda, H., Kurihashi, K., et al. (2000) Dynamic MR dacryocystography: a new method for evaluating nasolacrimal duct obstructions. American Journal of Roentgenology, 175, 469–473. Theon, A.P., Madewell, B.R., Harb, M.F. & Dungworth, D.L. (1993) Megavoltage irradiation of neoplasms of the nasal

and paranasal cavities in 77 dogs. Journal of the American Veterinary Medical Association, 202, 1469–1475. Thun, R., Helper, R.S. & Kungliga, L.C. (1975) Effect of tetracycline on tear production in the dog. Journal of the American Animal Hospital Association, 11, 802–804. Tutton, M.K. & O’Donnell, N.P. (1995) Endonasal laser dacryocystorhinostomy under direct vision. Eye, 9, 485–487. van der Woerdt, A., Wilkie, D.A. & Gilger, B.C. (1996) Congenital epiphora in a calf associated with dysplastic lacrimal puncta. Agricultural Practice, 17, 7–11. van der Woerdt, A., Wilkie, D.A., Gilger, B.C., et al. (1997) Surgical treatment of dacryocystitis caused by cystic dilatation of the nasolacrimal system in three dogs. Journal of the American Veterinary Medical Association, 211, 445–450. Voelter‐Ratson, K., Hagen, R., Grundmann, S. & Spiess, B.M. (2015) Dacryocystitis following a nasolacrimal duct obstruction caused by an ectopic intranasal tooth in a dog. Veterinary Ophthalmology, 18, 433–436.

Wearne, M.J., Pitts, J., Frank, J. & Rose, G.E. (1999) Comparison of dacryocystography and lacrimal scintigraphy in the diagnosis of functional nasolacrimal duct obstruction. British Journal of Ophthalmology, 83, 1032–1035. White, R.A.S., Herrtage, M.E. & Watkins, S.B. (1984) Endoscopic management of a cystic naso‐lacrimal obstruction in a dog. Journal of Small Animal Practice, 25, 729–735. Wilkins, R.B. & Pressly, J.P. (1980) Diagnosis and incidence of lacrimal calculi. Ophthalmic Surgery, 11, 787–789. Wilkie, D.A. & Rings, M. (1990) Repair of anomalous nasolacrimal duct in a bull by use of a conjunctivorhinostomy. Journal of the American Veterinary Medical Association, 196, 1647–1650. Williams, D.L., Long, R.D. & Barnett, K.C. (1998) Lacrimal pseudotumor in a young Bull Terrier. Journal of Small Animal Practice, 39, 30–32. Yakely, W.L. & Alexandra, J.E. (1971) Dacryocystorhinography in the dog. Journal of the American Veterinary Medical Association, 159, 1417–1421.

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17 Diseases and Surgery of the Canine Lacrimal Secretory System Elizabeth A. Giuliano Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA

This chapter focuses on clinical aspects of the canine lacri­ mal secretory system. The origin of tear components, func­ tions of the preocular tear film, and diagnostic procedures aimed at detecting or confirming tear deficiencies are reviewed. Because tear abnormalities are among the most common causes of canine ocular surface disease, the patho­ genesis and resulting surface changes are emphasized. Medical and surgical procedures applicable to treatment of tear‐deficient ocular surface diseases are discussed. Clinical findings and treatment of other conditions of the lacrimal secretory system (i.e., neoplasia, cysts) are also presented.

Formation and Dynamics of Tear Components The precorneal tear film (PTF) is crucial for the maintenance of ocular surface health and clear vision because it is the first refractive surface of the eye. Its functions include: primary oxygen source to the avascular cornea; lubricant between the lids and ocular surface; source of protective antimicro­ bial proteins; and removal of debris and exfoliated cells through drainage. The PTF is classically described as a superimposition of three structurally and functionally unique layers consisting of lipid, aqueous, and mucin com­ ponents (Fig. 17.1) and in some references, a fourth inner­ most layer of glycocalyx extending from the superficial layer of the ocular surface epithelia is described (Leonard et al., 2016; Levin et al., 2011). Over the past two decades, emerg­ ing research regarding tear film dynamics support the con­ cept that there is no clear‐cut barrier between the three “classic” components of the PTF and that the lipid, aqueous, and mucin layers are intricately mingled (Sack et al., 2000; Tiffany, 2008). Tear film thickness is a key variable in the study of normal tears and dry eye diseases. In humans, cur­ rently accepted PTF thickness is estimated to be 3.4 ± 2.6 µm (Levin et al., 2011; Wang et al., 2006). However, measuring a

changing fluid layer is challenging. Reports of the static human tear film thickness have varied widely as newer opti­ cal techniques utilizing laser interferometry, confocal microscopy, and meniscometry have shown that earlier esti­ mates by mechanical and chemical techniques, which dis­ turb PTF structure during sampling, may substantially underestimate tear film thickness (Prydal & Campbell, 1992; Prydal et al., 1992; Prydal et al., 1993; Tung et al., 2014; Yokoi & Komuro, 2004). Reports of total tear film thickness have ranged from 332 to 40 μm in humans with no consensus (Carrington et al., 1987b; Carrington et al., 1988; King‐Smith et  al., 1999; King‐Smith et  al., 2004; Prydal & Campbell, 1992; Prydal et al., 1992; Prydal et al., 1993; Wang et al., 2006; Yokoi & Komuro, 2004). As technology advances and use of newer imaging modalities such as real‐time optical coher­ ence tomography (OCT) become more available, differences between central tear film thickness and tear menisci of the upper and lower eyelids are being discovered (Wang et al., 2006). The important role between tear film and vision emphasizes the need for further research in veterinary oph­ thalmology (Koh & Maeda, 2007; Montés‐Micó, 2007; Montés‐Micó et  al., 2010). Further validation of tear film composition and thickness in various species is still needed. For descriptive purposes in this chapter, the three compo­ nents of the PTF will be discussed separately. The lipid layer is secreted by the tarsal (i.e., meibomian) glands, and provides a thin, oily component to the PTF, thus retarding evaporation and promoting a stable, even spread of tears over the cornea (Bron et  al., 2004; Butovich, 2011; Butovich et al., 2008; Butovich et al., 2012; Floyd et al., 2012; Mathers, 2004). Meibomian glands are holocrine, modified sebaceous glands arranged linearly within the dense connec­ tive tissues (i.e., tarsal plate) of the eyelid margin (Fig. 17.2). Meibomian secretions consist of wax monoesters, sterol esters, hydrocarbons, triglycerides, diglycerides, free sterols (i.e., cholesterol), free fatty acids, and polar lipids (including phospholipids) (Levin et al., 2011). The molecular weight of

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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d

Figure 17.1  The precorneal tear film is classically depicted with three layers, consisting of a deep mucin layer (a), an intermediate aqueous tear layer (b), and a superficial lipid layer (c). These three layers are secreted by conjunctival goblet cells and surface epithelial cells, nictitans and orbital lacrimal glands, and meibomian glands, respectively. Enlargement (d) depicts extensions (microplicae) of corneal surface cells, which are believed to provide an interface between the membrane‐bound mucin, a product of the surface epithelial cells, and the conjunctiva‐derived mucin. (Source: Courtesy of G. Constantinescu.)

meibomian lipids (i.e., meibum) is higher, and the polarity is lower, than that of sebum, thus meibomian lipids are fluid at body temperature (Driver & Lemp, 1996). Some models have proposed that a combination of PTF proteins and lipids could interact and behave similarly to lung surfactant to pro­ vide a noncollapsible viscoelastic gel that would allow for proteins to remain in their lowest free energy states while in contact with lipids (Butovich, 2011; Butovich et  al., 2008; Rantamaki et al., 2011). Meibomian glands are highly developed in the dog, with 20–40 glands per eyelid typically being present (Pollock, 1979). Glands are located within the tarsal plate, in which they form linear aggregates of secretory acini that are usu­ ally visible through the semitransparent palpebral conjunc­ tiva. These acini open into central ductules arranged at right angles to the eyelid margin, and they deliver lipid to the sur­ face of the eyelid through small openings just external (i.e., anterior) to the mucocutaneous junction (Pollock, 1979). Openings from the meibomian glands form a trough or line on the eyelid margin, which is sometimes referred to as the “gray line.” Gentle pressure applied to the eyelid margin may express secretions from the gland openings and help in the identification of the “gray line,” an important surgical land­ mark for most blepharoplastic procedures. Compression of the eyelids during normal blinking contributes to release of meibomian secretions, but the precise neural and hormonal mechanisms regulating the secretion of meibomian lipid are not well understood (Dartt, 2004; Davidson & Kuonen, 2004;

McCulley & Shine, 2004; Sullivan et al., 2000). Noninvasive meibometry can be used in conscious dogs and has been described as a means to quantify meibomian gland secre­ tions in this species. However, results have been variable (Benz et al., 2008; Ofri et al., 2007). The aqueous component of canine tears is secreted by lac­ rimal glands of the orbit and nictitating membrane (Fig. 17.2 and Fig. 17.3). Gross anatomy and morphometric evaluation of the canine lacrimal and third eyelid glands as well as com­ puted tomographic imaging characteristics of the normal canine lacrimal glands have been reported in recent years (Park et  al., 2016; Zwingenberger, 2014). The aqueous tear serves most of the avascular cornea’s metabolic needs by sup­ plying glucose, electrolytes, oxygen, and water to the superfi­ cial cornea. Aqueous fluid also lubricates the cornea, conjunctiva, and nictitating membrane. In addition, it removes metabolites such as carbon dioxide and lactic acid, and it flushes away particulate debris and bacteria from the ocular surface. The aqueous portion of the PTF is 98.2% water and 1.8% solids (i.e., mostly proteins) and consists of water, electrolytes, glucose, urea, surface‐active polymers, glycopro­ teins, and tear proteins (Davidson & Kuonen, 2004; Winiarczyk et al., 2015). Examples of primary tear proteins include globulins (i.e., secretory IgA, IgG, IgM), albumin, lysozyme, lactoferrin, lipocalin, epidermal growth factor, transforming growth factors, lacritin, and interleukens (Bron, 1997; Dartt, 2004; Klenkler et  al., 2007; Levin et  al., 2011; McKown et  al., 2009; Roberts & Erickson, 1962; Selinger

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c

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b

a

b

d

Figure 17.2  Anatomic location of the primary secretory tissues responsible for production of the tear components. a. Meibomian glands located within the tarsal plate. b. Conjunctival goblet cells. c. Orbital lacrimal gland. d. Nictitans lacrimal gland. (Source: Courtesy of G. Constantinescu.)

et al., 1979; Winiarczyk et al., 2015). Alterations in tear film composition is commonly investigated in dogs with corneal disease (Sebbag et  al., 2017; Williams & Burg, 2017; Wichayacoop et al., 2009). Alterations may also occur in dogs affected with cancer (de Freitas Campos et  al., 2008). However, further research is warranted. Antibodies, immu­ noglobulins, lysozyme, lactoferrin, transferrin, ceruloplas­ min, and glycoproteins all contribute to the antibacterial properties of tears (Bron et al., 2004; Fullard & Tucker, 1994). Certain topical medications (e.g., EDTA) may reduce the gelatinase activity present in tears of normal dogs (Couture et al., 2006). The PTF contains proteinase inhibitors as well as proteinases that play an important role in both ocular immu­ nity and in the prevention of excessive degradation of normal healthy ocular tissues (de Souza et  al., 2006; Winiarczyk et al., 2015). Two matrix metalloproteinases (MMP‐2, synthe­

sized by keratocytes, and MMP‐9, synthesized by corneal epi­ thelial cell and/or neutrophils after corneal wounding) are of major importance in corneal stromal remodeling and degra­ dation. Because of the intimate association between the PTF and the cornea, tears have commonly been used to evaluate these proteinases. The total proteolytic activity in tears has been found to be significantly increased after corneal wound­ ing. More specifically, ulcerative keratitis in animals has been associated with initially high levels of tear film proteolytic activity which decrease as ulcers heal and proteinase levels in melting ulcers remain elevated leading to rapid progression of the ulcers (Ollivier et al., 2007). The lacrimal glands of the orbit and the nictitating mem­ brane are tubuloacinar and histologically similar (Cabral et al., 2005; Martin et al., 1988). Ductules from these glands deliver aqueous tear secretions into the conjunctival for­ nices. In the dog, three to five ductules from the orbital lacri­ mal gland open into the dorsolateral conjunctival fornix (see Fig. 17.2), whereas the nictitans gland delivers aqueous tears onto the corneal surface through multiple ducts opening between lymphoid follicles on the posterocentral third eye­ lid (Fig. 17.4) (Moore et al., 1996; Park et al., 2016). The relative contributions by each of the main lacrimal glands to reflex tear secretion have been investigated in the dog by surgical removal of either one or both glands and measurement of the resulting tear production (Helper, 1970; Helper, 1976; Helper et al., 1974; Saito et al., 2001). The vol­ ume of tear fluid produced by each gland varied considera­ bly among animals. The orbital lacrimal gland was the main source of aqueous tears in some dogs, whereas the nictitat­ ing membrane gland was the main source in others (Helper et al., 1974). When either gland was removed singly, a com­ pensatory increase in tear production appeared to occur in the remaining gland. Removal of both glands resulted in near‐total absence of secretions, thereby suggesting that accessory conjunctival glands may not be present in the dog, or that they play an inconsequential role in aqueous secre­ tions. The role of each gland (i.e., orbital or nictitans glands) in the production of basal secretions versus reflex tear secre­ tions has not been determined. The chemical mediators of lacrimal gland secretion are cholinergic agonists, released from parasympathetic nerves, and norepinephrine, released from sympathetic nerves, located in both the cornea and conjunctiva (Dartt, 2004; Dartt, 2009; Tiffany, 2008). These neurotransmitters activate signal transduction pathways affecting the myoepithelial, acinar, and duct cells, and blood vessels of the lacrimal gland leading to secretion. Other stimuli of lacrimal gland secre­ tion include various proteins (i.e., EGF growth factor, neuro­ peptide Y, substance P, calcitonin gene‐related peptide) and hormones (Dartt, 2004; Davidson & Kuonen, 2004; Lemp, 2008). Androgen deficiency results in lacrimal tissue degen­ eration, decreased total volume of tears, and decreased tear protein content (Baudouin, 2001; Sullivan et  al., 2000).

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Figure 17.3  Topographic location of the orbital and nictitans lacrimal glands in the dog. a. Orbital gland. b. Nictitans gland. (Source: Courtesy of G. Constantinescu.)

Figure 17.4  Scanning electron micrograph of the bulbar surface of a canine third eyelid (nictitating membrane). A nictitans ductule opening onto the posterocentral surface of the third eyelid is well visualized. (Original magnification, 800×.)

Estrogen effects on the lacrimal gland remain controversial. Some studies have linked estrogen deficiency to the develop­ ment of KCS, whereas others have shown no change in lac­ rimal gland or tear film (Sullivan et al., 1998). Mucus, the third component to the PTF, is composed of mucin, immunoglobulins, urea, glycoproteins, salts, glucose, leukocytes, cellular debris, and enzymes (Davidson & Kuonen, 2004; Nichols et  al., 1985; Royle et  al., 2008). The mucus layer helps to provide a smooth refractive surface over the cornea, lubricates the cornea and conjunctiva, anchors the aqueous tear film to the corneal epithelium thus decreas­ ing shear forces, inhibits bacterial adherence, and prevents desiccation (Davidson & Kuonen, 2004; Leonard et al., 2016). Neurologic regulation of goblet cell mucin ­production is more thoroughly reviewed elsewhere (Levin et  al., 2011).

Ocular surface mucins show differences in species‐specific glycan expression, which likely has implications for their defensive properties where different microbial and environ­ mental challenges are encountered (Royle et  al., 2008). Mucins, classified as either secretory or membrane‐bound, are hydrated glycoproteins produced largely by the conjuncti­ val goblet cells but also by corneal and conjunctival epithelial cells, glycocalyx, and the lacrimal gland (Corfield, 1997; Ellingham et al., 1997; Hicks et al., 1997; Leonard et al., 2016; Watanabe, 2002). At present, many mucin (MUC) genes have been identified (Hicks et  al., 1997; Hicks et  al., 1998; Hirt et al., 2012; Leonard et al., 2016; Watanabe, 2002). Membrane‐ associated mucins are believed to: (1) promote water reten­ tion; (2) provide a barrier function against pathogens and debris; (3) participate in signal transduction (through EGF‐ like domains); and (4) interact with the actin cytoskeleton (Gipson, 2004; Leonard et  al., 2016). Membrane‐bound mucins are concentrated on the tips of the microplicae of stratified ocular surface epithelial cells and form a dense gly­ cocalyx at the epithelial tear film interface (Gipson, 2004). Secreted mucins are soluble in the tear film and are distrib­ uted over the ocular surface during blinking, eventually shunted to the nasolacrimal duct. In this way, secreted mucins act both as debris‐removing multimeric networks and by their hydrophilic nature, hold fluid in place and harbor defense molecules secreted by the lacrimal gland (Gipson, 2004). By contrast, membrane‐bound mucins form a dense barrier in the glycocalyx at the epithelial tear film interface. This barrier both prevents pathogen penetrance and lubri­ cates the ocular surface, allowing eyelid epithelia to glide over the corneal epithelia without adherence, thus decreasing shear forces and enhancing the spread, stability, and coher­ ence of aqueous tears. The secreted mucins move easily over the glycocalyx mucins because both have anionic character that creates repulsive forces between them (Gipson, 2004).

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Section IIIA: Canine Ophthalmology

Conjunctival goblet cells are aprocrine secretory cells. In the dog, they are found at highest density in the conjunctival fornices and are the major source of preocular mucins (see Fig.  17.2) (Moore et  al., 1987). Mature goblet cells become filled with mucin glycoprotein packaged as small droplets, which coalesce into larger droplets as the secretions move toward the cell’s apex. After deposition of secretions onto the conjunctival surface, goblet cells lose their connections to the epithelial basement membrane and are desquamated. Bacteria and foreign particles are trapped by mucoproteins. Mucin also harbors immunoglobulins (i.e., immunoglobulin A) and lysozyme, and it aids in lubrication and hydration of the conjunctiva and cornea. Origin, secretion, and functions of ocular mucins have been thoroughly reviewed elsewhere in the veterinary ophthalmic literature (Davidson & Kuonen, 2004; Leonard et al., 2016). In addition to the production of normal secretory compo­ nents, health and function of the PTF depends on eyelid integrity, normal ocular motility, and an intact blink mecha­ nism (King‐Smith et al., 2008; Knop et al., 2010). As the eye­ lids close, the superficial lipid accumulates on the eyelid margins, where it is compressed into a relatively thick layer between the upper and lower eyelid margins. The melting range of PTF lipid ensures fluidity for its delivery from the meibomian glands to the tear film. However, lipid secretions exhibit a higher viscosity at the cooler temperature of the ocular surface, thus slowing tear evaporation from the ocu­ lar surface (Bron et al., 2004). Basal levels of aqueous tears are secreted into the conjunctival cul‐de‐sacs and bathe the globe with most of the tear volume remaining under the eye­ lids. It is believed that polar lipids, interacting with lipid‐ binding proteins in aqueous tears (i.e., lipocalin), spread in advance of the nonpolar components, which form the bulk of the tear film. With movement of the eyelids and globe, stretching of the fornix, and contact between the palpebral conjunctiva and cornea, mucin is released and spreads over the glycocalyces of surface cells. The continuous distribu­ tion of mucus glycoprotein over the ocular surface provides a hydrophilic interface between aqueous tear and the hydro­ phobic corneal and conjunctival epithelial cell membranes. The tear film, lacrimal glands, and eyelids act together with the ocular surface as a functional unit to preserve the quality of the refractive surface of the eye and to protect the globe from injury (Maggio & Pizzirani, 2009a). Important to any discussion of the homeostasis of this functional unit is the mucosal immune system. The conjunctiva forms a continu­ ous mucosal surface from the eyelid margin to the cornea and continuously contacts airborne antigens as well as those on adjacent eyelid skin and in the PTF (Chodosh & Kennedy, 2002; Stern et al., 2010). Conjunctival lymphoid follicles, rou­ tinely identified on the bulbar surface of the nictitans in dogs, will undergo hyperplasia upon stimulation by a variety of pathogens (Fig  17.5) (Alexandre‐Pires et  al., 2008; Cabral et al., 2005; Hong et al., 2011; Schiegel et al., 2003). In addi­

Figure 17.5  A canine third eyelid from a healthy research dog with a normal ocular examination and minimum ophthalmic database was removed and photographed immediately after humane euthanasia. Multiple lymphoid follicles can be visualized as round, raised nodules on the bulbar surface of the third eyelid. This is a common clinical finding in dogs when examining the bulbar (posterior) surface of the third eyelid and, without evidence of conjunctivitis or ocular irritation, is considered normal. The lymphoid follicles are important components of the conjunctiva‐ associated lymphoid tissue (CALT).

tion to innate defense mechanisms, an increasing body of evidence supports the role of conjunctival lymphoid cells to the normal homeostasis of the ocular surface as part of the body’s larger mucosa‐associated lymphoid tissue (MALT) (Chodosh & Kennedy, 2002; Knop & Knop, 2005; Huanga et al., 2010; Neutra & Kozlowski, 2006; Phillips et al., 2010). More specifically, eye‐associated lymphoid tissue (EALT) is composed of conjunctiva‐associated lymphoid tissue (CALT) and lacrimal drainage‐associated lymphoid tissue (LDALT) (Knop & Knop, 2000, 2001, 2002a, 2002b, 2005; Steven & Gebert, 2009). Specialized antigen‐sampling cells, known as M‐cells, are found in the follicle‐associated epithelium above organized lymphoid tissue in many mucosae (Liu et al., 2005; Meagher et al., 2005; Neutra & Kozlowski, 2006). M‐cells play a key role in initiating the mucosal immune response and act as a site of entry for opportunistic pathogens. Canine and feline CALT contains M‐cells analogous to those described in other regions of MALT (Fig  17.6) (Giuliano & Finn, 2011; Giuliano et  al., 2002). The follicle‐associated epithelium

A

B Figure 17.6  A. Representative scanning electron microscopy image of a feline conjunctival M cell. The follicle‐associated epithelium on feline nictitan follicles show darker staining M cells that possess fewer, shorter, and less organized microvilli compared with the adjacent epithelial cells. B. M cells in mucosa‐associated lymphoid tissue (MALT) have been shown to be responsible for antigen uptake. Note that the feline conjunctival follicle‐ associated epithelium M cell in this image appears to have bacteria, probably a Staphylococcus, adhered to its apical surface (arrow) and may be preparing to phagocytize this microorganism. (Source: Reprinted with permission from Giuliano, E.A. & Finn, K. (2011) Characterization of membranous (M) cells in normal feline conjunctiva‐associated lymphoid tissue (CALT). Veterinary Ophthalmology, 14(Suppl. 1), 60–66.)

­ verlying CALT in dogs and cats shows morphologic charac­ o teristic of M cells, including an attenuated apical cell surface with blunted microvilli and microfolds, invaginated basolat­ eral membrane forming a cytoplasmic pocket containing lymphocytes and macrophages, and diminished distance between the apical and pocket membrane.

Pathogenesis of Tear Film Disease Ocular surface health is ensured by a close relationship between the PTF and normal adnexal conformation and function. Normal tear production in dogs fluctuates slightly

during the day (differences of less than 2 mm/min) in a pre­ dominantly nocturnal acrophase (Giannetto et  al., 2009; Piccione et al., 2009) and decreases with age (Hartley et al., 2006). Tear production in puppies reaches normal levels by 9–10 weeks of age (Broadwater et  al., 2010; da Silva et  al., 2013; Verboven et  al., 2014). Abnormalities in either the quantity or quality of any tear component (lipid, aqueous, mucus) may alter tear fluid dynamics and compromise tear function (Beckwith‐Cohen et  al., 2014; Bron et  al., 2009; Foulks, 2007; Perry, 2008). Hypertonicity and dehydration of conjunctival and corneal epithelia are initial pathophysio­ logic events associated with tear deficiency (Sebbag et  al., 2017). Hypoxia of the corneal epithelium and subepithelial corneal stroma also occurs early in the course of tear film disease (Johnson and Murphy, 2004). Lack of appropriate lubrication results in frictional irritation of the ocular sur­ face by the eyelids and third eyelid. Potentially toxic tissue metabolites (i.e., lactic acid, desquamated cells, denatured mucus, other “micro” debris) may accumulate on the ocular surface as well. In tear‐deficient patients, microorganisms more readily colonize affected eyes, thereby resulting in increased incidence of ocular surface infections (Petersen‐ Jones, 1997). Whatever the underlying cause of tear film dis­ ease, ocular surface inflammation results, which in turn becomes the cause and consequence of cell damage, creating a self‐perpetuating cycle of deterioration (Maggio & Pizzirani, 2009b; Schaumburg et al., 2011; Stern et al., 2004). In experimental canine keratoconjunctivitis sicca (KCS), thickening and degeneration of the conjunctival and cor­ neal epithelium has been shown by electron microscopy (Kern et al., 1988). The intimate relationship between ocu­ lar surface cells and PTF is appreciated during tear‐deficient diseases in which the surface epithelia undergo squamous metaplasia or necrosis (or both) with resultant inflamma­ tory disease (Calonge et al., 2010; Izci et al., 2015; Johnson & Murphy, 2004; Tseng & Tsubota, 1997). Squamous meta­ plasia results in loss of expression of membrane‐bound gly­ coproteins by the epithelial cells, thus preventing mucin adherence and resulting in further destabilization of the tear film. Because ocular surface epithelia and PTF are so closely related and function as a unit, the phrase “ocular surface and tear disorders” has been proposed as a more explicit description of these ocular surface phenomena (Tseng & Tsubota, 1997). Disease states may cause decreased secretion of tear com­ ponents by affecting the secretory tissues either directly or indirectly (e.g., by compromising the nerve supply to lacri­ mal glands). KCS, or dry eye, is the clinical condition associ­ ated with lacrimal gland hyposecretion. Insufficient aqueous fluid production is considered to be synonymous with quan­ titative tear deficiency. Abnormalities or deficiencies of tear components other than aqueous fluid are considered here to be qualitative disorders (Moore, 1990). Distributional abnor­ malities resulting from lagophthalmos, buphthalmos, eyelid

1013

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17: Diseases and Surgery of the Canine Lacrimal Secretory System

1014

Section IIIA: Canine Ophthalmology

paresis, corneal anesthesia, eyelid or nictitans deformities, or frictional irritants may result in abnormal tear coverage, with rupture of the tear film and concurrent surface drying. These disorders must be distinguished from primary quanti­ tative or qualitative tear deficiencies.

SECTION IIIA

Quantitative Tear Deficiency KCS is a common ocular disease in the dog (Carter & Colitz, 2002; Williams, 2008). It is characterized by aqueous tear deficiency resulting in desiccation and inflammation of the conjunctiva and cornea, ocular pain, progressive corneal disease, and reduced vision (Fig.  17.7). In one report, the incidence of KCS in canine patients, as presented to the North American Veterinary Medical Colleges, is approxi­ mately 1% (i.e., 9–12 cases per 1000 admissions) (Table 17.1) (Helper, 1996).

Causes of Aqueous Tear Deficiency Absence or reduction of lacrimal secretions may result from a single disease process or a combination of conditions affecting the orbital and nictitans glands (Table 17.2) (Carter & Colitz, 2002; Kaswan et al., 1998; Moore, 2000). Infectious causes of lacrimal adenitis in the dog include canine distem­ per virus (de Almeida et al., 2009; Martin & Kaswan, 1985), chronic blepharoconjunctivitis (Helper, 1996), and other ocular surface infections (Severin, 1973; Williams, 2008). Congenital causes include acinar hypoplasia (i.e., congenital alacrima), recognized as a breed‐related cause in miniature breeds (Aguirre et al., 1971), and ichthyosiform dermatosis in Cavalier King Charles Spaniels (Forman et  al., 2012; Hartley et  al., 2012a, 2012b). Cases of congenital lacrimal

Figure 17.7  Left eye of a dog with keratoconjunctivitis sicca. Note the intense conjunctival hyperemia, thick mucopurulent discharge, and chronic keratitis characteristic of a subacute or chronic aqueous tear deficiency.

gland hypoplasia are often unilateral, and they are character­ ized by extreme dryness (i.e., xerosis). Drug‐induced KCS may occur in the dog after systemic sulfonamide therapy or administration of topical atropine. Systemically administered sulfonamides causing KCS in dogs include phenazopyridine, sulfadiazine, sulfasalazine, and trimethoprim‐sulfonamide combinations (Berger & King, 1998; Berger et al., 1995; Collins et al., 1986: Morgan & Bachrach, 1982: Trepanier, 2004; Trepanier et al., 2003). The mechanism for toxicity is not completely understood but may be caused by a T‐cell mediated response to proteins hap­ tenated by oxidative sulfonamide metabolites (Trepanier, 2004). With administration of relatively short duration, adverse effects on lacrimation are usually transient, and lac­ rimal function returns with discontinuance of the drug. Prolonged, systemic usage of these agents may cause perma­ nent KCS after complete atrophy and fibrosis of the secretory structures. In one study, dogs receiving oral trimethoprim‐ sulfadiazine weighing less than 12 kg were at significantly greater risk of developing KCS (Berger et al., 1995). Certain nonsteroidal anti‐inflammatory drugs have also been associ­ ated with KCS in dogs (Stiles, 2004). A retrospective study examined the features of KCS associated with oral adminis­ tration of etodolac (EtoGesic®, Fort Dodge Animal Health, Fort Dodge, IA, USA) in 211 dogs (Klauss et al., 2007). In this report, dogs administered oral etodolac for less than 6 months prior to the diagnosis of KCS were 4.2 times more likely to experience complete resolution of KCS than dogs that were treated for 6 months or longer. One study examin­ ing the oral administration of diphenhydramine to dogs over 21 days showed decreased corneal sensitivity and tear film breakup time, although these effects were not deemed clini­ cally important and a second study found no significant decrease in aqueous tear production in normal dogs after administration for 20 days (Evans et al., 2012; Montgomery et al., 2011). Atropine administered as a preanesthetic agent transiently decreases tear production (Ludders & Heavner, 1979). Topically applied atropine, often used to treat anterior uveitis associated with ulcerative keratitis, may significantly decrease tear production in the dog (Hollingsworth et  al., 1992). When corneal ulceration has occurred in cases of bor­ derline or unrecognized tear deficiency, administration of atropine will exacerbate the dryness and complicate the ulcerative disease. Therefore, it should be used only “to effect” to achieve pupillary dilation. Single dose 1% tropi­ camide does not significantly lower tear production rates as measured by the STT in normal dogs, but further research is needed to evaluate multiple doses of tropicamide on canine tear production (Margadant et al., 2003). Both preanesthetic and anesthetic agents are also known to reduce tear secretion for at least 24 hours after an anesthetic event (Collins et al., 1995; Costa et al., 2015; Doering et al., 2016; Herring et al., 2000; Komnenou et al., 2013; Mayordomo‐Febrer et al., 2017;

17: Diseases and Surgery of the Canine Lacrimal Secretory System

1015

      Year

    Total new canine admissions all schools

      Cases of KCS

1975

69,561

261

1976

54,731

277

1977

51,300

1978

54,688

1979 1980

    KCS/100 admissions

    Parotid transposition

Percent of KCS cases treated by parotid duct transposition

3.75

36

13%

5.06

40

14%

278

5.42

50

17%

271

4.96

39

14%

51,471

325

6.31

53

16%

53,677

373

6.95

58

16%

1981

49,478

366

7.40

27

7%

1982

48,267

375

7.77

46

12%

1983

53,351

451

8.45

53

12%

1984

55,403

630

11.37

39

6%

1985

50,566

641

12.68

45

7%

1986

48,978

605

12.35

46

7%

1987

49,475

646

13.06

57

9%

1988

56,993

746

13.09

32

4%

1989

48,529

675

13.91

15

2%

1990

75,997

725

9.54

29

1.6%

1991

60,068

681

11.34

10

1.7%

1992

49,994

563

11.26

17

3.0%

1993

46,789

562

12.01

7

1.2%

1994

39,258

473

12.05

8

1.7%

1995

33,303

381

11.79

7

1.8%

1996

20,605

188

9.12

5

2.6%

(Source: Modified from Helper, L.C. (1996) The tear film in the dog. Causes and treatment of diseases associated with overproduction and underproduction of tears. Animal Eye Research, 15, 5–11.)

Pontes et al., 2010; Sanchez et al., 2006; Vestre et al., 1979). The duration of anesthesia has been shown to affect STT lev­ els significantly, with anesthetic events longer than 2 hours in duration having a prolonged effect compared with those lasting less than 2 hours (Herring et al., 2000). Importantly, clinicians should be careful to regularly monitor all patients for development of KCS after cataract surgery (Gemensky‐ Metzler et al., 2015). The nictitans gland is a significant contributor to the aque­ ous component of the PTF; thus, removal of this gland in dogs is an important iatrogenic cause of KCS (Plummer et al., 2008; Saito et al., 2001; Saito et al., 2004). Third eyelid removal may also increase the already high risk of KCS in breeds predisposed to the disease (Table  17.3) (Dees et  al., 2015; Helper, 1996). Other conditions associated causally with canine KCS include uncorrected nictitans gland pro­ lapse, traumatic or inflammatory orbital diseases, loss of parasympathetic innervation to the lacrimal glands (cranial

nerve VII), and loss of sensory innervation (i.e., sensation) to the ocular surface (cranial nerve V) (Carter & Colitz, 2002; Kaswan & Salisbury, 1990; Kaswan et al., 1989; Kern & Erb, 1987; Wieser et al., 2013). KCS may also be a complication of local irradiation of head neoplasms (Pinard et  al., 2012; Roberts et al., 1987) or seen as a long‐term sequela to evis­ ceration/prosthesis (Blocker et  al., 2007). Decreased aque­ ous tear production may also occur secondary to trauma or systemic metabolic diseases such as hypothyroidism, diabe­ tes mellitus, and Cushing’s disease (Carter & Colitz, 2002; Kaswan & Salisbury, 1990; Sansom & Barnett, 1985) and congenital diseases such as ichthyosiform dermatosis in Cavalier King Charles Spaniels (Forman et al., 2012; Hartley et al., 2012a, 2012b). Several breeds are disproportionately affected by acquired KCS, thus suggesting a genetic predisposition (Helper, 1996; Kaswan & Salisbury, 1990). In a review of 754 cases, Helper (Helper, 1996) found the breeds at greatest relative risk (RR)

SECTION IIIA

Table 17.1  Cases of canine keratoconjunctivitis sicca (KCS) and parotid duct transposition reported by the American Veterinary Medical Data Program (1975–1996).

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Section IIIA: Canine Ophthalmology

SECTION IIIA

Table 17.2  Causes of keratoconjunctivitis sicca in the dog. Chronic blepharoconjunctivitis Congenital: Pug Yorkshire Terrier Cavalier King Charles spaniel Drug‐induced: Topical/general anesthesia Topical/parenteral atropine Drug toxicity: 5‐Aminosalicylic acid Phenazopyridine Sulfadiazine Sulfasalazine Trimethoprim/sulfonamide Immune‐mediated: Local Systemic Breed disposed (See Table 17.3) Irradiation Neurogenic Surgically induced: Excision of lacrimal/nictitans glands Evisceration/prosthesis Systemic disease: Canine distemper Metabolic disease Trauma to the eye and orbit (Source: Modified from Gelatt, K.N. (1991) Canine lacrimal and nasolacrimal systems. In: Veterinary Ophthalmology (ed. Gelatt, K.N.), p. 283. Philadelphia: Lea & Febiger.)

of developing KCS were English Bulldogs (RR, 12.5), West Highland White Terriers (RR, 5.5), and Pugs (RR, 4.5). Other breeds found to have a high RR (>2.0) were Yorkshire Terriers, American Cocker Spaniels, Pekingese, Miniature Schnauzers, and English Springer Spaniels. Kaswan and Salisbury (Kaswan & Salisbury, 1990) later confirmed an increased risk in six of the top seven breeds listed by Helper, and they added Boston Terriers, Cavalier King Charles Spaniels, Lhasa Apsos, Bloodhounds, and Samoyeds as addi­ tional high‐risk breeds (see Table 17.3). Gender has also been identified as a significant factor in West Highland White Terriers, whereby females are predisposed to KCS. More recent studies have supported earlier findings of breed and gender predispositions for this disease (Barnett, 2006; Herrera et al., 2007; Sanchez et al., 2007; Westermeyer et al., 2009). Although the list of possible causes of KCS is extensive (see Table  17.2), in many cases the definitive cause is not determined. Histopathologic studies of the lacrimal tissue from dogs affected with idiopathic KCS have revealed ­varying degrees of mononuclear cell (i.e., lymphocytic‐­ plasmacytic) infiltrates associated with acinar atrophy,

Table 17.3  Breed disposition to keratoconjunctivitis sicca (KCS). Breed

Relative risk of KCS

  Cavalier King Charles Spaniel English Bulldog Lhasa Apso Shih Tzu West Highland White Terrier Pug Bloodhound American Cocker Spaniel Pekingese Boston Terrier Miniature Schnauzer Samoyed All breeds

  11.5 10.8 9.8 6.2 5.5 5.2 4.5 4.1 4.0 2.0 1.8 1.7 1.0

(Source: Modified from Kaswan, R.L. & Salisbury, M.A. (1990) A new perspective on canine keratoconjunctivitis sicca: treatment with ophthalmic cyclosporine. Veterinary Clinics of North America: Small Animal Practice, 20, 583.)

thereby suggesting an immunologic basis for the disease (Kaswan et al., 1984). Given these histopathologic features, reports of concurrent immunopathies (i.e., hypergamma­ globulinemias) (Kaswan et  al., 1983), and the response to immunomodulating therapy (discussed later), immune‐ mediated KCS is believed to constitute a large percentage of clinical cases. KCS may be associated with systemic autoim­ mune conditions (Kaswan et  al., 1985), but canine KCS appears to occur more often as a localized tissue‐specific, immune‐mediated disorder.

Clinical Findings in Keratoconjunctivitis Sicca Clinical signs of KCS will vary depending on the period of time since onset and the extent of dryness. A very acute, severe form of KCS is sometimes seen, in which the eye becomes acutely painful in association with corneal ulcera­ tion. In such cases, suppurative inflammation may result in progressive corneal disease with stromal malacia, desceme­ tocele formation with resultant staphyloma, and iris pro­ lapse (Fig.  17.8). In most cases, however, onset of KCS is more gradual, with increasing severity over a period of sev­ eral weeks. In the early stage of the typical disease, affected eyes ini­ tially appear to be red and inflamed, with intermittent mucoid or mucopurulent discharge. Because clinical signs are non­ specific in early disease, KCS may be misdiagnosed as an irri­ tant or primary bacterial conjunctivitis (Fig.  17.9). As the severity of the KCS increases, however, the ocular surface becomes lackluster, the conjunctiva appears to be extremely hyperemic, and persistent tenacious mucopurulent ocular

1017

SECTION IIIA

17: Diseases and Surgery of the Canine Lacrimal Secretory System

Figure 17.8  Acute onset keratoconjunctivitis sicca in a 5‐year‐ old female pug with mucopurulent discharge, hyperemic conjunctiva, and an infected axial corneal ulcer, stromal malacia, diffuse corneal edema, and ciliary flush OD.

Figure 17.9  A 4‐year‐old female spayed Boston Terrier with keratoconjunctivitis sicca (KCS). This patient presented early in the course of her disease. Note mucoid ocular discharge, moderate conjunctival hyperemia, and mild chemosis OD. The dog had Schirmer tear test values of 8 and 10 mm of wetting/60 seconds OD and OS, respectively. This case illustrates the importance of performing a complete ophthalmic minimum database to avoid the misdiagnosis of KCS as an allergic or primary bacterial conjunctivitis.

discharge is observed. If KCS is not recognized and treated appropriately, progressive keratitis characterized by extensive corneal vascularization and pigmentation with or without ulceration may occur (Fig. 17.10 and Fig. 17.11). Severe pig­ mentary keratitis may be refractory to medical and surgical therapy (Fig. 17.12) (Stiles et al., 1995). Blepharitis and perio­ cular dermatitis often occur simultaneously with an accumu­

Figure 17.10  A 6‐year‐old male, castrated mixed‐breed dog with chronic keratoconjunctivitis sicca. Note the marked conjunctival hyperemia, lackluster appearance to the corneal surface, and superficial corneal neovascularization OS.

Figure 17.11  A 10‐year‐old female spayed Chihuahua with keratoconjunctivitis sicca. Conjunctival hyperemia is evident as the upper eyelid is retracted in this extraocular photograph, and extensive pigmentary keratitis precludes the view of the pupil OS.

lation of exudates on the eyelid margins and periocular skin. With progressive disease, the level of discomfort intensifies, thus resulting in persistent blepharospasm. In acute KCS, the initial histopathologic changes of the cornea include epithelial degeneration with vacuolization and thinning of the epithelium (Fig. 17.13). The cornea is not initially infiltrated with inflammatory cells or blood vessels, but with progressive loss of epithelium, suppura­ tive keratitis and stromal ulceration may occur, thereby inducing a marked fibrovascular response. In chronic KCS,

Section IIIA: Canine Ophthalmology

SECTION IIIA

1018

Figure 17.12  An 8‐year‐old female spayed Shih Tzu with chronic keratoconjunctivitis sicca. Note the mucopurulent discharge highlighted by fluorescein stain and the extensive pigmentary keratitis OS. In addition to tear deficiency, predisposing factors for the pigmentary keratitis include an inherently heavily pigmented eye, conformational exophthalmos, and frictional irritation to the cornea (entropion‐trichiasis).

Figure 17.14  Chronic keratoconjunctivitis sicca in a dog. Note the increased thickness and pigmentation of the corneal epithelial layer. Rete formation is also present (arrows). (Original magnification, 400 ×. Hematoxylin and eosin.) (Source; Reprinted with permission from Gelatt, K.N. (1991) Canine lacrimal and nasolacrimal diseases. In: Veterinary Ophthalmology (ed. Gelatt, K.N.), 2nd ed., pp. 276–289. Philadelphia: Lea & Febiger.)

Diagnosis of Aqueous Tear Deficiency

Figure 17.13  Acute keratoconjunctivitis sicca in a dog. Note the evidence of corneal epithelial degeneration and increased thickness of this layer. (Original magnification, 400×. Hematoxylin and eosin.) (Source: Reprinted with permission from Gelatt, K.N. (1991) Canine lacrimal and nasolacrimal diseases. In: Veterinary Ophthalmology (ed. Gelatt, K.N.), 2nd ed., pp. 276–289. Philadelphia: Lea & Febiger.)

the corneal epithelium becomes hyperplastic and kerati­ nized, and melanin pigment granules are noted throughout the epithelium and anterior stroma (Fig. 17.14). With chro­ nicity, the basal epithelium appears to be undulated, form­ ing epithelial pegs, and the anterior corneal stroma becomes extensively vascularized and diffusely infiltrated with plasma cells and lymphocytes.

The diagnosis of KCS is made on the basis of typical clinical signs, positive ocular staining using vital stains, and reduced quantitative tear readings. Rose Bengal stain will detect devitalized cells, subtle epithelial defects on either the con­ junctiva or corneal surfaces, and adherent mucus tags (Gelatt, 1972). The phenol‐red‐thread tear test is a method of tear measurement that employs a small thread placed in the ventral conjunctival fornix for 15 seconds; a normal range of 30–38 mm of wetting per 15 seconds has been determined by one study (Brown et al., 1996) and 29.3 mm ± 3.45 mm of wetting per 15 seconds in another (Saito & Kotani, 2001). Fluorescein stain detects concurrent corneal ulceration and may also be used to evaluate tear breakup (discussed later). Tear ferning and strip meniscometry have been recently reported (Rajaei et  al., 2017; Williams & Hewitt, 2017). The Schirmer tear test (STT), however, remains the standard means for quantifying aqueous tear production (Gelatt et al., 1975). Canine patients with a red, irritated eye and ocular discharge, with or without corneal disease, should undergo STTs. STTs may be done either without (i.e., STT I) or with (i.e., STT II) use of topical anesthetic (Berger & King, 1998; Gelatt et al., 1975; Hamor et al., 2000). STT I measures the ability of the eye to produce reflex tears in addition to basal secretions, and is the most commonly performed test, whereas STT II estimates only basal tear secretion (Hamor et al., 2000). STT I and STT II values are significantly ­different in the ­normal dog (Berger & King, 1998; Gelatt et al., 1975;

17: Diseases and Surgery of the Canine Lacrimal Secretory System

●● ●● ●● ●●

15 mm/min = normal production 11–14 mm/min = early or subclinical KCS 6–10 mm/min = moderate or mild KCS 5 mm/min = severe KCS

Variation in absorbency among tear test strips manufac­ tured by different companies has been documented in a number of different studies, therefore the same brand should be used for repeated measures in a given patient (Hawkins & Johnson, 1985; van der Woerdt & Adamcak, 2000; Wyman et al., 1995). Some tear test strips are impreg­ nated with a dye that marks the test strip at the level of tear fluid migration, thereby allowing easier reading of the results (Wyman et al., 1995). In a comparison of test results from conventional strips versus color‐bar strips, no signifi­ cant differences were found (Hirsh & Kaswan, 1995). For additional information, the reader is referred to the ocular examination Chapter 10, Part 1. Repeat STT measurement is advised in dogs stressed by examination or receiving medical therapy for ulcerative cor­ neal disease, because either factor (i.e., sympathetic stimula­ tion or current topical treatments such as atropine) may reduce tear secretions. A relatively small percentage of affected dogs will not have clinically apparent disease despite low STT readings. These cases may represent transient or borderline KCS cases and they should be closely monitored with follow‐up examinations, including subsequent STTs. Fluctuations in STT values may occur on both a daily and a weekly basis; however, only weekly fluctuations are consid­ ered to be biologically significant (Hawkins & Johnson, 1985; Hawkins & Murphy, 1986). Body weight also has a sig­ nificant effect on STT values, with higher values being meas­ ured in larger dogs (Hawkins & Murphy, 1986). The evaluation of patients with KCS should include exam­ ination for possible associated systemic diseases (e.g., hypo­ thyroidism), assessment of eyelid function and blink reflexes, and in selected cases, ocular surface cultures and cytology (Calonge et al., 2004). Secondary bacterial conjunctivitis is common in dogs with KCS, and resistant organisms can develop after prolonged administration of topical antibiotics or long‐term immunosuppressive therapy (Beckwith‐Cohen et al., 2016; Driver & Lemp, 1996). Therefore, antibiotic sus­ ceptibility testing may be an important adjunctive compo­ nent to the diagnostic assessment of a dog with KCS.

Qualitative Abnormalities Problematic cases of KCS can occur in which aqueous tear volume appears to be adequate and other recognized causes of surface disease (e.g., infection, frictional irritation,

i­ neffectual blinking) have been excluded. In such instances, qualitative tear deficiency from an abnormality of either the lipid or the mucin tear components may be a primary (or a contributing) cause of the surface disease.

Causes of Qualitative Tear Deficiencies Disturbances of the tarsal or meibomian glands may result in abnormal secretions and subsequent disruption of the superficial lipid layer of the tear film (Bron & Tiffany, 1998; Bron et al., 2004; Butovich, 2011). With diseased meibomian glands, highly polar lipids are produced that disrupt the non­ polar lipid surface of the tear fluid (Holly, 1987; McCulley & Sciallis, 1977; McCulley & Shine, 2004). The resultant loss of the normal oily covering may allow premature dispersion of the aqueous layer. Abnormal lipids may also be directly toxic to surface cells. Surface disease probably results from a com­ bination of insults, including poor surfacing of the tear film, frictional irritation from disturbed eyelid margins, and toxic effects from abnormal secretion or inflammatory products (Pflugfelder et al., 2007). Inflammation of the mucocutaneous junction, which is referred to as marginal blepharitis, usually involves the mei­ bomian glands. Marginal blepharitis, blepharoconjunctivi­ tis, and meibomianitis are commonly caused by suppurative bacterial infections (i.e., Staphylococcus sp.) and result in swelling of the eyelid margin, accumulation of exudates, and abnormal lipid secretions (Moore, 1990). Yeast organ­ isms, including Candida and Malassezia sp., may also cause infectious blepharitis. Yeast infections most often occur after chronic administration of topical antibiotic–corticosteroid combinations. Dogs with generalized seborrhea may produce abnormal meibomian lipids. By affecting the mucocutaneous junctions, autoimmune diseases such as lupus erythematosus and bul­ lous pemphigoid may affect the eyelid margins and meibo­ mian secretions. It should be noted that some dogs have relatively serious meibomian gland disease with little or no apparent corneal changes. These patients usually have abun­ dant aqueous tear production, thus suggesting that reflex tear­ ing may compensate for the lack of tear conservation. It is also possible that toxic inflammatory products and abnormal lipids are simply diluted or flushed away by the aqueous tears. Deficiency of meibomian secretion resulting from malde­ velopment of the meibomian glands, though rare, has been reported in humans (Bron & Mengher, 1987). Eyelid agene­ sis is a relatively uncommon congenital condition of small companion animals in which affected areas of the eyelid are devoid of normal eyelid tissue, including meibomian glands. Most cases are seen in cats and the predominant clinical signs are epiphora, conjunctivitis, and superficial keratitis. Surface pathology presumably results from the combined insults of absent meibomian secretions, exposure, trichiasis, and in some cases, spastic blepharitis.

SECTION IIIA

Hamor et  al., 2000) and vary with age (Broadwater et  al., 2010; Hartley, 2008). In the clinical setting, STT I readings in dogs are generally interpreted as follows:

1019

SECTION IIIA

1020

Section IIIA: Canine Ophthalmology

Insufficient production of preocular mucin also results in loss of tear film stability, with subsequent corneal desicca­ tion (Bron, 1997; Moore, 1990). In the dog, pathogenesis of spontaneously occurring, mucin‐deficient dry eye disease may vary among cases (Moore & Collier, 1990). Chronic, dif­ fuse conjunctival inflammatory cell infiltrates may reduce or eliminate goblet cells. Although the cause for these infil­ trates is often not determined, both infectious and immune‐ mediated mechanisms have been hypothesized (Moore & Collier, 1990). Severe cicatrization after diffuse ulcerative conjunctival disease is another cause of abnormal epithelium and goblet cell loss. The relative avascularity of the conjunctiva that occurs with scarring has been proposed to result in decreased blood supply and local deficiency of essential nutrients (e.g.,  vitamin A) in the conjunctival mucosa (Tseng, 1985; Tseng & Tsubota, 1997; Tseng et al., 1984, Tseng et al., 1985). Experimentally induced vitamin A deficiency results in squamous metaplasia of the conjunctiva, with abnormal keratinization of the secretory epithelium and loss of con­ junctival goblet cells (Soong et al., 1988).

Clinical Findings in Qualitative Tear Abnormalities Dogs with acute meibomianitis typically have swollen eyelid margins, with slight “pointing” of the meibomian openings. Affected openings may be plugged with dried or discolored meibum. Chronic meibomianitis may result in rupture of glandular acini and release of lipid secretions into the per­ iacinar tissues. Formation of lipid granulomas and multiple chalazia may frictionally irritate the eye and complicate any tear film abnormality present (Fig 17.15).

Figure 17.15  Seven‐year‐old female spayed Maltese with meibomianitis (Source: Courtesy of Dr. Claudia Hartley, Animal Health Trust, UK.)

In some cases of chronic meibomianitis, superficial kerati­ tis is also present. Clinical findings in this keratopathy may be somewhat subtle, with faint localized or geographic epi­ thelial edema, small and multifocal punctate areas of rough­ ened epithelium that may or may not retain fluorescein stain, as well as fine and superficial perilimbal vascular infil­ trates. The corneal disease present in such cases likely may be attributable to both deficient lipid with unstable tear film and direct frictional effects from roughened eyelid margins. Loss of conjunctival goblet cells results in an unstable tear film, as manifested by rapid breakup of the PTF, lackluster appearance of the ocular surface, and corneal desiccation (Moore & Collier, 1990). Clinical features of preocular mucin deficiency in the dog may include chronic keratoconjuncti­ vitis, corneal ulceration, and absence of appreciable ocular discharge in the presence of adequate aqueous tear measure­ ments. In some cases, the conjunctiva may appear to be thickened and inelastic.

Diagnosis of Qualitative Tear Deficiencies Making the diagnosis of lipid tear abnormalities depends on findings from a detailed examination using a focused light and a magnifying source. A slit‐lamp biomicroscope is rec­ ommended, though binocular magnifying loupes and a sep­ arate focal light source (e.g., a Finoff transilluminator) may be used. During examination, particular attention is focused on the appearance of the eyelid margins and meibomian glands. With the eyelid everted, the serial arrangement of multiple meibomian glands is normally noted just beneath the tarsal conjunctiva. Individual glands should appear par­ allel to adjacent glands and perpendicular to the eyelid mar­ gin. Visualization of the glands may be enhanced by transillumination of the eyelid. Swollen, rounded eyelid margins indicate acute or suba­ cute marginal blepharitis. Hyperemia of the mucocutaneous junction, with dry, crusty, porphyrin‐stained exudates on the lid margins, is also indicative of marginal blepharitis. Any elevated, focal, beige subconjunctival masses typical of chalazia should be noted (Fig. 17.16). When present, chala­ zia indicate chronic meibomianitis with periglandular gran­ ulomatous inflammation. After administration of a topical anesthetic solution, gen­ tle manipulation of the eyelid margin using blunt‐tipped for­ ceps with shallow serrations will allow inspection of secretions expressed from the meibomian glands. Normal meibomian lipid is a relatively clear, viscous oil, similar in appearance to vegetable cooking oil. Abnormal meibomian secretions are typically thick, opaque, and may appear to be inspissated, with a cream‐cheese consistency. Expression of coiled, semisolid strands of abnormal lipid is not uncommon in chronic meibomian disease. The technique of polarized light biomicroscopy has been used to characterize ocular surface lipid morphology in

Figure 17.16  Right upper eyelid of a dog with meibomian gland disease and multiple chalazia. Note the beige nodules resulting from inspissated contents of obstructed meibomian glands. Mild superficial keratitis is also present. (Source: Reprinted with permission from Moore, C.P. (1990) Qualitative tear film disease. The Veterinary Clinics of North America. Small Animal Practice, 20, 565–581.)

Figure 17.17  Tear film breakup time (TBUT) test can be performed in the dog with some difficulty. Immediately after instillation of one drop of fluorescein stain, the eyelids are digitally held open, and the dispersion of fluorescein is observed with a portable slitlamp microscope using a cobalt filter. The TBUT is the time from instillation of the dye to the first appearance of fluorescein dissipation, as evidenced by the appearance of dark spots on the cornea.

­ ormal dogs and to study surface abnormalities in dogs with n confirmed or suspected tear film disease (Carrington et al., 1987a, 1987b). Patterns of lipid distribution were described, and the overall thicknesses of surface lipids using polarized light biomicroscopy were judged to be between 0.013 and 0.581 μm in normal dogs. Further research is needed to con­ firm normal canine ocular lipid thickness and to validate this technique. Other techniques such meibometry in dogs have been reported with variable results (Benz et al., 2008; Ofri et al., 2007). The clinical diagnosis of canine ocular mucin deficiency may be supported by the results of a tear film breakup time test (Fig. 17.17). The diagnosis may also be confirmed by the results of conjunctival biopsy and quantification of epithelial goblet cells. The tear breakup time evaluates the ability of the corneal surface to retain a homogeneous tear covering. Tear film breakup time is performed by instilling one drop of fluo­ rescein stain into the eye, then manually holding the eyelids open. The time is recorded from the last blink to the appear­ ance of the first dry spot, which appears as a dark area in the yellow‐green fluorescent film. A cobalt‐blue filter should be used when viewing the cornea. The normal breakup time in dogs should be 20 seconds or longer (Moore et al., 1987). In animals affected with mucin deficiency, however, tear breakup usually occurs in less than 5 seconds (Moore & Collier, 1990). Determination of goblet cell numbers from conjunctival biopsy specimens provides an indirect measure of mucin pro­ duction. Collecting a sample of conjunctiva for histopathol­ ogy involves instilling a topical anesthetic solution, using Bishop‐Harmon forceps to tent an area of conjunctiva from the ventral fornix just anterior to the base of the third eyelid, and removing a 3‐ × 4‐mm specimen with conjunctival ­scissors. Because a heterogeneous density and distribution of

conjunctival goblet cells has been shown in the dog, a con­ junctival site with the highest and most predictable density of goblet cells should be selected for sampling; the reader is referred to the original article for complete description of technique and interpretation of results (Moore et al., 1987). In dogs suspected to be mucin‐deficient, the most optimal area for conjunctival biopsy is the lower medial fornix, between the third eyelid and the lower eyelid.

Treatment of Tear Film Deficiencies Medical Treatment Medical therapy is the primary means of treating tear‐­ deficient ocular surface disease. Specific treatment regimens are tailored to individual patients and are influenced by the underlying pathogenesis, disease severity, and owner’s abil­ ity to comply with recommended treatment schedules. Treatment generally consists of some combination of the fol­ lowing: tear stimulation, tear replacement, topical and/or oral antimicrobial agents, mucinolysis, and anti‐inflamma­ tory therapy. Lacrimostimulants

Lacrimostimulants, which are drugs administered to pro­ mote tear secretion, include two categories of therapeutic agents: cholinergics and immunomodulators. Cholinergic Agents

The lacrimal gland is innervated by both the parasympa­ thetic and sympathetic branches of the autonomic nervous system (Dartt, 2009; Klauss & Constantinescu, 2004; Matheis

1021

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Section IIIA: Canine Ophthalmology

et al., 2012). The parasympathetic innervation of the lacri­ mal gland has enabled cholinergic drugs to be used to stimu­ late tear secretions in select cases. Ophthalmic pilocarpine solution has been administered, either topically or orally, as a tear stimulant (Matheis et al., 2012; Rubin & Aguirre, 1967; Smith et al., 1994). The use of pilocarpine for dry eye is indi­ cated in cases of KCS resulting from parasympathetic dener­ vation of the lacrimal glands (e.g., neurogenic KCS) and will only be effective if some functional lacrimal gland remains (Klauss & Constantinescu, 2004; Tsifetaki et al., 2003; Vivino et al., 1999) (Fig. 17.18). Oral administration has consisted of applying 1%–2% ophthalmic solution to the food; a safe ini­ tial oral dosage is one drop of 2% topical pilocarpine per 10 kg of body weight twice daily. The dose may be increased by one‐drop increments at each dosing until signs of sys­ temic toxicity develop (i.e., salivation, vomiting, diarrhea, cardiac arrhythmias). The dose should then be lowered to the previously tolerated dose. Alternatively, topical dilute pilocarpine has been applied directly to the eyes. Concentrations of either 0.125% or 0.25% have been formu­ lated by adding 1 mL of 2% pilocarpine to 15 mL of artificial tears (0.125% solution) or 2 mL of 2% pilocarpine to 14 mL of artificial tears (0.25% solution). Topical pilocarpine may cause blepharospasm, conjunctival hyperemia, and miosis. In some cases, sufficient irritation results for topical treat­ ments to be discontinued. The irritative effects of topical pilocarpine may be controlled with use of topical steroidal or nonsteroidal anti‐inflammatory agents (Giuliano, 2004; Holmberg & Maggs, 2004). The route of pilocarpine admin­ istration is determined by the individual patient’s tolerance

Figure 17.18  Extraocular photograph taken by the author of a 6‐year‐old male castrated West Highland White Terrier exhibiting classic clinical signs of neurogenic keratoconjunctivitis sicca OD.

of one method over the other. One study performed on nor­ mal dogs found that topically applied pilocarpine did not significantly increase tear production (Smith et al., 1994). Immunomodulating Agents

Cyclosporine A (CsA), a derivative of the fungus Tolypocladium inflatum, and tacrolimus (formally FK 506), a macrolide antibiotic produced by Streptomyces tsukubaensis, are both T‐cell activation inhibitors initially developed for their systemic uses in preventing graft rejection after organ transplantation. Although structurally nonhomolo­ gous, the mechanism of action of both CsA and tacrolimus is similar: T‐cell proliferation and activation are altered by the inhibition of interleukin (IL)‐2 gene expression in CD4+ T helper lymphocytes. IL‐2 transcription blockage leads to impaired T‐helper and T‐cytotoxic proliferation (Moore, 2004). More specifically, CsA binds intracellularly to a spe­ cific immunophilin known as cyclophilin (CpN) and tac­ rolimus binds to immunophilins called FK506‐binding proteins (FKBPs). Calcium‐dependent calcineurin (CaN), sometimes called phosphatase 2B, is a key rate‐limiting enzyme in T‐cell signal transduction via its effect on nuclear transcription factors of activated T cells. In brief, when CsA crosses the lymphocyte’s cell membrane, it binds to CpN and the resulting complex (CsA‐CpN) binds to CaN, thus preventing CaN’s normal induction of IL‐2 production. More detailed description of the intracellular mechanisms of action have been reviewed elsewhere (Moore, 2004). In addition to reduction of IL‐2 release from lymphocytes, these drugs interfere with IL‐2 receptors on lymphocyte sur­ faces. CsA and tacrolimus have been reported to reduce eosinophil production, block mast cell degranulation, and suppress tumor necrosis factor‐α by B cells (Moore, 2004; Thomson, 1992; Vaden, 1997). Topical CsA has also been noted to reduce conjunctival epithelial apoptosis in chronic canine and human KCS (Gao et al., 1998; Stonecipher et al., 2005; Strong et al., 2005). When administered systemically as an immunosuppres­ sive agent to humans with normal tear flow, CsA stimulates lacrimal secretions (Palmer et al., 1995, 1996). The ability of CsA to stimulate tear production in the dog is well docu­ mented (Bounous et  al., 1995; Fullard et  al., 1995; Hadži‐ Milić et al., 2013; Kaswan & Salisbury, 1990; Kaswan et al., 1989). Both immuno‐modulating and tear‐stimulating prop­ erties appear to account for the dramatic responses observed in many affected dogs after topical application (Fullard et al., 1995). In animal models of immune‐mediated lacrimal dis­ ease, the balance between T‐suppressor and T‐helper cells plays an important role in lacrimal gland regulation. T‐suppressor cells normally predominate, but in immune‐ mediated KCS, T‐helper cells become the prevalent T lym­ phocytes (Jabs & Prendergast, 1987). Therefore, it is believed that by inhibiting T‐helper cells in KCS, CsA allows the T‐suppressor cells to sustain normal lacrimal function.

Most cases of canine KCS are presumed immune medi­ ated. CsA has been the primary treatment for KCS in the dog for over two decades (Bounous et al., 1995; Izci et al., 2002; Kaswan & Salisbury, 1990; Sansom et al., 1995; Olivero et al., 1991) and has now been approved for topical use in people with dry eye (Perry & Donnenfeld, 2004; Sall et  al., 2000; Stevenson et al., 2000; Stonecipher et al., 2005; Tang‐Liu & Acheampong, 2005). Before the commercial availability of CsA for ophthalmic use, 1%–2% oil‐based solutions were compounded from 10% oral CsA solution using a vegetable oil (i.e., olive or corn oil) solvent. Currently, either the 0.2% commercial ointment (Optimmune®, Merck Animal Health, Madison, NJ, USA) is prescribed or different formulations (e.g., aqueous‐based, higher concentrations of CsA) are obtained through compounding pharmacies. The vehicle used for the commercial product is reported to maximize the bioavailability of active drug (Fullard et  al., 1994). Use of episcleral cyclosporine implants in canine KCS patients is useful in those cases where daily topical drug therapy has proven difficult because of either patient or client compli­ ance issues (Barachetti et  al., 2015). Tacrolimus and pime­ crolimus, calcineurin inhibitors, have both been shown to improve tear production in dogs (Berdoulay et  al., 2005; Hendrix et  al., 2011; Nell et  al., 2005; Ofri et  al., 2009; Radziejewski & Balicki, 2016). In two studies, the efficacy of topical tacrolimus compared with cyclosporine for treating KCS in dogs, both drugs were found to increase STT values significantly in affected dogs over time and tacrolimus may be effective in dogs nonresponsive to cyclosporine (Hendrix et al., 2011; Radziejewski & Balicki, 2016). Investigation into new agents for the treatment of canine KCS is on‐going, including autografts and stem cell therapy (Arnold et  al., 2014; Bittencourt et  al., 2016; Bunya et  al., 2017; Chen & Powell, 2015; Cherry et al., 2018; Gilger et al., 2013; Linares‐ Alba et  al., 2016; Murphy et  al., 2011; Park et  al., 2013; Spatola et al., 2018; Villatoro et al., 2015; Wood et al., 2012). To stimulate tear production, these agents are generally recommended for initial application every 12 hours to affected eyes; however, in severe cases, treatments may be initially administered every 8 hours. Several weeks of con­ tinuous treatment are usually needed before substantial increases in tear production are observed. Alternatively, in cases where treatments have been administered every 12 hours, if STT values remain at or less than 10 mm/min after 3 weeks of topical therapy, the topical frequency may then be increased to every 8 hours. To provide the most accu­ rate assessment of response to CsA, measuring tear produc­ tion 3 hours after topical administration is recommended (Kaswan & Salisbury, 1990). If a favorable response to treat­ ment every 12 hours restores tears to physiologic levels (i.e., STT >20 mm/min), topical immunomodulating therapy can usually then be reduced to once daily, as maintenance ther­ apy. Dogs with STT values of 0–1 mm/min have an approxi­ mately 50% chance of responding to topical CsA with

increased tear secretion; dogs with pretreatment STT values of 2 mm/min or greater have a more than 80% chance of improved tear production (Kaswan & Salisbury, 1990). In responsive animals, return of functional secretory tissues has been shown histologically after topical CsA treatment (Bounous et al., 1995). Most dogs will show clinical improve­ ment as evidenced by a decrease in mucopurulent discharge, corneal vascularization, and pigmentation even without increased tear production, including those with STT values of 2 mm/min or less. Many dogs benefit from the transition to, or the addition of, topical tacrolimus (Fig.  17.19 and Fig. 17.20). A number of other presumed immune‐mediated keratopa­ thies have been treated successfully with topical immu­ nomodulating therapy including chronic superficial keratitis (pannus), plasmacytic conjunctivitis, eosinophilic kerato­ conjunctivitis, superficial punctuate keratitis, and nodular granulomatous episclerokeratitis (Jackson et  al., 1991; Moore, 2004; Nell et al., 2005; Williams et al., 1995). Although topical CsA therapy has been widely used for over two dec­ ades and appears relatively free of undesirable side effects, it does reach the systemic circulation in both dogs and people (Gilger et  al., 1995; Small et  al., 2002). In dogs, topical 2% cyclosporine has been shown to cause a suppression of lym­ phocyte proliferation after 1–3 months of use in one study (Gilger et al., 1995). Another study, using radioimmunoassay and enzyme‐multiplied immunoassay techniques, found no change in lymphocyte stimulation index and low blood ­levels of cyclosporine after topical administration of either 0.2% or 2% cyclosporine (Williams, 2010). Although ­clinically ­evident altered peripheral cellular immunity has not been documented with long‐term use of topical CsA ­ophthalmic

Figure 17.19  A 10‐year‐old male castrated Shih Tzu with chronic keratoconjunctivitis sicca. Treated with intermittent topical antibiotic/steroid combination ointment and twice‐daily topical CsA therapy for 4 years. Note extensive dried eyelid exudate, marked thickened mucopurulent ocular discharge, moderate conjunctival hyperemia, and corneal neovascularization OD.

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Section IIIA: Canine Ophthalmology

SECTION IIIA

1024

Figure 17.20  Same dog as in Fig. 17.19 1 month after discontinuing topical CsA therapy and instituting twice daily topical 0.02% tacrolimus ointment. The patient exhibited a marked improvement in mucopurulent discharge and ocular comfort. Corneal neovascularization was slightly improved from previous examination 1 month prior.

preparations at doses that are clinically efficacious for ­treating canine KCS, long‐term topical immunomodulating therapy may predispose canine patients to surface disease and infection (Beckwith‐Cohen et  al., 2016). A report of a Chinese Pug undergoing treatment for chronic KCS with a combination of 0.2% CsA, 0.03% tacrolimus, and neopolydex ointments in both eyes over a 6‐year period may have predis­ posed the dog to corneal and conjunctival infections with Toxoplasma gondii (Swinger et  al., 2009). Chronic KCS treated with topical immunosuppressive therapy may also be a risk factor for developing primary corneal SCC in dogs (Dreyfus et al., 2011). Tear Substitutes (Lacrimomimetics)

Tear substitutes contain ingredients, or combinations of ingredients, to replace deficiencies in one or more of the three primary tear components (i.e., aqueous, mucin, lipid). Many ophthalmic solutions and ointments are commercially available for tear replacement therapy (Table 17.4) and new products frequently emerge on the market. Selection of a particular agent is influenced by the nature of the deficiency, availability, cost, clinician preference, patient compatibility, and owner acceptance. Aqueous tear replacement agents may initially be applied four to six times daily to affected eyes and are generally used concurrently with other topical thera­ peutic agents. Although more frequent applications (i.e., q. 1 or 2 hours) are often desirable, this treatment regimen is rarely possible or practical for the pet owner to accomplish. Despite their limitations, lacrimomimetics are warranted in the treatment of qualitative tear film abnormalities and as

an adjunct to lacrimostimulant therapy for quantitative tear film deficiencies. Given the plethora of commercially avail­ able lacrimomimetics today, veterinarians are cautioned to carefully review any literature that professes improved corneal “repair” (e.g., wound healing times) by use of one or more such substances (Williams & Mann, 2014, 2013; Williams et al., 2012). Published references rarely compare the test product to a topical control with similar viscosity, thus rhealogical biomechanics between eyelid and PTF are dramatically different (for example, hyaluronic acid or carboxymethylcellulose test agents compared with saline controls). A recent study found that topical addition of a vis­ coelastic lacrimomimetic did not accelerate corneal wound healing compared with a topical control with similar viscos­ ity in dogs (Gronkiewicz et al., 2017). Methylcellulose products are virtually inert, water‐­soluble, viscous, semisynthetic cellulose colloids. Because cellulose derivatives are nonirritating to the eye and compatible with most drugs, they are commonly used as aqueous tear substi­ tutes and aqueous vehicles for other ophthalmic prepara­ tions. Polyvinyl alcohol (PVA) is a synthetic hydrophilic resin that is less viscous than methylcellulose but has good corneal adhesive properties. Usually provided as a 1.4% solu­ tion, PVA is the primary ingredient in a number of artificial tear products. Because nonviscous polymers are very well tolerated by most human patients, many products contain­ ing PVA have been formulated and marketed commercially. Viscous lubricants enhance ocular surface wettability and have extended contact time with the ocular surface. Linear polymers such as dextran and polyvinylpyrrolidone (povi­ done) have mucinomimetic properties. Polymers have been combined with buffered solutions of substituted cellulose esters to form preparations for treating deficiencies of both the aqueous and mucin components of the preocular tear film. Among tear substitutes advocated for their lubricating and hydrating properties, solutions containing linear poly­ mers remain on the eye for longer periods than solutions without these derivatives. Viscoelastic substances with mucinomimetic properties include sodium hyaluronate, chondroitin sulfate, and 1%–2% methylcellulose preparations (Nepp et  al., 2001). Sodium hyaluronate is a naturally occurring, high‐molecular‐weight glycosaminoglycan with excellent viscoelastic and lubricat­ ing properties. Evaluation of the biologic and physical prop­ erties of these substances typically show excellent rheologic properties (i.e., elasticity, viscosity, and pseudoplasticity), thereby indicating these lacrimomimetic formulations should serve as effective viscoelastic and protectants for the ocular surface (Gronkiewicz et  al., 2017; Larson & Balazs, 1994). Chondroitin sulfate, which is a glycosaminoglycan polymer made of disaccharide units, is slightly less viscous than sodium hyaluronate.

17: Diseases and Surgery of the Canine Lacrimal Secretory System

1025

Table 17.4  Tear substitutes.a Viscosity agents/concentration(s)

Preservative

Source

Polyvinyl alcohol solutions AKWA Tears Artificial Tears LiquiTears

  PVA 1.4% PVA 1.4% PVA 1.4%

   BAC BAC BAC

   Akorn Many Major

Cellulose‐based solutions Refresh Celluvisc GenTeal Mild GenTeal Mild to Moderate GenTeal Moderate to Severe Gonak Goniovisc Bion Tears Isopto Tears Plain Refresh Tears Refresh Plus Retaine

   CMC 1% HPMC 0.2% HPMC 0.3% HPMC 0.3% CMC 0.25%   HPMC 2.5% HPMC 2.5% HPMC 0.3% HPMC 0.5% CMC 0.5% CMC 0.5% CMC 0.5%

   None None None None     BAC BAC None BAC None None None

   Allergan Alcon Alcon Alcon     Akorn Contacare Alcon Alcon Allergan Allergan Ocusoft

Polymer combinations GenTeal Mild Lubricant Natural Balance Tears Nature’s Tears GenTeal Moderate Tears Naturale Forte Optixcare Clear Eyes Natural Tears FreshKote Lubricant Hypo Tears Bion Tears Moisture Eyes Moisture Eyes Liquid Gel Refresh Classic Refresh Optive  Refresh Optive Advanced  Lubricant Eye Drops  Systane Lubricant   Visine Dry Eye Relief  Visine Pure Tears Portables

  DEX‐70 0.1%, HPMC 0.3% DEX‐70 0.1%, HPMC 0.3% DEX‐70 0.1%, HPMC 0.3% DEX‐70 0.1%, Glycerin 0.2%, HPMC 0.3% DEX‐70 0.1%, Glycerin 0.2%, HPMC 0.3% Carbomer, Sorbitol PVA 0.5%, Povidone 0.6% Povidone 2%, PVA 2.7% PEG‐400 1%, PVA 1% HPMC 0.3%, DEX‐70 0.1% Glycerin 0.3%, Propylene glycol 1% DEX‐70 0.1%, HPMC 0.8% PVA 1.4%, Povidone 0.6%  CMC 0.5%, Glycerin 0.9% CMC 0.5%, Glycerin 1%, PSB 0.5% PEG‐400 0.4%, Propylene glycol 0.3%  PEG‐400 0.4%, Propylene glycol 0.3% Glycerin 0.2%, HPMC 0.2%, PEG‐400 1%  Glycerin 0.2%, HPMC 0.2%, PEG‐400 1%

  POLYQUAD or PF BAC BAC None POLYQUAD EDTA, Cetrimide BAC POLYQUAD BAC None BAC BAC or PF None  None None  None   POLYQUAD or PF  BAC   None

  Alcon Major Rugby Alcon Alcon CLC Medica Meditech Focus Alcon Novartis Bausch & Lomb Bausch & Lomb Allergan  Allergan Allergan  Rugby   Alcon  McNeil   McNeil

Viscoelastic Products i‐drop Vet Gel i‐drop Vet Plus Remend Drops Remend Gel

  Hyaluronate 0.3%, Glycerin Hyaluronate 0.25% 0.4% Hyasent‐S 0.75% Hyasent‐S

  None None None None

  I‐Med Pharma I‐Med Pharma Bayer Bayer

SECTION IIIA

Product

(Continued)

1026

Section IIIA: Canine Ophthalmology

SECTION IIIA

Table 17.4  (Continued) Product

Viscosity agents/concentration(s)

Preservative

Source>

Glycerin, propylene glycol, and PEG Products Clear Eyes Pure Relief Systane Opti‐Free Balance Moisture Eyes Blink Tears

     Glycerin 0.25% Propylene glycol 0.6% Propylene glycol 0.6% Propylene glycol 0.95% PEG‐400 0.25%

     None POLYQUAD POLYQUAD None Sodium Chlorite

     Meditech Alcon Alcon Bausch & Lomb Abbott

Ointments AKWA Tears Ointment  Soothe Night Time Refresh PM  Stye Sterile Lubricant  Puralube GenTeal Nighttime PM Sterilube Nighttie Artificial Tears Systane Nighttime Tears Naturale PM Refresh Lacri‐Lube Advanced Eye Relief Nighttime

  White petrolatum 83%, MO 15%, lanolin 2% White petrolatum 80%, MO 20% White petrolatum 57.3%, MO 42.5% White petrolatum 57.7%, MO 31.9% White petrolatum 85%, MO 15% White petrolatum 85%, MO 15% White petrolatum 85%, MO 15% White petrolatum 57.3, MO 42.5% White petrolatum 94%, MO 3% White petrolatum 94%, MO 3% White petrolatum 56.8%, MO 42.5% White petrolatum 80%, MO 20%

  None  None None  None  None None None None None None Chlorobutanol  None

  Akorn  Bausch & Lomb Allergan  Meditech  Paddock Novartis FERA Rugby Alcon Alcon Allergan  Bausch & Lomb

BAC, benzalkonium chloride; CMC, carboxymethyl cellulose; DEX, dextran; EDTA, ethylenediaminetetraacetic acid; GEL, gelatin; HEC, hydroxyethyl cellulose; HPMC, hydroxypropyl methylcellulose; MC, methylcellulose; MO, mineral oil; PEG, polyethylene glycol; POLYQUAD, polyquaternium‐1; PSB, polysorbate 80; PVA, polyvinyl alcohol; PF, preservative free. a  Percentage composition given where information available. (Source: Compiled December 1, 2017, courtesy of Brandon Haake, PharmD)

Lanolin, petrolatum, and mineral oil are used as bases for ophthalmic lubricating ointments. These ingredients mimic the function of naturally occurring meibomian lipids by pre­ venting evaporation, thus preserving existing tears. Because ointments may cause blurring of vision in humans, use of these products is primarily limited to bedtime, as an adjunct to artificial tears used throughout the day. Nonmedicated ophthalmic ointments containing one or more of these ingredients are used to lubricate and protect eyes when cor­ neal exposure is a problem, such as during anesthesia and surgery or in cases of eyelid paresis or eyelid swelling. Ointment vehicles prolong corneal and conjunctival con­ tact for agents such as corticosteroids and antibiotics. Antibiotic ointments may be more economical than and as effective as straight lubricants, with the additional advan­ tage of antibacterial effects. Ointment bases may also pro­ vide a sustained‐release mechanism for delivering lipophilic agents such as CsA. Although ophthalmic ointments remain on the eye longer, they may be more difficult than drops for some owners to apply. With the ointment cap firmly sealed, warming the tube of ointment under hot water for

10–15 seconds immediately prior to ointment instillation can facilitate application. Preservatives (e.g., benzalkonium chloride, chlorobutanol, methylparthimerosal) are often used in lacrimomimetic for­ mulations to maintain stable solutions in multiple‐dose bot­ tles and to prolong shelf life (Grahn & Storey, 2004). If a tear replacement containing preservative is recommended, topi­ cal application should be limited to six or fewer applications per day to avoid epithelial toxicity (Ubels et  al., 1995). Preservative‐free tear solutions should be used when more frequent application is indicated. Antibacterials

Antibiotics with broad‐spectrum activity, such as triple anti­ biotic ointment or solution, are commonly administered to control secondary bacterial infections which occur in KCS cases because of inadequate cleansing of the ocular surface (Petersen‐Jones, 1997). Initially, frequency of treatment is usually three to four times daily, which may then be reduced to twice daily as mucopurulent discharge decreases and eventually discontinued when signs of infection have abated

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1027

(Kern, 2004). In cases of persistent mucopurulent discharge, bacterial culture and sensitivity testing as well as fungal cul­ ture should be performed. Good ocular hygiene (i.e., frequent cleansing of discharges) is essential to minimize the accumulation of debris with degra­ dative enzymes that contribute to ocular surface inflamma­ tion and ulceration. To facilitate removal of copious exudates and mucoid debris that may accompany KCS, a 5%–10% solu­ tion of acetylcysteine may be applied topically two to four times daily. In addition, the anticollagenase properties of ace­ tylcysteine may aid in preventing enzymatic degradation of surface tissues and may be useful in treatment of corneal ulceration. Acetylcysteine solution has been advocated as one component of a combination solution for treating dry eye (i.e., Severin’s KCS solution), which also contains artificial tears, pilocarpine, and an antibiotic. At present, Severin’s KCS solu­ tion is infrequently used because of the sometimes irritating nature of this combination and the newer, more effective lac­ rimostimulants (e.g., CsA, tacrolimus) currently available. Anti‐Inflammatory Therapy

Anti‐inflammatory therapy may be a valuable adjunct to other medical therapy in improving clinical signs of KCS (Giuliano, 2004; Holmberg & Maggs, 2004). Topical corticos­ teroids are commonly administered to minimize conjuncti­ vitis, to alleviate discomfort, and to reduce corneal opacities associated with chronic keratitis. Triple‐antibiotic ointment in combination with dexamethasone is beneficial in many KCS patients. Caution must be exercised, however, when administering topical corticosteroids, because their use may significantly complicate healing of an ulcerated cornea. Therefore, these agents are contraindicated when the cornea retains fluorescein stain. Chronic administration of topical corticosteroids can also cause local immunosuppression and predispose the eye to secondary infections and ulceration (Beckwith‐Cohen et al., 2016). In addition to its marked lacrimostimulant effects, topical CsA also has beneficial anti‐inflammatory properties (e.g., reducing corneal inflammatory infiltrates). Although some conflicting reports exist, use of CsA is deemed safe in the presence of noninfected corneal ulceration, and CsA does not appear to substantially alter corneal wound healing or ocular surface flora (Salisbury et al., 1995) (Fig 17.21). CsA and other immunomodulators (e.g., tacrolimus, pimecroli­ mus) may also be beneficial in reducing corneal vasculariza­ tion in dogs with chronic keratitis from causes other than KCS (Jackson et al., 1991). Miscellaneous Considerations Other Considerations in Aqueous Tear Deficiency

Cases of acute KCS may present with corneal stromal ulcer­ ation requiring aggressive medical or surgical therapy (or

Figure 17.21  KCS‐affected eye after 3 weeks of treatment with topical CsA. Initial Schirmer tear test (STT) reading was 2 mm/min, and a central stromal ulcer was present before treatment. Note the absence of discharge and minimal conjunctival hyperemia. STT reading increased to 13 mm/min after topical therapy. Granulation tissue seen in the axial cornea is a result of the resolving stromal ulceration.

both). Because opportunistic infections may contribute to rapid degradation of ulcerated cornea, bacterial culture of the ulcer margins with subsequent sensitivity testing is indicated. When corneal ulceration occurs as a sequela to KCS, local atropine administration should be used judi­ ciously and only for as long as is necessary to treat the con­ current uveitis, because surface drying will be exacerbated by its application. In cases of deep stromal ulceration or descemetocele formation, reconstructive corneal surgery (i.e., conjunctival grafting) may be necessary to stabilize the cornea and to stimulate fibrovascular resolution of the ulceration (Fig. 17.22). Special Considerations in Qualitative Tear Deficiencies

Specific treatment of lipid tear abnormalities depends on the particular meibomian disorder. Because opportunistic and pathogenic infections are often present in cases of acute and chronic meibomianitis, aerobic bacterial cul­ tures of expressed secretions may be indicated. Antibiotics should be selected on the basis of antibacterial susceptibil­ ity testing results. Bacterial meibomianitis should be treated with both topical and systemic antibiotics. Oral tet­ racyclines and omega 3 fatty acids are commonly recom­ mended in people (Lemp, 2008) and have been shown to reach the tear film in dogs (Collins et  al., 2016). Chronic bacterial meibomianitis is often recurrent and requires intermittent, intensive treatments or continuous, low‐level maintenance therapy; topical application of an antibiotic ointment two to three times daily may be indicated as long‐ term maintenance therapy in some cases. In such cases, periodic expression of meibomian material from the glands with blunt‐tipped, mildly serrated thumb forceps after application of topical anesthesia may also be helpful in removing inspissated secretions.

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Mucinolytic–Anticollagenase Agents

Section IIIA: Canine Ophthalmology

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Figure 17.22  A 5‐year‐old female spayed Pug with keratoconjunctivitis sicca and corneal ulceration. A conjunctival pedical graft was performed 4 weeks prior. The graft is vascularized and well‐adhered to the corneal stromal defect. Tear production has improved on topical CsA therapy; however, pigmentary keratitis persists.

In cases of granulomatous blepharitis secondary to rup­ tured meibomian glands, concurrent administration of sys­ temic corticosteroids may be necessary to resolve the diffuse eyelid swelling. Surgical curettage of chalazia is indicated to permit resolution of focal granulomas. Warm, moist com­ presses applied to the eyelids for several minutes two to three times daily may stimulate local vasodilation and result in improved hemodynamics to the affected areas. In addi­ tion, exudates may be softened and removed by regular use of moist eyelid compresses, particularly during the initial treatment period. Another aspect of treating diffuse meibomian diseases is providing lipid substitutes through topical emollients con­ taining petrolatum, mineral oil, liquid lanolin, or some com­ bination of these ingredients (see Table 17.4). In addition to serving as lipid substitutes, emollients lubricate the ocular surface, which is especially beneficial during treatment of conjunctival granulomas (Fig.  17.15 and Fig.  17.16). Antibiotic or antibiotic–corticosteroid ointments contain emollients and may be quite useful in treating surface dis­ ease resulting from meibomianitis. Congenital absence of meibomian glands associated with eyelid agenesis is usually treated both medically and surgi­ cally. Grafting of periocular skin into the defective area using either a pedicle or sliding/rotational skin flaps will partially restore eyelid function (Whittaker et al., 2010). In addition to surgical reconstruction of the affected eyelid, topical appli­ cation of lubricant ointments will generally provide a lipid‐ like effect to enhance wetting of the ocular surface. Treatment for mucin‐deficient keratoconjunctivitis con­ sists of topical mucin replacements (i.e., mucinomimetics),

symptomatic treatment of corneal ulcers if present, and topi­ cal anti‐inflammatory therapy in selected cases. Topical mucinomimetics (see Table  17.4) applied at 4‐ to 6‐hour intervals are the mainstay of therapy. The more viscous lubricants mimic mucin by enhancing ocular surface wetta­ bility and providing extended contact time with the epithe­ lial surfaces. Conjunctival inflammatory cells appear to inhibit normal goblet cell populations (Moore, 1990), thus topical anti‐ inflammatory therapy may be indicated when marked mucosal and submucosal mononuclear inflammatory cell infiltrates are noted on histopathology. When ulcerative ker­ atitis is present, corticosteroids should not be administered until the ulcerations have healed, as evidenced by negative fluorescein stain retention. In addition, any concurrent infections must be treated simultaneously with appropriate antimicrobials (Kern, 2004). Results of in vitro studies have shown CsA to increase mucus production in a secretory cell line capable of producing goblet cell mucin (Phillips et al., 2000). In addition to its known anti‐inflammatory effects, these in vitro findings, together with a canine KCS in vivo study whereby 2% CsA restored conjunctival mucin stores to control levels over a 4‐week period after surgical removal of both lacrimal and nictitans, suggest CsA may also be benefi­ cial in treating mucin deficiencies because of its direct secre­ tagogue activity (Moore et al., 2001). Use of topical retinoic acid in treatment of mucin‐­deficient ocular surface disease has been reported. In people with KCS, Stevens–Johnson syndrome, ocular pemphigoid or drug‐induced pseudopemphigoid, and surgery or radiation‐ induced dry eye, all‐trans retinoic acid ointment has resulted in some reversal of squamous metaplasia as evidenced by impression cytology, as well as clinical improvements in symptoms, vital stain testing, and STT in some reports (Tseng, 1985; Tseng et al., 1985). Other studies have found no real beneficial effect of topical retinoid therapy for vari­ ous ocular abnormalities characterized by squamous meta­ plasia (Soong et  al., 1988). Naturally occurring vitamin A deficiency is extremely uncommon in the dog, so the availa­ bility of retinoic acid products suitable for topical applica­ tion has been limited to experimental protocols. Therefore, topical vitamin A has not generally been recommended for treatment of mucin‐deficient surface disease in dogs. Miscellaneous therapies for KCS include the use of topi­ cal androgen and topical nerve growth factor, but further research is warranted to fully understand their potential applications in veterinary ophthalmology (Coassin et  al., 2005; Worda et al., 2001). Acupuncture has been advocated by some veterinary ophthalmologists and scattered reports exist in the human literature (Gronlund et al., 2004). A pre­ liminary study was performed to evaluate the effectiveness of oral use of interferon‐alpha (IFN‐alpha) in the treatment of naturally occurring, immune‐mediated, canine KCS (Gilger et al., 1999). Study dogs were each given either two

17: Diseases and Surgery of the Canine Lacrimal Secretory System

Surgical Treatment of Tear Deficiencies Surgical procedures indicated for treatment of selected KCS cases are parotid duct transposition (PDT), which provides saliva as a substitute for tears, and permanent partial tarsor­ rhaphy, which reduces exposure and enhances blinking. Nasolacrimal puncta occlusion is commonly used in humans as a tear‐conserving procedure by blocking tear drainage and has been reported in the treatment of canine KCS (Gelatt et al., 2006; Williams, 2002). However, in the total absence of tears these puntal occluders are not effective. Replacement of the nictitans gland (versus gland removal) is regarded as a preventative surgical procedure for canine KCS. Parotid Duct Transposition

Physiologic similarities between saliva and tear fluid, includ­ ing similar osmolarity and pH, led to the supposition that saliva might serve as a substitute for tears (Table 17.5). PDT surgery was subsequently developed for humans to provide symptomatic relief in cases of refractory KCS. From the mid‐ 1960s to mid‐1980s, before CsA was available, this surgery was also being performed successfully in dogs affected with KCS nonresponsive to medical therapy (Baker & Formston, 1968; Gelatt, 1970; Glen & Lawson, 1971; Jensen, 1979; Lavingnette, 1966; Severin, 1973). After the introduction of CsA in 1987, the percentage of KCS cases treated by PDT declined dramatically (see Table  17.1) (Helper, 1996). Nonetheless, the few dogs with persistent absolute sicca

(STT, 0 mm/min) after several weeks of medical treatment remain candidates for PDT (Rhodes et al., 2012). Preoperative Considerations

In the dog, PDT is usually delayed until KCS has proved unresponsive to at least 8 weeks of conventional medical therapy. For cases in which even a minimal response is noted to medical treatment during this period, treatment should be extended for an additional 4 weeks before recommending PDT. Dogs with KCS may occasionally have xerostomia and these animals are not candidates for PDT surgery. Testing flow of salivary fluid from the parotid duct is easily done by administering a bitter substance (e.g., one drop of ophthal­ mic atropine solution or lemon juice) to the tongue and observing for salivary flow from the papilla. The parotid gland is located at the junction of the head and neck, near the base of the ear canal. From a lateral per­ spective, the parotid gland is a “V”‐shaped structure, with the apex of the gland directed ventrally (Fig.  17.23). The main duct is formed by the convergence of two or three small branches arising from the ventral anterior border of the gland and uniting over the masseter muscle, several millimeters from the gland. The duct extends subcutane­ ously over the surface of the masseter muscle, courses for­ ward across the face, and opens into the buccal cavity at a

Table 17.5  Composition of parotid and tear secretions in humans. Characteristic

Parotid secretion

Lacrimal secretion

  pH

  5.2–8.4

  5.3–7.8

Osmolarity

Physiologic

Physiologic

Lysozyme

Present

Present

Translucency

Clear

Clear

Total solids (%)

1.8

1.6

Ash

1.05

0.81

(Source: From Gelatt, K.N. (1991) Canine lacrimal and nasolacrimal systems. In: Veterinary Ophthalmology (ed. Gelatt, K.N.), p. 283. Philadelphia: Lea & Febiger.

Figure 17.23  Location of the left parotid gland and the duct coursing rostrally through the facial soft tissues to its point of exit into the oral cavity. Dashed lines illustrate the course of the transposed duct resulting from parotid duct transposition surgery. Insert: placement of the oral papilla after transposition and attachment of papilla to the ventral conjunctival fornix via interrupted 7‐0 polyglactin 910 sutures. (Source: Courtesy of G. Constantinescu.)

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or three separate escalating doses (20, 40, 80 IU) of the IFN‐ alpha. A favorable response was observed in 55% (11/20) of all dogs treated. Clinical findings of those dogs that responded included increased wetting of the eyes, decreased mucus discharge, and fewer signs of discomfort. Nutraceutical diets as an adjuvant to pharmacological treatment in dogs affected by KCS has been reported (Destefanis et al., 2016).

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Figure 17.24  Location of the parotid papilla adjacent to the fourth upper premolar and presurgical cannulation with monofilament nylon suture. The incision around the papilla is outlined with dashed lines. The shaded area rostral to the papilla represents the area included in the initial incision around the cannula suture. The circular area around the papilla represents the area of mucosa subsequently retained and sutured to the conjunctiva. (Source: Courtesy of G. Constantinescu.)

single papilla slightly posterior and lateral to the fourth upper premolar tooth and rostral to the zygomatic papilla (Fig.  17.24). Duct size and length vary depending on the breed, with mesocephalic breeds having a diameter of approximately 1.5 mm and a length of approximately 6 cm. Small dogs and brachycephalic breeds typically have smaller and shorter ducts, respectively. Because the parotid duct lies in close proximity to the dorsal and ventral buccal nerves (including the interconnecting branches) as well as the facial vein, care must be taken not to damage these structures during PDT surgery. The teeth should be cleaned before PDT surgery, and when periodontal disease is present, systemic antibiotics should be administered for 7–10 days before the operation. The choice of anesthetic is not particularly critical when performing PDT but use of atropine in the preanesthetic regimen has caused concern because of the possibility of impeding duct cannulation. Although systemic atropine transiently reduces salivary secretions, experienced PDT veterinary ophthalmol­ ogists do not report any particular difficulty in cannulating the parotid duct as a result of preanesthetic atropine. After induction of general anesthesia and insertion of an endotracheal tube, the oral cavity is flushed and swabbed with betadine solution diluted (1 : 10) with physiologic saline. The parotid duct is cannulated by placing a monofila­ ment nylon suture into the duct opening. Optimal suture size may range from 0‐0 to 2‐0 depending on the size of the duct. Suture with a swaged‐on cutting needle is necessary so that the needle may subsequently be used to anchor the

suture to the oral mucosa. Before cannulation, the tip of the nylon suture may be momentarily flamed, forming a small, smooth “bulb” on the end of the suture. Curved mosquito forceps are used to grasp the nylon suture 4 to 5 mm from the end and to direct the suture tip into the duct. The mucosa in grasped just anterior to the papilla with Bishop‐Harmon for­ ceps, and the blunted suture end is inserted into the opening as the mucosa is gently pulled forward. After the suture has been introduced into the duct, it is gently threaded with the curved forceps to the proximal end of the duct until the suture exhibits slight resistance or recoil. The suture should not be forced beyond this point. The attached needle is inserted into the mucosa just rostral to the papilla, is pulled through, and the slack is drawn out, leaving only a small loop of suture between the papilla and mucosal anchor. Using this loop, a knot is tied, and the suture is securely anchored to the mucosa (Fig. 17.25). The mucosal anchor suture allows the suture material with attached mucosa to be manipulated during surgery, thereby minimizing direct manipulation of mucosa and any possible associated trauma to the parotid papilla. As a final step in preparation for the surgery, cotton or gauze soaked with betadine solution is placed against the mucosa and over the papilla, and the lip is returned to its normal position. Either of two approaches (i.e., closed [oral] or open [lat­ eral]) may be used when performing PDT surgery. Both approaches appear to be equally effective, and the choice of an open versus closed PDT procedure is simply one of sur­ geon preference.

Figure 17.25  Before performing parotid duct transposition surgery, the parotid duct is cannulated with monofilament nylon suture. To minimize surgical manipulation of the papilla during the procedure, the suture is anchored to the oral mucosa approximately 1 cm rostral to the papilla, and the resulting loupe of suture is grasped and handled during the surgical procedure. The mucosal incision is then made around the papilla and anchor suture.

Closed Procedure

In the closed PDT procedure, the antiseptic‐soaked cotton or gauze packing is removed from the mouth. An oral speculum is placed between the canine teeth of the opposite side, and the lip is raised and stretched, thereby exposing the papilla. Using a No. 15 Bard‐Parker blade, an elliptical incision is made in the oral mucosa, around the papilla posteriorly and the fixed nylon suture anteriorly. A minimum of 3 mm of mucosal tissue should be left surrounding the papilla posteri­ orly. More than this is left anteriorly, however, because the incision is made rostral to the anchor suture (see Fig. 17.24). The submucosal space is entered with conjunctival scis­ sors, and the papilla and attached mucosa (including the anchor suture) are carefully dissected from the submucosa and adjacent circumpapillary oral mucosa. As the duct ini­ tially courses posteriorly, it is closely adherent to the mucosa, which necessitates a slow, careful dissection. Once the papilla and an initial 1 cm of duct are free from the overlying mucosa, the remaining duct is more easily dissected from the relatively loose connective tissues present posteriorly. This additional posterior dissection may be achieved using either conjunctival or small Metzenbaum scissors. After dissecting as much of the duct as possible through the initial incision, the buccal mucosa is opened further by extend­ ing the incision caudally and parallel to the gum line, which maximizes exposure and facilitates additional dissection of the duct. Dissection should free the duct sufficiently to provide an adequate length for reaching the lower conjunctival fornix with little resistance. During dissection, the duct is kept from twisting by grasping the suture with forceps and maintaining a steady grasp and a constant position. Handling only the anchored suture prevents damage to the mucosa around the papilla. After the duct is free, curved Metzenbaum scissors are used to tunnel, subcutaneously, dorsally from the point near where the duct attaches to the gland and to dissect bluntly toward the ventral lateral canthus of the eye. As the subconjunctival space is subsequently entered, the ventral fornix con junctiva is tented by the tips of the scissors. The tented conjunctiva is then grasped and externalized, and a 6‐mm stab incision is made with a No. 15 Bard‐Parker blade between the lower eyelid and the lateral insertion of the nictitans. This fornix incision ­creates a recipient conjunctival site for anchoring the papilla. For cases in which the eyelid conformation is relatively tight, a ­lateral canthotomy may facilitate this step. After making the conjunc­ tival incision, the tips of the scissors are inserted through this opening, thus establishing communication with the previously dissected tunnel. The subcutaneous tunnel is enlarged by blunt dissection, and the scissors are removed. Next, small curved forceps are replaced into the conjuncti­ val opening. The forceps are inserted into the tunnel and passed toward the now‐free parotid duct. The anchor suture (with attached papilla) is grasped, and the duct is pulled into the subcutaneous tract. Taking care not to twist the duct, it is brought through the lower conjunctival fornix incision.

Once the papilla is in the fornix, and before trimming any excess mucosa, the posterior half of the circumpapillary mucosa is sutured to the conjunctiva with four simple inter­ rupted 7‐0 polyglactin 910 sutures (Fig 17.26). Magnification is necessary for proper suture placement. After the four initial sutures have been placed, the mucosa is carefully trimmed so that the retained rostral half of the circumpapillary mucosa is nearly symmetrical with the pos­ terior half. This is accomplished by inserting conjunctival scissors between the papilla and the fixed suture, then trim­ ming and releasing the mucosa with attached suture. The long portion of the suture is left in the duct as a cannula (see Fig  17.26). The external portion with attached knot is trimmed 3–4 mm external to the papilla. After the excess mucosa (with anchor suture) is removed and discarded, four additional simple interrupted sutures are placed in the ros­ tral half of the retained peripapillary mucosa, thus finishing the conjunctival–mucosal repair and completely securing the papilla into the conjunctival fornix. The buccal mucosa is sutured using 5‐0 polyglactin 910 in a continuous submucosal pattern so that the knots are bur­ ied. If a lateral canthotomy was necessary, it is closed rou­ tinely. Facial swelling and postoperative discomfort are minimal with the closed technique, and healing occurs rap­ idly. Antibiotics are administered both topically and systemi­ cally for 7–10 days postoperatively. After PDT surgery, multiple daily feedings are recommended to stimulate

Figure 17.26  Parotid duct transposition surgery in a dog. The papilla has been surgically transposed into the ventral conjunctival fornix and the posterior half of the circumpapillary mucosa is sutured to the conjunctiva with four simple interrupted 7‐0 polyglactin 910 sutures. The originally placed 2‐0 black nylon suture can be seen emerging from the duct opening.

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17: Diseases and Surgery of the Canine Lacrimal Secretory System

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Section IIIA: Canine Ophthalmology

parotid secretions. Soft food is recommended for the first postoperative week. Because there is no skin incision or external sutures, a restraint collar is usually not needed after closed PDT.

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Open Procedure

The open PDT procedure was the original technique described by Lavingnette (Lavingnette, 1966). It involves exposing the parotid duct through a facial skin incision. The cannulated duct is palpated, and an incision is made over the duct through the skin and superficial facial muscles. The duct is carefully dissected from the masseter muscle and retracted using umbilical tape or a muscle hook (to mini­ mize surgical trauma). The duct is then dissected from the masseter muscle posteriorly to the angle of the mandible and rostrally to the buccal mucosa. The duct continues sub­ mucosally for 0.5–1.0 cm before terminating at the papilla in the buccal mucosa. During dissection, the facial vein and anastomotic branch between the dorsal and ventral buccal nerves must be avoided. After elevating the lip, the mucosa around the papilla and suture is incised with a scalpel and penetrated just to the level of the submucosa. (Some surgeons prefer to use a 6‐mm trephine to make the peripapillary incision; however, this precludes anchoring the nylon suture to the oral mucosa and necessitates leaving the suture end free to extend slightly beyond the papilla.) The papilla and surrounding mucosa are carefully dissected free using conjunctival scissors, and the papilla with retained suture and duct are retracted back into the facial incision. Using small Metzenbaum scissors, a subcutaneous tunnel is established and directed to the ven­ tral lateral conjunctival fornix (as described previously for the closed PDT procedure). Placement and suturing of the papilla as well as removal of excess mucosa are identical to the closed PDT procedure. The oral incision is closed using 5‐0 polyglactin 910 in a submucosal pattern. Skin closure involves two layers, with a continuous subcutaneous layer of 4‐0 or 5‐0 absorbable material and simple interrupted skin sutures using 4‐0 or 5‐0 nonabsorbable suture. A restraint collar may be needed to prevent self‐trauma after the open PDT; otherwise, the same recommendations for postopera­ tive care apply.

from the extensive surgical dissection. Regardless of the approach, exercising great care when dissecting and manip­ ulating the duct cannot be overemphasized, because damage to the duct during surgery can result in temporary malfunc­ tion or, in the worst scenario, permanent dysfunction, thus negating any potential benefit from the operation. Causes for delayed failure in PDT surgery include retrac­ tion of the papilla into the subcutaneous space with fibrous closure of the conjunctival opening, occlusion of the duct by sialoliths, and acute or chronic sialoadenitis (Betts & Helper, 1977; Harvey & Koch, 1971; Jensen, 1979; Termote, 2003). The ability to salvage function depends on the cause and, in some cases, the promptness of intervention. The most fre­ quent cause of PDT failure is occlusion of the transposed duct, either at or near the conjunctival attachment (Harvey & Koch, 1971; Schmidt et al., 1970). This usually results from inadequate dissection of the duct, thereby causing increased tension and retraction of the papilla from the recipient site into the adjacent subconjunctival space. Such occlusions may be successfully repaired by making a facial incision, redissecting the duct, and reattaching the papilla to the con­ junctiva (Betts & Helper, 1977). Saliva contains a higher concentration of minerals com­ pared with tears and owners should be advised that mineral deposits are considered a normal sequel on the cornea and eyelid margins after PDT surgery (Fig. 17.27) (Rhodes et al., 2012). Should this occur, a chelating solution containing 1%–2% EDTA (ethylenediaminetetraacetic acid) in artificial tears may be applied topically two to three times daily to aid in control of the mineral precipitates. Some practitioners use oral doxycycline as a chelating agent; however, long‐term

Complications, Sequelae, and Postoperative Considerations

Various postoperative complications have been reported after PDT surgery (Guinan et al., 2007; Rhodes et al., 2012). Twisting, laceration, or trauma to the parotid duct may occur with either the closed or the open PDT procedure. Some sur­ geons indicate a greater chance of twisting and damaging the duct with the closed approach, whereas Jensen (Jensen, 1979) discusses potential difficulties associated with the open PDT procedure, including trauma associated with dis­ section of the highly vascular and innervated facial tissues, increased postoperative swelling, and potential discomfort

Figure 17.27  Right eye of a 7‐year‐old female spayed Yorkshire Terrier 9 months after parotid duct transposition surgery, showing mineral precipitates on the ocular surface and eyelids.

17: Diseases and Surgery of the Canine Lacrimal Secretory System

Figure 17.28  A 6‐year‐old male castrated Siberian Husky 10 months after parotid duct transposition surgery. Note the chronic keratitis with superficial neovascularization, mineral deposition on the axial cornea, and chronic, moist, mucoid blepharitis extending to include moderate periocular dermatitis.

genera, with many uncommon isolates and some potential pathogens (Petersen‐Jones, 1997). The heavy bacterial colo­ nization does not appear to be associated with overt ocular disease, but it may contribute to the blepharitis sometimes seen as a sequela to overflow of saliva from the conjunctival sac (Petersen‐Jones, 1997). Partial Tarsorrhaphy

A partial permanent tarsorrhaphy may be beneficial in dogs with KCS, especially among brachycephalic breeds, to afford greater corneal protection and to conserve existing tears. Lateral canthoplasty is easier to perform, but medial cantho­ plasty provides additional protection from medial canthal trichiasis, especially in brachycephalic breeds. The technique is the same as the one used for treating ocular exposure resulting from conformational exophthalmos. When per­ forming medial canthoplasty, care should be taken not to damage the lacrimal puncta or canuliculi. Replacement of a Prolapsed Nictitans Gland

Removing a prolapsed nictitans gland or allowing chronic prolapse without treatment may predispose an affected eye to KCS (Kaswan & Martin, 1985; Kaswan et  al., 1984). Repair of a prolapsed nictitans gland using an appropriate replacement procedure may prevent the sequela of KCS (Kaswan & Martin, 1985; Kaswan et  al., 1984; Plummer et al., 2008; Sapienza et al., 2014). A number of replacement techniques have been described, and the reader is referred to Chapter 18.

Cysts, Foreign Bodies, and Neoplasms of the Lacrimal Secretory System Cysts involving lacrimal tissue or surrounding conjunctiva, though uncommon, have been reported and may originate from either the orbital or the nictitans glands (Delgado, 2013; Lamagna et  al., 2012; Latimer et  al., 1983; Martin et  al., 1987; Ota et  al., 2009; Playter & Adams, 1977). Depending on the site of origin, cysts may distend the con­ junctiva and protrude into the palpebral fissure, expand within the orbit and cause displacement of the globe, or both (Fig.  17.29). Possible causes include developmental defects, blunt trauma, foreign‐body injury, or inflamma­ tion affecting the ducts. Basset Hounds and Labrador Retrievers may be predisposed (Ota et al., 2009). Lacrimal cysts are characterized histopathologically by inflamma­ tion of the cyst wall, which is lined by ­flattened, cuboidal epithelium and affected glands exhibit features of secretory stasis (i.e., dilated acini and ducts, ­epithelial atrophy). Surgical excision of cysts is curative (Fig. 17.30). Tear secre­ tion may be compromised depending on the amount of lacrimal gland involved initially or excised subsequently.

SECTION IIIA

use of oral antibiotics is not without possible side‐effects. In an attempt to alter the pH and mineral content of saliva, a number of anecdotal improvements have been discussed in various nonpeer reviewed forums including oral supplemen­ tation with tomato juice, vitamin C, calcium carbonate, but­ termilk, and systemic carbonic anhydrase inhibitors. To the author’s knowledge, no evidence‐based medicine exists to support or refute the use of such agents after PDT surgery. Continued use of topical CsA or similar agent also appears to be helpful in reducing irritation from mineral deposits, probably by virtue of its lubricant, mucinogenic, and anti‐ inflammatory properties. An overabundance of salivary secretions may result in facial wetting and discoloration, which can be objectionable to some owners, especially in light‐coated dogs (Fig 17.28). In rare cases, overproduction may prompt consideration of partial duct ligation (Kuhns & Keller, 1979; Schilke & Sapienza, 2012), reversal of the surgery, or enucleation (Rhodes et  al., 2012; Young et  al., 2018). A recent report found additional complications after PDT surgery to include bullous keratopathy, corneal ulceration with associated stro­ mal mineral deposition, iatrogenic corneal ulceration, lower lid entropion, recurrent epithelial erosion, and stromal abscessation (Rhodes et al., 2012). An orbital sialocele after enucleation of a globe previously treated for KCS by PDT has been reported (Guinan et al., 2007). Despite ligating the duct distally at the time of enucleation, sialocele development 1 month later necessitated further surgical exploration to remove the abnormal tissue and re‐routing of the remaining proximal normal portion of the parotid duct back into the oral cavity. After PDT, the bacterial flora of the eyes changes signifi­ cantly and will consist of large numbers of mixed bacteria

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1034

Figure 17.29  Dacryops in a 3‐year‐old female spayed Labrador Retriever.

Figure 17.31  One‐year‐old male English Bulldog with cyst formation of the nictitating membrane occurred approximately 7 weeks after morgan pocket surgery was performed by the primary care veterinarian.

Figure 17.30  Intraoperative photograph of cyst dissection of a 1‐year‐old male castrated Labrador Retriever. The cystic mass has been partially dissected from the surrounding tissue and is being gently lifted from underlying associated connective tissue. (Source: Reprinted with permission from Ota, J., Pearce, J.W., Finn, M.J., Johnson, G.C. & Giuliano, E.A. (2009) Dacryops (lacrimal cyst) in three young Labrador Retrievers. Journal of the American Animal Hospital Association, 45, 191–196.)

Figure 17.32  Same patient as in Fig. 17.31 in surgery demonstrating successful marsupialization of the cyst wall performed by the author. The author advocates that marsupialization be performed on the palpebral aspect of the nictitating membrane to avoid any iatrogenic damage to the cornea from suture irritation.

Cysts of the canine nictitating membrane may arise sec­ ondary to Morgan pocket surgical repair of a prolapsed gland of the third eyelid (Fig.  17.31). Marsupialization of these cysts is effective at resolving the problem and main­ taining important third eyelid contributions to the PTF (Fig. 17.32) (Barbe et al., 2017).

Although lacrimal neoplasms are also uncommon in the dog, primary adenomas and adenocarcinomas of the orbital and nictitans glands have been reported (Headrick et  al., 2004; Miyazaki et  al., 2015; Rebhun & Edwards, 1977; Wilcock & Peiffer, 1988). These tumors tend to be locally invasive and have a guarded prognosis. Adenocarcinoma of the nictitans gland constitutes one of the rare indications for

17: Diseases and Surgery of the Canine Lacrimal Secretory System

complete excision of the nictitans. Mucosal grafting is pos­ sible after this procedure (Kuhns, 1981). Orbital exentera­ tion with adjunctive irradiation or chemotherapy may be indicated for cases of adenocarcinoma of the orbital lacrimal gland. In one report, 15 cases of lobular adenomas of the

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orbit were reviewed. These tumors presented clinically and histologically as a benign neoplasm of lacrimal or salivary gland origin. Recurrence was likely unless the mass was completely excised, at times requiring orbital exenteration (Headrick et al., 2004).

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SECTION IIIA

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17: Diseases and Surgery of the Canine Lacrimal Secretory System

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Williams, D.L. (2002) Use of punctal occlusion in the treatment of canine keratoconjunctivitis sicca. Journal of Small Animal Practice, 43, 478–481. Williams, D.L. (2008) Immunopathogenesis of keratoconjunctivitis sicca in the dog. Veterinary Clinics of North America: Small Animal Practice, 38, 251–268. Williams, D.L. (2010) Lack of effects on lymphocyte function from chronic topical ocular cyclosporine medication: a prospective study. Veterinary Ophthalmology, 13, 315–20. Williams, D.L. & Burg, P. (2017).Tear production and intraocular pressure in canine eyes with corneal ulceration. Open Veterinary Journal, 7, 117–125. Williams, D.L., Hoey, A.J. & Smitherman, P. (1995) Comparison of topical cyclosporin and dexamethasone for the treatment of chronic superficial keratitis in dogs. Veterinary Record, 137, 635–639. Williams, D.L. & Mann, B.K. (2013) A Crosslinked HA‐based hydrogel ameliorates dry eye symptoms in dogs. International Journal of Biomaterials, 460437. Williams, D.L. & Mann, B.K. (2014) Efficacy of a crosslinked hyaluronic acid‐based hydrogel as a tear film supplement: a masked controlled study. PLoS One, 9, e99766.

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18 Diseases and Surgery of the Canine Conjunctiva and Nictitating Membrane Claudia Hartley1 and Diane V.H. Hendrix2 1 2

Langford Vets, University of Bristol Veterinary School, Langford, Bristol, UK Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA

Conjunctiva The conjunctiva is associated with many adnexal and bulbar diseases because of its exposure and close proximity to ocu­ lar structures. Conjunctival disease may be indicative of sys­ temic or severe disease, and therefore a thorough physical and ophthalmic examination should be undertaken. The cause of localized conjunctival disease can often be deter­ mined solely on the basis of history and a complete ocular examination. When the cause is not obvious after a complete examination, the conjunctiva is easily accessible for cytology or biopsy.

Functional Anatomy and Physiology The conjunctiva is a mucous membrane with roles in tear dynamics, immunologic protection of the eye, ocular move­ ment, and corneal healing. The palpebral conjunctiva lines the inside of the eyelids, beginning at the eyelid margin (and continuous with the epidermis of the eyelid) and extending deep toward the orbit to become a conjunctival fornix (i.e., “cul‐de‐sac”). From here the conjunctiva reverses direction and extends over the globe to the limbus as the bulbar con­ junctiva and is continuous with the corneal epithelium. Medially, the conjunctiva covers both the palpebral and bulbar surfaces of the nictitating membrane (NM). Red­ undancy of the conjunctiva at the fornices allows ocular movement. Attachment of the bulbar conjunctiva to the bul­ bar fascia and insertions of the rectus muscles prevent the bulbar conjunctiva from drooping over the cornea (Srinivasan et al., 1992). The substantia propria of the palpe­ bral conjunctiva is tightly adhered to the tarsus and there­ fore is not freely movable. The bulbar conjunctiva, however, is freely movable, except near the limbus. As the bulbar con­ junctiva approaches the limbus, it fuses to Tenon’s capsule (Jakobiec & Iwamoto, 1992). The lack of adhesion between the bulbar conjunctiva and the deeper tissues facilitates use

of the conjunctiva in many surgical procedures and as a site for injecting medications.

Microscopic Anatomy Histologically, the conjunctiva is composed of nonkerati­ nized, stratified squamous epithelium and an underlying substantia propria. The substantia propria is divided into superficial and deep layers. The superficial layer contains many lymphoid nodules, which are the major components of the conjunctiva‐associated lymphoid tissue (CALT; Srinivasan et al., 1992). The purpose of CALT is to receive antigen and to present it to circulating mononuclear cells (Eichenbaum et  al., 1987). The lymphatics that drain this area represent the only known lymphatic drainage of the normal canine eye (Eichenbaum et al., 1987), although lym­ phatic vessels have been immunohistologically demon­ strated within the inflamed cornea (Kafarnik, C., personal communication). The deeper layer of the substantia propria is fibrous and contains the conjunctival vessels and nerves (Srinivasan et al., 1992). While the NM of the dog shows evi­ dence of microfold cells (M cells), they have not been observed in the remaining conjunctiva (Chodosh et al., 1998; Giuliano et  al., 2002). M cells are unique epithelial cells overlying a lymphoid follicle that function to sample antigen at a mucosal surface and transcytose it to the underlying lymphoid cells (see Chapter 6). Goblet cells are also present in the epithelial layer of the conjunctiva. These cells produce a gel‐like mucin, which forms the deepest of the three layers of the preocular (i.e., precorneal) tear film (Chiapino & Dawson, 1985; Lemp & Wolfley, 1992). This mucin protects the ocular surface by trapping debris and bacteria, and by providing a medium for adherence of immunoglobulins (i.e., immunoglobulin A, IgA) and microbicidal lysozymes (Holly & Lemp, 1971; Lemp et al., 1970; Nichols et al., 1983). The areas of highest canine goblet cell density are the lower nasal fornix, lower

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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middle fornix, and lower nasal tarsal region. Goblet cells are essentially absent from the upper and lower bulbar areas (Moore et al., 1987).

SECTION IIIA

Vascular Supply and Innervation The vascular supply of the conjunctiva is extensive. Branches of the dorsal and ventral palpebral and malar arteries, as well as terminal branches from the anterior ciliary arteries, provide the conjunctiva with its blood supply (Murphy & Pollock, 1993). Innervation is provided by branches of the long ciliary, zygomaticofacial, zygomaticotemporal, infra­ trochlear, and frontal nerves (Murphy & Pollock, 1993).

Normal Bacterial and Fungal Flora Bacteria can be cultured from the conjunctival sac in 46%–90% of normal dogs (Bistner et al., 1969; McDonald & Watson, 1976; Teixeira et al., 2002; Thangamuthu & Rathore, 2002; Urban et al., 1972). Gram‐positive aerobes are the most commonly cultured, with Staphylococcus spp., Bacillus spp., Corynebacterium spp., and Streptococcus spp. predominating (Bistner et  al., 1969; McDonald & Watson, 1976; Teixeira et  al., 2002; Thangamuthu & Rathore, 2002; Urban et  al., 1972; Wang et al., 2008). Canine conjunctival bacterial cul­ ture rates in normal dogs varied with season (highest in spring and summer) in Beijing, China (Wang et  al., 2008). Gram‐negative bacteria have been recovered from the con­ junctival sac in 7%–8% of normal dogs (Bistner et al., 1969; McDonald & Watson, 1976; Urban et al., 1972). Anaerobes are rarely isolated (McDonald & Watson, 1976; Thangamuthu & Rathore, 2002). In a recent study, fungal organisms were cultured from 22% of dogs (most frequently Alternaria, Cladosporium, Penicillium, and Aspergillus spp.) in Southern France (Verneuil et al., 2014). In this study the presence of conjunctival fungal organisms was correlated to the pres­ ence of fungi on the skin. In another study, conjunctival fungi were rare (most commonly cultured Cladosporium oxysporum, Curvularia lunata, and Malassezia pachydermatis; Samuelson et al., 1984).

Normal Cytology Cytologic examination of scrapings from normal conjunctiva reveals sheets of epithelial cells with large, round, homoge­ nous nuclei and abundant cytoplasm. Keratinized epithelial cells are uncommon. Bacteria are occasionally seen and leu­ kocytes are rare (Lavach et al., 1977). Cytologic samples are easy to obtain from the conjunctiva. After administration of a topical anesthetic, a cytobrush, the blunt end of a scalpel blade, or even an impression using a membrane filter can be effective for obtaining cells (Bauer et al., 1996; Bolzan et al., 2005; Braus et al., 2017; Willis et al., 1997).

General Response to Disease The conjunctiva responds to insult with a limited number of mechanisms. Chemosis, hyperemia, blepharospasm, and cellular exudation characterize acute conjunctivitis (Yanoff & Fine, 1989). The loose arrangement of the conjunctival stroma, extensive vascular supply, and presence of lymphoid tissue allow marked edema to develop rapidly after trauma or exposure to allergens or toxins, as well as hyperemia and a cellular response. Chronically, multinucleated giant cells are seen as a nonspecific change (Lavach et al., 1977). The normally nonkeratinized epithelial cells may become kerati­ nized secondary to prolonged exposure associated with ectropion, lagophthalmos, or keratoconjunctivitis sicca (KCS); keratinization may also occur with vitamin A defi­ ciency and irradiation (Murphy, 1988). Goblet cell prolifera­ tion occurs with KCS, chronic conjunctivitis, and vitamin A deficiency (Murphy, 1988). Conjunctival flora is altered in dogs with various diseases. Bacteria are more likely to be isolated from the conjunctiva of dogs with ulcerative keratitis than from dogs with healthy eyes (Prado et  al., 2005). Malassezia pachydermatis, alipo­ philic yeast that is most commonly associated with otitis and dermatitis, was found to be present in 23% of eyes with cor­ neal ulceration and only 3% of healthy eyes (Prado et  al., 2004). The increased number of bacteria and yeast cultured from dogs with ulcerative keratitis could be caused by decreased ocular defenses, increased phospholipids second­ ary to inflammation, or decreased concentration of tear lysozyme from increased tear production secondary to ulcer­ ation (Murphy et al., 1978; Prado et al., 2005). Another study evaluating cytologic and culture differences between the conjunctiva of dogs with atopic dermatitis and normal dogs found that affected dogs had significantly more bacteria, keratinized and nonkeratinized epithelial cells, eosinophils, and lymphocytes, and had more positive cultures regardless of clinical parameters (Furiani et al., 2011). The incidence of culturing M. pachydermatis from the conjunctiva of atopic dogs varies between studies (Nardoni et  al., 2007; Prado et al., 2008). Ocular redness, which can result from conjunctival hyper­ emia or episcleral congestion, occurs with many diseases, including abnormal eyelid conformation, abnormal cilia, allergic conjunctivitis, corneal disease, KCS, anterior uveitis, glaucoma, orbital disease, and toxic or septic shock. Conjunctival hyperemia should be differentiated from epis­ cleral injection and ciliary flush, which occur with glaucoma and anterior uveitis. Generally, the conjunctival vessels are smaller in diameter, have a branching pattern, blanch quickly with topical application of 1%–2% epinephrine, and are mobile. Episcleral vessels are larger in diameter, do not branch as frequently, do not blanch quickly with topi­ cal  application of epinephrine, and are not mobile. The

18: Diseases and Surgery of the Canine Conjunctiva and Nictitating Membrane

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Infectious Conjunctivitis Infectious conjunctivitis indicates the association with spe­ cific pathogens and is uncommon in the dog.

Figure 18.1  Neutrophils, cocci, and conjunctival epithelial cells in a cytologic specimen from a dog with bacterial conjunctivitis. (Diff‐Quik; original magnification, 330×.)

Bacterial Conjunctivitis

Viral Conjunctivitis

Primary bacterial conjunctivitis is an uncommon disease in the dog. In most cases, bacterial conjunctivitis develops sec­ ondary to eyelid abnormalities or KCS. Bacterial conjuncti­ vitis is usually caused by Staphylococcus spp. and other gram‐positive organisms (Gerding et  al., 1988; Murphy et al., 1978). Multiple dogs with conjunctivitis were screened for Chlamydiaceae and were found to be negative in one study (Holst et  al., 2010). Another study identified Chlamydophila psittaci genotype C infection in four dogs in the same location that had recurrent keratoconjunctivitis, respiratory distress, and reduced litter size (Sprague et al., 2009). Cytologic examination of conjunctival scrapings from dogs with bacterial conjunctivitis can help to confirm the diagnosis. Neutrophils with few mononuclear cells, many bacteria, and degenerating epithelial cells are present in acute infections (Fig. 18.1; Lavach et al., 1977; Murphy, 1988). In chronic disease, neutrophils remain the predomi­ nant cell type, but there are many more mononuclear cells. Additionally, degenerate or keratinized epithelial cells are seen, with the presence of bacteria being variable (Lavach et al., 1977; Murphy, 1988). Generally, a complete ophthal­ mic examination, appropriate ancillary tests such as cytol­ ogy, culture with sensitivities, and appropriate treatment (usually consisting of broad‐spectrum ophthalmic antibiot­ ics in solution or ointment) lead to a rapid response. Pending culture results, topical chloramphenicol, erythromycin or bacitracin, neomycin, and polymyxin B can be used for gram‐positive bacteria conjunctivitis, and tobramycin, ofloxacin, gentamicin, or topical bacitracin, neomycin, and polymyxin B can be used for bacterial conjunctivitis caused by gram‐negative bacteria (Gerding et al., 1988). Antibiotic resistance can develop rapidly to some topical antibiotics and therefore chronic use or prophylactic use should be carefully considered (Sandmeyer et al., 2017).

In the past, viral conjunctivitis was most commonly associ­ ated with canine distemper virus; however, a recent virologic survey and other research have brought attention to canine herpes virus‐1 (CHV‐1). The survey evaluated for multiple viruses using virus isolation and polymerase chain reaction (PCR) on samples from dogs with conjunctivitis and control dogs. Of 30 dogs with conjunctivitis, 5 were positive for CHV‐1 and 2 for canine adenovirus‐2. Being sexually intact and having frequent exposure to dogs outside the household were positively associated with viral detection in the con­ junctivitis group (Ledbetter et al., 2009b). An outbreak of CHV‐1 in a closed colony of Beagles caused conjunctivitis and keratitis in all dogs, ulcers in 26% of dogs (punctate, dendritic, or geographic), and nonulcerative kera­ titis in 19% of dogs. All dogs tested were positive for CHV‐1 on PCR and virus isolation (Ledbetter et  al., 2009c). Experimentally, dogs inoculated topically with CHV‐1 in one eye developed signs of mild to moderate conjunctivitis in both eyes that peaked at 7 days in the inoculated eye and 10 days in the noninoculated eye (Fig. 18.2). The conjunctivitis began to decrease in severity over the following 15 days and returned to normal by day 35. In general, ocular disease scores were higher and increased more quickly in the inocu­ lated eye versus the noninoculated eye. No dogs developed keratitis or signs of systemic disease. Ocular viral shedding was detected in all infected dogs between days 3 and 10 postinfection. All infected dogs also developed CHV‐1 serum‐neutralizing antibody titers, beginning at 7 days post­ inoculation and peaking on day 21 (Ledbetter et al., 2009a). Recrudescent CHV‐1 disease has been induced in dogs with latent CHV‐1 infection by administration of an immu­ nosuppressive dosage of prednisolone for 7 days. Bilateral mild to moderate conjunctivitis, characterized by intermit­ tent blepharospasm, conjunctival hyperemia, chemosis, and

SECTION IIIA

e­ piscleral vessels associated with ciliary flush form a branch­ ing ­network near the limbus. Because many ocular diseases can cause a “red eye,” a complete ophthalmic examination should always be performed when this clinical sign is pre­ sent. Trauma, allergic or bacterial conjunctivitis, mechanical irritants, conjunctival parasites, orbital inflammation, and other ocular and systemic infectious agents can cause con­ junctivitis. Conjunctival ulceration, while uncommon in dogs, can occur secondary to varying kinds of trauma, including alkali burns (Singh et al., 2004).

Section IIIA: Canine Ophthalmology

SECTION IIIA

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Figure 18.2  Experimentally induced recurrent canine herpesvirus‐1 conjunctivitis in a dog. Courtesy of Eric Ledbetter.

mucoid‐to‐mucopurulent ocular discharge or keratitis, was detected in 83% of dogs between days 3 and 18 after initiat­ ing the prednisolone. In vivo confocal microscopic abnor­ malities included conjunctival leukocyte infiltration and corneal leukocyte infiltration, abnormal epithelial cell mor­ phology, and Langerhans cell infiltration. Ocular viral shed­ ding was detected in half of the dogs, and fourfold elevations in CHV‐1 serum neutralization antibody titers were detected in all dogs. Mean duration of ocular disease was 8.6 days (Ledbetter et al., 2009d). As with cats, it appears as if con­ junctival herpesvirus infections are self‐limiting. Two dogs with CHV‐1 keratitis responded to treatment with idoxuri­ dine or trifluridine, both administered 6–8 times daily for 48 hours and then every 6 hours (Ledbetter et al., 2009d). In a further experimental study, 10 CHV‐1‐inoculated Beagles responded to topical trifluridine (on the same schedule) with reduced ocular disease scores and viral shedding (Spertus et  al., 2016). Topical cidofovir twice daily has also been reported to be beneficial, but may be associated with more adverse reactions (Gervais et al., 2012). A subunit vaccine for CHV‐1 was successful in inducing peripheral immunity (as demonstrated by T and B lympho­ cyte subpopulation percentage distributions, lymphocyte expression of major histocompatibility complex Classes I and II, CHV‐1 virus‐neutralizing antibody titers, lymphocyte proliferation, and interferon‐g levels), but did not prevent ocular disease or viral shedding (although clinical disease scores were reduced in the 2‐week postvaccinal period; Ledbetter et al., 2016). Canine distemper virus is associated with conjunctivitis, chorioretinitis, KCS, and optic neuritis (Fischer, 1971; Gelatt et al., 1985; Jubb et al., 1957; Martin & Kaswan, 1985; Render et al., 1982; Sansom & Barnett, 1985). Conjunctivitis

generally occurs with the rhinitis and tracheobronchitis that accompany the initial febrile episode (Peiffer, 1981). A mucopurulent discharge is often present (Gelatt et  al., 1985; Peiffer, 1981). Initially, mononuclear cells are seen on cytology, followed by increasing numbers of neutrophils, and plasma cells, goblet cells, and cellular debris are also seen (Lavach et al., 1977). Canine distemper virus can cause similar clinical signs in a range of carnivores, including wolves, raccoon dogs, foxes, bears, lions, tigers, hyaenas, civ­ ets, ferrets, and mink (Beineke et al., 2015; Zhao et al., 2015). Distemper virus reaches the epithelial cells 6–9 days after exposure, and then the virus levels decrease with antibody formation (Appel, 1969). Distemper viral antigens can be detected using direct immunofluorescence and PCR (Decaro et al., 2004; Fairchild et al., 1967). In experimentally infected dogs, the antigens can be detected in conjunctival smears on days 7 through 35 using direct fluorescence antibody testing (Sen et  al., 2002). An immunochromatography assay that does not require special instrumentation has shown 100% specificity and sensitivity when run on conjunctival swab samples from naturally infected dogs (An et al., 2008). Scarce cytoplasmic inclusion bodies may be infrequently found in the conjunctival epithelial cells after 6 days of infection and are seen more frequently in cells acquired from the NM (Appel & Gillespie, 1972; Erno, 1964). Dogs have been reported to be highly sensitive to H5N1 avian influenza virus, resulting in pyrexia, conjunctivitis, and respiratory signs (Chen et al., 2010). Conjunctivitis has also been reported in conjunction with respiratory signs in a dog infected with H5N2 influenza virus in China, and subse­ quent studies demonstrated that dog‐to‐dog, dog‐to‐cat, and dog‐to‐chicken transmission was possible (Hia‐Xia et  al., 2014; Qian‐Qian et al., 2013).

Fungal Conjunctivitis Fungal conjunctivitis is very rare in the dog. Infection with Blastomyces dermatitidis can cause nodule formation in the inferior conjunctiva. The diagnosis can be made on the basis of cytology or biopsy results. Treatment with systemic ­itraconazole may resolve the condition (Brooks, 1991). Aspergillus spp. infection has been associated with tarantula hair foreign bodies in the conjunctiva and cornea of a Rat terrier (Reed et al., 2016).

Rickettsial Conjunctivitis Infection with Rickettsia rickettsii is frequently associated with ocular lesions of the conjunctiva, uvea, and retina. Evidence of conjunctivitis usually begins with the onset of fever and includes conjunctival hyperemia, chemosis, pete­ chial hemorrhages, and a mucopurulent‐to‐purulent ocular discharge (Davidson et al., 1989; Keenan et al., 1977). Canine ehrlichiosis can cause conjunctival hyperemia, serous ocular discharge, conjunctival hemorrhages, anterior uveitis, and

retinal hemorrhages (Davidson et al., 1989; Kuehn & Gaunt, 1985; Swanson & Dubielzig, 1986).

Parasitic Conjunctivitis Canine ocular thelaziasis occurs in the western United States, Europe, Southeast Asia, and Russian far east (Dorchies et al., 2007; Gardiner et al., 1993; Hermosilla et al., 2004; Khrustelev et al., 2015; Magnis et al., 2010; Yang et al., 2006) and is a zoonotic disease. Thelazia is a nematode that can be found under the NM and in the conjunctival sac and lacrimal duct. Both Thelazia callipaeda and Thelazia californiensis infect the dog (Hermosilla et al., 2004; Nimsuphan & Prihirunkij, 2000; Otranto & Traversa, 2005). The milky white worms are approximately 10–14 mm long (Hermosilla et al., 2004; Nimsuphan & Prihirunkij, 2000). The lateral ser­ rations of the cuticle of the nematodes cause mechanical damage to the conjunctiva and cornea, leading to lacrimal secretions upon which nonbiting diptera feed. The adult nematodes live under the eyelids or behind the nictitans. The first‐stage larvae are ingested by flies. Then, after under­ going two molts, the third‐stage larvae are transferred back to the eye when the fly feeds (Bianciardi & Otranto, 2005). Musca autumnalis in North America and Phortica variegata in Asia are known intermediate hosts (Bowman et al., 2011; Otranto et al., 2006). Foxes and wolves may be important in the spread and maintenance of disease (Dorchies et al., 2007; Otranto & Traversa, 2005). The parasitic infection causes a unilateral or bilateral purulent conjunctivitis with blepha­ rospasm, epiphora, conjunctivitis, keratitis, and intense lac­ rimal secretion. Topical moxidectin (1% aqueous solution) and tetramisole (0.5% solution), spot‐on imidacloprid (10%) and moxidectin (2.5%), oral milbemycin/praziquantel, and physical removal of the nematodes are effective treatments (Bianciardi & Otranto, 2005; Lia et  al., 2004; Motta et  al., 2012; Otranto et al., 2016; Peng & Jiang, 1983). Toxoplasma gondii was diagnosed in a dog with KCS that had a yellow/tan conjunctival mass located at the limbus. Histopathology revealed protozoa and necrotizing conjunc­ tivitis. On immunohistochemistry, the protozoa were identi­ fied as Toxoplasma gondii. The lesions recurred in the opposite eye after treatment with clindamycin, but resolved with treatment with ponazuril. Since titers were negative, it was hypothesized that the lesion was secondary to local immunosuppression from tacrolimus used to treat KCS (Swinger et al., 2009).

and dust mites. Clinical signs include conjunctival hypere­ mia, chemosis, facial pruritis, periocular alopecia, and ­ocular discharge. With chronic antigenic stimulation, con­ junctival lymphoid follicles develop. History, physical examination, and intradermal skin testing are used to make the diagnosis of atopy in the dog. Results of cytology and histopathology performed on conjunctival scrapings and biopsy specimens, respectively, can suggest the presence of an allergic response. Finding one eosinophil on cytologic examination of a conjunctival scraping is considered to be diagnostic for an allergic process; however, plasma cells and lymphocytes are more commonly seen with allergic responses in the dog (Lavach et al., 1977). The conjunctival provocation test using dust mite allergens showed an etio­ logic relationship between conjunctivitis and specific mite sensitizations, and may be a new tool for confirming an eti­ ologic diagnosis for allergic conjunctivitis (Lourenco‐ Martins et al., 2011). Avoidance of the offending allergen, hyposensitization, and pharmacologic modification of the clinical signs are the primary forms of treatment. Intermittent use of a topical ophthalmic hydrocortisone or dexamethasone may be nec­ essary to relieve clinical signs; alternate‐day treatment with systemic corticosteroids initiated for the skin disease may also relieve the ocular signs (Glaze, 1991). Topical antihista­ mines, such as naphazoline, and mast cell stabilizers may have some benefit, but studies on their efficacy in the dog have not been reported. Intense chemosis and blepharedema may occur as an immediate‐type reaction mediated by histamine and immu­ noglobulin E after food absorption, drug administration, and envenomation by ant, bee, wasp, or hornet stings as well as spider bites (Fig. 18.3). The chemosis is often bilateral, and the actual area of trauma (if caused by an insect) is rarely identified and may be distant from the eyes. These cases usu­ ally respond rapidly to intravenous or intramuscular short‐ acting corticosteroids and an antihistamine with or without topical corticosteroid ophthalmic ointments administered 3–4 times daily.

Noninfectious Conjunctivitis Allergic Conjunctivitis Allergic conjunctivitis occurs frequently in the dog and is often a component of atopic dermatitis (Glaze, 1991; Lourenco‐Martins et al., 2011). Atopy is a Type 1 hypersen­ sitivity reaction. The common allergens are pollens, molds,

Figure 18.3  Chemosis associated with a bee sting.

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Follicular Conjunctivitis Follicular conjunctivitis develops secondary to chronic anti­ genic stimulation (Bromberg, 1980). There is no evidence to link follicle formation to a viral or bacterial cause (Jackson & Corstvet, 1980; Nell et  al., 2000). Semitransparent follicles form primarily on the bulbar surface of the NM, but they may also form elsewhere on the conjunctiva (Fig. 18.4). The follicles on the bulbar surface of the NM that are present with this disease greatly outnumber those normally seen, and they can be significantly larger. Frequently, hyperemia of the conjunctiva and a mucoid ocular discharge are pre­ sent concurrently. This condition occurs most frequently in dogs younger than 18 months of age. The diagnosis is made on the basis of characteristic clinical signs. Cytologic results of conjunctival scrapings will confirm the diagnosis by revealing the lymphoid nature of the folli­ cles (Glaze, 1991). Most cases respond to treatment with saline irrigation and symptomatic use of ophthalmic dexa­ methasone administered 3–4 times daily (Glaze, 1991). Irrigation appears to play a large role in decreasing follicular formation, especially in dogs with deep fornices exposed to large amounts of vegetative matter, such as Labrador Retrievers in field training. Some authors recommend that nonresponsive cases are treated by mechanically debriding the follicles, although studies demonstrating benefit clini­ cally, histologically, or prognostically are lacking. After instil­ lation of ophthalmic anesthetic, the follicles are debrided with dry gauze placed over the tip of a cotton‐tipped applica­ tor. The follicles should not be sharply excised with a blade or cauterized with copper sulfate crystals, because the lymphoid tissue is critical to the ocular defense system (Glaze, 1991).

Environmental Irritants and Contact Hypersensitivity Over 60% of the dogs deployed to assist in relief efforts at the World Trade Center site following the terrorist attacks in

Figure 18.4  Follicular conjunctivitis involving the bulbar conjunctiva of the nictitating membrane.

2001 developed acute conjunctival irritation characterized by severe conjunctival hyperemia, tearing, squinting, and face rubbing. Conjunctival irritation and fatigue were the most common health problems to affect the dogs. The irrita­ tion was secondary to exposure to toxic chemicals, smoke, and massive amounts of particulate matter. Affected animals were treated by means of gentle irrigation of the conjuncti­ val fornices with eye solution (Fox et al., 2008). Ophthalmic medications can occasionally lead to contact hypersensitivity reactions, which are exhibited by blephari­ tis and conjunctivitis. Neomycin, gentamicin, dorzolamide and timolol combinations, thimerosal, and benzalkonium chloride are the most likely drugs used in canine ophthal­ mology that can cause this reaction. Affected dogs usually present with a history of conjunctivitis that is nonresponsive to topical medications. The skin ventral to the medial can­ thus may become swollen, hyperemic, and eventually ulcer­ ate (Glaze, 1991). Initially, a serous discharge may be present, which becomes purulent if the conjunctiva is secondarily infected with bacteria. Diagnosis and treatment involve cessation of all medica­ tions for 1 week. If negligible improvement occurs, further diagnostic studies, such as a conjunctival scraping or biopsy, should be performed. If improvement is seen but the initial disease process is still present, medications should be changed to different, less irritating drugs (Glaze, 1991). While any medication can be irritating in certain individ­ uals, some medications such as topical commercial pilocar­ pine (pH 4–5) are notorious for causing conjunctival hyperemia and chemosis (Carrier & Gum, 1989; Smith et al., 1994).

Conjunctivitis Associated with Tear Deficiencies KCS is a frequent cause of conjunctivitis in the dog, and it is the most common cause of secondary bacterial conjunctivi­ tis. Thus, the Schirmer tear test (STT) should be performed on all dogs with conjunctivitis. Cytologic examination of conjunctival scrapings from dogs with chronic KCS reveals increased and altered mucins, increased goblet cells, and keratinization; cytology from dogs with acute KCS reveals bacteria, neutrophils, mucus, and debris (Lavach et  al., 1977). Impression cytology of the bulbar conjunctiva in dogs with KCS before and after treatment with cyclosporine shows a change from moderate squamous metaplasia with neutrophils to improvement with a more normal cuboidal epithelium (Bounous et  al., 1998). Treatment of KCS with cyclosporine has been shown to result in greater intraepithe­ lial mucin quantities in vivo and to promote goblet cell dif­ ferentiation in vitro (Moore et  al., 2001). Treatment with cyclosporine, tacrolimus, or pimecrolimus decreases the conjunctival inflammation and mucous discharge associ­

ated with KCS (Berdoulay et al., 2005; Hendrix et al., 2011; Moore et al., 2001; Ofri et al., 2009). Loss of conjunctival goblet cells can lead to a qualitative tear film deficiency, resulting in keratoconjunctivitis and keratitis with absence of ocular discharge. These dogs have adequate aqueous tear production but shortened tear film breakup times (see Chapter 17; Moore & Collier, 1990).

Ligneous Conjunctivitis Ligneous conjunctivitis is a rare disorder in dogs that results in thickened, hyperemic palpebral conjunctivae with proliferative, opaque membranes (Fig.  18.5). It has been reported in four Doberman Pinschers, a Golden Retriever, a Yorkshire Terrier, and three related Scottish Terriers (Mason et al., 2016; McLean et al., 2008; Ramsey et  al., 1996a; Torres et  al., 2009). The age range of those reported is from 2 months to 6 years, and all but three have been female. There are varying degrees of concurrent sys­ temic illness (e.g., mucosal ulceration and fibrinous mem­ branes elsewhere in the body). A plasminogen deficiency was diagnosed in two dogs (McLean et  al., 2008; Torres et  al., 2009). A genetic cause has been postulated more recently (Mason et  al., 2016). Histologically, the affected conjunctiva has a thick, amorphous, eosinophilic, hyaline‐ like material in the substantia propria, with a moderate mononuclear infiltrate. Topical therapies have included corticosteroids, heparin, and cyclosporine or tacrolimus. Systemic treatment with prednisone, azathioprine, fresh frozen plasma, danazol, and diethylstilbestrol has been attempted, but generally yields poor results (McLean et al., 2008; Ramsey et al., 1996a; Torres et al., 2009).

Conjunctival Neoplasia

angiokeratomas, papillomas, lymphosarcomas, histiocyto­ mas, and transmissible venereal tumors all may affect the canine conjunctiva (Bonney et al., 1980; Boscos et al., 1998; Buyukmihci & Stannard, 1981; Collier & Collins, 1994; Collins et  al., 1993; George & Summers, 1990; Gwin et  al., 1982; Hare & Howard, 1977; Hargis et  al., 1978; Johnson et al., 1988; Kilrain et al., 1994; Scherlie et al., 1992; Thomsen et  al., 1991). The paucity of large studies and case reports, however, supports the clinical impression that conjunctival neoplasia occurs infrequently in the dog. Melanomas of the conjunctiva most commonly involve the NM, but they have also been reported to originate from the upper palpebral con­ junctiva (Collins et  al., 1993). These tumors tend to be malignant, and recurrences and metastasis are common. No correlations between mitotic index and likelihood of local recurrence or metastasis have been found. The Weimaraner breed may be predisposed. Combined excision and ­cryotherapy appear to be the most effective treatment (Collins et al., 1993). Mast cell tumors can arise from the bulbar or palpebral conjunctiva or the NM (Fig. 18.6; Barsotti et al., 2007; Fife et al., 2011; Johnson et al., 1988). Some dogs may have a his­ tory of intermittent swelling and redness of the conjunctiva (Johnson et al., 1988). These tumors are easily diagnosed via fine needle aspirate. Surgical excision is usually curative. Conjunctival mast cell tumors have a low risk of recurrence and are unlikely to metastasize regardless of tumor grade or having incomplete surgical margins (Barsotti et  al., 2007; Fife et al., 2011). Papillomatosis occurs on the palpebral and bulbar con­ junctivae as well as the NM. The lesions are well demarcated, rough, and papillary or sessile (Fig.  18.7). Histopathology shows various degrees of epithelial hyperplasia, acanthosis, hyperkeratosis with koilocytosis, and vascular and connec­ tive tissue cores (Bonney et  al., 1980; Brandes et  al., 2009; Hare & Howard, 1977). Some lesions have been tested and

Melanomas, squamous cell carcinomas, angioendothelioma­ tosis, mast cell tumors, hemangiomas, ­hemangiosarcomas,

Figure 18.5  Ligneous conjunctivitis in a Doberman Pinscher.

Figure 18.6  Conjunctival mast cell tumor in the temporal conjunctiva.

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Figure 18.7  Multiple papillomas on the skin and bulbar conjunctiva. Courtesy of Nancy McLean.

are positive for gene fragments of canine oral papillomavirus DNA. While most lesions in young dogs regress spontane­ ously, excision is curative and may be necessary if the lesion is irritating (Bonney et al., 1980; Brandes et al., 2009; Collier & Collins, 1994; Hare & Howard, 1977). Squamous cell carcinoma of the perilimbal area is seen infrequently. These tumors are white to pink, elevated, and papillomatous (Gwin et al., 1982; Hargis et al., 1978). While p53 immunostaining has been found in squamous cell carci­ nomas of several mammalian species, including horses, cat­ tle, and cats, p53 immunostaining was not found to be positive in the one case of canine squamous cell carcinoma evaluated (Sironi et al., 1999). Conjunctival hemangiomas and hemangiosarcomas tend to occur at the nonpigmented, leading edge of the NM and  at  the temporal bulbar conjunctiva (Fig.  18.8). Hemangiosarcomas of the conjunctiva can encroach on the cornea, thereby causing corneal edema and vascularization (Hargis et al., 1978). These tumors have a propensity to occur in breed groups that tend to have increased outdoor activity, and occur most frequently in middle‐aged dogs (Pirie et al., 2006). There is also a linear trend showing an increased risk of tumor development with increased ultraviolet (UV) expo­ sure, and there is a statistically significant risk for con­ junctival hemangiosarcoma development, compared to hemangioma, with increased UV levels (Pirie et  al., 2006). However, these tumors do not adhere to deeper tissue. Histologically, hemangioma and hemangiosarcoma are dif­ ferentiated by the degree of cellular differentiation and local tissue invasion. Resection appears to be curative in most cases, but recurrences are possible (Gwin et al., 1982; Hargis et al., 1978; Pirie et al., 2006). Metastasis has not been con­ firmed (Hargis et al., 1978). Angiokeratomas are rare, benign vascular tumors or telan­ giectasias of mucocutaneous tissue or skin. They can involve the bulbar conjunctiva and nictitans. Angiokeratomas are generally single, small, raised red masses, but they may also

Figure 18.8  A 5‐year‐old male neutered border collie with conjunctival and corneal hemangiosarcoma.

Figure 18.9  Infiltration of the bulbar conjunctiva and conjunctiva of the nictitating membrane by lymphosarcoma. The conjunctiva was thickened and firm. Cytology from a conjunctival scraping revealed neoplastic lymphoblasts.

be black. Excision appears to be curative (Buyukmihci & Stannard, 1981; George & Summers, 1990). Lymphosarcoma can infiltrate the conjunctiva, causing conjunctival thickening (Fig.  18.9; McCowan, 2014; Moore, 1989). In one case series all canine (n=5) conjunc­ tival lymphoma cases were of T‐cell origin (McCowan et al., 2014). In another retrospective study of ocular and periocular lymphoma cases, only one canine case had conjunctival involvement and this was of T‐cell origin (Ota‐Kuroki et al., 2014). Cytology of a conjunctival scrap­ ing may be diagnostic for lymphosarcoma, but in one known case of lymphosarcoma a scraping revealed only reactive lymphoid hyperplasia (Vascellari et  al., 2005). Histopathologically, the conjunctival substantia propriae is infiltrated by a diffuse arrangement of polygonal ­neoplastic lymphoid cells with a high nucleus : cytoplas­ mic ratio, moderate amounts of lightly eosinophilic ­cytoplasm, multiple nuclei, and frequent mitotic figures.

While ­conjunctival lymphosarcoma is ­usually considered to be associated with systemic lymphosarcoma, apparent ocular extranodal presentation has been reported with T‐cell (Vascellari et  al., 2005) and B‐cell phenotypes (Olbertz et al., 2013). An extranodal B‐cell lymphoma has also been reported affecting the mucosal‐associated lym­ phoid tissue of the NM conjunctiva in an American Cocker Spaniel (Hong et al., 2011). Canine lobular orbital adenomas can appear as a subcon­ junctival mass, eyelid swelling, or exophthalmos. The masses are either nodular or solid and extend into the orbit. They can be bilateral and commonly recur after excision. Histopathology reveals well‐differentiated, lobulated, glan­ dular tissue resembling either lacrimal or zygomatic salivary gland, with a mucoserous secretory pattern and a complete lack of ductular structures. These tumors differ from regular adenomas in that they extend into the loose orbital connec­ tive tissue (Headrick et al., 2004).

Nonneoplastic Conjunctival Masses Nonneoplastic conjunctival masses can be inflammatory nodules, dermoids, displaced orbital fat, or cysts. Specific inflammatory diseases of the sclera, including episcleritis and scleritis, cause conjunctival hyperemia and swelling; they are described in Chapter 19.

Inflammatory Masses Nodular granulomatous episclerokeratitis, fibrous histiocy­ toma, and recurrent proliferative keratoconjunctivitis are thought to represent very similar diseases, or even an identi­ cal disease syndrome. Collies appear to be predisposed, but the disease occurs in many breeds (Latimer et  al., 1983b; Paulsen et al., 1987; Wheeler et al., 1989). This group of non­ neoplastic diseases primarily affecting the cornea, limbus, episclera, and nictitans often presents as a subconjunctival mass. Limbal masses infiltrate the corneal stroma, causing vascularization and edema (Fig. 18.10). Histopathologically, the lesions are primarily granulomatous with lymphocytes, plasma cells, histiocytes, fibroblasts, and reticulin forma­ tion. The lesions tend to recur when excised, but excision with adjunctive cryotherapy is reported to be a successful mode of therapy (Wheeler et  al., 1989). Some lesions will respond to 1% ophthalmic prednisolone acetate with treat­ ment initiated four times a day and very gradually tapered to the lowest effective dose. Unfortunately, many dogs will develop lipid corneal degeneration with chronic topical ster­ oid usage. Additionally, azathioprine, with or without topi­ cal corticosteroids, can be used to induce resolution of the lesions. Typically, treatment is initiated with 2.2 mg/kg once daily for approximately 3–10 days, and then slowly tapered based on response to the lowest effective dose, with possible

Figure 18.10  Nodular granulomatous episcleritis with associated corneal edema.

discontinuation after several months (Latimer et al., 1983b; Paulsen et al., 1987). Dogs should be monitored for hepato­ toxicity and myelosuppression every 4–6 weeks. Cryotherapy or intralesional triamcinolone at 4–12 mg per eye, with higher dosages for larger dogs, can also be used (Regnier & Toutain, 1991; Wheeler et al., 1989). Ocular nodular fasciitis, which may be a different disease syndrome, usually causes subconjunctival, scleral, corneal, nictitans, limbal, and eye­ lid masses (Fig. 18.11). Histopathologically, fibroblasts and abundant reticulin formation are the primary changes, with lower numbers of lymphocytes, plasma cells, and histiocytes occurring as well (Bellhorn & Henkind, 1967; Gwin et  al., 1977; Lavignette & Carlton, 1974). Excision of the lesions, even when incomplete, is curative (Bellhorn & Henkind, 1967; Gwin et al., 1977). Idiopathic sterile granulomatous disease has been diag­ nosed in dogs with multiple masses on the conjunctiva, eyelids, nictitans, and skin (Collins et  al., 1992). One report described plaque‐like lesions in the sclera, a 360° area of perilimbal infiltrate, thickening of the conjunc­ tiva, and concurrent raised white plaques in both nasal passages (Gionfriddo et  al., 2003). Histopathologically, granulomatous inflammation with large epithelioid cells, plasma cells, and lymphocytes, primarily T lymphocytes, is seen. Treatment with l‐asparaginase, azathioprine, interferon α2a, and topical and systemic prednisone have all been successful (Collins et al., 1992; Gionfriddo et al., 2003; Riis, 2000).

Dermoids A dermoid is a benign congenital mass of ectodermal and mesodermal origin, usually affecting the lateral limbal region, but it can also involve the cornea, sclera, conjunctiva, eyelid, or NM (Fig. 18.12). Frequently, the presence of a der­ moid is not appreciated until long, coarse hair extends from the surface and causes irritation. Histopathologically, the

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Figure 18.11  Nodular fasciitis on the temporal aspect of the globe. An immature cataract is also present.

Figure 18.12  Conjunctival dermoid with hair at the temporal aspect of the globe.

tumor resembles normal haired skin, and excision is cura­ tive (Gwin et al., 1982).

Subconjunctival Fat Prolapse Subconjunctival prolapse of orbital fat is seen as a nonpain­ ful, movable, light pink mass at the limbus (Fig.  18.13). Cytologic examination reveals multiple lipid droplets and few mononuclear cells. It most likely occurs secondary to a weakness in Tenon’s capsule. Surgical removal, while cura­ tive, should not be overzealous, as enophthalmia can result (Allevi et al., 2003; Grahn & Wolfer, 1993).

Parasitic Granulomas Onchocerciasis causes bean‐sized masses in the conjunctiva, nictitans, and sclera (Fig. 18.14; Gardiner et al., 1993; Orihel et al., 1991; Sreter et al., 2002; Szell et al., 2001). The surface of the masses is generally irregular, with nodular thicken­ ings caused by the coiled adult worms (Sreter et al., 2002).

Figure 18.13  Orbital fat prolapse in the ventral fornix.

Figure 18.14  Onchocerca granuloma in the ventral bulbar conjunctiva. Courtesy of Dr. Nancy McLean.

Other common ophthalmic manifestations are periorbital swelling, exophthalmos, excessive lacrimation, discharge, discomfort, photophobia, conjunctival congestion, protru­ sion of the NM, granuloma formation, localized corneal edema, and anterior and posterior uveitis (Komnenou et al., 2003; Zarfoss et al., 2005). Histopathologically, a pyogranu­ lomatous or granulomatous reaction with eosinophils is asso­ ciated with the presence of adult worms. Lymphoplasmacytic uveitis, preiridal fibrovascular membranes, and evidence of secondary glaucoma are also seen (Zarfoss et  al., 2005). Microfilariae are seen in the uteri of females and in the tis­ sues surrounding them and can be isolated from skin biopsy specimens (Szell et al., 2001). While there is debate as to whether the organism is Onchocerca lienalis or Onchocerca lupi, the morphology of parasites found in different parts of the world differs slightly (Gardiner et  al., 1993; Komnenou et  al., 2003; Szell et  al., 2001; Zarfoss et  al., 2005). However, a comparison of the Onchocerca isolated from dogs in Greece and Hungary, done by testing sequences of the cytochrome oxidase gene of the filarial parasites and the 16S ribosomal RNA gene from the

Wolbachia endosymbionts, showed that they were the same species (Komnenou et al., 2003). Treatment includes surgi­ cal removal of the masses followed by medical therapy (Gardiner et al., 1993; Komnenou et al., 2003; Zarfoss et al., 2005). Medical therapy includes prednisolone 0.5 mg/kg orally (PO) twice a day (BID) for 3–4 weeks and doxycycline 5 mg/kg PO BID for 6–8 weeks. One week after surgery, 2.5 mg/kg of melarsomine is given intramuscularly twice within 24 hours, followed by ivermectin 50 μg/kg subcutane­ ously (SC) and melarsomine 1 month after surgery. Or where melarsomine is not available, ivermectin at 200 μg/kg PO or SC as a single dose alone 1 week after surgery cases can be effective (Komnenou, A., personal communication). Subconjunctival Dirofilaria repens has been reported in a German Shepherd dog, resulting in a conjunctival mass and follicular conjunctivitis. Treatment with spot‐on 10% imidacloprod and 2.5% moxidectin was successful (Agapito et al., 2018). Granulomatous lesions with intralesional protozoal organ­ isms (Acanthomoeba, Toxoplasma, Leishmania spp.) in the absence of systemic involvement have been reported in five dogs receiving long‐term immunosuppression (Beckwith‐ Cohen et al., 2016). Cases were reported to improve on ces­ sation of immunosuppressive therapy in conjunction with partial or complete surgical excision, with two dogs also receiving systemic antiprotozoal therapy (Beckwith‐Cohen et al., 2016).

Cysts Multiple causes of cyst formation in the conjunctiva have been described, but all occur only rarely in the dog. Conjunctival epithelial inclusion cysts, cystic neoplasms, parasitic cysts, lacrimal cysts (i.e., dacryops), orbital cysts with conjunctival fistula formation, and cysts of the canali­ culi can occur (Gerding, 1991; Harvey et al., 1968; Murphy et al., 1989; Playter & Adams, 1977). A lacrimal gland cyst appears as a fluctuant mass dorsolateral to the globe (Harvey et  al., 1968; Playter & Adams, 1977). Surgical resection is curative. One dog had a fistula open to the conjunctival for­ nix. Histopathology revealed cysts with associated ducts and lacrimal glandular tissue (Harvey et  al., 1968; Playter & Adams, 1977).

Conjunctival Hemorrhages Conjunctival and subconjunctival hemorrhages occur commonly in the dog and most frequently result from trauma. When this condition is caused by trauma, no treat­ ment is necessary if the remaining ophthalmic and physi­ cal examinations are normal (Fig.  18.15). If there is no history or evidence of trauma, a coagulopathy or vasculitis must be considered as the possible cause. Specifically,

Figure 18.15  Conjunctival hemorrhage secondary to trauma in a dog. Note the miosis indicating anterior uveitis that is also a result of the trauma.

c­ onjunctival hemorrhage has been reported with angios­ trongylosis and von Willebrand factor deficiency (Whitley et  al., 2005). No treatment is needed specifically for the conjunctival hemorrhages. Subconjunctival hemorrhage, especially in conjunction with subconjunctival pigment migration, extending through 360° has been reported to be associated with open globe injury (e.g., scleral rupture) in humans (Hartley et al., 2007; Moraczewski, 2007). Anecdotally, this has also been wit­ nessed in veterinary patients with open globe injuries due to blunt trauma.

Foreign Bodies Physical irritation caused by foreign bodies lodged within the conjunctiva or NM can cause a severe reaction, including blepharospasm, mucoid discharge, hyperemia, and corneal ulceration. Grass awns and other plant material are the most common culprits (Brennan & Ihrke, 1983). Results of a ret­ rospective study of grass awn migration showed that in 174 dogs, the grass awn was lodged in the conjunctiva or NM in 26 cases (Fig. 18.16; Brennan & Ihrke, 1983). Most foreign bodies can be removed with forceps after administration of a topical ophthalmic anesthetic (Bromberg, 1980). Chemical exposure can also cause irritation. Conjunctival hyperemia, chemosis, and corneal ulceration occurred in a dog that was sprayed by a walking stick insect (Anisomorpha buprestoides; Dziezyc, 1992). Several dogs developed severe conjunctivitis and tongue necrosis associated with ingestion of the pine processionary moth caterpillar, Thaumetopoea wilkinsoni. The conjunctivitis was thought to be secondary to irritation from the caterpillar hairs or to histamine‐mediated effects (Bruchim et al., 2005). Tarantula hair foreign bodies of the cornea and conjunctiva have also been reported in a Rat ter­ rier (Reed et al., 2016).

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Figure 18.16  Plant foreign body protruding from the temporal conjunctiva.

Figure 18.17  Severe conjunctivitis associated with systemic and retrobulbar blastomycosis.

Orbital Disease

Anatomic Abnormalities

The conjunctiva is frequently affected by orbital disease. The redundancy and elasticity of the conjunctiva allow it  to be the path of least resistance; therefore, it may be the  first tissue to show swelling or displacement (Fig.  18.17). Conjunctival hyperemia also occurs com­ monly with orbital disease (Attali‐Soussay et  al., 2001; Wang et al., 2001). Zygomatic mucoceles can cause protrusion of the con­ junctiva beyond the palpebral fissure, in addition to caus­ ing exophthalmos, prolapse of the NM, and periorbital swelling (Schmidt & Betts, 1978). A ranula and mucocele of the zygomatic salivary gland and duct were diagnosed surgically in a dog with fluctuant swelling under the con­ junctiva of the lower lid and under the upper lip; marsupi­ alization to the oral mucosa was curative (Martin et  al., 1987). A conjunctival swelling that occurred only when a dog was placed in dorsal recumbency, the head was low­ ered, or pressure was applied to the jugular veins resulted from an orbital varix. In this dog, the pink conjunctival swelling was aspirated and found to be blood‐filled (Millichamp & Spencer, 1991). Orbital cellulitis can be localized or associated with sinus disease. Clinical signs of cellulitis can include pro­ lapsed necrotic NM, severe mucopurulent discharge, fis­ tulous tracts, blepharedema, and exophthalmos (Homma & Schoster, 2000; Willis et  al., 1999). Infectious organ­ isms include bacteria, fungi such as Blastomyces and Aspergillus, and parasites such as Toxocara canis (Laus et  al., 2003; Willis et  al., 1999). Occasionally, periapical abscesses, slab fractures of the fourth maxillary premo­ lar, and extraction or fracture of the first or second maxil­ lary molars can cause the same clinical signs (Ramsey et al., 1996b).

Conjunctival disease can develop secondary to anatomic defects that cause inadequate tear drainage, chronic expo­ sure, and other changes.

Medial Canthal Pocket Syndrome Medial canthal pocket syndrome refers to the chronic con­ junctivitis occurring in dogs with deep orbits, enophthalmia, narrow skulls, slight entropion, and inadequate tear drain­ age. It has been reported in the Afghan Hound, Doberman Pinscher, Golden Retriever, Gordon Setter, Great Dane, Great Pyrenees, Ibizan Hound, Labrador Retriever, Newfoundland, Standard Poodle, Rottweiler, Samoyed, and Weimaraner (Rubin, 1989). Selective breeding for the spe­ cific head shape has made these dogs slightly enophthalmic. This enophthalmia then creates a “pocket” in the ventral conjunctival fornix that collects dust, dirt, and other foreign material. The resultant clinical signs include conjunctival and nictitans hyperemia, as well as a slight mucoid discharge (Rubin, 1989). The conjunctivitis occurs secondary to the irritation and poor tear drainage, and it is poorly responsive to medical therapy. In certain dogs, especially those that are active outdoors, frequent flushing of debris from the ventral fornix with eye wash may help to alleviate the clinical signs. Fortunately, in most cases this syndrome does not result in significant corneal disease.

Medial Aberrant Dermis (Caruncular Trichiasis) Aberrant dermis derived from the facial skin may continue past the intermarginal space in the medial canthus and onto the conjunctiva and caruncle. When this occurs, irritation from the hair, which can grow very long, can cause keratitis,

epiphora, or both. The condition has been observed in the Pekingese, Shih Tzu, and Lhasa Apso. Surgical treatment with the medial pocket canthoplasty or removal of the aber­ rant dermis using conjunctiva and the medial palpebral liga­ ment for closure can be done (Carter, 1973; Rubin, 1989). Cryotherapy can also be used to destroy the hair follicles, but depigmentation of the caruncle can result (Rubin, 1989).

Conjunctival Manifestations of Systemic Disease Many systemic diseases cause conjunctival manifestations. Some diseases, such as canine distemper, may cause a pri­ mary conjunctivitis, while others cause anterior uveitis, which leads to a ciliary flush or episcleral injection that is often misinterpreted as conjunctivitis. Because intraocular disease can lead to blindness, and because the diagnosis of anterior uveitis aids in narrowing the list of differential diag­ noses in a dog with systemic disease, any dog with a red­ dened conjunctiva should have a complete ophthalmic examination. Several diseases that commonly cause con­ junctival manifestations are mentioned here; for further dis­ cussion, see Chapter 36, Part 1. Leishmaniasis caused by Leishmania infantum can mani­ fest with conjunctivitis, keratitis, blepharitis, retinitis, ante­ rior uveitis, lymphadenomegaly, cutaneous signs, cachexia, abnormal locomotion, and other clinical signs (McConnell et  al., 1970; Nicolau & Perard, 1936; Pena et  al., 2000; Slappendel & Ferrer, 1990; Swenson et al., 1988). The use of PCR from conjunctival swabs and conjunctival biopsies is helpful in assessing exposure, screening, and diagnosis of leishmaniasis (Ferreira et  al., 2008; Gramiccia et  al., 2010; Leite et al., 2010; Solano‐Gallego et al., 2001; Strauss‐Ayali et  al., 2004). Experimentally infected dogs are positive by conjunctival PCR at 45 days of infection before seroconver­ sion. Treatment of canine leishmaniasis with allopurinol leads to a significant improvement in clinical signs, but does not eliminate the organisms (Koutinas et al., 2001). Dogs experimentally inoculated with Leptospira kirschneri serovar grippotyphosa developed clinical signs including conjunctivitis with a thick ocular discharge, lethargy, diar­ rhea, dehydration, vomiting, and icterus (Greenlee et  al., 2004). Conjunctivitis along with dermatologic signs, ano­ rexia, lethargy, fever, and vomiting has been reported in dogs with Babesia gibsoni infection. Rapid improvement was seen with treatment with imidocarb dipropionate (Tarello, 2003). Conjunctivitis, neurologic signs, and pancytopenia have occurred in a dog with generalized Listeria monocytogenes infection (Schroeder & van Rensburg, 1993). Several dogs from Nigeria with hepatozoonosis had conjunctivitis, fever, anorexia, and lameness (Ibrahim et al., 1989).

Multisystemic inflammatory disease was reported in a Borzoi that presented with conjunctivitis and signs referable to other organ systems; however, the cause of this inflamma­ tion could not be determined (Cheeseman et  al., 1995). Weimaraners with low serum immunoglobulin concentra­ tions may develop conjunctivitis as well as other recurrent diseases involving the alimentary tract, joints, skin, lymph nodes, and central nervous system (Day et al., 1997). Engorged conjunctival blood vessels have been observed in a dog with complications from a thymoma and in four dogs with type C botulism (Cornelissen et al., 1985; Peaston et  al., 1990). Bilateral conjunctivitis, mucopurulent dis­ charge, keratitis, and erosions, as well as ulcerations of the nose and foot pads, were present in a dog with tyrosinemia (Kunkle et al., 1984). Dogs with multiple myeloma can develop congested con­ junctival blood vessels in association with anterior uveitis and retinal changes (Kirschner et al., 1988). A thickened and hyperemic conjunctiva infiltrated perivascularly with histio­ cytes, lymphocytes, and plasma cells occurred in a dog with systemic histiocytosis; other ocular and orbital tissues were also involved (Scherlie et  al., 1992). Conjunctival involve­ ment of systemic lymphoma is also reported (see “Conjunctival Neoplasia”). Severe anemia can cause pallor of the conjunctiva and other mucous membranes, as well as lightness of the reti­ nal vessels. Polycythemia can cause “brick red” mucous membranes (Clerc & LaForge, 1995; Curtis et  al., 1991). Clotting deficiencies can cause periocular hemorrhages, but more commonly cause intraocular hemorrhages (Fig. 18.18; Martin, 1982). Jaundice is most easily seen in the dog in the mucous membranes, sclera, and skin. Jaundice is an indication of hemolysis, hepatic disease, or biliary tract obstruction (Dimski, 1995). Many systemic

Figure 18.18  Petechial and ecchymotic hemorrhages are present in the conjunctiva of the nictitating membrane in a dog with thrombocytopenia.

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­ iseases in humans are well documented as causing con­ d junctival changes; however, they are either infrequently seen or not documented in the dog.

A  subconjunctival sustained‐release cyclosporine delivery device for the treatment of KCS has been studied and appeared to be effective in a wolf (Acton et al., 2006; Beale et al., 2004).

Effects of Radiation

Surgical Procedures

Because of the close proximity of the globe and adnexa to the nasal and paranasal sinuses, the globe is frequently within the field of irradiation used in treatment of sinus neoplasia. Mild to severe conjunctivitis is the most fre­ quently occurring early ocular complication (Fig.  18.19), and this conjunctivitis is usually poorly responsive to medi­ cal therapy (Jamieson et al., 1991; Roberts et al., 1987). The conjunctival disease results from a direct effect of radiation on the basal epithelial stem cell layer (Nakissa et al., 1983). KCS can occur as an early or a late complication; therefore, an STT should be performed on all dogs that develop con­ junctivitis as a complication of radiation therapy (Jamieson et al., 1991; Roberts et al., 1987).

The conjunctiva is an invaluable tissue to ophthalmic sur­ geons. Because of its redundancy and rather loose bulbar adhesions, the bulbar conjunctiva can be easily resected and relocated. Conjunctival biopsy specimens can be sim­ ply and quickly obtained and are an effective diagnostic modality in patients with chronic conjunctivitis or con­ junctival masses. Conjunctival grafts created by incising the conjunctiva and relocating a part of it to the cornea are used to deliver a focal blood supply to an otherwise avascu­ lar cornea in the face of progressive infection or deep cor­ neal defects. Conjunctival grafts can be used alone for the treatment of deep ulcers, or can be used to cover tectonic corneal grafts and porcine small intestinal submucosa used for the repair of full‐thickness corneal defects (Bussieres et al., 2004; see Chapter 19).

Pharmacologic Research Conjunctivitis is a frequently noted sign of toxicity in experi­ mental studies of new drugs administered both systemically and topically (Aguirre et  al., 2009; Dominick et  al., 1993; Kerry et al., 1993; Lanigan, 2001; Mally & Thiebault, 1990). Pharmacologic studies have investigated the systemic absorp­ tion of drugs administered by the topical conjunctival route (Buhring et al., 1990; Nomura et al., 1990, 1994). A soluble, bioadhesive ophthalmic drug insert has been developed that was tolerated by dogs in one study (Baeyens et  al., 2002).

Conjunctival Biopsy Conjunctival biopsy is quite easy to perform and usually can be done in conscious dogs. After several drops of a topical ophthalmic anesthetic have been applied, the conjunctival area in question is gently elevated with fine‐toothed for­ ceps, and the conjunctiva is then excised with tenotomy scissors. Extra anesthesia can be achieved by holding a cot­ ton‐tipped swab soaked in topical anesthetic onto the intended biopsy site. The conjunctival defect (smaller than 1 cm diameter) is allowed to heal by second intention. In addition, an antibiotic ophthalmic solution is instilled for 5–7 days. Conjunctival biopsies are indicated for chronic conjunctivitis that is nonresponsive to therapy and for sus­ pected neoplasia.

Excision of Small Masses

Figure 18.19  Blepharitis, conjunctivitis, and keratoconjunctivitis sicca in a terrier dog following radiotherapy for a nasal adenocarcinoma (eyes included in field of radiotherapy).

Conjunctival neoplasia occurs infrequently; however, com­ plete excision of the tumor, with or without ancillary treat­ ment, is usually the treatment of choice. Most conjunctival neoplasms do not invade the sclera and are rather easily dis­ sected from the underlying tissue. Dermoids can also occur in the conjunctiva and often need to be excised. With small masses, excisional biopsies can be done in the awake animal. When excising a neoplasm, the surgeon should try to obtain a 2 mm margin. Small defects can be allowed to heal by sec­ ond intention, but defects larger than 1 cm in diameter should be closed in a simple, continuous pattern with 5‐0 to 7‐0 polyglactin 910 suture.

18: Diseases and Surgery of the Canine Conjunctiva and Nictitating Membrane

Small lacerations of the conjunctiva (< 1 cm) can be allowed to heal by secondary intention (Fig. 18.20). Large lacerations should be carefully cleansed, but debridement should be kept to a minimum. Any foreign material is removed. Severe conjunctival lacerations are rare and may be associated with intraocular damage, and the sclera underlying the conjunc­ tival defect should be carefully evaluated for damage, espe­ cially if hyphema is present. After the area has been cleansed and explored, simple interrupted, 5‐0 to 7‐0 absorbable sutures are used to appose the edges. Most commonly, con­ junctival lacerations are associated with lacerations of the entire eyelid, and repair of these lacerations is described in Chapter 15.

Treatment of Symblepharon Symblepharon occurs rarely in the dog and is usually sec­ ondary to trauma or chemical burns. Repair involves excis­ ing fibrous adhesions that have developed between the conjunctiva and the cornea or eyelid. A superficial keratec­ tomy is performed to remove any adhesions between the conjunctiva and the cornea; if the adhesions continue into the conjunctiva beyond the limbus, these too are severed. After the abnormal tissue has been excised, the edge of the remaining normal conjunctiva is sutured to the limbus, and a soft corneal contact lens is placed to allow the cornea to reepithelialize before the conjunctiva readheres. A silicone‐ sheeting implant may also be placed in the conjunctival for­ nix to prevent interconjunctival adhesions (Gelatt & Gelatt, 2011). Amnion graft scaffolds are utilized in humans with unilateral symblepharon to provide limbal stem cells and

Figure 18.20  Conjunctival laceration that resulted from a dog bite.

avoid recurrence, a common sequela in veterinary patients (Amescua et al., 2014; Basu et al., 2016).

Surgical Repair of Conjunctival Defects Conjunctival defects smaller than 1 cm in diameter can either be allowed to heal by second intention or can be closed with 5‐0 to 7‐0 polyglactin 910 suture in a simple interrupted or simple continuous pattern. Burying the knots decreases postoperative irritation. Repair of defects larger than 1 cm in diameter usually involves autografts from the bulbar con­ junctiva of the other eye or from the buccal mucosa (Gelatt & Gelatt, 2011).

Conjunctival Autografts to the Cornea Conjunctival autografts are used to treat deep corneal ulcers for several reasons. They preserve corneal and ocular integ­ rity, replace lost corneal tissue, and supply vascularization (Peiffer et  al., 1977). Many types of grafts have been described. Selection of the conjunctival graft in a clinical situation depends on the ulcer size, depth, and position; the presence of infection; the surgeon’s abilities; and the availa­ ble instrumentation.

Necessary Instrumentation and Surgical Fundamentals Specialized ophthalmic instrumentation is necessary to per­ form conjunctival grafting procedures. An eyelid speculum, Steven’s tenotomy scissors, Colibri forceps or tying forceps with 1 × 2 teeth for fixation, and ophthalmic needle holders are the minimal necessary instruments. Generally, 7‐0 to 10‐0 polyglactin 910 suture is used, with 8‐0 or smaller suture being more satisfactory. Magnification with a head loop or operating microscope is preferable to no magnification for corneal procedures. Maintenance of the blood supply and prevention of graft retraction are both important in assuring success. Grafts must be wide enough that an adequate blood supply is maintained, and the base should be wider than the tip. To prevent graft retraction, Tenon’s capsule should be dis­ sected from the substantia propria (Fig.  18.21). The graft should be thin enough that the tips of the scissor blades can be seen through it. The graft tissue should also be suffi­ ciently loose so that when positioned over the corneal lesion, it does not retract. This is accomplished with ade­ quate undermining and dissection with tenotomy scissors. In addition, it is imperative that the graft created is larger (~1–2 mm) than that necessary to cover the wound to allow for graft contraction. During dissection and removal of Tenon’s capsule, the surgeon must use care to avoid creat­ ing holes in the graft, because these holes tend to expand and cause failure of the graft. If a small hole is created,

SECTION IIIA

Laceration Repair

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Figure 18.21  During harvest of a conjunctival graft, Tenon’s capsule is dissected from the substantia propria of the conjunctiva to prevent graft retraction. Tenon’s capsule is pulled away from the overlying conjunctiva so that it can be excised.

placing a suture of 8‐0 to 10‐0 polyglactin 910 across it may prevent the hole from enlarging. Preparation of the ulcer site is important for graft reten­ tion. Necrotic and collagenolytic corneal stroma should be debrided using a scalpel blade. Frequently, a partial‐thick­ ness keratectomy is indicated to remove the necrotic tissue. Sutures must be placed in healthy corneal stroma to prevent dehiscence of the graft. Grafts will not adhere to corneal epi­ thelium; therefore, if corneal epithelium is present at the edge of the wound, it should be excised with a scalpel blade (e.g., Beaver No. 64) if the graft is to cover that specific area.

The graft can be made to cover any part of the cornea. Vision can usually be retained while the graft is in place. The graft moves in relation to the globe. No tension is created with the eyelid movement.

The graft is most easily created from the area lateral and dorsal to the limbus, where exposure is greatest and incorpo­ ration of the third eyelid into the graft can be avoided (Fig.  18.22). Three factors have been associated with graft dehiscence: aqueous leakage, keratomalacia, and a graft direction of more than 45° from the vertical (Hakanson & Merideth, 1987; Hakanson et al., 1988). If the pedicle is very wide or corneal perforation has occurred, a suture should be placed through the midline of the pedicle and into firm cor­ neal stroma at the dorsal edge of the ulcer. When placing this suture, care should be taken to avoid the major conjunctival vessels (Hakanson et al., 1988). Alternatively, sutures can be placed on both edges of the pedicle extending to the limbus. Another alternative is to suture a separate layer(s) of graft material as an aqueous‐tight layer (e.g., extracellular colla­ gen matrix or amnion), which is then overlaid with a con­ junctival graft. Typically, if the cornea has healed well, the pedicle of the graft is excised using tenotomy scissors after administration of a topical anesthetic 6–8 weeks postsurgery (Fig. 18.23). The graft will not be adhered where corneal epi­ thelium was present at the time of surgery. The scissor blades are slid beneath the pedicle and closed. Care should be used so that traction is not placed on the graft, which could pull the pedicle off the corneal lesion.

Tarsoconjunctival Pedicle Graft Island Grafts Island grafts can be created from the palpebral conjunctiva of the upper eyelid. A chalazion clamp may be placed on the dorsal eyelid before harvesting the graft to decrease hemor­ rhage. Grafts should be sized 10% greater than the corneal lesion to allow for graft contraction. Grafts are then sutured into the prepared ulcer bed using a simple interrupted pat­ tern. To help ensure the success of this type of conjunctival graft, sutures must be placed very close to each other, and the graft must be in perfect apposition to the edges of the prepared corneal defect. Generally, the grafts will remain a blanched white for approximately 10 days, by which time corneal vascularization has usually invaded the graft tissue (Scagliotti, 1988). Because island grafts are not vascularized, they should not be used in cases of bacterial infection and are ideally used in already vascularized corneas.

Bulbar Pedicle Graft The pedicle graft created from the bulbar conjunctiva is the graft used most frequently by veterinary ophthalmologists. The advantages of this procedure include the following:

The tarsoconjunctival pedicle graft can be used for deep cor­ neal ulcers (Peiffer et  al., 1977). To prepare the graft, the

Figure 18.22  Pedicle bulbar conjunctival graft. A viable conjunctival graft 2 weeks postsurgery. Multiple vessels are seen extending to the edges of the graft. The polyglactin 910 sutures are still present. The remaining corneal edema resolved, and the corneal vessels regressed with time. While not visible in this image, the pupil was mydriatic.

A

B

Figure 18.23  A. A pedicle graft 8 weeks postsurgery. The graft is viable, and the pupil is pharmacologically dilated. B. A pedicle graft immediately posttransection of the pedicle.

upper eyelid is clamped and everted with a chalazion clamp. The graft is created by dissecting a pedicle of palpebral con­ junctiva from the underlying orbicularis oculi muscle of the superior eyelid using sharp dissection with a Bard‐Parker No. 15 or Beaver No. 64 blade and tenotomy scissors. The pedicle is created with the base toward the eyelid margin. The base of the graft should be wide enough to ensure an adequate blood supply, and the length should be constructed to minimize tension and to allow eyelid mobility. The graft is then sutured to the corneal defect in a simple interrupted pattern (Peiffer et  al., 1977). Disadvantages of this type of graft include the potential for eyelid movement causing pre­ mature retraction of the graft and the greater difficulty of harvesting the palpebral conjunctiva compared with the bul­ bar conjunctiva. A temporary tarsorrhaphy should be placed to decrease tension on the graft, minimizing the probability of retraction caused by eyelid movement.

Bridge Grafts A bridge graft has a blood supply feeding the graft from both ends. The graft is created by using tenotomy scissors to make two concentric conjunctival incisions, one near and parallel to the limbus and one parallel to the limbus but distant enough from the first incision to create a graft of the appro­ priate width. Tenon’s capsule should be dissected from the graft. The graft should be wide enough to ensure adequate perfusion. Both edges of the graft are sutured to the cornea after sliding the graft over the corneal defect (Gelatt & Gelatt, 2011). The leading edge of the remaining bulbar conjunctiva can be sutured to the limbus depending on the size of the defect created.

Advancement Grafts (180‐Degree or Hood) Hood grafts, also known as advancement or 180‐degree grafts, are most useful for dorsal and lateral paracentral

c­ orneal defects and peripheral corneal defects. The graft is created by incising the bulbar conjunctiva near the limbus and dissecting the conjunctiva from the underlying Tenon’s capsule caudally toward the fornix. The conjunctiva is then sutured to the cornea so that the graft extends beyond the defect. Finally, supporting sutures are placed along the remainder of the leading edge of the graft (Gelatt & Gelatt, 2011). These grafts tend to have more tension than pedicle grafts and therefore may be more likely to dehisce. An excep­ tionally thin hood graft, termed keratoleptynsis, is being used for the treatment of severe corneal edema. After a thin keratectomy is done down to clear cornea, a thin conjuncti­ val graft is sutured over the effected cornea. If a large area is affected, the graft may be made to cover only two‐thirds to three‐fourths of the corneal surface (Horiakawa et al., 2016; Miller, 2010).

Complete Bulbar Grafts (360‐Degree) A 360‐degree bulbar conjunctival graft, also known as a complete bulbar graft, can be used to surgically treat central and paracentral, as well as very large‐diameter, corneal defects. To create the graft, limbal traction is created to rotate the globe ventrally. A 180‐degree incision is made parallel to, but at sufficient distance from, the limbus so that the graft created will be wide enough to cover the cornea. After the limbal‐based graft is created, a 360‐degree peritomy is made, and the graft is slid into position and sutured either to the inferior and superior limbal cornea, the episclera, or the inferior and superior conjunctival incisions (Gelatt & Gelatt, 2011; Gundersen, 1960). A modification to this procedure is to make a 360‐degree peritomy and undermine the conjunc­ tiva toward the fornix; the edges are then brought together as a horizontal line across the middle of the cornea and apposed with horizontal mattress sutures (Fig. 18.24). The graft can be also directly sutured to the corneal defect if corneal rup­ ture is imminent or aqueous humor is leaking. This type of

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Figure 18.24  A 360‐degree bulbar conjunctival graft 2 weeks postsurgery. The stents of the temporary tarsorrhapy are visible.

graft has several disadvantages, however, because the entire cornea is covered by the graft. The patient is blind while the graft is in place, evaluation of the eye is impossible, penetra­ tion of topical drugs is probably impaired, and dehiscence is common if there is tension on the graft.

Corneoconjunctival Transposition Corneoconjunctival transposition is a modification of the conjunctival graft. Partial‐thickness cornea adjacent to the defect is mobilized into the defect, with the attached bul­ bar conjunctiva sliding into the area from which the cor­ neal transplant was harvested. This graft is most frequently used with axial corneal lesions, because there is typically less scar tissue associated with the transplanted corneal tissue than with a conjunctival pedicle graft. However, brachycephalic breeds such as the Pug may develop pig­ mentation of the transplanted corneal tissue as well as the conjunctival portion. The corneoconjunctival transposi­ tion is not recommended for use in infected cornea, and some surgeons find it more time‐consuming to create than a bulbar pedicle graft. An alternate, even more time‐con­ suming technique, known as corneoscleral transposition, transplants cornea with attached sclera into the defect (Gelatt & Gelatt, 2011). This procedure is described more fully in Chapter 19.

General Postoperative Care and Success Rates Treatment for a corneal ulcer after conjunctival graft place­ ment includes topical ophthalmic antibiotics and parasym­ patholytic drugs. Because a blood supply is created, systemic antibiotics will be able to reach the corneal ulcer and there­ fore are often initiated. Serum, which is frequently used for its anticollagenase and antiproteinase properties, is not nec­ essary; the graft will supply this therapy. Generally, the base of a conjunctival pedicle graft is severed from the limbus

6–8 weeks postoperatively (Hakanson & Merideth, 1987). Leaving the pedicle intact has been recommended in some instances (e.g., following corneal sequestrum removal) to maintain a patent blood supply to the cornea involved. Conjunctival grafts are a highly successful treatment modality for deep and perforated corneal ulcers in the dog (Hakanson & Merideth, 1987; Hakanson et al., 1988; Wagner et  al., 1992). In one study, corneal clarity compatible with useful vision was achieved in 25 of 35 cases, and graft dehis­ cence occurred in only 3 of 35 eyes (Hakanson & Merideth, 1987). In another study, structural integrity of the cornea was reestablished in 91% of eyes with bacterial ulcerative keratitis that underwent conjunctival graft placement, and partial or total graft dehiscence occurred in 32% of eyes (Wagner et al., 1992). Graft failure has been associated with incorrect corneal graft‐bed preparation or suturing, incom­ plete covering of keratomalacia, aqueous leakage, a graft direction of more than 45% from the vertical, and excessive stretching of the graft between opposite sutures (Hakanson & Merideth, 1987; Hakanson et al., 1988).

Nictitating Membrane The NM, which is also called the membrana nictitans, third eyelid, or haw, is a thin sheet of tissue found in the medial canthus of most domestic animal species. The primary pur­ pose of the NM is physical protection of the cornea. Its gland also contributes significantly to normal tear production and distribution. The NM is affected by a number of inflamma­ tory and neoplastic conditions as well as anatomic malfor­ mations that require surgical correction.

Anatomy, Histology, and Function The basic shape of the canine NM is defined by a T‐shaped piece of hyaline cartilage (Fig.  18.25). The “arm” of the T parallels the free margin of the NM, and the “shaft” is per­ pendicular to the free edge. The shaft of the NM cartilage is cone shaped at the basal end and terminates to form a trian­ gular plate. The arm or “crossbar” at the leading edge of the NM is crescent shaped with a prominent bulge. The cartilage is of hyaline material, with some elastic fibers detectable only in the neighboring connective tissue (Schlegel et  al., 2001). The ventral extent of the shaft originates from the periorbital connective tissue associated with the inferonasal aspect of the globe. The base of the NM is intimately associated with the fas­ ciae of the ocular musculature (Constantinescu & McClure, 1990). Conjunctiva covers the anterior and posterior sur­ faces of the NM. The conjunctival mucosa on the posterior surface is contiguous with the bulbar conjunctiva mucosa; the conjunctival mucosa on the anterior surface is contigu­ ous with the palpebral conjunctival mucosa. In addition to

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A

D Figure 18.26  Completely encircling nictitating membrane in an American Cocker Spaniel. Figure 18.25  Normal canine NM. Note the leading edge (A), its base (B), the T‐shaped hyaline cartilage (C), and the superficial gland of the nictitans (D). (Reproduced with permission from Gelatt, K.N. & Gelatt, J.P. (2011) Surgical procedures for the conjunctiva and the nictitating membrane. In: Veterinary Ophthalmic Surgery (eds. Gelatt, K.N. & Gelatt, J.P.), pp. 157–190. Edinburgh: Elsevier‐Saunders.)

the cartilage, a fibrous connective tissue stroma is present between the anterior and posterior conjunctival surfaces (Mane et  al., 1990). Numerous lymphoid aggregates popu­ late the posterior subconjunctiva of the NM, and goblet cells are found between the lymphatic nodules and the epithe­ lium (Prince et  al., 1960). The NM of dogs lacks inherent musculature (Bromberg, 1980; Samuelson, 2007). The move­ ment of the NM is accomplished passively when the globe is retracted, which displaces orbital fat and thereby pushes the NM across the cornea. The NM sweeps over the cornea from inferonasal to superotemporal. In most dogs, 4–5 mm of the free edge of the NM is visible at the medial canthus and is usually pigmented. Some indi­ vidual animals have an encircling NM in which the free mar­ gin continues circumferentially around the eye posterior to the limbus (Fig. 18.26; Bromberg, 1980), but does not result in ocular pathology. A tubuloacinar gland surrounds the ventral portion of the cartilage shaft. When the NM is in its normal position, the gland is deeply seated posterior to the orbital rim and is not visible. Histochemical studies have shown that in the canine NM gland, the tubular cells are primarily serous, the acinar cells are primarily mucus, and the principal mucus secretory product is sialomucin (Alexandre‐Pires et al., 2008; Martin et  al., 1988). Lipid‐secreting acini similar to those in the Harderian gland, which is present in many animals but not the dog, have been identified in the canine NM gland. The function of the Harderian gland is hypothesized to have been incorporated into the NM gland in dogs (Martin et al., 1988; Munnell & Martin, 1988; Samuelson, 2007). The NM gland contributes a significant proportion of the aqueous

tear film as measured by the STT (STT‐1 without topical anesthesia; STT‐2 with topical anesthesia followed by drying of the lower conjunctival sac; Chang & Lin, 1980; Helper et  al., 1974). Studies have shown that third eyelid removal causes a temporary decrease in results of the phenol‐red‐ thread test and STT‐1 and a continued decrease of 60% of the STT‐2. Furthermore, the pH of the tears is increased, tear breakup time is reduced, and vital staining is seen (Saito et al., 2001, 2004). The NM also provides immunologic support to the ocular surface. IgA‐positive plasma cells are located near the sur­ face of the conjunctival epithelium of both sides of the NM and within the connective tissue stroma of the nictitating gland (Schlegel et al., 2003). Additionally, the follicle‐associ­ ated epithelium overlying the CALT located on the bulbar surface of the NM in dogs has cells with an appearance char­ acteristic of M cells, which includes attenuated apical cell surfaces with blunted microvilli and microfolds, invaginated basolateral membranes forming cytoplasmic pockets, and a diminished distance between apical and pocket membrane. These M cells are believed to act as antigen‐presenting cells within the conjunctiva. The presence of B‐cell germinal centers and T‐cell apical caps in the lymphoid follicles are further support that this tissue is analogous to mucosal‐asso­ ciated lymphoid tissue (MALT) in other tissues (Giuliano et al., 2002). The blood supply of the NM is supplied by the malar artery. As the artery enters the base of the NM, it divides into smaller branches that cross almost the entire length superfi­ cially to the free border, before ramifying deeply toward an inner segmental level. Thus, the first ramifications of the primary artery run to the free edge of the NM, postulated to improve vascularization efficiency. The larger veins are also located superficially. It is thought that this spatial microvas­ cular arrangement probably results from an adaptation of the NM normally being compressed into a small area (Alexandre‐Pires et al., 2008).

SECTION IIIA

B

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Section IIIA: Canine Ophthalmology

Anomalous, Congenital, and Developmental Disorders

SECTION IIIA

Bent Cartilage Eversion of the shaft of the NM cartilage is a commonly occurring anomaly in large breeds (Bromberg, 1980; Gelatt, 1970, 1972; Martin, 1970) and may be hereditary in German Shorthaired Pointers (Fig.  18.27A; Martin, 1970). It is thought to result from more rapid growth of the posterior portion of the cartilage compared with that of the anterior portion (Martin, 1970). The everted cartilage appears as an anterior folding of the leading edge of the NM with exposure of the posterior aspect. The result is chronic conjunctivitis and ocular discharge. Many therapies, including placement of an NM flap for 10–14 days, resection of the NM margin and cartilage, radi­ cal resection of the NM cartilage and gland, shortening of the NM, and NM cartilage transplant, have been reported to be successful (Kuhns, 1975, 1977a, 1977b, 1981a, 1981b; Mane et al., 1990; Martin, 1970; Peruccio, 1981). The most

A

popular surgical correction is simple excision of the folded portion of the NM cartilage (Barnett, 1978; Bromberg, 1980; Crispin, 1991; Gelatt, 1972; Peiffer et al., 1987; Stades, 1976; Fig. 17.27B). A rare anomaly of the NM is inversion of the medial and lateral tips of the NM cartilage arm. Irritation from this car­ tilage can result in keratitis and corneal ulceration. The bent tips can be surgically excised, however, without conjunctival dissection or suturing (Ward, 1999).

Prolapse of the Gland Prolapse of the NM gland (or “cherry eye”) is the most common primary disorder of the NM (Fig.  18.28). The pathogenesis of this disorder has not been determined; however, it is thought to result from weakness in the con­ nective tissue attachment between the NM ventrum and the periorbital tissues (Severin, 1996). This weakness allows the gland, which normally is located ventrally, to flip up dorsally to protrude above the leading edge of the

B

Figure 18.27  A. Eversion of the cartilage of the nictitating membrane (NM) in a Great Dane. B. To repair, a linear incision is made over the folded portion of the cartilage (posterior surface of the NM). The section of the everted cartilage is excised, and the wound does not need to be apposed. (Reproduced with permission from Gelatt, K.N. & Gelatt, J.P. (2011) Surgical procedures for the conjunctiva and the nictitating membrane. In: Veterinary Ophthalmic Surgery (eds. Gelatt, K.N. & Gelatt, J.P.), pp. 157–190. Edinburgh: Elsevier‐Saunders.)

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gland had a lower incidence of KCS later in life than dogs that were not treated or had the prolapsed gland excised (Morgan et al., 1993).

Figure 18.28  Prolapse of the gland of the nictitating membrane (“cherry eye”) in an English Bulldog.

NM, where it then becomes enlarged and inflamed from chronic exposure. Prolapse of the NM gland can be either unilateral or bilateral, and it generally occurs before 2 years of age (Dugan et al., 1992; Morgan et al., 1993). Prolapse of the NM gland is common in the American Cocker Spaniel, Lhasa Apso, Pekingese, Beagle, and English Bulldog (Morgan et al., 1993; Severin, 1996). Pedigree analysis and test breeding of two closed canine breed lines supported the hypothesis that prolapse of the NM gland has an inher­ ited basis. The mode of inheritance was not determined (although simple Mendelian inheritance was excluded) and was suggested to be complex and possibly multigenic (Edelmann et al., 2015). The prolapsed gland appears as a smooth, red mass protruding from behind the leading edge of the NM. If uncorrected, chronic conjunctivitis and ocu­ lar discharge occur (Dugan et al., 1992). The reduction in tear production seen with excised glands or glands surgi­ cally repositioned was not clinically important in a 6‐month study (Dugan et  al., 1992). However, a long‐term study showed that dogs treated with surgical replacement of the

When the importance of the NM gland in tear production became apparent, surgical repositioning of the gland, rather than excision, became widely recommended (Chang & Lin, 1980; Helper et al., 1974). While many modifications of repo­ sitioning techniques have been published, the surgical tech­ niques can be divided into methods that anchor the gland and methods that create a pocket for the gland. In the origi­ nal anchoring technique described by Blogg (1980), the pro­ lapsed gland is sutured to the inferior episcleral tissue. Following a posterior conjunctival incision, a suture of 3‐0 polyglycolic acid is placed into the deep episcleral tissues on the inferonasal aspect of the globe. The suture is then passed through the ventral aspect of the gland and pulled tight, thus retracting the gland. Gross (1983) modified this technique by anchoring the gland to the inferior sclera with 5‐0 chromic gut rather than to the episcleral tissues. Albert et al. (1982) anchored the proximal end of the cartilaginous NM shaft to the origin of the ventral oblique muscle in two cats with eversion of the NM cartilage. Presumably, this technique could also be used to reposition prolapsed NM glands in dogs. A perilimbal incision is made in the bulbar conjunctiva 4 mm from the inferonasal limbus, and the episcleral tissues are dissected away, thus exposing the inferior oblique mus­ cle. A second conjunctival incision is made perpendicular to the first, so exposing the gland. A 5‐0 silk suture is passed through the ventrum of the gland and then through the ten­ dinous origin of the muscle, tucking the gland into its natu­ ral position. Sapienza et al. (2014) described a technique of anchoring the NM gland to the ventral rectus muscle inser­ tion in 100 dogs with a 0% recurrence rate. Theorizing that the approaches from the posterior aspect of the NM used in these anchoring techniques could damage the excretory ductules of the gland, Kaswan and Martin (1985) sutured the gland to the periosteum of the ventral orbital rim using an anterior approach (Fig. 18.29). A modi­ fication of this technique, which facilitates the approach to the orbital periosteum, has been described by Stanley and Kaswan (1994). Plummer et al. (2008) described a technique that anchors the gland to the cartilage of the NM, allowing mobility. For this procedure, a 4‐0 nylon suture is passed from the anterior surface of the third eyelid through the base of the cartilage to the posterior aspect, and tunneled circum­ ferentially beneath the conjunctiva over and around the pro­ lapsed gland. The suture is then passed through the cartilage again to the anterior face of the third eyelid. The gland returns to its normal position as the suture is slowly tight­ ened and then tied on the anterior aspect of the NM (Plummer et al., 2008).

SECTION IIIA

Surgical Repositioning

Section IIIA: Canine Ophthalmology

SECTION IIIA

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Figure 18.29  In the orbital rim–anchoring technique of Kaswan and Martin (1985) to treat “cherry eye” in the dog, an incision parallel to the orbital rim is made in the anterior conjunctiva near the ventrum of the nictitating membrane, and 4‐0 nonabsorbable monofilament suture material is inserted into the medial extent of the resulting conjunctival pocket and directed toward the orbital rim. A blind bite is taken into the periosteal tissues and directed out of the pocket at its lateral extent; this bite can also be taken from lateral to medial. Adequate purchase into the periosteal tissues should be confirmed by firmly tugging at the suture before proceeding. A T‐shaped continuous suture is then placed to encompass the gland by reinserting the suture at each exit point, and the suture is pulled tight, thus anchoring the gland to the orbital rim. The conjunctiva can either be left open or closed with 6‐0 polyglactin 910 suture material in a simple continuous pattern. (Reproduced with permission from Gelatt, K.N. & Gelatt, J.P. (2011) Surgical procedures for the conjunctiva and the nictitating membrane. In: Veterinary Ophthalmic Surgery (eds. Gelatt, K.N. & Gelatt, J.P.), pp. 157–190. Edinburgh: Elsevier‐Saunders.)

Rather than anchoring the gland, some advocate burying it in a pocket created by conjunctiva on the anterior or poste­ rior surface of the NM (Moore, 1983, 1990; Morgan et  al., 1993; Twitchell, 1984). In the Twitchell technique, an inci­ sion is made in the conjunctiva on the palpebral surface of the NM, and a pocket is created by dissection of subconjunc­ tival tissues (Twitchell, 1984). The gland is then reduced into the pocket and sutured anteriorly with 5‐0 absorbable suture material. Moore described resection of the posterior con­ junctiva from over the prolapsed gland and then imbrication of it with two simple interrupted sutures of 7‐0 absorbable suture material (Moore, 1983). A later modification did not involve conjunctival resection (but suggested light scarifica­ tion) and used a single purse‐string suture (Moore, 1990). The Morgan technique may be the most commonly used pocket technique (Fig. 18.30; Morgan et al., 1993). The choice of repositioning technique is a matter of per­ sonal preference. The pocket techniques of Moore and

Morgan may be the easiest to learn, but the anchoring tech­ niques, once mastered, are simple and quick to perform. No systematic studies have compared effects on tear production among all the described techniques. Success rates with the pocket techniques have been reported as 87.5% to 97% (Dehghan et  al., 2012; Mazzucchelli et  al., 2012; Morgan et al., 1993; Premont et al., 2012). Reprolapse rates were com­ pared in one large retrospective study comparing a pocket technique with the same pocket technique combined with an orbital rim tacking procedure (described by Stanley and Kaswan, 1994) and demonstrated a slightly lower recurrence rate using the combined technique (Multari et al., 2016). Tear production following both anchoring and pocket techniques, however, is superior to that following gland excision, and Moore et  al. (1994) demonstrated that nei­ ther posterior pocket technique alters tear production or the morphology of the NM gland excretory ductules (Dugan  et  al., 1992; Morgan et  al., 1993). Results of one

A

B

Figure 18.30  Morgan pocket technique to treat “cherry eye” in the dog. A. Two parallel incisions are made into the posterior conjunctiva dorsal and ventral to the prolapsed gland. B. The gland is reduced into the pocket, and the pocket is closed with a simple continuous suture of 5‐0 or 6‐0 polyglycolic acid or polyglactin 910, securing the knot on the anterior surface. Suturing should begin and end 1–2 mm from the ends of the incision to prevent cyst formation because of the entrapment of tears within the pocket. At the end of the suture run, another run using a Cushing pattern may be placed in the opposite direction to conceal the sutures, but this is not necessary and may result in an increased suture reaction. (Reproduced with permission from Gelatt, K.N. & Gelatt, J.P. (2011) Surgical procedures for the conjunctiva and the nictitating membrane. In: Veterinary Ophthalmic Surgery (eds. Gelatt, K.N. & Gelatt, J.P.), pp. 157–190. Edinburgh: Elsevier‐Saunders.)

study ­demonstrated a significantly lower reprolapse rate with a pocket technique compared to an anchoring tech­ nique, but others have reported reprolapse rates of 0%–4% following anchoring techniques (Gross, 1983; Kaswan & Martin, 1985; Morgan et al., 1993; Stadsvold, 1992). After the pocket technique is done, cysts can form if the ellipti­ cal incisions are connected, which then prevents tears from escaping (Fig. 18.31). Creation of a stoma allows the tears to escape. When properly performed, all techniques result in a cosmetically acceptable outcome. Reprolapse of the gland is a possible complication of any of the proce­ dures and is more common in large‐breed dogs such American Bulldogs and Mastiff breeds. The same or another procedure can be repeated and is often successful. While surgical repositioning is recommended, it should not be assumed that retention of the gland guarantees that dry eye will not develop, since many breeds that com­ monly develop prolapsed NM glands are also predisposed to KCS.

Protrusion Primary protrusion of the NM without prolapse of the gland can occur in several large breeds (Peruccio, 1981). Though principally a cosmetic problem, the protrusion sometimes causes conjunctivitis and epiphora. The NM can be short­ ened surgically to return it to a more normal position (Peruccio, 1981).

Figure 18.31  A cyst developed in the nictitating membrane of this Bassett Hound after the pocket technique was done and the ends of the incisions were sutured together.

Protrusion can also occur secondary to enophthalmos, microphthalmos, and space‐occupying retrobulbar lesions (Barnett, 1978). If the primary problem can be resolved, the NM often returns to its normal position. Protrusion may also occur in Horner’s syndrome, dysautonomia, cannabis intoxi­ cation, tetanus, and rabies (Bagley et al., 1994; Harkin et al., 2002; Johnson & Miller, 1990; Martin, 1990; Schrauwen et al., 1991; Valentine, 1992; Wise & Lappin, 1989). In animals with one pigmented and one nonpigmented NM margin, an optical illusion makes the nonpigmented NM appear to protrude abnormally (Barnett, 1978). In most

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instances, no problems result from lack of pigmentation, and no treatment is necessary. Occasionally, however, solar conjunctivitis occurs, which can be treated with topical anti‐ inflammatory drugs (Bromberg, 1980).

SECTION IIIA

Neoplasia Neoplasia of the NM, like neoplasia in the rest of the con­ junctiva, is uncommon in the dog. Melanomas, adenocarci­ nomas, squamous cell carcinomas, mastocytomas, papillomas, hemangiomas, hemangiosarcomas, angiokera­ tomas, lymphosarcoma, and basal cell carcinoma have all been reported (Buyukmihci & Stannard, 1981; Collier & Collins, 1994; Collins et al., 1993; Hallstrom, 1970; Johnson et al., 1988; Lavach & Snyder, 1984; Liapis & Genovese, 2004; Peiffer et al., 1978; Rodriguez Galarza et al., 2016; Saunders & Rubin, 1975; Wilcock & Peiffer, 1988). Additionally, tumors described above for the conjunctiva can also affect the NM. Results of one study revealed adenocarcinomas (several varieties), papillomas, and malignant melanomas to be the most common primary tumors of the third eyelid (Schäffer et al., 1994). Papillomas have papillary, cauliflower‐like sur­ faces. Excision of the masses with a margin of normal tissue appears to be curative (Collier & Collins, 1994). When mela­ nomas of the conjunctiva develop, they most commonly occur on the NM (Collins et al., 1993). Conjunctival melano­ mas tend to be malignant, and recurrences and metastasis are common. There is no correlation between the mitotic index and the likelihood of local recurrence or metastasis (Collins et al., 1993; Schäffer et al., 1994). A breed predilec­ tion for the Weimaraner may exist. Combined excision and cryotherapy appear to be the most effective treatment for melanomas of the conjunctiva and NM (Collins et al., 1993).

Adenocarcinoma The most common neoplasm of the canine NM gland is adenocarcinoma (Dees et  al., 2016). Adenocarcinomas of the NM gland generally are localized, firm, smooth, pink swellings that appear to involve the gland (Wilcock & Peiffer, 1988). These are typically tumors of older dogs. Examination of histopathologic sections may reveal clean margins, but recurrence is common (Schäffer et al., 1994). Removal of the entire third eyelid is currently the recom­ mended treatment (Wilcock & Peiffer, 1988). With recur­ rence, surgery in conjunction with external beam radiation therapy can be successful. Adenomas of the NM gland also occur (Fig. 18.32).

Other Neoplasms Squamous cell carcinoma has been reported to arise from both the palpebral and bulbar surfaces of the NM, and it may

Figure 18.32  Adenoma of the gland of the nictitating membrane.

appear dark in color. Excision of the third eyelid is curative (Lavach & Snyder, 1984). When extensive, squamous cell carcinoma of the NM may invade the orbit (Miller & Dubielzig, 2001). In one case of a mastocytoma, the mass was very firm, and local excision appeared to be curative (Hallstrom, 1970). Hemangiomas (Fig. 18.33), hemangiosar­ comas, and angiokeratomas of the NM appear as red, prolif­ erative, protruding masses (George & Summers, 1990; Liapis & Genovese, 2004; Peiffer et  al., 1978; Pirie et  al., 2006; Saunders & Rubin, 1975). Local surgical excision tends to be curative (George & Summers, 1990; Liapis & Genovese, 2004). Bilateral lymphosarcoma of the NMs was reported in a German Shepherd (Guaguere et  al., 1993). These NMs were thickened, hyperemic, and multifocally depigmented, and the animal was euthanized shortly after diagnosis because of progression of systemic disease. Bilateral MALT lymphoma of the NM was diagnosed in a 4‐year‐old American Cocker Spaniel, and lobulated masses were pre­ sent on the bulbar surface of both NMs. Histologically, there were proliferations of lymphoid follicles surrounded by lym­ phoid cells forming a marginal zone, with some occasionally infiltrating into the conjunctival epithelium. Excision appeared curative for one NM; there was no growth in the opposite NM over the following year. There was no apparent associated ocular or systemic involvement (Hong et  al., 2011). Myoepithelioma of the NM gland has been reported in a dog (Bondoc et al., 2014).

Inflammatory Conditions Nodular Granulomatous Episclerokeratitis Nodular granulomatous episclerokeratitis is an inflamma­ tory disease that most commonly arises from the temporal limbus, but it may involve the NM as well. Collies are predis­ posed (Dugan et  al., 1993; Paulsen et  al., 1987). Clinically, the affected NM is hyperemic, depigmented, and edematous,

reveals a subepithelial inflammatory infiltrate consisting primarily of plasma cells, with fewer lymphocytes and stro­ mal pigmentary incontinence (Alonso‐Alegre et  al., 1999; Barnett, 1978; Helper, 1981; Rubin, 1989; Teichert, 1966). Treatment generally consists of topical ophthalmic dexa­ methasone 4 times daily initially, or subconjunctival or sys­ temic corticosteroids (Barnett, 1978; Helper, 1981; Rubin, 1989; Teichert, 1966). Topical ophthalmic cyclosporine oint­ ment, tacrolimus drops, or 1% pimecrolimus administered 2–3 times daily are also effective (Bigelbach, 1994; Nell et al., 2005; Read, 1995). Comparison of 2% cyclosporine solution and 0.1% dexamethasone showed that dexamethasone gave more rapid results, but the disease returned more slowly in the cyclosporine‐treated dogs (Alonso‐Alegre et  al., 1999). Once there is resolution, medication administration is slowly decreased to the lowest effective frequency.

Idiopathic Granulomatous Disease

Figure 18.33  Hemangioma of the nictitating membrane in a Bassett Hound.

with multiple, smooth, tubular‐shaped thickenings involv­ ing the palpebral surfaces. On histopathology, these lesions show a chronic granulomatous inflammatory response. The disease process is generally controllable with use of systemic prednisone and azathioprine, but oral doxycycline and niaci­ namide have also been used successfully (Dugan et al., 1993; Hurn et al., 2005; Latimer et al., 1983b; Paulsen et al., 1987).

Plasma Cell Infiltration (Plasmoma) Plasma cell infiltration of the NM, or “plasmoma,” can cause thickening, depigmentation, and follicle formation (Fig.  18.34; Barnett, 1978; Bromberg, 1980; Helper, 1981; Read, 1995; Rubin, 1989; Teichert, 1966). Pannus (i.e., chronic superficial keratitis) is often associated with this condition. German Shepherds appear to be predisposed, and plasmoma has bilateral potential in the Belgian Sheepdog, Borzoi, Doberman Pinscher, English Springer Spaniel, and German Shepherd breeds (Barnett, 1978; Bromberg, 1980; Read, 1995; Rubin, 1989; Teichert, 1966). Histopathology

Idiopathic sterile granulomatous disease manifests as multi­ ple masses on the conjunctiva, eyelids, NM, and skin. On histopathologic examination, granulomatous inflammation with large epithelioid cells, plasma cells, and lymphocytes is seen. Treatment with l‐asparaginase, prednisone, or azathi­ oprine has shown some efficacy (Collins et  al., 1992; Gionfriddo et  al., 2003; Latimer et  al, 1983b; Riis, 2000). Treatment with tetracycline and niacinamide was successful for resolution of the granulomas in one report; however, optic neuritis developed, presumably secondary to treatment with the niacinamide (Rothstein et  al., 1997). Anecdotally, treatment with tetracycline or doxycycline alone may be suc­ cessful in some cases.

Follicular Conjunctivitis Follicular conjunctivitis most frequently involves the bul­ bar aspect of the NM, but the follicles can be present any­ where on the conjunctiva (see Fig.  18.4). A small area of lymphoid follicles is normally present on the bulbar side of the NM, closely associated with the NM gland. With follic­ ular conjunctivitis, the follicles are more numerous and larger than normal in size, and conjunctival hyperemia as well as a mucoid discharge commonly are present. (See the conjunctival section of this chapter for more information and treatment.)

Ocular Nodular Fasciitis Ocular nodular fasciitis most commonly affects the sclera, episclera, and corneal stroma, but it has also been reported to involve the NM. In the one case described, an irregular nodular thickening involved the anterior aspect of the NM (Lavignette & Carlton, 1974). The mass was excised and there was no recurrence. On histopathologic examination,

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with visceral leishmaniasis developed a grayish white, fibrous appearance to its NM, along with keratoconjuncti­ vitis, thickened eyelids, and anterior uveitis (McConnell et al., 1970).

SECTION IIIA

Nictitating Membrane Surgery

Figure 18.34  Plasma cell infiltration of the nictitating membrane (plasmoma) in a German Shepherd.

histiocytes, fibroblasts, capillaries, fibrous connective tis­ sue, and a few inflammatory cells were seen (Lavignette & Carlton, 1974).

Trauma, Reconstruction, and Foreign Bodies Trauma to the medial canthal area may result in lacerations of the NM. Small lesions heal spontaneously, but larger lesions should be sutured with 6‐0 braided, absorbable suture material, taking care not to leave sutures or knots where they could abrade the cornea. If the NM has been removed because of neoplasia or extensive areas were lost because of trauma, it may be reconstructed from oral and labial mucosa (Kuhns, 1977b, 1981a, 1981b). Foreign bodies lodged either within or behind the NM can cause persistent corneal ulceration as well as inflammation of the NM. Other frequently observed clinical signs are epi­ phora, blepharospasm, protrusion of the NM, and severe dis­ comfort. The foreign bodies, which are commonly grass awns, seeds, or other plant material, usually are loosely embedded and can be removed using thumb forceps follow­ ing instillation of a topical anesthetic. Generally, topical ophthalmic antibiotic should be used after removal of the foreign body, especially if the cornea is ulcerated (Brennan & Ihrke, 1983; Bromberg, 1980).

Miscellaneous Diseases A cyst of the NM gland has been treated successfully by excision of the well‐demarcated mass (Latimer et  al., 1983a). Clinically, the mass was pigmented and could be visualized from both sides of the NM. Cysts of the NM gland may also be treated by marsupialization of the cyst to the conjunctival surface (Barbe et  al., 2017). One dog

The NM can be used as a corneal shield in select cases of cor­ neal ulceration. These NM “flaps” have been purported to aid in the healing of midstromal ulcers, iatrogenic ulcers created by lamellar keratectomy in brachycephalic animals, and, in particular, refractory indolent ulcers. They have also been used in conjunction with frozen lamellar corneal grafts to pro­ tect the graft from blinking movements and to help maintain pressure on the graft’s surface (Hansen & Guandalini, 1999).

Nictitating Membrane Flaps Several types of flaps have been described. In the most widely advocated technique, the free margin of the NM is sutured to the temporal aspect of the superior eyelid (Bistner et al., 1977; Gelatt & Gelatt, 2011; Peiffer et al., 1987; Quinn, 1990). Two to three horizontal mattress sutures of 3‐0 mono­ filament nonabsorbable material are placed between the free edge of the NM and the lateral aspect of the superior lid. The lid sutures should be placed well within the supe­ rior cul‐de‐sac, and the NM sutures should be approxi­ mately 2 mm from the free edge, incorporating cartilage into the center suture (Fig. 18.35A). Alternatively, a single mattress suture can be placed between the superior lid and the midpoint of the cartilage shaft (Helper & Blogg, 1983). The surgeon must be careful to seat the NM margin as deeply as possible in the superior conjunctival fornix. If the NM margin is too far from the cul‐de‐sac, corneal injury from sutures is likely. Alternatively, the NM margin can be sutured to the superotemporal episcleral tissue (Slatter, 1990; Fig. 18.35B). Care must be taken to place the sutures deeply enough to ensure that the NM is held securely, but not placed so deeply as to perforate the globe. The advan­ tage of this technique is that the flap moves in concert with the globe, minimizing corneal trauma and stimulation of any exposed corneal nerve endings (i.e., pain). When an NM flap is sutured to the superior lid, movements of the globe cause the cornea to rub against the posterior aspect of the NM, theoretically exacerbating corneal disease; however, serious consequences of the superior lid technique are rare. Complete corneal coverage by the NM may not be possible in individuals with physiologic exophthalmia. For these animals, the NM may be sutured to the superotemporal con­ junctiva several millimeters away from the limbus, thus avoiding the deeper episcleral tissue. The mobile conjunc­ tiva will pull down over that part of the cornea not ade­ quately covered by the NM. A fourth technique is to dissect

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A

B

Figure 18.35  A. Nictitating membrane (NM)‐to‐superior‐lid flap. Two to three horizontal mattress sutures of 3‐0 monofilament nonabsorbable material are placed between the free edge of the NM and the superior lid. The lid sutures should be placed well within the superior cul‐de‐sac, and the NM sutures should be approximately 2 mm from the free edge, incorporating cartilage into the central suture. B. NM‐to‐episclera flap. Suturing the free edge of the NM to the superotemporal episclera allows the cornea and flap to move in concert, thus minimizing corneal trauma. Illustration courtesy of Roser Tetas Pont.

the superior 180 degrees of bulbar conjunctiva free from the underlying episclera, pull it down over the uncovered portion of the cornea, and suture it to the free edge of the NM (Kuhns, 1975). A combined local anesthetic technique including auriculopalpebral nerve block, topical anesthesia of the eye, and infiltration anesthesia of the superotemporal bulbar conjunctiva and palpebral surface of the NM has been described for use when placing an NM to superotem­ poral bulbar conjunctiva flap. The technique facilitated placement of the flap without general anesthesia or seda­ tion (Park et al., 2009). Complications of NM flaps include necrosis of the upper lid if sutures are placed too tightly in the NM‐to‐superior‐lid technique, and inadvertent penetration of the globe in the NM‐ to‐episclera technique (Quinn, 1990). Corneal trauma from inadvertent suture contact as a result of poorly placed NM flap sutures may also result in corneal ulceration or delayed healing of an established corneal ulcer. The sutures are generally left in place for 2–3 weeks, but with the NM‐to‐ episclera technique sutures may pull free prematurely (Slatter, 1990). It should be remembered that these flaps obscure vis­

ualization of the cornea and intraocular structures. They also do not deliver a blood supply or give as much support as a conjunctival pedicle graft, and they may inhibit topical medications from reaching the cornea. To allow visualiza­ tion of the cornea, the suture ends can be left long so that the flap can be released and retied (Gelatt & Gelatt, 2011; Helper & Blogg, 1983; Quinn, 1990). Generally, NM flaps should be avoided in cases of infected ulcers, collagenolytic ulcers, and descemetoceles. Instead, a conjunctival graft should be placed.

Other Surgeries Both the strength and pliability of the NM can be an advantage in cases of eyewall defects. Blogg et  al. (1989) used island and pedicle grafts of NM to repair full‐ and partial‐thickness corneoscleral resections in dogs with epi­ bulbar melanomas. These grafts remained healthy in all cases, and the authors theorized that these same tech­ niques could be used to repair traumatic avulsions of the fibrous tunics.

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Agapito, D., Aziz, N.A., Wang, T. et al. (2018) Subconjunctival Dirofilaria repens infection in a dog resident in the UK. Journal of Small Animal Practice, 59(1), 50–52.

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‐24, ‐26, ‐30, ‐33, ‐52, and ‐53 butyl ethers. International Journal of Toxicology, 20(4), 39–52. Latimer, C.A., Wyman, M., Szymanski, C., et al. (1983a) Membrana nictitans gland cyst in a dog. Journal of the American Veterinary Medical Association, 183(9), 1003–1005. Latimer, C.A., Wyman, M., Szymanski, C., et al. (1983b) Azathioprine in the management of fibrous histiocytoma in two dogs. Journal of the American Animal Hospital Association, 19(2), 155–158. Laus, J.L., Canola, J.C., Mamede, F.V., et al. (2003) Orbital cellulitis associated with Toxocara canis in a dog. Veterinary Ophthalmology, 6(4), 333–336. Lavach, J.D. & Snyder, S.P. (1984) Squamous cell carcinoma of the third eyelid in a dog. Journal of the American Veterinary Medical Association, 184(8), 975–976. Lavach, J.D., Thrall, M.A., Benjamin, M.M., et al. (1977) Cytology of normal and inflamed conjunctivas in dogs and cats. Journal of the American Veterinary Medical Association, 170(7), 722–727. Lavignette, A.M. & Carlton, W.W. (1974) A case of ocular nodular fasciitis in a dog. Journal of the American Animal Hospital Association, 10(5), 503–506. Ledbetter, E.C., Dubovi, E.J., Kim, S.G., et al. (2009a) Experimental primary ocular canine herpesvirus‐1 infection in adult dogs. American Journal of Veterinary Research, 70(4), 513–521. Ledbetter, E.C., Hornbuckle, W.E., & Dubovi, E.J. (2009b) Virologic survey of dogs with naturally acquired idiopathic conjunctivitis. Journal of the American Veterinary Medical Association, 235(8), 954–959. Ledbetter, E.C., Kim, S.G., & Dubovi, E.J. (2009c) Outbreak of ocular disease associated with naturally acquired canine herpesvirus‐1 infection in a closed domestic dog colony. Veterinary Ophthalmology, 12(4), 242–247. Ledbetter, E.C., Kim, S.G., Dubovi, E.J., et al. (2009d) Experimental reactivation of latent canine herpesvirus‐1 and induction of recurrent ocular disease in adult dogs. Veterinary Microbiology, 138(1–2), 98–105. Ledbetter, E.C., Kim, K., Dubovi, E.J., et al. (2016) Clinical and immunological assessment of therapeutic immunization with a subunit vaccine for recurrent ocular canine herpesvirus‐1 infection in dogs. Veterinary Microbiology, 197, 102–110. Leite, R.S., Ferreira, S.A., Ituassu, L.T., et al. (2010) PCR diagnosis of visceral leishmaniasis in asymptomatic dogs using conjunctival swab samples. Veterinary Parasitology, 170(3–4), 201–206. Lemp, M.A., Holly, F.J., Iwata, S., et al. (1970) The precorneal tear film: I. Factors in spreading and maintaining a continuous tear film over the corneal surface. Archives of Ophthalmology, 83(1), 89–94. Lemp, M.A. & Wolfley, D.E. (1992) The lacrimal apparatus. In: Adler’s Physiology of the Eye (ed. Hart, W.M., Jr.), 9th ed., pp. 18–28. St. Louis, MO: Mosby Year Book. Lia, R.P., Traversa, D., Agostini, A., et al. (2004) Field efficacy of moxidectin 1 per cent against Thelazia callipaeda in

naturally infected dogs. The Veterinary Record, 154(5), 143–145. Liapis, I.K. & Genovese, L. (2004) Hemangiosarcoma of the third eyelid in a dog. Veterinary Ophthalmology, 7(4), 279–282. Lourenco‐Martins, A.M., Delgado, E., Neto, I., et al. (2011) Allergic conjunctivitis and conjunctival provocation tests in atopic dogs. Veterinary Ophthalmology, 14(4), 248–256. Magnis, J., Naucke, T.J., Mathis, A., et al. (2010) Local transmission of the eye worm Thelazia callipaeda in southern Germany. Parasitology Research, 106(3), 715–717. Mally, C. & Thiebault, J.J. (1990) Ocular toxicity in beagle dogs with lortalamine, a non tricyclic antidepressant compound. Drug and Chemical Toxicology, 13(4), 309–323. Mane, M.C., Vives, M.A., Barrera, R., et al. (1990) Results and histological development of various surgical techniques for correcting eversion of the third eyelid in dogs. Histology Histopathology, 5(4), 415–425. Martin, C.L. (1970) Everted membrana nictitans in German Shorthaired Pointers. Journal of the American Veterinary Medical Association, 157(9), 1229–1232. Martin, C.L. (1982) Ocular signs of systemic diseases, part 4. Modern Veterinary Practice, 63(12), 935–940. Martin, C.L. (1990) Ocular infections. In: Infectious Diseases of the Dog and Cat (ed. Greene, C.E.), pp. 197–212. Philadelphia, PA: Lea & Febiger. Martin, C.L. & Kaswan, R. (1985) Distemper‐associated keratoconjunctivitis sicca. Journal of the American Animal Hospital Association, 21, 355–359. Martin, C.L., Kaswan, R.L., & Doran, C.C. (1987) Cystic lesions of the periorbital region. Compendium on Continuing Education for the Practicing Veterinarian, 9(10), 1022–1029. Martin, C.L., Munnell, J., & Kaswan, R. (1988) Normal ultrastructure and histochemical characteristics of canine lacrimal glands. American Journal of Veterinary Research, 49(9), 1566–1572. Mason, S.L., Fisher, C., Ressel, L., et al. (2016) Presentation, clinical pathological and post‐mortem findings in three related Scottish Terriers with ligneous membranitis. Journal of Small Animal Practice, 57, 271–276. Mazzucchelli, S., Vaillant, M.D., Weverberg, F. et al. (2012) Retrospective study of 155 cases of prolapse of the nictitaing membrane gland in dogs. Veterinary Record, 170, 443–445. McConnell, E.E., Chaffee, E.F., & Cashell, I.G. (1970) Visceral leishmaniasis with ocular involvement in a dog. Journal of the American Veterinary Medical Association, 156(2), 197–203. McCowan, C., Malcolm, J., Hurn, S., et al. (2014) Conjunctival lymphoma: Immunophenotype and outcome in five dogs and three cats. Veterinary Ophthalmology, 17(5), 351–357. McDonald, P.J. & Watson, A.D. (1976) Microbial flora of normal canine conjunctivae. Journal of Small Animal Practice, 17(12), 809–812. McLean, N.S., Ward, D.A., Hendrix, D.V., et al. (2008) Ligneous conjunctivitis secondary to a congenital plasminogen deficiency in a dog. Journal of the American Veterinary Medical Association, 232(5), 715–721.

Miller, P.E. & Dubielzig, R.R. (2001) Ocular tumors. In: Small Animal Clinical Oncology (eds. Withrow, S.J. & MacEwen, E.G.), 3rd ed., pp. 532–545. Philadelphia, PA: W.B. Saunders. Miller, W.W. (2010) Keratoleptynsis for treatment of canine corneal endothelial cell dystrophy. 2010 American College of Veterinary Ophthalmologists 41st Annual Conference, 109. Millichamp, N.J. & Spencer, C.P. (1991) Orbital varix in a dog. Journal of the American Animal Hospital Association, 27(1), 56–59. Moore, C.P. (1983) Alternate technique for prolapsed gland of the third eyelid (replacement technique). In: Current Techniques in Small Animal Surgery (ed. Bojrab, M.J.), pp. 52–53. Philadelphia, PA: Lea & Febiger. Moore, C.P. (1989) Conjunctival disorders. In: Current Veterinary Therapy X: Small Animal Practice (ed. Kirk, R.W.), pp. 673–678. Philadelphia, PA: W.B. Saunders. Moore, C.P. (1990) Imbrication technique for replacement of prolapsed third eyelid gland. In: Current Techniques in Small Animal Surgery (ed. Bojrab, M.J.), pp. 126–128. Philadelphia, PA: Lea & Febiger. Moore, C.P. & Collier, L.L. (1990) Ocular surface disease associated with loss of conjunctival goblet cells in dogs. Journal of the American Animal Hospital Association, 26(5), 458–466. Moore, C.P., Frappier, B.L., & Linton, L.L. (1994) Effects of two surgical replacement techniques on excretory ducts of normal canine third eyelid glands. Proceedings of the American College of Veterinary Ophthalmologists 25th Annual Conference, 25. Moore, C.P., McHugh, J.B., & Thorne, J.G. (2001) Effect of cyclosporine on conjunctival mucin in a canine keratoconjunctivitis sicca model. Investigative Ophthalmology & Visual Science, 42(3), 653–659. Moore, C.P., Wilsman, N.J., Nordheim, E.V., et al. (1987) Density and distribution of canine conjunctival goblet cells. Investigative Ophthalmology & Visual Science, 28, 1925–1932. Moraczewski, A.L. (2007) History and examination of the eye. In: Ocular Trauma (ed. Banta, J.T.), pp. 19–32. St. Louis, MO: Saunders Elsevier. Morgan, R.V., Duddy, J.M., & McClurg, K. (1993) Prolapse of the gland of the third eyelid in dogs: A retrospective study of 89 cases (1980–1990). Journal of the American Animal Hospital Association, 29(1), 56–60. Motta, B., Schnyder, M., Basano, F.S. et al. (2012) Therapeutic efficacy of milbemycin oxime/praziquantel oral formulation (Milbemax®) against Thelazia callipaeda in naturally infected dogs and cats. Parasitology Vectors, 5, 85. Multari, D., Perazzi, A., Contiero, B., et al. (2016) Pocket technique or pocket technique combined with modified orbital rim anchorage for the replacement of a prolapsed gland of the third eyelid in dogs: 353 dogs. Veterinary Ophthalmology, 19, 214–219. Munnell, J.F. & Martin, C.L. (1988) Lipid secreting (Harderian‐ like) acini in the canine superficial gland of the third eyelid. Anatomia Histologia Embryologia, 17, 91.

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Murphy, C.J., Bellhorn, R.W., & Buyukmihci, N.C. (1989) Bilateral conjunctival masses in two dogs. Journal of the American Veterinary Medical Association, 195(2), 225–228. Murphy, C.J. & Pollock, R.V.S. (1993) The eye. In: Miller’s Anatomy of the Dog (ed. Evans, H.E.), 3rd ed., pp. 1009–1057. Philadelphia, PA: W.B. Saunders. Murphy, J.M. (1988) Exfoliative cytologic examination as an aid in diagnosing ocular diseases in the dog and cat. Seminars in Veterinary Medicine and Surgery (Small Animal), 3(1), 10–14. Murphy, J.M., Lavach, J.D., & Severin, G.A. (1978) Survey of conjunctival flora in dogs with clinical signs of external eye disease. Journal of the American Veterinary Medical Association, 178(1), 66–68. Nakissa, N., Rubin, P., Strohl, R., et al. (1983) Ocular and orbital complications following radiation therapy of paranasal sinus malignancies and a review of literature. Cancer, 51, 980–986. Nardoni, S., Dini, M., Taccini, F., et al. (2007) Occurrence, distribution and population size of Malassezia pachydermatis on skin and mucosae of atopic dogs. Veterinary Microbiology, 122(1–2), 172–177. Nell, B., Gelbmann, W., & Mostl, K. (2000) Occurrence of bacteria, fungi, chlamydia, mycoplasma, herpesvirus and adenovirus in dogs with follicular conjunctivitis, erosive keratitis and chronic superficial keratitis. Wiener Tierärztliche Monatsschrift, 87(11), 314–321. Nell, B., Walde, I., Billich, A., et al. (2005) The effect of topical pimecrolimus on keratoconjunctivitis sicca and chronic superficial keratitis in dogs: Results from an exploratory study. Veterinary Ophthalmology, 8(1), 39–46. Nichols, B.A., Dawson, C.R., & Togni, B. (1983) Surface features of the conjunctiva and cornea. Investigative Ophthalmology & Visual Science, 24, 570. Nicolau, S. & Perard, C. (1936) Etude histo‐physiopathologique de l’oeil et du système nerveaux dans la leishmaniose géneralisée du chien. Annales de I’lnstitut Pasteur, 57, 463–486. Nimsuphan, B. & Prihirunkij, K. (2000) Ocular thelaziasis in a dog. Journal of the Thai Veterinary Medical Association, 51(1/2), 27–32. Nomura, M., Kubota, M.A., Kawamori, R., et al. (1994) Effect addition of hyaluronic acid to highly concentrated insulin on absorption from the conjunctiva in conscious diabetic dogs. Journal of Pharmacy and Pharmacology, 46(9), 768–770. Nomura, M., Kubota, M.A., Sekiya, M., et al. (1990) Insulin absorption from conjunctiva studied in normal and diabetic dogs. Journal of Pharmacy and Pharmacology, 42(4), 292–294. Ofri, R., Lambrou, G.N., Allgoewer, I., et al. (2009) Clinical evaluation of pimecrolimus eye drops for treatment of canine kerato‐conjunctivitis sicca: A comparison with cyclosporine A. Veterinary Journal, 179(1), 70–77. Olbertz, L., Lima, L., Langohr, I., et al. (2013) Supposed primary conjunctival lymphoma in a dog. Veterinary Ophthalmology, 16(Suppl. 1), 100–104.

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Scherlie, P.H., Smedes, S.L., Feltz, T., et al. (1992) Ocular manifestation of systemic histiocytosis in a dog. Journal of the American Veterinary Medical Association, 201(8), 1229–1232. Schlegel, T., Brehm, H., & Amselgruber, W.M. (2001) The cartilage of the third eyelid: A comparative macroscopical and histological study in domestic animals. Annals of Anatomy, 183(2), 165–169. Schlegel, T., Brehm, H., & Amselgruber, W.M. (2003) IgA and secretory component (SC) in the third eyelid of domestic animals: A comparative study. Veterinary Ophthalmology, 6(2), 157–161. Schmidt, G.M. & Betts, C.W. (1978) Zygomatic salivary mucoceles in a dog. Journal of the American Veterinary Medical Association, 172(8), 940–942. Schrauwen, E., Ham, L.V., Maenhout, T., et al. (1991) Canine dysautonomia: A case report. Veterinary Record, 128(22), 524–525. Schroeder, H. & van Rensburg, I. (1993) Generalised Listeria monocytogenes infection in a dog. Journal of the South African Veterinary Association, 64(3), 133–136. Sen, I., Turgut, K., Celik, I., et al. (2002) The importance of lymphocyte enzyme profile, inclusion bodies in circulating leukocytes and conjunctival smear samples in the diagnosis on canine distemper virus infection. Indian Veterinary Journal, 79(3), 213–217. Severin, G.A. (1996) Third eyelid. In: Severin’s Veterinary Ophthalmology Notes (Severin, G.A.), 3rd ed., pp. 207–221. Fort Collins, CO: American Animal Hospital Association. Singh, A., Cullen, C.L., & Grahn, B.H. (2004) History and clinical signs. Canadian Veterinary Journal, 45(9), 777–778. Sironi, G., Riccaboni, P., Mertel, L., et al. (1999) p53 Protein expression in conjunctival squamous cell carcinomas of domestic animals. Veterinary Ophthalmology, 2(4), 227–231. Slappendel, R.J. & Ferrer, L. (1990) Leishmaniasis. In: Infectious Diseases of the Dog and Cat (ed. Greene, C.E.), 2nd ed., pp. 450–458. Philadelphia, PA: W.B. Saunders. Slatter, D. (1990) Principles of ophthalmic surgery. In: Slatter’s Fundamentals of Veterinary Ophthalmology (Slatter, D.), 2nd ed., pp. 137–139. Philadelphia, PA: W.B. Saunders. Smith, E.M., Buyukmihci, N.C., & Farver, T.B. (1994) Effect of topical pilocarpine treatment on tear production in dogs. Journal of the American Veterinary Medical Association, 205(9), 1286–1289. Solano‐Gallego, L., Morell, P., Arboix, M., et al. (2001) Prevalence of Leishmania infantum infection in dogs living in an area of canine leishmaniasis endemicity using PCR on several tissues and serology. Journal of Clinical Microbiology, 39(2), 560–563. Spertus, C.B., Mohammed, H.O., & Ledbetter, E.C. (2016) Effects of topical ocular application of 1% trifluridine ophthalmic solution in dogs with experimentally induced recurrent ocular canine herpesvirus‐1 infection. American Journal of Veterinary Research, 77(10), 1140–1147.

Sprague, L.D., Schubert, E., Hotzel, H., et al. (2009) The detection of Chlamydophila psittaci genotype C infection in dogs. The Veterinary Journal, 181(3), 274–279. Sreter, T., Szell, Z., Egyed, Z., et al. (2002) Ocular onchocercosis in dogs: A review. The Veterinary Record, 151(6), 176–180. Srinivasan, B.D., Jakobiec, F.A., & Iwamoto, T. (1992) Conjunctiva. In: Duane’s Foundations of Clinical Ophthalmology (eds. Tasman, W. & Jaeger, E.A.), vol. 1, pp. 1–28. Philadelphia, PA: J.B. Lippincott. Stades, F.C. (1976) Modified surgical treatment of eversion and inversion of the third eyelid in dogs (author’s translation). Tijdschrift voor Diergeneeskunde, 101(19), 1079–1083. Stadsvold, N. (1992) Prolapse of the gland of the third eyelid in dogs: Surgical treatment with preservation of the gland. Dansk Veterinaertidsskrift, 75(15), 637–639. Stanley, R.G. & Kaswan, R.L. (1994) Modification of the orbital rim anchorage method for surgical replacement of the gland of the third eyelid in dogs. Journal of the American Veterinary Medical Association, 205(10), 1412–1414. Strauss‐Ayali, D., Jaffe, C.L., Burshtain, O., et al. (2004) Polymerase chain reaction using noninvasively obtained samples, for the detection of Leishmania infantum DNA in dogs. Journal of Infectious Disease, 189(9), 1729–1733. Swanson, J.F. & Dubielzig, R.R. (1986) Clinical and histopathologic characteristics of acute canine ocular ehrlichiosis: A pilot study. Proceedings of the American College of Veterinary Ophthalmologists 17th Annual Meeting, 219–232. Swenson, C.L., Silverman, J., Stromberg, P.C., et al. (1988) Visceral leishmaniasis in an English foxhound from an Ohio research colony. Journal of the American Veterinary Medical Association, 193(9), 1089–1092. Swinger, R.L., Schmidt, K.A., Jr., & Dubielzig, R.R. (2009) Kerato‐conjunctivitis associated with Toxoplasma gondii in a dog. Veterinary Ophthalmology, 12(1), 56–60. Szell, Z., Erdelyi, I., Sreter, T., et al. (2001) Canine ocular onchocercosis in Hungary. Veterinary Parasitology, 97(3), 243–249. Tarello, W. (2003) Concurrent cutaneous lesions in dogs with Babesia gibsoni infection in Italy. Revue de Médecine Vétérinaire, 154(4), 281–287. Teichert, G. (1966) Plasmozellulare Infiltration des dritten Augenglides beim Hund. Berliner und Muenchener Tierärtztliche Wochenschrift, 23, 449–451. Teixeira, A.L., Maia, F.B.N., Alvarenga, L.S., et al. (2002) Aerobic conjunctival flora of healthy dogs in Sao Paulo. American College of Veterinary Ophthalmologists 2002 Proceedings Rocky Mountain Eye Meeting, p. 9. Thangamuthu, R.V.J.P. & Rathore, B.S. (2002) Conjunctival flora of clinically healthy and diseased eyes of dogs. Haryana Veterinarian, 41, 38–40. Thomsen, M.K., Jensen, A.L., Bindseil, E., et al. (1991) Impairment of neutrophil functions in a dog with an eosinophilic dermatosis. Acta Veterinaria Scandinavica, 32(4), 519–526. Torres, M.D., Leiva, M., Tabar, M.D., et al. (2009) Ligneous conjunctivitis in a plasminogen‐deficient dog: Clinical

management and 2‐year follow‐up. Veterinary Ophthalmology, 12(4), 248–253. Twitchell, M.J. (1984) Surgical repair of a prolapsed gland of the 3rd eyelid in the dog. Modern Veterinary Practice, 65(3), 223. Urban, M., Wyman, M., Rheins, M., et al. (1972) Conjunctival flora of clinically normal dogs. Journal of the American Veterinary Medical Association, 161(2), 201–206. Valentine, J. (1992) Unusual poisoning in a dog. The Veterinary Record, 130(14), 307. Vascellari, M., Multari, D., & Mutinelli, F. (2005) Unicentric extranodal lymphoma of the upper eyelid conjunctiva in a dog. Veterinary Ophthalmology, 8(1), 67–70. Verneuil, M., Durand, B., Marcon, C., et al. (2014) Conjunctival and cutaneous fungal flora in clinically normal dogs in Southern France. Journal of Medical Mycologyi, 24, 25–28. Wagner, J., Nasisse, M.P., & Davidson, M.G. (1992) A retrospective study of conjunctival flaps in 67 dogs and 17 horses 1987–1991. Veterinary Pathology, 29(5), 476. Wang, F.I., Ting, C.T., & Liu, Y.S. (2001) Orbital adenocarcinoma of lacrimal gland origin in a dog. Journal of Veterinary Diagnostic Investigation, 13(2), 159–161. Wang, L., Pan, Q., Zhang, L., et al. (2008) Investigation of bacterial microorganisms in the conjunctival sac of clinically normal dogs and dogs with ulcerative keratitis in Beijing, China. Veterinary Ophthalmology, 11(3), 145–149. Ward, D.A. (1999) Diseases and surgery of the canine nictitating membrane. In: Veterinary Ophthalmology (ed. Gelatt, K.N.), 3rd ed., pp. 609–618. Philadelphia, PA: Lippincott Williams & Wilkins. Wheeler, C.A., Blanchard, G.L., & Davidson, H.J. (1989) Cryosurgery for treatment of recurrent proliferative

keratoconjunctivitis in five dogs. Journal of the American Veterinary Medical Association, 195(3), 354–357. Whitley, N.T., Corzo‐Menendez, N., Carmichael, N.G., et al. (2005) Cerebral and conjunctival haemorrhages associated with von Willebrand factor deficiency and canine angiostrongylosis. Journal of Small Animal Practice, 46(2), 75–78. Wilcock, B. & Peiffer, R.L., Jr. (1988) Adenocarcinoma of the gland of the third eyelid in seven dogs. Journal of the American Veterinary Medical Association, 193(12), 1549–1550. Willis, A.M., Martin, C.L., & Stiles, J. (1999) Sino‐orbital aspergillosis in a dog. Journal of the American Veterinary Medical Association, 214(11), 1644–1647. Willis, M., Bounous, D.I., Hirsh, S., et al. (1997) Conjunctival brush cytology: Evaluation of a new cytological collection technique in dogs and cats with a comparison to conjunctival scraping. Veterinary and Comparative Ophthalmology, 7(2), 74–81. Wise, L.A. & Lappin, M.R. (1989) A syndrome resembling feline dysautonomia (the Key‐Gaskell syndrome) in a dog. Journal of Veterinary Internal Medicine, 3(2), 119. Yang, C.H., Tung, K.C., Wang, M.Y., et al. (2006) First Thelazia callipaeda infestation report in a dog in Taiwan. Journal of Veterinary Medical Science, 68(1), 103–104. Yanoff, M. & Fine, B.S. (1989) Ocular Pathology: A Text and Atlas, 3rd ed. Philadelphia, PA: J.B. Lippincott. Zarfoss, M.K., Dubielzig, R.R., Eberhard, M.L., et al. (2005) Canine ocular onchocerciasis in the United States: Two new cases and a review of the literature. Veterinary Ophthalmology, 8(1), 51–57. Zhao, J., Shi, N., Sun, Y., et al. (2015) Pathogenesis of canine distemper virus in experimentally infected raccoon dogs, foxes, and minks. Antiviral Research, 122, 1–11.

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19 Diseases and Surgery of the Canine Cornea and Sclera R. David Whitley1,2 and Ralph E. Hamor1 1 2

Departments of Small and Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA Gulf Coast Veterinary Specialists, Houston, TX, USA

The cornea is a unique portion of the outer fibrous tunic of the eye. It is transparent and serves a major refractive function while maintaining an impermeable physical barrier between the eye and the environment. The transparency of the cornea enables it to perform two main functions: to refract light and to allow sufficient quantity and quality of light into the eye to form an image on the retina. Despite exposure to environmental hazards, the cornea must maintain the smooth outer surface necessary for retinal image formation. This is partially achieved by the continuous replacement of the surface epithelium and maintenance of a healthy preocular tear film. The relatively simple structure of the cornea limits its pathologic responses to insults. Since most pathologic corneal responses are associated with a loss of transparency, many different corneal disorders can lead to opacification and loss of vision. Fortunately, most corneal pathology is amenable to medical or surgical therapy. The most important goals of corneal treatment are to preserve or improve the quantity and quality of light entering the eye in the presence of corneal opacities (e.g., eyes with scarring or dystrophy) and to promote corneal healing (e.g., eyes with ulceration or neoplasms). To achieve these goals, damage to normal corneal tissues should be avoided and therapies selected to induce as little trauma as possible. Minimizing corneal trauma reduces the likelihood and severity of scarring and maintains maximal corneal transparency. This chapter provides an overview of corneal and scleral disorders in the canine eye and should serve as a stimulus to further elucidate the clinical, histopathologic, ultrastructual, biochemical, and genetic aspects of corneal disease.

Corneal Anatomy and Pathophysiology Review of Corneal Anatomy The fibrous tunic of the canine eye consists of the sclera and the cornea. The limbus is the transition zone between the

cornea anteriorly and the sclera posteriorly. The canine cornea consists of the corneal epithelium externally, the corneal stroma, Descemet’s membrane, and corneal endothelial cells (Fig. 19.1) (Shively & Epling, 1970; Spreull, 1966). Descemet’s membrane, the basement membrane underlying endothelial cells (Abrams et al., 2002), becomes thicker with age as it is continuously produced. Canine endothelial cells are hexagonally shaped with a normal density of approximately 2500– 3175 cells/mm2 (Gwin, et al., 1982b; Kafarnik, et al., 2007; Nasisse, et al., 1986). Endothelial cells decrease in number with age, with the number of cells in older dogs being frequently below 2100 cells/mm2 (Gwin et al., 1982b), resulting in an increased diameter per endothelial cell to compensate for the reduced number. The peripheral cornea is thicker on average than the central cornea (Gilger et al., 1991). In neonatal puppies, there is a decrease in corneal thickness until approximately 6 weeks of age; then it increases with age until approximately 30 weeks (Montiani‐Ferreira et  al., 2003). In adult dogs, corneal thickness increases gradually with age (Gilger et al., 1991). Mean corneal thickness, as measured by ultrasonic pachymetry (USP) and in vivo confocal microscopy (IVCM), is 562 ± 6.2 μm and 585 ± 79 μm, respectively (Gilger et  al., 1991; Kafarnik et al., 2007). Spectral‐domain optical coherence tomography (SD‐OCT) in normal dogs showed that the epithelial thickness (ET) was 72.3 ± 4.6 μm, non‐epithelial thickness (NET) was 538.9 ± 42.5 μm and central corneal thickness (CCT) was 611.2 ± 40.3 μm (Alario & Pirie, 2014a). There were no significant differences for all measurements based on eye, age or gender. The same authors compared USP and SD‐OCT in normal dogs (Alario & Pirie, 2014b). The mean CCT by SD‐OCT was 587.72 ± 32.44 μm and by USP was 598.54 ± 32.28 μm. There was no significant difference in CCT based on age or sex and USP consistently overestimated CCT by a mean value of 10.82 μm. The mean CCT and ET by SD‐OCT in normal dogs were similar at 535 μm and 55 μm, respectively (Famose, 2014). The same study

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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Tear film Corneal epithelium

Descemet’s membrane Endothelium

Figure 19.1  The canine cornea consists of the corneal epithelium externally, the corneal stroma, Descemet’s membrane, and corneal endothelial cells.

showed the efficacy of SD‐OCT in the evaluation of pathologic disease states of the cornea in both dogs and cats. A diurnal variation in CCT measured by USP was found in normal dog corneas with CCT values significanltly lower in the evening (Martin‐Suarez et  al., 2014). In normal dogs, increased intraocular pressures (IOPs) over time had CCTs that were significantly increased when measured by USP (Park et  al., 2013). The increases in CCT were particulary evident when the IOP was >45 mmHg for over 40 minutes, greater than 60 mmHg for over 20 minutes and greater than 75 mmHg for over 10 minutes. When CCT was evaluated by USP in normal dogs in relation to IOP, every 100 μm increase in CCT was associated with an elevation of 1 mmHg (Tono‐ Pen® XL, Reichert Inc., Buffalo, NY, USA) and an elevation of 2 mmHg (TONOVET®, Vantaa, Finland) (Park et  al., 2011). When evaluated in both normal and diseased canine eyes, mean CCT (measured by USP), had no significant effect on IOP measured by (Tono‐Pen® XL) or by (AccuPen®, Keeler Instruments Inc., Malvern, PA, USA) (Kato, 2014). In the same study, the mean CCT tended to decrease with age. In normal female dogs, high‐resolution IVCM allowed detailed noninvasive evaluation of corneal epithelial cells, nerve fiber diameter, keratocyte density, and endothelial cell density (Table 19.1) (Strom et al., 2016b). In another study of

normal dogs, high‐resolution time‐domain and fourier‐ domain optical coherence tomography (TD‐OCT and FD‐ OCT) and USP were used to evaluate cornea and conjunctival data (Strom et  al., 2016a). The mean CCT was 497.54 ± 29.76 μm, 555.49 ± 17.19 μm and 594.81 ± 33.02 μm when measured by FD‐OCT, USP, and TD‐OCT, respectively. The central, superior paraxial and superior perilimbal ET were 52.38 ± 7.27 μm, 56.96 ± 6.47 μm and 69.06 ± 8.84 μm when measured by FD‐OCT. When comparing measurement techniques, USP and TD‐OCT generated significantly greater values compared with FD‐OCT and CCT significantly increased with both age and body weight in both male and female dogs. The corneal stroma consists primarily of collagen fibrils, keratocytes, nerves, and glycosaminoglycans (GAG). Corneal collagen fibrils exist in broad belts called lamellae that run approximately parallel to the corneal surface. Keratan sulfate, chondroitin sulfate, and dermatan sulfate are the predominant GAG in the cornea (Scott & Bosworth, 1990a, 1990b). Keratan sulfate is present at high levels in the human corneal stroma and Descemet’s membrane. High levels of chondroitin sulfate are found in human epithelium, endothelium, and keratocytes (Bairaktaris et al., 1998). In the equine cornea, chondroitin 4‐sulfate is more concentrated in the

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Corneal stroma

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Table 19.1  Normal corneal measurements in dogs by in vivo confocal microscopy. Superficial epithelial cell diameter

43.25 ± 6.64 μm

Basal cell diameter

4.43 ± 0.67 μm

Subepithelial nerve fiber diameter

2.38 ± 0.69 μm

Anterior stromal nerve fiber diameter

16.93 ± 4.55 μm

Anterior stroma keratocyte density

993.38 ± 134.24 cells/mm2

Posterior stroma keratocyte density

789.38 ± 87.13 cells/mm2

Endothelial cell density

2815.18 ± 212.59 cells/mm2

deep central, peripheral, and middle central layers of the cornea compared with chondroitin 6‐sulfate (Biros et  al., 2002). This may be important because chondroitin 6‐sulfate tends to hold more water than does chondroitin 4‐sulfate. Aquaporins are transmembrane proteins that transport water across the cell membranes of many cell types. Aquaporins 1, 3, and 5 have been identified in various cell types comprising the cornea of dogs and other species, suggesting their involvement in water homeostasis in the canine cornea (Karasawa et al., 2011; Nautscher et al., 2016). The canine cornea is innervated by an average of 11.5 large “trunks” of the trigeminal nerve (cranial nerve V) that enter the midstromal region circumferentially at the limbus (Barrett et al., 1991). These trunks course radially to the central cornea forming anterior and posterior nerve plexuses in the anterior stroma (Barrett et al., 1991; Marfurt et al., 2001). Subepithelial plexus formation and extensions into the basal epithelium with free nerve endings extending to the epithelial wing layers also occurs. Axons from the subepithelial plexus give rise to the sub‐basal nerve plexus after penetrating the epithelial basal lamina (Fig.  19.2). The nerve fiber density of the central subepithelial nerve plexus, as determined by IVCM, was 12.39 ± 5.25 mm/mm2 in mesocephalic dogs and 10.34 ± 4.71 mm/mm2 in brachycephalic dogs (Kafarnik et al., 2008). The nerve fiber density of the central sub‐basal nerve plexus was 14.87 ± 3.08 mm/mm2 in mesocephalic dogs and 11.80 ± 3.73 mm/mm2 in brachycephalic dogs. In one study, 99% of canine corneal nerves contained both calcitonin gene‐related peptide and substance P, approximately 30% contained tyrosine hydroxylase, and none contained vasoactive intestinal polypeptide (Marfurt et al., 2001). Corneal sensitivity, or corneal touch threshold (the minimum stimulation of the corneal surface by a Cochet‐Bonnet esthesiometer to elicit a blink reflex), was higher in dogs with dolichocephalic skull types compared with dogs with mesaticephalic or brachycephalic (which had the least sensitive cornea) skull types (Barrett et al., 1991). In general, the central corneal region was most sensitive, followed by the nasal, temporal, dorsal, and then ventral corneal regions (Barrett et al., 1991). Dogs with diabetes mellitus have reduced corneal

Figure 19.2  In vivo confocal photomicrograph of the canine sub-basal nerve plexus. (Bar = 50 μm.)

s­ ensitivity in all corneal regions (Good et al., 2003). Topically applied 0.5% proparacaine significantly lowered corneal sensitivity as expected but had little effect on IOP measurements in dogs and rats (Kim et al., 2013). No correlation between corneal sensitivity and the quantity of reflex tearing was noted in dogs, cows, horses, sheep, goats, cats, rabbits, and guinea pigs (Wieser et al., 2013). Ambient humidity has an effect on corneal sensitivity measurements, because decreasing ambient humidity was significantly associated with an increase in corneal sensitivity measurements (Dorbandt et al., 2017). In the same study, administration of topical 0.1% diclofenac or 0.03% flurbiprofen did not have any significant effect on corneal sensitivity. A similar study showed that topical 0.1% diclofenac significantly decreased corneal sensitivity at 75 and 90 minutes after instillation, topical 0.5% ketorolac had no significant effect at any time point, topical 0.03% flurbiprofen significantly increased corneal sensitivity at 15 minutes and topical 0.01% benzalkonium chloride significantly increased corneal sensitivity at 15 minutes (Cantarella et al., 2017). These results suggest that, aside from a potential irritative effect of topical 0.03% flurbiprofen, topical NSAIDs do not have any significant effect on corneal sensitivity. Compared with a placebo, topically applied 0.3% naltrexone had no effect on corneal sensitivity in normal brachycephalic dogs (Arnold et al., 2014). Similar findings were noted in dogs with uncontrolled keratoconjunctivitis sicca (KCS) (Chen & Powell, 2015). Opioid growth factor and its receptor are present in the corneal epithelium of normal dogs (Robertson & Andrew, 2003). Opioid growth factor has been shown to delay wound

19: Diseases and Surgery of the Canine Cornea and Sclera

Corneal Clarity Factors supporting transparency of the normal canine cornea include the absence of blood vessels and pigment, the absence of keratinization of the anterior surface epithelium, a well‐organized stromal collagen lattice, and the small diameter of the collagen fibrils (Goldman & Benedek, 1967; Goldman et  al., 1968; Maurice, 1957). The collagen fibrils that comprise the corneal stroma are themselves composed of parallel arrays of long collagen molecules held together by intermolecular bonds. The collagen fibrils in the cornea have a uniform diameter of approximately 25 nm (Komai & Ushiki, 1991). Some nonfibrillar collagens are also found in the corneal stroma, types VI and XII being the most notable. They are believed to interact with fibrillar collagen and are likely to be important physiologically (Komai & Ushiki, 1991; Meek & Fullwood, 2001a; Meek & Quantock, 2001b). Studies suggest that corneal clarity may not be dependent only on the absolute size of the stromal collagen or spacing of the fibrils. Rather, the fibril volume fraction (i.e., the proportion of the stroma that is occupied by hydrated collagen fibrils) may also be a major factor in clarity (Connon et al., 2000; Meek & Fullwood, 2001a; Meek & Quantock, 2001b; Meek et al., 2003a, 2003b). The sclera is composed of collagen fibrils with various diameters ranging from 25 to 230 nm (Komai & Ushiki, 1991). Scleral collagen fibrils are arranged in irregular, nonparallel bundles that vary in width and thickness, intertwine with each other, and branch extensively (Komai & Ushiki, 1991). The corneal endothelium uses physiologic pumps (i.e., water and ion transport systems) to remove and transport fluid from the corneal stroma into the anterior chamber. In this way, the corneal endothelium regulates hydration of the corneal stromal collagen matrix, which provides mechanical strength (Arndt et al., 2001; Befanis et al., 1981; Gwin et al., 1983b).

A variety of corneal diseases, accidental injury, and surgery can lead to changes that affect corneal transparency. There are very few objective corneal clarity grading scales in human and veterinary medicine; a novel corneal clarity score has recently been tested in dogs (Sanchez et al., 2016b). The following scoring system was used to describe corneal clarity: note G4 is clear cornea, G0 is the most opacity of the cornea. G0: no fundus reflection is visible on retroillumination (RI) using a head‐mounted indirect ophthalmoscope. G1: a fundus reflection is visible with RI. G2: a 0.1 mm diameter light beam is visible on the anterior surface of the iris and/or lens. G3: gross fundic features are visible when viewed with indirect ophthalmoscopy (IO) using a head‐mounted indirect ophthalmoscope and a hand‐held 30D lens, although fine details are not clear G4: fine details of the fundic features are clearly visible with IO.

Intra‐ and interuser reliability was excellent with the scoring system (Sanchez et al. 2016b).

Corneal Wound Healing Epithelial Healing

The corneal epithelium is maintained by a constant cycle of proliferation of cells in the basal layer and shedding of cells at the surface. Renewal of basal cells also occurs by centripetal migration of stem cells from the limbus (Cenedella & Fleschner, 1990). An epithelial defect of the cornea heals by epithelial sliding and mitosis. After a short lag period of approximately 1 hour, the normal epithelium at the edge of the defect flattens, retracts, thickens, and loses its hemidesmosomal attachments to the basement membrane (Pepose & Ubels, 1992). The cells enlarge and the epithelial sheet begins to migrate by amoeboid movement to cover the defect. During this process, the corneal epithelium develops a migratory phenotype. Molecular mechanisms underpinning corneal healing are being elucidated. Heat shock proteins, specifically Hsp70, appear to play an important role in corneal wound healing because they are potent inducers of cellular migration and proliferation. Suppressed expression of Hsp70 may contribute to the pathophysiology of nonhealing corneal defects (Peterson et al., 2016). Slug, a member of the Snail family of transcription factors, plays a role in modulating the transition to a migratory phenotype, and increased expression of the mesenchymal markers smooth‐muscle‐specific α‐actin and tropomyosin facilitate cellular migration (Chandler et  al., 2007). The cytokine, interleukin‐11 (IL‐11), which modulates immune and inflammatory processes, has been

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healing in ulcerated corneas (Zagon et al., 2000), and inhibitors of opioid growth factor (such as naltrexone) may improve corneal epithelialization, especially in diabetics (Zagon et al., 2002). In another study, opioid receptors (primarily Δ‐receptors and only a small number of μ‐receptors) were identified in normal corneas of dogs, and use of topical 1% morphine sulfate provided analgesia to dogs with corneal ulcers and did not delay corneal epithelialization (Stiles et al., 2003). A noncontact infrared thermometer (NCIT) was compared with a standard rectal digital thermometer (RDT) in 300 dogs (Kreissl & Neiger, 2015). Median body temperature measured by the RDT and NCIT were 38.3 °C (35.5–41.1 °C) and 37.7 °C (35.9– 40.1 °C), respectively. Overall, there was poor agreement between body temperatures taken over low, normal, and high values as well as between experienced and inexperienced investigators. The NCIT tended to overrecognize hypothermic and hyperthermic conditions.

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detected in corneal epithelium, keratocytes, and endothelium of normal canine eyes and can be strongly induced in cultured corneal cells by treatment with TGF‐β1, a regulator of cell proliferation and differentiation. The presence of IL‐11 in the normal canine cornea suggests its involvement in corneal inflammation and immunity (Richards et  al., 2014). Striatin protein has been localized to the basement membrane in the area containing hemidesmosomes suggesting that striatin protein plays a likely role in cell adhesion (Stern et al., 2015). Small leucine rich proteoglycans (SLRPs) are constituents of the extracellular matrix (ECM) and are involved in the production, organization, and remodeling of collagen and elastin. The presence of SLRPs was noted in the corneal epithelium of dogs, with little to no stromal staining and no staining of the corneal endothelium (Yang et  al., 2012). Initially, the healing epithelial layer is thinner than the normal corneal epithelium, but mitotic cell division of the epithelium restores normal thickness. If the entire corneal epithelium is removed, the cornea will be covered by sliding conjunctival epithelium in most species within 48–72 hours (Gilger et al., 2007). Larger corneas, such as in horses, may take longer because the epithelial growth rate has been estimated at 0.6 mm/day in horses (Neaderland et al., 1987). After 4–5 weeks, in rabbits, the conjunctival epithelium assumes the morphologic characteristics of normal corneal epithelium (Shapiro et al., 1981). Corneal epithelium is completely replaced in approximately 2 weeks (Cenedella & Fleschner, 1990). Limbal stem cells appear to play an important role in the maintenance of corneal epithelial health and corneal clarity (Sanchez et  al., 2016a). The limbal epithelium in multiple animal species has been examined for the stem cell crypts found in humans (Patruno et al., 2017). While the limbal epithelium showed invagination similar to humans, no crypt‐ like structures were found in dogs. Canine corneal epithelial stem cells appear to reside in the limbus and give rise to proliferative cells in response to stimulation (Morita et  al., 2015). Canine limbal epithelial cells have been collected and cultivated on denuded canine amniotic membrane, temperature‐responsive culture dish, and atelocollagen gel (Nam et al., 2015). Corneal epithelial cell sheets have also been cultivated from limbal stem cells on amniotic membrane (Nam et al., 2013). Each culture technique may allow for the potential of the use of corneal epithelial sheets in the treatment of corneal surface disease in the future. When seeded on a canine xenogeneic acellular matrix in vitro, rat mesenchymal stem cells expressed multiple growth factors (VEGF, EGF, and TGF‐β1) at a higher level than rat limbal stem cells (Zhang et  al., 2012). Neurotropic keratitis in a dog has occurred secondary to a partial limbal stem cell deficiency after metaherpetic corneal disease (Ledbetter et  al., 2013). Canine corneal models, both in vivo and ex vivo, have been developed to allow documentation of corneal healing with and without therapies that may improve corneal healing and

clarity (Berkowski et  al., 2018; Gronkiewicz et  al., 2016; Proietto et al., 2017). Stromal Healing

Epithelial sliding and stromal replacement mainly accomplish healing of corneal defects that involve the epithelium and anterior stroma. Stromal replacement requires synthesis and crosslinking of collagen, proteoglycan synthesis, and gradual wound remodeling. Epithelium from the edge of the injured area flattens and slides over the wound to fill the defect. Mitosis of the epithelium then results in a normal, or slightly greater than normal, epithelial thickness, but it may not restore the normal corneal curvature. The stroma adjacent to the defect exhibits edema early, followed by an influx of neutrophils from the tear film (via the lacrimal gland and conjunctival blood vessels) within 1–2 hours of injury. Regional keratocytes transform into fibroblasts that proliferate and rapidly synthesize collagen and other components of the ECM. Stromal fibroblasts produce fibronectin, an ECM glycoprotein that stimulates cell adhesion, cell migration, and protein synthesis (Schultz et al., 1992a). Shortly thereafter, fibroblastic proliferation begins in the stroma. Fibroblasts also arise from the stromal histiocytes, and as the fibrous reaction continues, the epithelium is displaced anteriorly to its normal surface level. New collagen fibers and lamellae are produced, but disorganized arrangement may result in opacity or corneal scarring. The main cell type involved in the corneal fibrosis and scarring is the myofibroblast. Fibrotic diseases are characterized by the presence of increased numbers of myofibroblasts, disorganized ECM, and subsequent tissue contraction (Bosiack et  al., 2012). Gene therapies have the potential for modulating corneal fibroplasia (Bosiak et al., 2012). Endothelial Healing

The endothelial cell layer is the inner limiting layer of the cornea. Endothelial cells normally form a hexagonal, mosaic pattern on Descemet’s membrane (Aguirre et  al., 1975; Arndt et  al., 2001; Befanis et  al., 1981; Gwin et  al., 1983b; Stapleton & Peiffer, 1979; Yee et al., 1987). The hexagonally shaped canine endothelial cells tend to enlarge in size and decrease in number with age (Gwin et  al., 1982b). In the young dog, the number of endothelial cells averages 2500– 3175 per mm2 (Chandler et al., 2003; Kafarnik et al., 2007). Injury to endothelial cells results in decreased cell density in dogs, suggesting a limited capacity for mitosis (Gwin et al., 1983b). Phacoemulsification, radiofrequency hyperthermia, and CO2 photokeratotomy resulted in damage to corneal endothelial cells in dogs (Glaze & Turk, 1986; Gwin et  al., 1983b; Hoffman et al., 2009). Intraocular irrigation with various saline solutions (Nasisse et al., 1986), low doses of tissue plasminogen activator (25 μg/100 μL) (Gerding et al., 1992), and transcorneal diode laser iridal photocoagulation (Chandler et al., 2003) did not appear to damage the corneal

endothelium or increase corneal thickness. Diabetic dogs, which were experimentally induced by feeding galactose, had endothelial changes characterized by marked polymegathism (i.e., increased size) and pleomorphism (i.e., cell shape variations) (Neuenschwander et  al., 1995; Yee et  al., 1985). Endothelial cell alterations in diabetic dogs may explain their increased corneal complications after cataract surgery and may contribute to delay of corneal wound healing (Good et al., 2003). Repair of Full-Thickness Corneal Laceration or Perforation

Healing of a full‐thickness corneal laceration may be divided into approximately six phases. The first, or immediate, phase is initiated by mechanical factors, the fibrin plug, and corneal stromal edema. The normal elasticity of stromal fibers causes retraction. Descemet’s membrane is also elastic and recoils when severed. This combination of retraction by the outer stromal fibers and recoiling by Descemet’s membrane leads to anterior and posterior gaping of the corneal wound. When the fibrinogen of the inflamed aqueous humor contacts the cut edges of the wound, it precipitates as fibrin and forms a plug that seals the wound and acts as a scaffold for the fibroblastic reparative processes. After a short delay (from 30 minutes to 5 hours), the second, or leukocytic, phase of healing begins, in which polymorphonuclear leukocytes migrate into the corneal wound. Similar to more superficial corneal wounds, most of the neutrophils arrive from conjunctival blood vessels and lacrimal gland via the tear film. In perforations, neutrophils may arrive via the aqueous humor, and with chronicity, from the perilimbal blood vessels. Mononuclear cells arrive after a delay of 12–24 hours, then act as scavengers or, in the case of monocytes, may transform into fibroblasts. The third, or epithelial, phase appears to begin after 1 hour of injury. By the process of sliding and mitosis, the epithelium grows into the anterior part of the wound during this phase. The initial epithelium in the wound appears to be an important moderator for healing of the underlying stroma. It plays a key role in the transformation of keratocytes and mononuclear cells into fibroblasts; if the epithelium does not cover the wound, healing is significantly delayed. Epithelium can synthesize collagen and may mediate stromal collagen elaboration by fibroblasts and keratocytes. Epithelium also secretes enzymes, such as collagenase, when the cells are damaged. Proteolytic enzymes, such as collagenase and protease that are released by epithelial cells, neutrophils, and keratocytes may be major factors in the continued progression of corneal ulcerations. Other regulators of corneal wound healing include peptide growth factors, such as epidermal growth factor (EGF), transforming growth factor beta (TGFβ), and platelet‐ derived growth factor (PDGF) (Swank & Hosgood, 1996). EGF increases protein synthesis and mitosis in corneal epithelium and stromal fibroblasts (Schultz et  al., 1992a, 1994). PDGF

stimulates the synthesis of fibronectin, hyaluronic acid, and collagenase (Schultz et al., 1992a, 1994). TGFβ can stimulate synthesis of ECM and chemotaxis of inflammatory cells (Imanishi et  al., 2000; Li et  al., 1999; Schultz et  al., 1992a). Studies are ongoing on the manipulation (i.e., inhibition, expression, supplemention) of these growth factors to enhance corneal healing. The fourth, or fibroblastic, phase begins after 12 hours. Fibroblasts are formed mainly from keratocytes, initially from the keratocytes closest to the wound margin. Fibroblasts may also form from mononuclear cells that have migrated to the cornea from the tears or perhaps from perilimbal vessels. The fibroblasts enlarge, multiply, and form an active fibroblastic tissue that elaborates collagen and ground substance composed of GAG. The epithelium is slowly pushed anteriorly as the new stroma increases the volume beneath the defect. The fifth, or endothelial, phase of corneal healing begins 24 hours after the injury. The endothelium appears to heal mainly by endothelial sliding or amitotic multiplication. In adult dogs, there appears to be minimal mitotic activity in the endothelial cells (Befanis et al., 1981). To cover posterior defects in the cornea, the endothelial cells initially enlarge and slide. The overall result, once healing is complete, is a reduction in endothelial cell density. The endothelial cells produce a new Descemet’s membrane after a few weeks. Duplication of Descemet’s membrane may occur in dogs after full‐thickness corneal wounds (Kafarnik et al., 2009). The sixth and final phase of corneal healing begins 7 days after injury. Cellularity in the cornea slowly diminishes, and nuclei in the fibers reorient themselves parallel to the corneal surface. At first, the fibroblastic tissue is highly cellular and unorganized, but with time, the cellularity decreases and the cells and fibrils reorient in a manner similar to that of the normal cornea. The fibroblastic tissue decreases in size and becomes less cellular, and a thin scar is formed. Corneal incisions heal to sufficient tensile strength for suture removal in 19 days (Gilger et al., 2007). Role of Proteases in Corneal Wound Healing

Healing of corneal wounds is a complex process involving the integrated actions of proteinases, growth factors, and cytokines produced by epithelial cells, stromal keratocytes, inflammatory cells, and the lacrimal glands. Multiple autocrine and paracrine interactions occur between epithelial cells, activated stromal fibroblasts, and the exocrine actions of factors secreted by lacrimal gland cells into the precorneal tear film (PTF). Various proteinases, proteinase inhibitors, growth factors, and cytokines in the tear film and aqueous humor play a role in the natural turnover of the corneal cells and corneal wound healing (Sivak & Fini, 2002). Proteinases and Proteinase Inhibitors

Maintenance and repair of the corneal stromal ECM require a tightly coordinated balance of ECM synthesis, degrada-

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tion, and remodeling (Ollivier et  al., 2007). Proteolytic enzymes (proteinases) perform physiological functions in the slow turnover and remodeling of the corneal stroma. Excessive degradation of normal healthy tissue is prevented by natural proteinase inhibitors in the PTF and cornea, such as α1‐proteinase inhibitor, α2‐macroglobulin, and tissue inhibitors of metalloproteinases (TIMPs) (Hibbets et  al., 1999; Twining et al., 1994a, 1994b). Pathological degradation of corneal stromal collagen and proteoglycans occurs when the balance between proteinases and proteinase inhibitors favors the proteinases (Geerling et al., 1999; Matsubara et al., 1991). The rapid degradation of the corneal stroma associated with some severe corneal ulcers is caused by proteolytic enzymes acting on the collagen, proteoglycans, and other components of the stromal ECM and is referred to as keratomalacia or “corneal melting” (Fig.  19.3). Imbalance with high levels of proteinases (matrix metalloproteinase [MMPs] or plasmin) might also contribute to the pathogenesis of certain types of superficial nonhealing ulcers in dogs (Bentley, 2005). Major Proteinases in the Cornea and Their Origin

Microorganisms, inflammatory cells (e.g., polymorphonuclear leukocytes and macrophages), corneal epithelial cells, and fibroblasts produce and release proteolytic enzymes (Fini & Girard, 1990; Twining et  al., 1994a). Endogenous proteinases are produced by host cells. Exogenous proteinases are secreted by infectious organisms (Gopinathan et al., 2001; Hibbets et  al., 1999; Zhu et  al., 1990). Examples of exogenous proteinases include the variety of proteases produced by Pseudomonas aeruginosa (e.g., alkaline protease, elastase A and B, protease IV, modified elastase, P. aerugi­ nosa small protease), and serine proteinases production by Aspergillus and Fusarium spp. (Gopinathan et  al., 2001;

Matsubara et al., 1991; Matsumoto, 2004; Zhu et al., 1990). Extracellular enzymes of bacterial or fungal origin also contribute indirectly to corneal proteolytic activity by activating endogenous proteinases (Gopinathan et  al., 2001; Twining et al., 1994a). Two important families of enzymes that affect the cornea are the MMPs and serine proteases. Neutrophil elastase, an abundant serine proteinase in tears, is synthesized by polymorphonuclear leukocytes and macrophages (Sathe et  al., 1998). It degrades native III and IV collagen as well as corneal ECM compounds such as laminin and fibronectin (Barletta et al., 1996). Two MMPs (MMP‐2 and MMP‐9) are of major importance in the remodeling and degradation of corneal stromal collagen (Fini et  al., 1992). MMP‐2 and MMP‐9 were identified by immunohistochemistry in both healthy and ulcerated corneas of humans, dogs, and a variety of other animal species (Carter et al., 2007; Kenney et al., 1998; Reviglio et al., 2003; Yang et al., 2003). In most species, MMP‐2 is constitutively present in the unwounded corneal epithelium and stroma and is upregulated after wounding, whereas MMP‐9 is found only in the wounded cornea (Kenney et al., 1998; Reviglio et al., 2003; Yang et al., 2003). In a study of nonhealing corneal ulcers in dogs, MMP‐9 was found predominantly at the level of the epithelium (Carter et al., 2007). In dogs with chronic superficial keratitis (CSK), MMP‐9 was present in both the corneal epithelium and anterior stroma (Chandler et al., 2008). Studies support a different origin and purpose for corneal MMP‐2 and MMP‐9. MMP‐2 is synthesized by corneal keratocytes and performs a surveillance function in the normal cornea, becoming locally activated to degrade collagen molecules that become damaged as a result of normal wear and tear (Matsubara et al., 1991; Twining et  al., 1994b). Alternatively, MMP‐9 is produced by epithelial cells and leukocytes after corneal wounding (Fini & Girard, 1990; Matsubara et al., 1991). Proteolytic Activity in Healthy and Diseased Corneas

Figure 19.3  Keratomalacia in a dog with bacterial keratitis.

In damaged corneas, proteinase activity increases in the tear film and is considered a fundamental response of the mammalian eye to corneal injury (Matsubara et al., 1991; Wang et al., 2008a). If infection is present, proteinases secreted by infectious organisms further contribute to corneal damage (Kernacki et  al., 1997). In dogs with traumatic keratoconjunctivitis, PTF levels of MMP‐9 were significantly increased compared with clinically normal dogs (Arican & Ceylan, 1999). In dogs with P. aeruginosa ulcerative keratitis, PTF concentrations of MMP‐2 and MMP‐9 were significantly higher than contralateral unaffected eyes and clinically normal dogs (Wang et al., 2008a). Protease levels subsequently decreased as corneal healing progressed after medical or surgical therapy. Markedly increased levels of MMP‐2 and MMP‐9 were detected in the corneal epithelium and stroma of dogs with CSK (Chandler et al., 2008). Corneal levels of MMP‐9 were significantly elevated relative to unwounded

corneas in dogs with acute experimental superficial corneal wounds, chronic experimental superficial corneal wounds, and naturally acquired spontaneous chronic corneal epithelial defects (Carter et  al., 2007). Treatment of superficial canine corneal ulcers with topical 0.2% hyaluronic acid had no significant effect on corneal epithelialization or MMP2 or MMP9 protein expression as compared with a similar viscosity topical vehicle control (carboxymethylcellulose) (Gronkiewicz et al., 2017).

Corneal Pigmentation Corneal pigmentation is most commonly associated with chronic inflammation. Corneal pigmentation is found in disorders such as CSK (i.e., pannus) in the German Shepherd; the pigmentary keratitis syndrome in brachycephalic breeds (Fig. 19.4), which may be a pigmentary or epithelial dystrophy; KCS; and scarring with ulcerative keratitis. Congenital corneal melanosis or pigmentation occurs infrequently in the dog. Corneal pigmentation results from migration of melanocytes from the limbal and perilimbal tissues (Bellhorn & Henkind, 1966). Melanin pigment may accumulate within corneal epithelial cells, macrophages, and fibroblasts in the dog. Other signs of active keratitis, such as corneal vascularization, stromal inflammatory cell infiltration, and granulation tissue formation, usually accompany pigment cell migration. Melanin is transferred to the basilar or suprabasilar cells of the cornea and the anterior stromal tissue (Bellhorn & Henkind, 1966). Superficial corneal pigment (SCP) in the dog has historically been defined in the veterinary literature broadly as ‘pigmentary keratitis’, a degenerative or inflammatory condition of the cornea, characterized by a brownish or black deposit.

Figure 19.4  Superficial corneal pigment in a Pug with chronic pigmentary keratitis.

Despite many descriptions of SCP and associated ocular surface inflammation (Azoulay, 2014; Bernays et  al., 1999; Kaswan et al., 1989; Ledbetter & Gilger, 2013; Slatter et al., 1977; Yi et al., 2006) few investigations have been performed to determine its underlying etiology or breed susceptibility (Labelle et al., 2013a). Only two previous studies investigating the histopathology of canine corneal pigment are available (Bellhorn & Henkind, 1966). Corneal epithelial melanin deposition is usually concurrent with blood vessels and inflammatory cells. Ocular surface disease and signalment certainly plays a role in the condition. Recent studies investigating corneal pigment in Pugs specifically, identified a high prevalence in this breed, with approximately 70%–82% of examined dogs affected (Krecny et al., 2015; Labelle et al., 2013a). Both studies also identified a high prevalence of ocular comorbidities, including disorders of the lacrimal system and eyelids. A statistical association between KCS and SCP was reported in one study, but it was also noted that SCP developed in the absence of KCS in other dogs (Krecny et  al., 2015). In the other study, no significant associations between eyelid conformation or tear film characteristics and the detection of corneal pigment were identified (Labelle et al., 2013a). The absence of consistently identifiable inflammatory risk factors (ocular adnexal or tear film abnormalities) and the detection of SCP were considered suggestive of a hereditary epithelial or pigmentary dystrophy in the Pug, or pigmentary keratopathy (Labelle et  al., 2013a). Like the Pug, several other brachycephalic dog breeds develop SCP commonly and without an identifiable underlying etiology. These breeds include the Boston Terrier, Lhasa Apso, Pekingese, and Shih Tzu (Christmas, 1992; Dreyfus et  al., 2011; Ledbetter & Gilger, 2013) Using IVCM, pigmentary keratitis was morphologically characterized by six specific pathological lesions that were common to Pugs and non‐Pug brachycephalic dogs (Vallone et al., 2017). Abnormalities were mostly confined to the corneal epithelium and included several cellular changes consistent with chronic inflammation. The significant presence of these inflammatory cellular markers supports the use of the term pigmentary keratitis to denote accurately the underlying chronic inflammatory pathology of this syndrome (Vallone et al., 2017). Pigmentary keratitis appears morphologically as a centripetal corneal migration of microanatomic features normally confined to the perilimbal region of the cornea. Additonal studies with biomicroscopy, IVCM, immunohistochemical staining, and electron microscopy are needed to characterize pigmentary keratitis better. Since a genetic basis has been postulated, additional pedigree analyses might elucidate an etiology. Another less common source of corneal pigmentation is anterior synechiae and the adherence of anterior uveal cysts to the cornea (Fig.  19.5) (Corcoran & Koch, 1993; Gelatt, 1972). Cysts of the anterior uvea may be either congenital or

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Figure 19.6  Afghan Hound with diffuse corneal edema after canine adenovirus type 1 vaccination. Figure 19.5  Pigment deposits on the endothelial surface of the cornea resulting from the rupture of uveal cysts. Several intact uveal cysts remain in the anterior chamber and adjacent to the corneal endothelium.

acquired (as the result of uveal inflammation or degeneration). The pigmented cells may arise from the pigment epithelium of the ciliary body, iridal stroma, and posterior iridal epithelium. These cysts can be large and attach to the corneal endothelium, or they can rupture and liberate pigment that adheres to the posterior aspect of the cornea.

Corneal Edema Corneal edema or swelling (i.e., corneal overhydration) may result from imbibition of fluid by the epithelium or stroma (Fig. 19.6). Corneal transparency depends both on its physical structure and on mechanisms that prevent overhydration. The major barriers to edema are the endothelium and the epithelium. In rabbits, removal of the epithelium produced an average increase in corneal thickness of 200% in 24 hours, whereas removal of the endothelium produced an increase of 500% (Maurice & Giardin, 1951). Alterations in endothelial cells result in the cornea absorbing aqueous humor and becoming edematous. The endothelium maintains corneal deturgescence by an energy‐dependent sodium potassium transport pump as well as by a physical barrier. The barrier function of the endothelium results from tight cellular junctions known as ‘zonula occludens.’ Traditionally, corneal edema was regarded simply as increased corneal water content that results in increased thickness, increased scattering of light, and decreased transparency; however, corneal edema also involves loss of stromal GAG and water uptake (Kangas et al., 1990). When the cornea swells, fluid is not uniformly distributed within the corneal stroma. Instead, posterior corneal lamellae are hydrated to a greater extent, possibly because of differences in the glycosaminoglycan

content between the anterior and posterior stroma or presence of lamellar interweave in the anterior stroma that limits the extent to which these lamellae can swell (Meek et al., 2003a, 2003b). Corneal edema in the dog may be associated with a variety of causes, including endothelial dystrophy, age‐related degeneration, endothelial damage associated with persistent pupillary membranes (PPMs), mechanical trauma, toxic reactions, anterior uveitis, endotheliitis, glaucoma, neovascularization, and ulceration. Endothelial dystrophy occurs in several breeds, including Boston Terriers, Chihuahuas, Dachshunds, and German Shepherds (Brooks et  al., 1990; Dice, 1980; Gwin et al., 1982a; Martin & Dice, 1982). Light microscopic findings have included stroma edema, fibrous tissue proliferation on a thickened Descemet’s membrane, and endothelial cell hypocellularity. This condition is similar to Fuchs’ dystrophy in humans and is commonly bilateral (see more information later in this chapter) (Bergmanson et al., 1999). Boston Terriers with endothelial dystrophy were evaluated by IVCM and FD‐OCT (Thomasy et  al., 2016). Affected dogs had significantly decreased corneal endothelial density and increased central corneal thickness compared with age‐matched controls, consistent with disrupted fluid homeostasis associated with reduced endothelial cell function. Corneal edema associated with endothelial changes is commonly seen with anterior uveitis in the dog. Intraocular inflammation results in corneal edema via an increase in endothelial permeability and a decrease in Na+/K+‐ATPase pump activity (MacDonald et al., 1987). The immune‐mediated Arthus‐type reaction of infectious canine hepatitis, which is an immune‐mediated, Arthus‐type reaction, develops in the anterior uveal tract and progresses to destruction of the corneal endothelium with resultant corneal edema, thus causing the “blue eye” appearance (Aguirre et al., 1975; Carmichael et  al., 1975; Curtis & Barnett, 1973a, 1973b, 1983). Corneal endothelial cell damage and secondary

corneal edema is a manifestation of type III hypersensitivity in which immune complex formation results from the release of virus from infected corneal endothelial cells (Curtis & Barnett, 1973a, 1973b). Natural infections or vaccination with modified live canine adenovirus type 1 may result in the development of corneal edema. Afghan Hounds are particularly susceptible (Fig.  19.6). Vaccination with canine adenovirus type 2 decreases the incidence to below 1%. Approximately 30% of dogs that develop corneal edema from adenovirus infection or vaccine do not completely resolve (Curtis & Barnett, 1973a, 1973b, 1983). Traumatic endothelial damage may occur with anterior lens luxation. Trauma to the endothelium may also result from intraocular surgery, such as phacoemulsification, intracapsular lens extraction, and intraocular lens replacement. Irrigation solutions used in phacoemulsification also damage the corneal endothelium (Gwin et al., 1983b). Results of one study on the response of canine corneal endothelium to intraocular irrigation solutions indicated that irrigating fluid composition has a less deleterious effect on the corneal endothelium than the volume of fluid and time of irrigation (less than 100 mL of fluid for less than 20 minutes had the least damaging effect) (Nasisse et al., 1986). In other canine studies, diode laser iridal photocoagulation showed no adverse effects on the corneal endothelium, but CO2 photokeratotomy resulted in multiple punctate and linear regions of endothelial cell destruction associated with a significant increase in corneal thickness (Chandler et al., 2003; Hoffman et al., 2009). There are a number of known compounds that result primarily in corneal edema in dogs. Chlorpromazine accumulates in the canine posterior corneal stroma, lens, and uveal tract. In addition to causing cataracts, it produces posterior corneal precipitates and pigmentation. Chlorpromazine is a phototoxic compound, and the cellular damage to endothelial cells occurs after light exposure (Barron et  al., 1972a, 1972b; Rubin et  al., 1970; Tousimis & Barron, 1970). Lortalamine, a nontricyclic antidepressant compound, produced high levels of the compound and its metabolite in the cornea after oral administration and resulted in bilateral mydriasis, conjunctivitis, epiphora, corneal edema, and ulcerations for the first week after therapy (Mally & Thiebault, 1990). Bilateral corneal edema occurred in three of 12 dogs after long‐term treatment (>3 months) with tocainide, an antiarrhythmic agent. Because of the lack of inflammation, this was presumed to be a direct endothelial toxic effect of the drug (Gratzek et al., 1996).

Corneal Vascularization Corneal stromal vascularization is a nonspecific response to corneal injury or inflammation (Lee et  al., 1998). The healthy canine cornea is avascular and the presence of blood vessels within the cornea represents pathologic

change. Vascularization is a normal component of the reparative response after injury in a variety of tissues; however, in the cornea, this process can result in disrupted corneal architecture, opacification, and reduced vision. The avascular state of the cornea is actively maintained by a balance of antiangiogenic and angiogenic factors (Pearce et al., 2007; Qazi et al., 2009). Corneal vascularization occurs when this balance is lost and the local corneal microenvironment favors angiogenic factors. The presence of VEGF receptor 1 and VEGF receptor 2 has been shown in normal canine eyes (Binder et  al., 2012). In the normal canine cornea, superficial and basal corneal epithelium, corneal endothelium, and limbal vascular endothelium contained VEGF receptor 1 whereas VEGF receptor 2 was found in the scleral vascular endothelium. Both VEGF receptor 1 and 2 were detected in pathologic vascular endothelium and corneal neovascularization. Any corneal insult that induces inflammation or hypoxia may result in corneal angiogenesis (Maddula et  al., 2011; Safvati et  al., 2009). Corneal vessels may arise from conjunctival, scleral, or iridal vessels. Once blood vessels penetrate the cornea, they grow along collagen lamellar planes (unless these planes are disrupted). The depth and appearance of corneal blood vessels is often indicative of the anatomic location of the underlying pathologic process inciting the vascular invasion (Cogan, 1962). Superficial corneal vessels are located in the subepithelial and anterior stromal regions and are typically a response to ocular surface or superficial corneal disease. Superficial vessels arise from conjunctival vessels and are bright red, fine, branch repeatedly, and can be observed to cross the limbus (Fig. 19.7). Deep corneal vessels are located in the posterior stroma and suggest deep corneal or intraocular disease. Deep corneal vessels arise from anterior ciliary vessels and appear dark red, straight with few or no branches, and do not cross the limbus (Fig.  19.8). Less commonly, deep corneal vessels may originate from iridal vessels when anterior synechiae are present.

Developmental Abnormalities and Congenital Diseases Microcornea Microcornea is a small cornea in an otherwise normal globe. The appearance in dogs is a cornea with a horizontal diameter of less than 12 mm. A small cornea may also occur with ocular or systemic conditions associated with multiple ocular anomalies. Microcornea is reported as a feature of merle ocular dysgenesis in a variety of breeds, including Australian Shepherds and Dachshunds (Dausch et  al., 1978; Gelatt & McGill, 1973; Gelatt & Veith, 1970). The Collie, Miniature and Toy Poodle, Miniature Schnauzer, Old English Sheepdog, St. Bernard, and possibly other breeds may be predisposed to

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been described in Alaskan Huskies affected by a polyneuropathy with ocular abnormalities and neuronal vacuolation similar to Warburg microsyndrome in humans (Wiedmer et al., 2016). Similar phenotypes have also been reported in Boxers, Rottweilers and Black Russian Terriers.

Megalocornea

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Megalocornea is a cornea of greater than normal size, normal being approximately 16–18 mm in horizontal diameter. This is a rare, congenital anomaly in the dog and is usually concurrent with congenital glaucoma and buphthalmus (or megalophthalmos).

Dermoids

Figure 19.7  Superficial corneal vascularization in a dog with chronic keratoconjunctivitis sicca.

A dermoid is a choristoma, or normal tissue in an abnormal position. Dermoids occur most commonly at the temporal limbus and can involve the eyelids, conjunctiva, cornea, or a combination of these structures (Fig. 19.9). Rarely, dermoids may involve the central cornea in dogs (Brudenall et  al., 2007). Dermoids may contain keratinized epithelium, hair, blood vessels, fibrous tissue, fat, nerves, glands, smooth muscle, and cartilage (Horikiri et  al., 1994; Lawson, 1975; Minamide & Suzuki, 1997). Dermoids are present at birth, but they may not be recognized clinically until the dog is several weeks old. If they are irritating or obstructing vision, dermoids can be treated by surgical removal. The procedure of choice for corneal dermoids is superficial lamellar keratectomy (see next section). In the uncommon situation where a dermoid requires deep keratectomy, a conjunctival graft may be warranted (Lee et al., 2005). Surgical placement of canine amniotic membrane after excision of large dermoids is reported to enhance healing and reduce corneal scarring (Kalpravidh et al., 2009). Small dermoids with few hair follicles may not be clinically problematic and can be left alone. Superficial Keratectomy

Figure 19.8  Deep corneal vascularization in a dog with chronic anterior uveitis.

microcornea and multiple ocular anomalies as well (Gilger et al., 2007). In these dogs, microcornea may be associated with microphthalmia, goniodysgenesis, and PPMs. Microcornea may also occur in dogs with the systemic connective tissue disorder Ehlers–Danlos syndrome (Barnett & Cottrell, 1987). Microphthalmia, including microcornea, has

As mentioned, one of the most common surgical procedures for removal of a corneal dermoid is superficial keratectomy. Other corneal lesions amenable to superficial keratectomy include indolent ulcers, corneal neoplasms, sequestrums, foreign bodies, corneal abscesses, inclusion cysts, bacterial and fungal keratitis (usually in conjunction with a conjunctival graft or flap), and corneal degeneration (Bentley et al., 2001; Bouhanna et  al., 2008; Brudenall et  al., 2007; Choi et  al., 2010; Dreyfus et  al., 2011; Karasawa et  al., 2008; Morgan & Abrams, 1994; Peiffer et  al., 1976a; Sansom & Blunden, 2010; Simonazzi et al., 2009; Takiyama et al., 2010). The specific procedure or method for the superficial keratectomy is determined by the type of lesion. Before performing a superficial keratectomy, determining the depth of the lesion using biomicroscopy, high‐frequency ultrasound,

A

B

Figure 19.9  A. A dermoid, or choristoma, at the temporal limbus in a young dog. B. A histologic section of a dermoid after keratectomy. Note the hair follicles and glands that are typical of haired skin. (Hematoxylin and eosin. 110×)

confocal microscopy, or optical coherence tomography will help in planning the surgery. If the resulting corneal wound extends deeper than one‐half corneal thickness, use of a conjunctival pedicle flap or amniotic membrane graft (Barros et al., 2005; Kalpravidh et al., 2009) is warranted to protect the cornea, to help prevent perforation, and to promote healing. Because corneal stromal tissue may not completely regenerate, the number of superficial keratectomies that can be performed at the same site is limited to two or three, depending on the depth of the tissue removed with each procedure. Superficial keratectomy is most commonly performed in veterinary medicine using traditional microsurgical instruments (see Chapter 12); however, it can also be performed using carbon dioxide or excimer laser ablation (Shieh et al., 1992). Use of magnification (e.g., an operating microscope) is essential to perform the surgery, and specialized surgical equipment (e.g., corneal dissector, dermatology punch, corneal trephine, micrometer diamond knife) greatly facilitates the removal of corneal tissue and may improve the clinical outcome. There are two common methods to perform a superficial keratectomy: the complete and the partial incision keratectomy. In the first method, the complete incision keratectomy, an initial corneal incision is made that surrounds completely the lesion to be removed. The incision needs to be at appropriate depth to allow complete removal of the lesion. It is made using a corneal trephine, diamond knife, or microsurgical blade (Fig.  19.10). The initial incision can be round, square, or triangular. After the initial incision is made, the edge of the tissue to be removed is grasped with forceps, and a corneal dissector (e.g., Martinez corneal dissector, microsurgical blade #6400 or #6900, iris spatula) is introduced and held parallel to the cornea. The dissector is used to separate the corneal lamella without penetrating deeper than the

original incision. The cornea is then separated until the opposite incision line is reached. In the second type of superficial keratectomy, the partial incision keratectomy, a small corneal incision is made adjacent to the lesion that is to be removed. This initial incision is made at the appropriate depth but only wide enough to allow insertion of the lamellar‐separating device (e.g., Martinez corneal dissector, microsurgical blade #6400 or #6900, iris spatula) to be inserted. Using this separator instrument through the initial incision, the entire lamellar plane under the lesion to be removed is separated, thus undermining the lesion. Corneal section scissors are then introduced into the initial incision and used to complete the keratectomy (Fig. 19.11). The carbon dioxide laser generates heat and coagulates tissue. It can effectively ablate superficial corneal lesions; however, the surrounding area of the cornea can be significantly damaged because of the heat generated, thus resulting in scarring and opacity (Gilmour, 2003). Surgical margins may be difficult to interpret if the laser is used exclusively for mass removal (Rizzo et al., 2004). Therefore, use of the carbon dioxide laser is not recommended for corneal surgery. However, the carbon dioxide laser can be used for adjunctive therapy after surgical removal of superficial corneal, limbal, or scleral neoplasms (English et al., 1990; Gilmour, 2003). In contrast to the carbon dioxide laser, the argon‐fluoride excimer laser removes precise (i.e., submicron) amounts of tissue with virtually no damage to adjacent tissue. The laser beam is controlled by a computer, and both the pattern and depth of the keratectomy can be precisely achieved. In the dog, treatment of crystalline corneal degeneration, corneal scarring, corneal calcification, and pigmentary keratitis with the excimer laser has achieved some success (Shieh et al., 1992). Following keratectomy, the cornea is treated much like a corneal ulcer with topical broad‐spectrum antibiotics to

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A B

C

D Figure 19.10  Complete incision superficial keratectomy. A. The initial corneal incision, which may be round, square, or triangular, should completely surround the lesion to be removed and can be made using a corneal trephine, diamond knife, or microsurgical blade. B and C. After the initial incision is made, the edge of the tissue to be removed is grasped by forceps and a corneal dissector (e.g., Martinez corneal dissector, Beaver No. 64 microsurgical blade, iris spatula) is introduced and held parallel to the cornea. The dissector is used to separate the corneal lamella without penetrating deeper than the original incision. The cornea is then separated until the opposite incision line, or limbus, is reached. D. Scissors may be needed to connect the dissection to the opposite incision or to remove the corneal tissue from the limbus.

prevent infection and with topical atropine to decrease ciliary spasm and discomfort. A potentially devastating complication after keratectomy is corneal perforation, which generally results from infection at the surgical site. The potential for infection is exacerbated by deep, extensive keratectomies but is largely preventable by use of conjunctival flaps or other supportive surgeries. Frequent reevaluations after surgery (with monitoring of healing by use of fluores-

cein dye application) and use of topical antibiotics should prevent most postsurgical complications.

Congenital Corneal Opacities Corneal opacities are commonly classified by the degree of opacity and are described as a nebula, macula, or leukoma. A nebula is a minor, diffuse, hazy opacity with indistinct

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Figure 19.12  Infantile corneal dystrophy, a congenital, nonhereditary, transient, subepithelial, geographic corneal opacity, in an 8-week-old puppy. Figure 19.11  Partial incision superficial keratectomy in a dog with a chronic indolent corneal ulcer. A small corneal incision is made adjacent to the lesion that is to be removed and a lamellarseparating device is inserted, in this case a #64 microsurgical blade. The entire lamellar plane under the lesion to be removed is separated, thus undermining the lesion. Corneal section scissors are then introduced into the initial incision and used to complete the keratectomy.

borders. A macula is a moderately dense opacity with a circumscribed border. A leukoma is a dense, white opacity. When iris tissue adheres to the posterior surface of the cornea beneath an area of corneal opacity, the condition is described as an adherent leukoma. Infantile Corneal Dystrophy

Infantile corneal dystrophy, or puppy keratopathy, is a congenital, subepithelial, geographic corneal opacity that is nonhereditary, transient, and observed in puppies younger than 10 weeks (Fig.  19.12). This type of noninflammatory corneal opacity occurs in many breeds of dogs, but is most common in Bichon Frise, Collie, English Springer Spaniel, Miniature Poodle, Shetland Sheepdog, and Yorkshire Terrier puppies (Gilger et al., 2007; Ledbetter & Gilger, 2013; Whitley & Gilger, 1999) The condition slowly resolves, and in most cases is absent by 12–16 weeks of age. There is no interference with functional vision and treatment is unnecessary. Corneal Opacities with Persistent Pupillary Membranes

PPMs are congenital lesions that occur in many canine breeds and are known to be hereditable in some. Persistent pupillary tissue strands arise from the iris collarette and represent failure of normal embryonic vasculature structures to

Figure 19.13  Dog with persistent pupillary membranes adherent to the posterior surface of the cornea and resulting in a focal corneal opacity.

completely regress. Corneal lesions (i.e., adherent leukomas) can be associated with adherence of PPMs (Fig. 19.13). Both focal and diffuse corneal opacities occur, but the former is more frequent (Mason, 1976; Peiffer & Gwin, 1977; Roberts & Bistner, 1968). Focal lesions appear as punctate, linear, or round deep corneal opacities that may be pigmented or unpigmented. Small focal opacities of the cornea are characterized by thickening and distortion of Descemet’s membrane in the area of the opacity. Larger, more diffuse corneal opacities also affect Descemet’s membrane and may result from generalized stromal edema (Peiffer & Gwin, 1977).

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PPM‐associated leukomas may be isolated anomalies or a component of a more extensive anterior segment dysgenesis. These conditions are, in general, poorly described in dogs (Peiffer & Fischer, 1983; Williams, 1993). Peter’s anomaly is a form of anterior segment dysgenesis in which abnormal cleavage of the anterior chamber occurs. There is paracentral corneal opacity, because of damaged corneal endothelium and Descemet’s membrane, and clear surrounding peripheral cornea. Iris strands extend from the collarette to the posterior surface of the cornea (Swanson et  al., 2001). The lens may be clear or cataractous.

Limbal Colobomas and Staphylomas Colobomas or staphylomas of the limbus or sclera are rare in the dog. The lesions are thin regions of the globe’s fibrous tunic lined by uveal tissue and appear as a tan, gray, or blue raised mass covered with conjunctiva. Strabismus may be present. Etiologies include congenital malformation and secondary to inflammation, glaucoma, neoplasia, trauma, or surgery (Barros & Safatle, 2000; Mitterer et al., 1987). Congenital, noninflammatory colobomas and staphylomas of the limbus or sclera occur most commonly in Miniature Dachshunds and with Collie eye anomaly and, in other breeds, with multiple ocular anomalies. Equatorial scleral staphylomas occur in the Australian Shepherd associated with multiple ocular anomalies (Gelatt & McGill, 1973; Gelatt & Veith, 1970). A case of congenital scleral staphyloma in a young Poodle was successfully repaired using a preserved homologous peritoneum graft (Barros & Safatle, 2000).

therapy, particularly at a very early age, resulted in significantly less GAG accumulation in the corneal stroma (Dierenfeld et al., 2010). A Miniature Poodle cross with mucopolysaccharide VI, caused by a deletion in the arylsulphatase B gene, had bilateral corneal stromal opacities along with multiple skeletal abnormalities (Jolly et al., 2012). Corneal endothelial cell hypertrophy and vacuolization are also prominent histopathologic features in dogs with mucopolysaccharide VII, but this is not reported to result in clinical endothelial dysfunction or corneal edema (Mollard et  al., 1996). Mucopolysaccharidosis VII is caused by a deficiency in β‐glucuronidase enzymatic activity and may result in GAG accumulation within the corneal stroma. Corrective β‐glucuronidase transfer with a helper‐ dependent canine adenovirus vector has been shown to reduce pathology in affected canine corneas (Serratrice et  al., 2014). Lysosomal acid lipase deficiency is reported in Fox Terriers and was associated with circular corneal lipid deposition (von Sandersleben et al., 1986). Tyrosinemia results from deficient enzymatic activity to catabolize tyrosine with subsequent accumulation of the amino acid in tissues. Naturally acquired and experimentally induced tyrosinemia in dogs is associated with formation of refractile stellate‐shaped corneal epithelial opacities (Kunke et  al., 1984; Lock et  al., 2006). Ehlers–Danlos syndrome is an inherited connective tissue disorder characterized by skin fragility, skin hyperextensibility, joint hypermobility, and vascular fragility. Corneal lesions reported in dogs with Ehlers–Danlos syndrome include microcornea, sclerocornea, and corneal granular opacities, edema, and pigmentation (Anderson & Brown, 1978; Barnett & Cottrell, 1987; Matthews & Lewis, 1990).

Metabolic and Connective Tissue Disorders Lysosomal storage diseases are a heterogeneous group of rare inherited disorders caused by deficient activity of one or more enzymes within the lysosomes. Lysosomal enzyme deficiency results in the accumulation of storage material within cells and a diverse array of clinical signs. Many canine lysosomal storage diseases may be associated with corneal pathology, including gangliosidosis and mucopolysaccharidosis (Skelly & Franklin, 2002). The circular or irregular‐shaped anterior stromal corneal opacities in Shiba Inus with GM1 gangliosidosis are the result of keratocyte accumulation of neutral carbohydrates, swelling, and dysfunction with subsequent irregular arrangement of stromal collagen fibers (Nagayasu et al., 2008). Multifocal or diffuse corneal opacities are reported in dogs with various types of mucopolysaccharide storage disorders and result from stromal keratocyte accumulation of GAG (Neer et al., 1995; Shull et al., 1994; Silverstein et  al., 2004; Wilkerson et  al., 1998). Mucopolysaccharidosis I is an inherited disorder that results from a deficiency of α‐L‐iduronidase and lysosomal accumulation of GAG in corneal stromal cells (Newkirk et  al., 2011). Accumulated GAG was found in corneal stromal cells and scleral fibroblasts and increases with age. Enzyme replacement

Inflammatory Keratopathies Corneal diseases may be categorized into inflammatory and noninflammatory causes. Inflammatory corneal disorders can be further classified into ulcerative and nonulcerative keratitis.

Ulcerative Keratitis Corneal ulceration, or ulcerative keratitis, is one of the most common ocular diseases in the dog. A corneal ulcer is present when there is a break in the corneal epithelium that exposes the underlying corneal stroma. Clinically, this results in lacrimation, blepharospasm, photophobia, conjunctival hyperemia, corneal edema, and possibly miosis and aqueous flare. The diagnosis of a corneal ulcer is made on the basis of these clinical signs and the retention of topically applied fluorescein dye by the corneal stroma (Fig. 19.14). Uncomplicated superficial ulcers usually heal rapidly, with minimal scar formation. Complicated deep ulcers, such as those with microbial infection, however, may lead to

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Figure 19.14  The diagnosis of a corneal ulcer is made on the basis of retention of topically applied fluorescein dye by the corneal stroma as observed in this superficial corneal ulcer.

impaired vision because of corneal scarring or, when corneal perforation occurs, to anterior synechia formation. Severe ulcerative keratitis may lead to loss of the eye because of endophthalmitis, glaucoma, phthisis bulbi, or a combination of these. Corneal ulcers are classified by depth of corneal involvement and by their underlying cause. The first step in treating all corneal ulcers involves identifying and removing the inciting cause, which may be eyelid abnormalities (e.g., masses, lagophthalmos, distichiasis, ectopic cilia), foreign bodies, trauma, and KCS. Chronic, infected, or progressive corneal ulcers should undergo microbiologic culture and antibiotic susceptibility tests and cytologic examination of corneal samples. These diagnostic procedures help guide specific antimicrobial therapy. Epithelial and superficial stromal foreign bodies may be successfully removed with saline hydropulsion, a cytobrush, an ophthalmic spear sponge, or a Kimura spatula (Labelle et  al., 2014; Pont et  al., 2016). This can generally be performed under topical anesthesia alone with excellent success rates. Stromal or penetrating foreign bodies, without lens involvement and without significant anterior uveitis, usually require general anesthesia for removal but have a good prognosis for vision retention after surgery (Pont et al., 2016). There is a report of a penetrating gunshot injury with lead shot entrapped within the choroid where the dog retained vision for 4.5 years after penetrating corneal and lenticular injury (Sansom & Labruyere, 2012). Ulcerative Keratitis: Depth of Corneal Involvement

Corneal ulcers are classified by the depth of corneal involvement and by their underlying cause. Depth of corneal involvement is reviewed first and includes superficial corneal ulcers, stromal corneal ulcers, descemetoceles, and perforations.

Superficial corneal ulcers (see Fig. 19.14) are further classified as uncomplicated, progressive, or refractory. For successful management of ulcerative keratitis, the inciting cause of the ulcer is identified and removed, the stage and severity of the ulcer is determined, and an appropriate therapeutic modality is selected. Identifying the cause or contributing factors requires a thorough ocular examination. Eyes should always be evaluated for eyelash abnormalities, eyelid structure and function, and preocular tear film disorders (e.g., Schirmer tear test, tear breakup time, rose Bengal retention). Uncomplicated superficial ulcers can resolve with topical antibiotic therapy applied three to four times daily to prevent secondary bacterial infection. Combination ophthalmic preparations (e.g., neomycin, bacitracin, and polymixin B), erythromycin, or oxytetracycline are frequently good antimicrobial selections which provide broad‐ spectrum coverage. Stimulation of the abundant sensory receptors in the cornea by ulceration results in a localized neurogenic reflex anterior uveitis associated with miosis of the pupil, iris hyperemia, and increased protein levels in the aqueous humor (i.e., aqueous flare). Therefore, a mydriatic agent (1% atropine or tropicamide) is applied topically once or twice daily to control ciliary muscle spasm, a dilated pupil, and the ocular discomfort associated with the secondary uveitis. The ulcer should resolve in 2–6 days; if not, it should be reevaluated for an undetected, underlying cause or contributing factor. Corneal erosions and superficial corneal ulceration have been documented as a complication of general anesthesia for non‐ophthalmic procedures in dogs, even those whose eyes were lubricated with topical lubricating gel (Dawson & Sanchez, 2016). Evaluation of 199 canine eyes lubricated before general anesthesia showed corneal ulceration in one eye and corneal erosion in 25 eyes. Neither the length of general anesthesia nor the service admitted were associated with corneal erosion or ulceration. The results of this study supports incorporating ocular examination with fluorescein staining in postanesthetic physical examinations. Spontaneous Chronic Corneal Epithelial Defects

Spontaneous chronic corneal epithelial defects (SCCEDs) in dogs are chronic superficial ulcers that fail to resolve through normal wound‐healing processes. A variety of terms are used to describe this entity, including indolent erosions or ulcers, canine recurrent erosions, refractory corneal ulcers, Boxer ulcers, nonhealing erosions, persistent corneal erosions, recurrent epithelial erosions, and idiopathic persistent corneal erosions (Champagne & Munger, 1992; English, 1989; Gelatt & Samuelson, 1982; Kirschner, 1990; Kirschner et al., 1989; Morgan & Abrams, 1994; Stanley et  al., 1998). Although originally referred to as Boxer ulcers because of a predilection for Boxer dogs, subsequent larger studies document occurrence in almost every breed (Murphy et al., 2001;

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Whitley & Gilger, 1999). Dogs affected with SCCEDs are typically middle‐aged, overrepresented by the Boxer breed, and exhibit varying degrees of blepharospasm. The initiating event in dogs with SCCEDs is likely superficial corneal trauma. These epithelial defects result in variable amounts of ocular discomfort along with the potential for corneal neovascularization, fibrosis, and edema (Aldave et al., 2009; Bentley 2005; Bentley & Murphy, 2004; Dawson et al., 2017; Dees et al., 2017; Lassaline‐Utter et al., 2014; Spertus et al., 2017; Stanley et al., 1998; Woof & Norman, 2015). Hallmark clinical and histologic features of SCCED include a superficial axial or paraxial corneal ulcer that does not extend into the stroma, associated with redundant, nonadherent corneal epithelial borders that may be associated with an acellular hyaline zone in the anterior stroma, neovascularization, and, when not treated adequately, may persist for weeks to months (Bentley 2005; Bentley & Murphy, 2004; Dawson et  al., 2017; Dees et  al., 2017; Spertus et  al., 2017; Stanley et  al., 1998; Woof & Norman, 2015). Therapeutic interventions for SCCEDs are aimed at removing non‐attached epithelium and the acellular hyaline zone from the superficial cornea to allow new healthy epithelium to form and adhere to the basement membrane. A condition similar to canine SCCEDs has been described in horses, with epithelium demonstrating dysmaturity and non‐adherence, and variable anterior stromal hyalinization, stromal inflammation, fibrosis, and neovascularization (Hempstead et al., 2014). The anterior stromal acellular hyaline zone commonly described in the canine counterpart is not a consistent finding in affected equine corneas (Hempstead et al., 2014). The pathophysiology of SCCEDs has not been completely elucidated; however, several morphologic and functional abnormalities are described in dogs with this condition. The epithelium adjacent to the defects exhibits dysmaturation and is poorly attached to the underlying stroma (Fig. 19.15) (Bentley et  al., 2001). The basement membrane and adhesion complexes are typically absent or present in small discontinuous segments on the surface of the exposed stroma, and fibronectin is present on the stromal surface (Bentley et al., 2001; Bentley, 2005; Dees et al., 2017; Kirschner, 1990; Ledbetter & Gilger, 2013; Murphy et al., 2001). A thin, superficial, acellular hyalinized zone in the anterior stroma is common and composed of collagen fibrils admixed with an ill‐defined amorphous or fine fibrillar material (Bentley et al., 2001). Stromal fibroplasia, vascularization, and leukocyte infiltrate are variably present. No abnormalities consistent with the basement membrane and anterior stromal dystrophies associated with recurrent erosions in humans have been identified (Bentley et al., 2001). Normal dogs subjected to repeated epithelial debridement for 8 weeks to mimic SCCEDs developed epithelial dysmaturation and nonadherence that was similar, but less extensive, to dogs with SCCEDs (Bentley et al., 2002). The experimen-

Figure 19.15  Photomicrograph of keratectomy sample from a canine patient with a spontaneous chronic corneal epithelial defect. Note the sheet of poorly attached epithelium that exhibits epithelial dysmaturation, or loss of the normal ordered epithelial architecture (arrow). Also note the superficial stromal hyalinized zone (arrowheads) with underlying stromal fibroplasia. (Hematoxylin and eosin, 200×.) (Source: Courtesy of Ophthalmology Optics and Anatomy Laboratories, University of Wisconsin-Madison.)

tally wounded corneas did not develop the superficial stromal hyalinized zone found in SCCED samples, suggesting the stromal changes in SCCED have a role in the underlying pathophysiology of the disease. A dense, abnormal plexus of substance P and calcitonin gene‐related peptide immunoreactive nerve fibers is present surrounding the erosion in the corneal stroma of dogs with SCCEDs (Murphy et al., 2001). This altered innervation was not present in the corneas of normal dogs undergoing weekly epithelial debridement for 4 weeks, suggesting these stromal changes were not secondary to the chronic epithelial defect. Substance P levels are elevated in the epithelial cells, but not the tears, of dogs with SCCEDs (Murphy et al., 2001). Upregulation of MMPs is postulated to cause the basement membrane loss in SCCEDs. Levels of MMP‐2 and MMP‐9 in keratectomy samples from dogs with SCCEDs and normal dogs that underwent repeated debridement to mimic SCCED were compared (Carter et al., 2007). MMP‐2 was not altered from normal in SCCED samples, chronically wounded samples, or acutely wounded samples. MMP‐9 levels were similar in keratectomy samples from dogs with SCCEDs and dogs that underwent multiple epithelial debridement procedures (Carter et al., 2007). MMP‐9 levels were lower in the SCCED and chronically wounded samples compared with acutely wounded corneas. These results suggest MMP‐2 does not play a role in SCCEDs, and alterations in MMP‐9 result from the presence of a chronic corneal epithelial defect and are not part of the underlying pathophysiology of SCCEDs. After corneal wounding in normal dogs, the corneal epithelium develops a migratory phenotype similar to that observed during the process of epithelial‐mesenchymal

transition (Chandler et al., 2007). Epithelial cells at the edge of the defect flatten, with partial dissolution of intracellular junctions, and cells migrate over the wound. Slug, a member of the Snail family of transcription factors, modulates epithelial–mesenchymal transition, and its expression is associated with markers of cell migration including internalization of E‐cadherin and β‐catenin from cell membranes and enhanced expression of smoothmuscle‐specific α‐actin, tropomyosin, and MMPs. Slug expression is enhanced and markers of cell migrations are evident at sites of epithelial cell migration in normal dogs with corneal wounds, but not in dogs with SCCEDs (Chandler et  al., 2007). TGFβ increases expression of the Snail family of transcription factors and decreased levels of TGFβ is reported in the tears of dogs with SCCEDs (Jurk et al., 2000). In summary, these studies suggest the stromal alterations (i.e., superficial hyalinized acellular zone, abnormal nerve plexus) are distinct to SCCEDs and play a pathophysiologic role in the disease. The high success rates of treatments (e.g., keratotomy and keratectomy) that breech or remove the abnormal stroma further support this theory. No evidence currently exists that SCCEDs in dogs are associated with basement membrane dystrophies as found in humans, and the older age distribution of dogs with this condition is inconsistent with a dystrophy. Diagnosis  SCCED should be considered in any middle‐ aged dog with an erosion that has not healed in 1–2 weeks. Studies of SCCED report an average age of 8–9 years (Bentley et  al., 2001; Morgan & Abrams, 1994; Murphy et  al., 2001; Stanley et al., 1998); therefore, young dogs with nonhealing erosions should be very carefully examined prior to a diagnosis of SCCED. Possible underlying causes for delayed wound healing must be ruled out by thorough examination. Causes for delayed wound healing can include mechanical trauma (e.g., eyelid abnormalities such as masses, entropion, and lagophthalmia), foreign bodies, infection, tear film abnormalities, exposure from poor conformation, facial nerve paralysis, neurotrophic keratitis, exophthalmia or buphthalmia, or corneal edema leading to bullous keratopathy. Addressing these underlying problems should result in resolution of the erosion; if not, or if no underlying causes are present, then a diagnosis of SCCED can be reached if the lesion has a compatible appearance. SCCEDs have a typical clinical appearance (Fig. 19.16 and Fig. 19.17). A ring of loose epithelium surrounds a SCCED, resulting in a diffuse ring or halo of less‐intense fluorescein staining around the defect as fluorescein diffuses underneath the poorly attached epithelium. A SCCED is always superficial, with no stromal loss. Defects are often in the axial or paraxial cornea, although any portion of the cornea may be affected. If corneal edema is present, it is mild and confined to the area of the defect. Severe, diffuse corneal edema suggests that the underlying cause is corneal edema

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Figure 19.16  Scanning electron micrograph of a keratectomy sample from a canine patient with a spontaneous chronic corneal epithelial defect. Note the bare stromal fibrils, demonstrating loss of basement membrane in the area of the defect. (Source: Courtesy of Ophthalmology Optics and Anatomy laboratories, University of Wisconsin-Madison.)

Figure 19.17  A large nonvascularized spontaneous chronic corneal epithelial defect in a 9-year-old Boxer dog. Note the axial location, ring of loose epithelium, and the decrease in intensity of the fluorescein staining as it migrates under the loose epithelium surrounding the defect.

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with secondary bullous keratopathy rather than an SCCED. Varying degrees of vascularization occur in SCCED, with studies reporting 58%–64% of lesions exhibiting neovascularization (Bentley et  al., 2001; Murphy et  al., 2001). Peripheral lesions are more likely to vascularize whereas central lesions may persist for months with no vascular response. The degree of pain shown by blepharospasm varies between dogs but tends to decrease with chronicity. Treatment  After diagnosis, clients should be educated that multiple treatments are sometimes required to resolve these lesions and recurrence in the same or contralateral eye is possible. Communication of the issues will increase owner compliance and satisfaction. A number of treatment options exist for the treatment of SCCEDs. With all treatments, prophylactic antibiotics should be administered q6h to q8h to prevent secondary infection of the compromised cornea. A cycloplegic (e.g., atropine) to improve comfort and Elizabethan collar to prevent self‐trauma are usually indicated. The exact treatments chosen are dependent on clinician preference because few controlled clinical trials for the treatment of SCCEDs have been performed to assist in evidence‐based decisions. A wide variety of medical therapies have been utilized in the therapy of SCCEDs. Treatment with topical polysulfated GAGs resulted in healing of 82% of the treated dogs (Miller, 1996). A separate study evaluated aprotinin, with a resulting healing rate of 33% (Morgan & Abrams, 1994). Both polysulfated GAGs and aprotinin are postulated to work by decreasing proteolytic activity. Only a portion of dogs with SCCEDs, however, demonstrate increased proteolytic activity in their tears; therefore, proteolytic inhibition may be beneficial in only a subset of dogs with SCCEDs (Willeford et al., 1998). Application of EGF led to healing in 80% of dogs in one study (Kirschner et  al., 1991). Treatment with topical substance P alone or combined with insulin‐like growth factor resulted in healing of erosions in 70% and 75% of dogs, respectively (Murphy et  al., 2001). A chondroitin sulfate– antibiotic combination brought about healing in 81% of treated dogs, but treatment had to be continued for 4 weeks, which is longer than many other reported therapies (Ledbetter et  al., 2006a). A non-randomized clinical trial evaluating topical treatment with aminocaproic acid, an antiproteolytic agent, resulted in SCCED healing in 94% of eyes after 3 weeks compared with 41% of control eyes treated with gentamicin (Regnier et al., 2005). Inhibition of MMPs has received attention as a novel therapy for the treatment of dogs with SCCEDs. Doxycycline and tetracycline inhibit MMPs in epithelial cell culture and tears (Ollivier et al., 2007). Recent work, however, showed no difference in MMPs in keratectomy samples from dogs with SCCEDs and dogs that underwent multiple epithelial debridement procedures as a model for SCCEDs (Carter et al., 2007). Specific treatment with MMP inhibitors, there-

fore, seems unlikely to directly resolve SCCEDs by this mechanism of action. A randomized, controlled clinical trial evaluated adjunct tetracycline treatment in dogs with SCCED (Chandler et al., 2010). All dogs were treated with manual debridement and grid keratotomy followed by oral doxycycline (5 mg/kg q12h) and topical triple antibiotic (q8h), topical oxytetracycline ophthalmic ointment (q8h) and oral cephalexin (22 mg/kg q12h), or a control group of topical triple antibiotic ointment and oral cephalexin. Dogs treated with topical oxytetracycline ophthalmic ointment healed significantly faster (74% healed within 2 weeks) than dogs in the control group (10% healed within 2 weeks). Dogs treated with oral doxycycline healed more rapidly than dogs in the control group, but the difference was not statistically significant. It was postulated that tetracyclines may be useful for the treatment of SCCEDs by mechanisms unrelated to MMP inhibition. Specifically, upregulation of specific growth factors (e.g., TGFβ and transcription factors) was hypothesized to promote corneal reepithelialization. The effects of topically applied heterologous serum versus isotonic saline was evaluated in 41 dogs with SCCEDs (Eaton et al., 2017). In this study, all dogs received epithelial debridement (at all visits) and grid keratotomy (at visits 2, 3, and 4) along with topical 0.3% tobramycin q8h and topical 1% atropine daily along with topical serum or saline q8h. Median time to epithelialization was not significantly different between serum or saline treated eyes and was not significantly different between Boxer versus non‐Boxer breeds. Regardless of treatment group, dogs with increased vascularization had slower time to reepithelialization. Topical corticosteroids generally should be avoided in SCCEDs because they decrease the rate of corneal wound healing and inhibit host defense mechanisms. Some clinicians believe that SCCEDs with excessive granulation tissue, however, may benefit from judicious use of topical corticosteroids, with the aim of reducing the formation of vision‐ obscuring scar tissue. While corticosteroids may accelerate the retreat of granulation tissue and vascular perfusion in the cornea, they do not decrease scar tissue formation in the cornea unless they are used prior to the infiltration of vessels into the cornea in humans and laboratory animals. Alternatively, topical nonsteroidal anti‐inflammatory drugs may be used to reduce corneal granulation tissue. Dog with epithelial defects should be monitored very carefully during treatment with topical corticosteroids or nonsteroidal medications. Most studies of topical medications for the treatment of SCCEDs consist of small, non-randomized, non-masked, and/or uncontrolled clinical trials. The lack of controls and small sample sizes makes interpretation of these results difficult, particularly because statistical power is often too low to detect a meaningful difference between treatment groups. Additionally, most studies of a medical treatment for

SCCEDs include epithelial debridement, and it is difficult to ascertain whether the debridement or the medical treatment led to healing. Furthermore, many of these treatments are cost prohibitive, unavailable, or require a frequency of application that is difficult for most owners, often making their use impractical in the usual clinical setting. The most common therapy for the treatment of SCCEDs is epithelial debridement, used alone or in combination with other medical or surgical therapies. After application of topical anesthetic, epithelial debridement is performed using multiple dry cotton‐tipped applicators, beginning in the center of the erosion and working out to the periphery with radial strokes (Fig. 19.18). Normal corneal epithelium cannot be removed with a cotton‐tipped applicator, so debridement should be continued until only firmly adhered epithelium remains. Debridement can also be performed with corneal burrs, excimer laser spatulas, scalpel blades, spatulas (Kimura and iris), or forceps. Some of these instruments can remove normal epithelium and damage the corneal stroma, so care must be taken to debride appropriately. Typically, debridement can be repeated at 7‐ to 14‐day intervals. Success rates and time to healing vary between studies from 20% in 14 days to 84% in an average of 23 days (Kirschner et  al., 1991; Morgan & Abrams, 1994; Stanley et al., 1998). The number of debridement surgeries, the time between procedures and examinations, and the number of dogs differed between studies, which may contribute to the wide range of success rates. All of these were small, uncontrolled trials, but combining the success rates results in an overall success rate of approximately 50%. It was noted that adding a soft contact lens or third eyelid flap increased healing rates

Figure 19.18  A vascularized spontaneous chronic corneal epithelial defect in a 10-year-old Boxer dog. Note the peripheral location of the erosion, superficial corneal vascularization, ring of loose epithelium surrounding the defect, and fluorescein leakage under surrounding loose epithelium.

after debridement to 58% and 64%, respectively (Morgan & Abrams, 1994). Third eyelid flaps and soft contact lenses may provide mechanical protection to the healing cornea from trauma and eyelid rubbing. Superficial corneal debridement performed with a diamond burr was described in dogs with SCCEDs and compared favorably with treatment by grid keratotomy (Davis & Gionfriddo, 2011; Gosling et  al., 2013; Sila et  al., 2009). Although uncommon (three of 100 dogs), keratomalacia was a complication in dogs treated with the diamond burr (Sila et al., 2009). Histologic evaluation of a specific protocol for diamond burr corneal debridement in normal dogs with experimental corneal wounds determined the instrument does not create defects beyond the epithelial basement membrane (da Silva et al., 2011). Making small punctures or linear scratches in the affected cornea is another common therapy for SCCEDs. Many different variations and names exist for these procedures, including punctate keratotomy, anterior stromal puncture (ASP), multiple punctate keratotomy, multifocal superficial punctate keratotomy, and grid keratotomy. All of these procedures use the same principle to improve healing by producing anterior stromal adhesions and can be grouped together. Immunohistochemical studies after ASP demonstrate increased ECM components, including collagen IV and laminin, which are important in epithelial adhesion and often absent in SCCED cases (Bentley et al., 2001; Hsu et al., 1993). To perform ASP or any variant thereof, a 25‐gauge needle is grasped with a hemostat so that the tip of the needle is barely exposed. This improves control of penetration depth. A commercially available needle with a small bend in the tip to control depth is also available. After administration of topical anesthetic, the epithelium is debrided prior to performing the procedure to determine the extent of corneal involvement and the area requiring treatment. In an ASP or punctate keratotomy, multiple small punctures are placed 0.5–1.0 mm apart over the entire affected cornea and extending 0.5–1.0 mm into the normal surrounding cornea (Fig. 19.19). In a grid keratotomy, small lines are placed in a crosshatched pattern across the surface of the cornea and extending approximately 1.0 mm into unaffected surrounding cornea. ASP or grid keratotomy can be repeated at 7‐ to 14‐day intervals. Multiple uncontrolled clinical studies of these procedures found success rates ranging from 68% using ASP to 87% using a grid keratotomy (Champagne & Munger, 1992; Morgan & Abrams, 1994; Stanley et  al., 1998). Combining success rates from these various studies leads to a success rate of approximately 80%. A contact lens or third eyelid flap may be used after these procedures. One study found that 12 of 12 eyes healed after treatment with grid keratotomy followed by a third eyelid flap (Stanley et al., 1998). In a study evaluating SCCEDs in Boxers, treatment by linear grid keratotomy combined with therapeutic

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SECTION IIIA

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Figure 19.19  Epithelial debridement of a spontaneous chronic corneal epithelial defect in a 9-year-old Golden Retriever. One cotton-tipped applicator is used to remove loose epithelium, while a second cotton-tipped applicator is used to prevent prolapse of the third eyelid.

soft contact lens showed that the use of bandage contact lenses (BCL, Acrivet™) had a statistically significant decrease in median healing time (7 days) compared with those without contact lenses (10 days). There was no difference in subjective comfort score between the two groups (Wooff et  al., 2015). In a European study, polyxylon BCL (AcriVet Pat D™, S&V Technologies AG, Acrivet Veterinary Division, Berlin, Germany) showed healing times of 14 days or fewer compared with a mean of 36 days in animals not receiving a BCL (Grinninger et  al., 2015). Blepharospasm resolved in 4 days after debridement with BCL use, compared with 30 days in the group without a BCL. A larger study of 237 dogs designed to evaluate the effect of BCL wear and type of postoperative medical treatment on corneal healing rates in dogs after debridement showed the effectiveness of BCL use and ofloxacin (Dees et al., 2017). In this study, overall BCL retention rate varied between contact lens brands. Superficial keratectomy can also be used for the treatment of SCCEDs. Superficial keratectomy works by completely removing the abnormal superficial layer of stroma and allowing reformation of normal epithelial adhesion complexes. Unlike the other procedures, the success rate is consistently 100% across studies, with healing resulting in a relatively short time period (Peiffer et  al., 1976a; Stanley et al., 1998). This high success rate implies that the stromal alterations are a critical part of the pathophysiology of this disease. Although superficial keratectomy results in rapid resolution, it is not always recommended as the first line of therapy because of the need for general anesthesia, increased cost, and increased likelihood of corneal scarring (Whitley & Gilger, 1999). Other small case series report alternative therapies for the treatment of SCCEDs. Thermal cautery resulted in healing

in nine of nine eyes in 2.1 weeks (Bentley et  al., 2004). Similar to the other procedures described, thermal cautery alters the abnormal superficial stroma, allowing normal epithelial wound healing to occur. This procedure has the potential to result in increased corneal scarring if not performed carefully, so it is generally reserved for cases that do not respond to other therapies. Thermal cautery is a reasonable option for dogs that are refractory to other treatments and cannot be anesthetized, because it can be performed under sedation. Cyanoacrylate tissue adhesive has been used as a treatment for nonhealing erosions and SCCEDs. In one study, non-healing erosions were present for a variety of reasons, but 20 eyes healed in a mean time of 3.4 weeks (range 2–8 weeks) after cyanoacrylate therapy (Bromberg, 2002). Cyanoacrylate can be applied using a 1‐mL syringe in conscious dogs, or it can be applied in anesthetized animals using a small‐gauge needle. A contact lens after application improves comfort and aids in cyanoacrylate retention. This procedure aids healing but appears to have a longer healing time than ASP, grid keratotomy, or superficial keratectomy. Stromal Corneal Ulcers

Ulcerative keratitis that extends into the corneal stroma usually involves a secondary microbial infection that initiates or participates in the stromal destruction. Less commonly, traumatic injuries can result in a wound that extends into the deeper stroma. Generally, any visible defect in the corneal surface suggests possible stromal involvement (Fig. 19.20) because most ulcers involving only the epithelium are not readily visible (except possibly for indolent corneal ulcers) and require fluorescein staining for definitive diagnosis. Any ulcer with a suspected stromal defect should be cultured and corneal scrapings for cytologic examination performed, prior to instillation of fluorescein or other topical substances, to determine the underlying etiology, because of the high likelihood of microbial infection. These diagnostic tests are performed first to maximize growth of the organisms on culture and to avoid altering surface organisms or cell types. Stromal ulcers may be divided into progressive and nonprogressive types. Non-progressive deep ulcers can be managed medically, similar to superficial ulcers, with treatment directed by the results of culture and susceptibility testing. Surgical intervention is indicated in deep corneal ulceration (i.e., when depth of the corneal lesion is 50% of the corneal thickness or deeper). Surgical procedures most commonly employed in these cases include grafts from conjunctiva, amniotic membrane, bovine pericardium, or porcine urinary bladder, cornea, or synthetic or bioengineered grafts (Barros & Safatle, 2000; Barros et al., 1998, 2005; Blogg et al., 1989; Brightman et  al., 1989; Dice et  al., 1973; Hacker, 1991; Hakanson & Merideth, 1987; Hakanson et al., 1987; Hansen & Guandalini, 1999; Keller et al., 1973; Kuhns, 1979; Lewin,

Figure 19.20  Anterior stromal puncture performed for treatment of a spontaneous chronic corneal epithelial defect in a dog. A commercially available hypodermic needle with a small bend at the tip to control depth of penetration is used for the procedure shown here. A cotton-tipped applicator is used to prevent prolapse of the third eyelid.

Figure 19.21  Central, deep stromal corneal ulcer in a brachycephalic dog.

1999; Mueller, 1968; Mueller & Formston, 1969; Parshall, 1973; Scagliotti, 1988). Progressive deep stromal ulcers in the dog are potentially vision‐ and globe‐threatening, and therapy must be aggressive. Antibiotic selection is frequently made on the basis of cytology, culture, and susceptibility test results. Topical 1% atropine is administered to minimize the discomfort from ciliary muscle spasm and to prevent synechiae formation. If rapid stromal loss or melting are present, intensive topical antibiotic therapy (every 1–2 hours) is indicated, and bactericidal antibiotics with a spectrum that includes Gram‐negative rods, such as Pseudomonas aeruginosa, and Gram‐positive cocci, such as Staphylococcus and Strepotococcus spp. should be empirically selected while culture results are pending. Monotherapy with a broad‐spectrum antimicrobial such as a late‐generation fluoroquinolone (e.g., moxifloxacin, gatifloxacin) or combination therapy with an early‐generation fluoroquinolone (e.g., ciprofloxacin, ofloxacin) or aminoglycoside (e.g., tobramycin), in addition to a first‐generation cephalosporin (e.g., cefazolin) or triple antibiotic, are good empiric choices (Ledbetter et  al., 2007a; Tolar et  al., 2006; Varges et al., 2009). After culture and susceptibility testing results are received, the antibiotic regimen can be altered to more specifically target the infectious agent. Topical anticollagenase–antiproteinase preparations are also strongly recommended in cases of progressive ulcerative keratitis.

­ rocedure for proper application of the tissue adhesive can p be difficult and involves use of topical anesthesia (if general anesthesia is not used); debridement of the defect (as necessary and judiciously); drying of the site with a cotton‐tipped swab, cellulose sponge, or a warm‐air (i.e., hair) dryer; application of a thin layer of tissue adhesive through a 25‐ to 30‐ gauge needle; and prevention of blinking for 15–60 seconds while the cyanoacrylate solidifies. Care must be taken to apply a minimal amount of adhesive. Tissue adhesives are recommended only as an alternative treatment for use in small corneal lesions (diameter 7000 ft above sea level were 7.75 times more likely to develop CSK than dogs living at elevations between 3000 and 5000 ft (Chavkin et  al., 1994). Dogs from lower elevations with CSK tend to respond more favorably and with less intensive topical therapy than animals with the disease living at higher elevations. The age of onset and breed of the affected animal are of prognostic value in this condition. In German Shepherds affected at a fairly young age (i.e., 1–5 years), the condition is usually rapidly progressive and severe. In those animals first affected later in life (i.e., 4–6 years), however, the lesions appear be less severe and to progress more slowly.

A Figure 19.48  Mild (A) and severe (B) chronic superficial keratitis in the German Shepherd breed.

B

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Greyhounds, however, tend to be affected at younger ages, usually less than 2 or 3 years, but exhibit relatively mild lesions (Lynch, 2007).

SECTION IIIA

Histopathologic Features of Chronic Superficial Keratitis

CSK appears initially as superficial corneal vascularization, with progressive infiltration of granulation tissue into the superficial corneal stroma. The invading fibrovascular tissue is accompanied by lymphocytes and plasma cells. Generally, the corneal epithelium remains intact, but may be variably hyperplastic or atrophied. Migration of pigment‐laden cells (i.e., corneal melanosis) commonly accompanies the fibrovascular inflammatory infiltrate invading the anterior stroma. Infiltrating CD4+ lymphocytes are the predominant cell types found in CSK, suggesting an immune‐mediated pathogenesis. The CD4/CD8 ratio of infiltrating lymphocytes was consistently above two and rose to above four at the advancing border of the lesion in one study (Williams, 1999). In another study, immunohistochemical staining for canine immunoglobulin was noted in the superficial conjunctival stroma near the limbus and, in some specimens, in the superficial corneal stroma, but immunoglobulin was not present in the overlying epithelium, differentiating this condition from several other autoimmune diseases such as the pemphigus group and systemic lupus erythematosus (Eichenbaum et  al., 1986). Increased stromal and epithelial cell MHC class II antigen expression was detected in the central cornea of dogs with CSK (Williams, 2005). Since upregulation of MHC class II expression occurs on peripheral antigen presenting cells during an inflammatory response and is associated with increased presentation of extracellular antigens and activation of an immune response, this finding suggests that these cells play a role in perpetuating corneal inflammation and permitting the development of autoimmune reactions to normal canine corneal antigens. Elevated expression of MMPs in the cornea of dogs with CSK is reported, and it was suggested that induction of MMPs activity by ultraviolent radiation may be linked to the development of CSK (Chandler et al., 2008). Combining the results of these two studies suggests that MMP‐mediated enzymatic generation of altered ECM components, may be subsequently presented by MHC Class II by corneal keratinocytes and/or stromal keratocytes, resulting in the generation of an immune response to the damaged matrix. Cause

The cause of CSK in the dog has not been established, but current evidence suggests the condition is an immune‐mediated disease with a genetic basis. The cornea possesses tissue‐specific antigens that may be modified by external factors such as ultraviolet light. Ultraviolet radiation may alter the antigenicity of susceptible corneas, thereby resulting in cell‐mediated inflammation in susceptible dogs (Campbell et  al., 1975; Eichenbaum et  al., 1986; Stanley,

1988). An MHC class II risk haplotype was identified in German Shepherds with CSK, strongly suggesting the autoimmune nature of the condition. Dogs with the risk haplotype were 2.7 times more likely to develop CSK than dogs with other haplotypes, and homozygosity of the risk haplotype increased this risk to more than 8 times (Jokinen et al., 2011). CSK is characterized by increased numbers of mast cells and increased degranulation of mast cells compared with those of normal dogs and dogs with other forms of keratitis. This increase in mast cell activity, as well as the hypersensitivity response to corneal proteins displayed by dogs with CSK, further suggests involvement of an immune‐ mediated mechanism (Campbell et al., 1975). An additional indication that CSK is an immune‐mediated condition is the clinical observation that CSK can be controlled by topical administration of corticosteroids and cyclosporine (Williams et al., 1995). Evaluations for underlying infectious agents did not demonstrate the presence of organisms in CSK. Evaluation of CSK samples for Chlamydia was negative (Campbell & Synder, 1973). The finding of cylindrical cytoplasmic inclusions in corneal fibroblasts, vascular endothelial cells, macrophages, and trabecular cells of the eyes of dogs with CSK, but not normal dogs, suggested a viral infection, but none was detected (Rapp & Kolbl, 1995). Diagnosis and Differential Diagnosis

Signalment and clinical appearance of the lesions are usually sufficient to allow a diagnosis of CSK to be made (see Fig.  19.48). CSK must be distinguished from pigmentary keratitis resulting from other causes (e.g., chronic irritation), KCS, and corneal granulation tissue resulting from vascular healing of corneal wounds. Treatment

CSK can usually be controlled by a variety of medical and surgical methods, but it cannot be cured. Owners should be advised of the need for lifelong therapy to control this disease and that both severity and prognosis depend on many factors, including age of onset, altitude, and geographic location. Vision can usually be preserved with medical therapy alone in areas of low to medium elevation (i.e., 21 mmHg) in the canine glaucomas. In the Basset Hound glaucoma pattern, electroretinographic (ERG) changes occur before significant elevations in IOP can be detected (Grozdanic et al., 2010). The difference in the presentation and detection of glaucoma between humans and animals has much to do with the differences between POAG and primary narrow-angle/angleclosure glaucomas (PACG). POAG is the most common form of glaucoma in humans worldwide. In contrast, PACG in human in North America and Europe is less common, but it is the most frequently diagnosed form of primary glaucoma in Asian countries. In PACG, IOP may be within normal limits and then suddenly experience a series of very high levels, sufficient to result in abrupt clinical signs and significant adverse changes in all retinal layers (RGCs, nerve fiber layers, and the photoreceptors) and even the choroid (Whiteman et al., 2002). While POAG has been recognized in dogs, most notably in a colony of Beagles with inherited glaucoma (Gelatt, 1972; Gelatt et al., 1977b), PACG is considerably more common in veterinary species. However, despite variances of presentation and classification, in-depth study may reveal similarities in pathogenesis despite distinctive etiologies. Recent studies of chronic PACG in the Basset Hound suggest early and gradual elevations in IOP in this breed, and later acute bouts of very high elevations in IOP, which can profoundly affect vision, develop superimposed on these already damaged outflow pathways (Grozdanic et al., 2010). The glaucomas in animals are all thought to result from the decrease in aqueous humor (AH) outflow through the pressure-affected trabecular meshwork and/or the pressureindependent uveoscleral outflow (the intrascleral pathway between the sclera and ciliary body and/or choroid that extends to the ONH).

Veterinary Ophthalmology: Volume I, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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SECTION IIIA

Epidemiology of Primary and Secondary Glaucomas in the Dog Meaningful epidemiology studies in the dog followed the development of applanation tonometers for animals, implementation of tonometry in the complete ophthalmic examination in veterinary medicine, and development of veterinary ophthalmology as a worldwide clinical specialty in the 1960s. Comparisons of many different animal species indicate that only the dog and the human share closely the frequency of primary and secondary glaucomas. Comparisons of human populations across the board indicate that the frequency of the glaucomas is about 1%–2% of the population. Studies in domestic dog populations also reveal a prevalence of glaucoma of 1%–2%. These studies also document breed dispositions to POAG and PACG. The popularity of breeds of dogs varies by region and country, and new breeds are constantly being introduced. The popularity of each breed as well as the percentage of dogs diagnosed with glaucoma can represent large numbers of potential patients if both factors are high! Martin (1977) reported the prevalence of the canine glaucomas as 0.5% using the Veterinary Medical Data Base (VMDB). In a larger study covering nearly four decades, it was noted that the frequency or prevalence of the primary or breed-related glaucomas and secondary glaucomas in dogs presented to all veterinary teaching hospitals in North America is gradually increasing (Table  20.1A, Table  20.1B; Gelatt & MacKay, 2004a, 2004b). Prevalence for the breedrelated or primary types has increased from 0.29% (1964– 1973), 0.46% (1974–1983), 0.76% (1984–1993), to 0.89% (1994–2002). Predisposed breeds varied by decade, but the American Cocker Spaniel (ACS), Basset Hound, Wire Fox Terrier, and Boston Terrier were constantly high from 1964 through 2002. Glaucoma above the baseline of mixed-breed dogs (0.71%) presented in 27 breeds. Gender effect varied among breeds by decade, and in some breeds females were more often affected (i.e., ACS, Basset Hound, Cairn Terrier, English Cocker Spaniel, Jack Russell Terrier, Norwegian Elkhound, Samoyed, and Siberian Husky). A similar effect occurs in humans with narrow- or closed-angle glaucoma, in which females are affected much more often. Age of presentation with these glaucomas varied by breed, but was generally between 4 and 10 years of age. Of the top 27 breeds identified, few have been investigated in detail and reported in the literature. There have also been reports of glaucoma populations in the dog based on censuses from university veterinary medical hospitals and their academic referral ophthalmology clinics. These reports, like those in medicine, described patient populations in small cities or islands, and provide important information on the prevalence of the specific types of the glaucomas, breeds of dogs predisposed, possible

Table 20.1A  Breeds of dogs with the primary glaucomas. Akita

Italian Greyhound

Alaskan Malamute

Lakeland Terrier

Basset Hound

Maltese

Beagle

Miniature Pinscher

Border Collie

Miniature Schnauzer

Boston Terrier

Norfolk Terrier

Bouvier des Flandres

Norwegian Elkhound

Brittany Spaniel

Norwich Terrier

Cairn Terrier

Poodle – Toy/Miniature

Cardigan Welsh Corgi

Samoyed

Chihuahua

Scottish Terrier

American Cocker Spaniel

Sealyham Terrier

Dachshund

Shih Tzu

Dalmatian

Siberian Husky

Dandie Dinmont Terrier

Skye Terrier

English Cocker Spaniel

Smooth Fox Terrier

English Springer Spaniel

Tibetan Terrier

German Shepherd

Welsh Springer Spaniel

Giant Schnauzer

Welsh Terrier

Greyhound

West Highland White Terrier

Irish Setter

Wirehaired Fox Terrier

geographic differences, and other factors. Interestingly, these reports of small patient populations provided similar results. Walde published several reports on the frequency of the glaucomas in the dog based at the Vienna Small Animal Hospital from 1975 to 1980 (Walde, 1982a, 1982b). Of the total of 167 glaucomatous dogs, primary glaucoma affected 51 dogs (30.5% of the glaucoma dogs; 84 eyes). Affected dogs included the Miniature Poodle (99), Fox Terrier (9), Welsh Terrier (8), Japanese Terrier (7), English Cocker Spaniel (6), mongrel (6), Dachshund (5), ACS (2), St. Bernard (2), German Shepherd (2), Airedale Terrier (2), Standard Schnauzer (2), and other breeds (17). One publication of this series included 116 dogs with secondary glaucomas. Causes for the secondary glaucomas included cataract, trauma, uveitis, zonular defects and lens displacement, chorioretinitis, intraocular tumor, uveokeratitis, corneal perforation, progressive retinal atrophy, aphakia, Collie eye anomaly, and retrobulbar tumors. Boevé and Stades (1985) reported on the canine and feline glaucoma patients during a 4-year period at the University of Utrecht, based on 421 patients that accounted for 8.6% of all of the Small Animal Clinic patients. In the canine population, 155 and 224 dogs presented with the primary and secondary glaucomas, respectively. Primary glaucoma occurred most frequently in the ACS, Bouvier des Flandres, Basset Hound and Basset Artésien Normand,

20: The Canine Glaucomas

1175

Table 20.1B  Breeds of dogs with the highest prevalence of the primary glaucomas in North America from 1994 to 2002.   No. of Individuals

  Overall

 

  American Cocker Spaniel

 

  Basset Hound

 

  Chow Chow

 

  Shar-Pei

 

  Boston Terrier

 

  Fox Terrier, Wire

 

  Norwegian Elkhound

 

  Siberian Husky

 

  Cairn Terrier

 

  Poodle, Miniature

 

  Samoyed

 

  Bichon Frise

 

  Shih Tzu

 

  Australian Cattle Dog

 

  Akita

 

  Jack Russell Terrier

 

  English Cocker Spaniel

 

  Lhasa Apso

 

  Bouvier Des Flandres

 

  Pekingese

 

  Poodle, Toy

 

267201 10591 2370 2083 1841 2151 832 405 2867 823 3684 1383 1766 4376 1461 1291 1679 591 2262 609 1562 3003

  No. with Glaucoma

                                           

2381 585 129 98 81 62 19 8 54 15 62 22 28 69 22 18 23 8 30 8 19 36

  % Affected

                                           

0.89 5.52 5.44

SECTION IIIA

  Breed

4.70 4.40 2.88 2.28 1.98 1.88 1.82 1.68 1.59 1.59 1.58 1.51 1.39 1.37 1.35 1.33 1.31 1.22 1.20 (Continued)

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Section IIIA: Canine Ophthalmology

Table 20.1B  (Continued)

SECTION IIIA

  Breed

  No. of Individuals

  Beagle

 

  Brittany Spaniel

 

  Saint Bernard

 

  English Springer Spaniel

 

  Poodle, Standard

 

  Dalmatian

 

  Mixed Breed

 

3457 1582 859 3111 2205 3061 55947

Beagle, Great Dane and German Shepherd, English Cocker Spaniel, and Toy and Miniature Poodle breeds. The secondary glaucomas were grouped into those with lens dislocations, iritis or uveitis, trauma, tumors, or postlens extraction. Of the secondary glaucomas, 182 (80%) had lens dislocations and were concentrated in the small terrier breeds, which indicated that glaucoma and possible zonulary defects were related. The most recent study from the University of Zurich in 2011 (Strom et al., 2011a, 2011b) reported 4 congenital, 123 primary, and 217 secondary cases of canine glaucoma documented from a period of 1995 through 2009. Primary glaucoma occurred with an overall male-to-female ratio (M : F) of 1 : 1.41 and an age of onset that ranged from 0.12 to 18.3 years (mean 7.3 ± 3.6 years). Breed predisposition occurred in the Siberian Husky, Magyar Vizsla, and Newfoundland. Secondary glaucomas affected dogs ranging in age from 88 days to 19 years (mean 7.7 ± 3.6 years), and accounted for 3.6% of all ophthalmology patients seen at the University of Zurich. Breed predisposition for the secondary glaucomas included the Cairn Terrier (ocular melanosis), Jack Russell Terrier (lens displacement), and English Cocker Spaniel breeds. For most cases with bilateral disease, both eyes shared the same risk factor (anterior uveitis or lens luxation). Causes identified with the secondary glaucomas included anterior uveitis (23.0%), lens luxation (22.6%), intraocular surgery (13.4%), intraocular neoplasia (10.6%), unspecified trauma to the globe (8.3%), ocular melanosis (6.9%), hypermature cataract (6.9%), and hyphema (3.23%). The prevalence of five different types of the secondary glaucomas in the dog in North America from 1964 to 2002

  No. with Glaucoma

             

38 15 8 23 16 22 395

  % Affected

             

1.10 0.95 0.93 0.74 0.73 0.72 0.71

varied by decade: 0.25% (1964–1973), 0.46% (1974–1983), 0.79% (1984–1993), and 0.80% (1994–2002) (Gelatt & MacKay, 2004b). The increasing prevalence may be real or may reflect better recognition of the condition, but in general, secondary glaucoma tends to be more prevalent than the primary forms. From the total population of 1,592,831 dogs, secondary glaucoma was diagnosed in 9,695 dogs (Gelatt & MacKay, 2004b). The secondary glaucomas investigated were limited to those associated with cataract formation, lens luxation, cataract surgery, uveitis of unknown cause (7.1%), hyphema of unknown cause (7.3%), and intraocular neoplasia (3.5%). It is likely that the real prevalence was underestimated. In this study, the preexisting condition (e.g., cataract, lens luxation) had to have been diagnosed prior to the onset of the ocular hypertension in order to confirm the secondary nature of the glaucoma. The secondary glaucomas associated with cataract formation and lens-induced uveitis represented 80+% of the total secondary glaucomas. A 5-year study from the University of California Davis reported secondary glaucoma occurring in 156 of 2,257 (6.9%) dogs examined because of ophthalmic disease. Both eyes were affected in 33 (21.2%) of these dogs (Johnsen et al., 2006). The most common causes of secondary glaucoma were nonsurgical anterior uveitis (44.9%), anterior uveitis associated with prior phacoemulsification (15.8%) and lens dislocation (15.2%). Certain breeds were predisposed to secondary glaucoma and included Parson Russell Terriers, Poodles, Boston Terriers, ACS, Rhodesian Ridgebacks, and Australian Cattle Dogs. No significant effects of gender and neuter status, age, or laterality on the cause of secondary glaucoma were detected.

Classification of the Glaucomas In comparative ophthalmology, a glaucoma classification that crosses all species including humans would be ideal. Because no single multispecies classification scheme is totally satisfactory, combinations of a variety of schemes are typically used in the dog. Canine glaucomas may be classified on the basis of the probable cause (primary, secondary, or congenital), the gonioscopic appearance of the filtration angle (i.e., open, narrow, or closed iridocorneal angle (ICA) and open, narrow, or collapsed ciliary cleft), and the duration or stage of the disease (Table 20.2). The first criterion of classification involves the likely etiology and makes a distinction between primary (open angle or narrow/closed angle), secondary, and congenital forms. In the primary glaucomas, the IOP elevation develops without concurrent ocular diseases, is hereditary in many canine breeds, and has the likelihood of bilateral development. Primary glaucomas may result from abnormal biochemical metabolism of the trabecular meshwork cells of the outflow system (in the POAG) or the physical effects of pupillary blockage and changes in the ICA and ciliary cleft (in the PACG). The canine ICA is the opening of the most anterior portion of the ciliary cleft ICA as viewed by gonioscopy (excluding the ciliary cleft and its contents). Only the pectinate ligaments, part of the uveal trabeculae, and the anterior opening of the ciliary cleft can be visualized via gonioscopy. The entire length of the ciliary cleft can be viewed only with Table 20.2  Types of glaucomas in dogs. A. Primary (Breed-Related) Glaucomas Open/normal-angle/cleft: Acute/chronic Narrow/closed-angle/cleft: Acute/chronic Narrow/closed-angle cleft and pectinate ligament abnormalities: Acute/chronic B. Secondary Glaucomas Uveitis Lens luxations Intumescent cataract Phakolytic/phacoclastic uveitis Hyphema Intraocular neoplasia Aphakic Malignant/ciliary block Melanocytic/pigment cell proliferation Pigment cell exfoliation/anterior uveal cysts Giant retinal tears (Schwartz–Matsuno syndrome) Anterior chamber silicone oil Postoperative ocular hypertension C. Congenital Glaucoma Pectinate ligament dysplasia Goniodysgenesis

advanced imaging techniques such as ultrasonography (usually 20 MHz or higher). The AH pathway remains constant among most domesticated species with formation by the nonpigmented ciliary body epitheliae, transport through the posterior chamber, pupil and into the anterior chamber, and exit from the eye through the conventional (trabecular meshwork) and unconventional (uveoscleral) pathways. In instances of glaucoma, elevation of IOP results from compromise of AH outflow. In the dog, the majority of the filtration angle (e.g., the deeper corneoscleral meshwork and all of the uveal trabecular meshwork) is located in the ciliary cleft. This anatomic arrangement seems to be based on the needs of the canine lens and accommodation, rather than on AH outflow; in fact, at the microscopic and ultrastructural levels, the AH outflow pathways are nearly identical among most reported species. It is probably more accurate to refer to the ICA as the filtration angle, corneoiridociliary angle, or anterior chamber angle. In the dog, the primary and breed-related glaucomas as well as the secondary glaucomas constitute the largest clinical groups. Open-angle glaucoma is characterized in this way when clinical signs and tissue degeneration develop in the face of an initially open filtration angle and ciliary cleft, as viewed with gonioscopy, high-resolution ultrasonography (HRUS), ultrasound biomicroscopy (UBM), or optical coherence tomography (OCT; see Chapter 10, Parts 2 and 3). However, as the disease progresses, there is gradual observable closure of the filtration apparatus. Narrow or angle-closure glaucoma typically presents with acute IOP elevations and obviously narrowed filtration angle as viewed with gonioscopy. Pectinate ligament dysplasia (PLD) or the consolidation of adjacent pectinate ligaments into broad sheets (initially termed mesodermal dysgenesis) with flow holes is common in the dog, and often described in PACG. Persistent mesodermal bands and PLD-associated glaucomas in selected breeds have been classified with the primary glaucomas because the clinical signs of these glaucomas occur later in life, even though the structural appearance of the filtration angle is abnormal from birth. As the basic pathogenesis for all breed-related glaucomas becomes documented, these glaucomas may be classified into more specific types. The term goniodysgenesis is frequently used in the veterinary literature, and in the dog it usually signals the failure of rarefaction to form pectinate ligaments at gonioscopy, though the status of deeper AH outflow tissues, especially the trabecular meshwork and trabecular extracellular matrix (ECM), is not known. A more accurate phrase than the inclusive goniodysgenesis is PLD. Tonometry of nearly all eyes with extensive PLD indicates a normal range of IOP. Tonographic evidence of outflow problems has not been demonstrated in eyes with PLD, but the persistence of broad sheets of tissue spanning the region of the pectinate ligaments has been frequently associated as a risk factor (but not direct causation), both goni-

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oscopically and histopathologically, for primary narrow or angle-closure glaucomas in the dog. Breed-specific glaucomas in dogs with PLD generally do not occur in early life but in middle‐aged to older dogs (i.e., 6–10 years). HRUS supplements routine gonioscopy by providing essential information on the anatomy of the entire ciliary cleft anterior opening and its length. PLD may also signal an underlying disease (or diseases) of the trabecular meshwork and ECM, as suggested by the results of histologic examination of the Bouvier des Flandres glaucoma, in which deposits of periodic acid‐Schiff (PAS)– positive material within the AH outflow pathways occurred concurrently with the PLD (van der Linde‐Sipman, 1987). Some percentage of undifferentiated pectinate ligaments may also be normal for the dog eye. The appearance of PLD has been reported to increase in severity with aging in the Basset Hound, Flat‐Coated Retriever, and English Springer Spaniel. A recent study in the Basset Hound colony has suggested the disease be classified “chronic angle‐closure glaucoma,” as tonometry of early‐affected dogs has documented that a slow and gradual increase in IOP occurs before the high‐pressure acute clinical appearance of the disease (which often prompts the first presentation of clinical patients; Grozdanic et al., 2010). In the secondary glaucomas, the increase in IOP is associated with some known antecedent or concurrent ocular disease that physically obstructs the aqueous outflow pathways. These tend to be unilateral conditions and are not inherited, except for those glaucomas related to the lens. Some of the conditions that may initiate these forms of glaucoma, however, may be genetically determined in certain breeds, such as those with cataracts and lens subluxation or luxation. Possible mechanisms for the development of the secondary glaucomas include ICA obstructed by preiridal fibrovascular membranes, endothelialization and descemetization or inflammatory cells and proteins or red blood cells, lens luxation, obstruction of the pupil or pupillary block, anterior synechiae, or obliteration of the AH outflow structures secondary to neoplasia or necrotizing inflammation (Smith et al., 1993). It is useful to assess the condition of the anterior chamber angle and ciliary cleft (open, narrow, closed) with gonioscopy. Unless there is concurrent inherited disease, compromise of the filtration angle in secondary glaucomas is the consequence of the underlying condition rather than being due to a programmed anatomic abnormality. As many glaucomas advance or progress, the anterior chamber angle may be observed to progressively narrow and eventually close with persistent damage. In some breeds in which PLD appears to increase in severity with age, inflammation may play a very important role in elevating IOP. Hence, gonioscopic findings of a glaucomatous eye can change as the disease progresses, which affects the classification of the type of glaucoma and the choice of medical and/or surgical therapies. Therefore, in

the classification of the POAG and PACG types, the results of early gonioscopy of the fellow “normotensive” eye is often critical, as secondary changes may have already developed in the hypertensive (presenting) eye. Prophylactic therapy of the fellow normotensive eyes in PACG patients has merit and can prolong vision (Miller et al., 2000). Congenital glaucomas, which typically present in the first few months of an animal’s life with overt and severe developmental anomalies of the anterior segment, are rare (Smith et al., 1993; Strom et al., 2011b). They usually present in puppies or dogs less than 6 months of age. The extent of the angle anomaly may affect the time of onset for the elevation of IOP: the more severe the defect, the sooner the elevation in IOP, and clinical signs, occurs. Classification of the canine glaucomas by duration (i.e., acute, subacute, chronic) is useful clinically, but may be misleading. The appearance of clinical signs (prompting presentation) may not correlate with the amount of damage already sustained. Corneal edema, episcleral injection, globe enlargement, and a dilated pupil may be the first clinical signs of glaucoma noticed by a pet owner or veterinarian. IOP in excess of 40 mmHg appears necessary for corneal endothelial dysfunction to develop, but these eyes may not truly be at an early or acute stage of the actual disease at presentation. Glaucoma in one eye, with mild or moderate elevation in IOP, is often not noticed by the owner; hence, most dogs are not presented to a veterinarian until extensive damage or even blindness is present in the first eye with primary glaucomas. The longer an eye suffers from elevated IOP, either periodic or persistent, the more damage that eye will sustain. Important also is the degree of elevation. An IOP of 35 mmHg in the short term is not nearly as damaging as an IOP of 70 mmHg. The acute‐onset high IOP with PACG tends to be more destructive of the entire retina, choroid, and ONH, whereas POAG dogs often preserve central vision (the peripheral retina is more sensitive to high IOP) for long periods of time.

Clinical Signs Clinical signs of the glaucomas depend on the stage of disease and, to some extent, on the type of glaucoma. Clinical signs are also directly related to the level and duration of the elevation in IOP. As the glaucomas are usually progressive diseases, the clinical signs of the disease also change and are used to ascertain the relative stage of the glaucoma. The stage of glaucoma may be asymmetric in the fellow eyes of the same dog, with one eye at advanced stages of disease and the other apparently normal or at very early stages. In the earliest phases of PACG and POAG in the dog, the disease is usually insidious, and the eyes are generally asymptomatic (Fig. 20.1). Early signs may be subtle and range from none to slight mydriasis, mild but transient corneal edema, variable episcleral congestion, to normal ONH appearance,

Figure 20.1  Early open-angle glaucoma in a dog. Slight mydriasis in a darkened room is the only clinical sign; intraocular pressure is 32 mmHg.

and IOPs are generally just slightly above reference ranges (approximately 25–30 mmHg). In the authors’ experience, dogs with early POAG may present only with mild, progressive vision loss, such as agility dogs who miss obstacles. Unless periodic and even diurnal tonometry and careful ophthalmoscopy are performed, these early glaucomatous eyes are not usually presented to the veterinarian for ophthalmic examinations until the disease advances to more overt clinical signs. Cases of POAG (but not PACG) can, however, be detected when tonometry is part of the complete eye examination that occurs with annual eye exams in purebred dogs checked for inherited eye diseases. Dogs with PACG are subject to sudden and marked elevations in IOP. Exactly what triggers this sudden increase in IOP is unknown, but the narrow ICA and ciliary cleft appear to collapse. Periodic tonometry has a low chance of encountering the precise timepoint of IOP elevation in PACG, but diurnal tonometry has not been evaluated as a substitute. In humans with PACG, larger diurnal IOP fluctuations are twice as great as in normal eyes (Baskaran et  al., 2009). Not infrequently, the first presentation of a dog with PACG has the initial affected eye already enlarged (buphthalmos) and blind, but the fellow eye may be normotensive (Fig. 20.2). Improvements in diagnostic technologies, such as high‐resolution imaging, allow detection of glaucoma at an earlier stage, for example thinning of retinal nerve fiber layer (RNFL) by OCT (Graham et  al., 2020), or narrowing of ciliary cleft by UBM (Hasegawa et al., 2016). The clinical signs of moderate glaucoma include more pronounced degrees of mydriasis (especially in a darkened room), episcleral congestion, variable degrees of corneal edema and striae, slight buphthalmia, early lens subluxation, variable retinal and ONH changes, and untreated IOPs of 30–40 mmHg. When primary glaucoma is advanced, clinical signs may include intermittent visual impairment to total blindness, persistent mydriasis, peripheral anterior synechiae and angle closure with peripheral corneal edema, diffuse corneal edema

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Figure 20.2  Chronic angle-closure glaucoma and pigmentary keratitis in a Shih Tzu. Note the profound buphthalmos of the left globe.

with corneal striae, buphthalmia, lens displacement from the patella fossa, cortical cataract formation, vitreous degeneration and syneresis, extensive retinal and ONH degeneration, and untreated IOPs of greater than 40–50 mmHg. Occasionally, with IOPs in excess of 50 or 60 mmHg, mild papilledema may be detected through a less than transparent ocular media. Presumably, the optic nerve fibers within the prelaminar ONH and peripapillary retina are enlarged because of impaired axoplasmic transport at the prelamina cribrosa. With very high elevations in IOP or chronicity, wedge‐shaped areas of chorioretinal degeneration based at the edge of the ONH may result, apparently from ischemia secondary decreased blood flow within individual short ciliary arteries (Burn et al., 2017). ONH cupping is usually slight and most obvious with advanced atrophy. Loss of myelin within the ONH in glaucoma results in round and smaller than normal optic discs. The signs of the secondary glaucomas are like those of the primary glaucomas, but the cause for the rise in IOP, such as an anterior uveitis, an intraocular mass, or a lens luxation, is evident. By gonioscopy the ICA and cleft may be open, narrow, or closed dependent on the inciting cause. The congenital glaucomas affect young puppies, usually within the first 1–6 months of life, and compared to the primary and secondary glaucomas are quite rare. Often, the first clinical sign in these animals is rapid onset of profound buphthalmia, inability to completely close the palpebral fissure, and the development of exposure corneal disease.

Diagnostics The three basic clinical procedures for the diagnosis and clinical management of glaucomatous patients are tonometry, gonioscopy, and ophthalmoscopy. However, high‐resolution

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imaging procedures, such as 20, 35, 50, 60, or 70 MHz ultrasonography and anterior segment OCT, are supplementing these clinical diagnostics to noninvasively and serially observe the trabecular meshwork and entire ciliary cleft.

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Tonometry Reliable tonometry is essential for optimal clinical management of canine glaucomas. Of the three types of tono­ metry  –  that is, indentation (Schiøtz), applanation, and rebound – only the latter two types are recommended in veterinary ophthalmology. Current tonometers for animals are based on either the Mackay–Marg applanation principle, the rebound magnetic effect, or the exchange of gas (now air) with the pneumatonograph. Applanation tonometers are fitted with a force plate in their tips that measures the amount of force necessary to indent or flatten a defined surface area of cornea. That force is then correlated to the IOP, an internal force that generates turgidity. In rebound tonometers, a magnetic field is induced that propels a small magnetized probe (plastic tip 1.4 mm in diameter) against the cornea. The probe “rebounds” from the cornea at different velocities (dependent upon the level of IOP), causing voltage changes within the tonometer’s collar, which are converted into electrical signals calibrated to different levels of IOP. For additional information, consult Chapter 10, Part 1. Clinical and experimental impressions suggest that the TonoVet® (rebound tonometer) measurements are slightly lower than those from the Tono‐Pen® XL (applanation tonometer) when IOPs are within the normal range (10–25 mmHg), but perhaps more accurate when IOP exceeds 40 mmHg. The pneumatonograph is an accurate tonometer for the dog that can provide paper verification, but requires 1 or 2 seconds of corneal contact for measurements. Repeated measurements can cause direct superficial corneal damage (the eye often moves during tonometry in the conscious dog). Other tonometers that also require a few seconds of corneal contact for IOP measurements, such as Perkins or Draeger, are not very useful in the dog (Andrade et al., 2009), but in species with limited eye movements (rabbit, sheep, cattle, horse, etc.) the pneumatonograph, available commercially, is quite useful. Normal variations of IOP have been documented in the dog and are dependent upon a variety of factors, including anatomic conformation, level of excitement, time of day, age, and the instrument used for estimating IOP. Several publications have given ranges for normal IOP with different instruments: 16.7 ± 4.0 mmHg (Tono‐Pen XL) and 15.7 ± 4.2 mmHg (Mackay–Marg), and in a larger group, 18.7 ± 5.5 mmHg (Tono‐Pen XL) and 18.4 ± 4.7 mmHg (Mackay– Marg; Gelatt & MacKay, 1998a) and 12.9 ± 2.7 mmHg (Tono‐ Pen XL) and 10.8 ± 3.1 mmHg (TonoVet; Leiva et al., 2006). Tonometry in the outpatient clinic provides only an “instant snapshot” or a single point in time, while multiple measure-

ments of IOP over a 24‐hour period can be more informative, because IOP is a biologic variable. The mental state of the dog must also be considered as animals that are highly nervous, or not used to being handled, or closely restrained may yield IOPs that are falsely elevated. Acclimation to the clinical environment and diurnal IOP measurements in these dogs can provide a more accurate estimation of the actual IOP and its trends. Diurnal variations in IOP has been documented in the dog, with higher levels in the early morning and the lowest readings in the early evening (Gelatt et al., 1981a). In the normal dog, these diurnal variations span approximately 2–4 mmHg, but in the dog with untreated POAG, the diurnal variations may increase to 6–10 mmHg or more. This difference can be informative and may prompt further investigation into the presence of or predisposition to glaucoma. Also, normotensive fellow eyes in a POAG dog will often have IOP differences that can exceed 4–6 mmHg (normal eyes have less than 2–3 mmHg difference). These same differences have been reported in Basset Hound PACG (Grozdanic et al., 2010). The peak levels of IOP are potentially the most damaging; in humans, both normal and with POAG, the diurnal IOP curves represent an inverted “U,” while the diurnal curves in human PACG patients form an inverted, steep‐troughed “V.” In PACG human patients, the highest IOP was at 06:00 and midnight, and there was a comparatively low IOP at 15:00. Following peripheral iridotomies, the diurnal curves of human patients usually convert to the shape associated with normotensive groups. This suggests that pupillary dilatation in these patients may account for the “V”‐shape diurnal curve (Baskaran et al., 2009). IOP screening in “spot checks” for PACG breeds of dog appears to be not very informative and predictive, and may have limited value to detect affected dogs (Sandberg & Miller 2005). Diurnal IOP variations have not been reported in eyes with early to advanced PACG in the dog. The same may not be true for breeds with POAG. Tonometry is an essential diagnostic for the clinical management of glaucomas in the dog. As discussed later in this chapter, monitoring for response to therapy and determination of whether or not “safe” and “target” IOP levels have been achieved is only possible when tonometry is routinely performed on the glaucomatous patient at every visit. Technologies that allow more frequent IOP measurements will allow more accurate early diagnosis and assessment of response to therapy in the future. Such methods may include user‐friendly home tonometry and continuous IOP monitoring with telemetric technologies (Komáromy et al. 2019). In the dog with POAG, the elevations in IOP become progressively higher, and IOPs of 35–40 mmHg may not initially produce dramatic clinical signs. Once overt clinical signs of glaucoma develop, it may be difficult to slow or prevent the progressive damage that results from IOP elevations. And in many forms of POAG, by the time

overt clinical signs have developed, the drainage angle may have already narrowed or closed.

Gonioscopy Gonioscopy is the noninvasive visual examination of the ICA and opening of the ciliary cleft (i.e., the filtration angle). The uveal trabeculae are located immediately posterior to the pectinate ligaments and are visualized directly during gonioscopy. Gonioscopy has been documented and performed in the dog since the 1930s (Troncoso, 1948), and it was an important diagnostic in the early reports of PACG in the ACS. Gonioscopy was widely embraced in clinical veterinary ophthalmology in the clinical management of canine glaucomas in the late 1970s (Bedford, 1973, 1977a, 1977b; Martin 1969). Gonioscopy permits classification of glaucoma on the basis of the ICA and anterior ciliary cleft morphology (i.e., open, narrow, and closed filtration angles and ciliary clefts; see Chapter 10, Part 1). Both direct and indirect gonioscopic lenses are used, with the former type of lenses most popular and less expensive. Gonioscopic findings in both POAG and PACG are dynamic, changing as the glaucoma and globe enlargement progress. Early diagnosis may be the only accurate method of separating POAG from PACG, because in the dog with enlargement of the globe caused by the IOP elevation, the ICA eventually narrows and the ciliary cleft collapses. Also with globe enlargement, zonular breakage can occur, resulting in lens subluxation to total luxation. The loss of zonular tension may also contribute to the ICA closure and ciliary cleft collapse. Accurate distinction between POAG and PACG often depends upon examination of the normotensive fellow eye, due to the confounding changes that may be present in the hypertensive eye.

The gonioscopic lens may be tilted at the apex and periphery of the cornea, thus indenting the cornea in an attempt to differentiate appositional angle closure (i.e., temporary, reversible) from angle closure with peripheral anterior synechiae (i.e., permanent, irreversible; Ekesten & Narfström, 1991). With only apposition of the basal iris across the outflow pathways, a progressive widening of the angle occurs. With peripheral synechial closure, this direct compression of the cornea does not result in a change in the gonioscopic appearance of anterior outflow pathway. If the pressure by the goniolens is applied on the peripheral cornea, the opposite ICA is most affected by the displacement of AH. HRUS (20 MHz), UBM (50–60 MHz), and OCT are useful methods of differentiating the temporary, appositional angle closure (only contact) from more permanent synechial closure (Sakuma et al., 1997) and of evaluating the entire ICA and sclerociliary cleft (see Chapter 10, Part 2; Bentley et al., 2003; Gibson et al., 1998; Mandell et al., 2003; Miller et al., 2004). The combination of gonioscopy with these new imaging modalities can markedly expand the diagnostic and monitoring approach to the canine glaucomas. Gonioscopy can also be used to detect PLD (or the consolidation or fusion of many pectinate ligaments) and the extent of involvement of the entire ICA circumference. Gonioscopy observations should evaluate the width of the ICA, depth of the sclerociliary opening and cleft, length and diameter of pectinate ligaments, as well as any other anatomic abnormalities such as PLD, extent of dysplastic areas, and number of flow holes by quadrant or degrees. Broader pectinate ligaments are referred to as fibrae latae. Ekesten in his investigation of the Samoyed PACG proposed a grading scheme to classify the width of the ICA and ciliary cleft (Ekesten & Narfström, 1991; Fig. 20.3).

Figure 20.3  Grading by gonioscopy and a schematic of the iridocorneal angle and opening of the sclerociliary cleft (left to right): closed, very narrow, narrow, open (or normal), and more open than normal.

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The information gleaned from gonioscopic examination may be useful for giving breeding advice for breeds predisposed to PLD and glaucoma. Recommendations to examine the ICA by gonioscopy as part of genetic eye screening and in giving breeding advice for dogs with PLD differ between the American College of Veterinary Ophthalmologists (ACVO) and the European College of Veterinary Ophthalmologists (ECVO). The ECVO has stricter guidelines regarding the need for gonioscopy and the exclusion of PLD‐affected animals from breeding. Gonioscopy is advised by the ECVO in the following breeds: ACS, all types of Bassets, Bouvier des Flandres, Chow Chow, Border Collie, Dandy Dinmont Terrier, Rough‐Haired Dutch Shepherd, English Springer Spaniel, Entlebucher Mountain Dog, Flat‐ Coated Retriever, Siberian Husky, Leonberger, Magyar Vizsla, Samoyed, and Tatra. PLD is classified by the ECVO, based on severity, as free, fibrae latae (abnormally broad and thickened pectinate ligament fibers), laminae (solid plates or sheets of pectinate ligament tissue), and occlusio (persistence of an embryonic sheet of ICA tissue and the absence of intraligamentary spaces, except for flow holes). Fibrae latae, laminae, and occlusio are associated with a narrow ICA. With fibrae latae affecting 50% or less of the pectinate ligament circumference, the animal can still be considered unaffected; however, a diagnosis of laminae in more than 50% of circumference is considered severely affected. In addition to PLD, the ECVO recommendations also include ICA width: open, narrow, or closed. Performing gonioscopy as part of genetic eye screening remains optional according to the ACVO, despite the recent issue of a special form by the ACVO Genetics Committee and the Orthopedic Foundation for Animals for information gathering and tracking information related to PLD. There are currently no ACVO guidelines against the breeding of PLD‐affected dogs. The less restrictive ACVO recommendations were justified by the poor predictive value of gonioscopy findings for PACG development in individual dogs and their offspring. Furthermore, without the additional assessment of the ciliary cleft width by HRUS or UBM, examination of the ICA by gonioscopy alone may not provide a complete picture of the status of the AH outflow pathways.

Ophthalmoscopy The third diagnostic procedure recommended in clinical management of the glaucomatous canine patient is a combination of direct and indirect ophthalmoscopy. The direct method permits higher magnification (magnification 17.2× lateral and 405× axial with direct; magnification 1.7× lateral and 4× axial with indirect when using a 20 D lens, respectively) to examine the ONH, while the indirect method facilitates examination of the peripheral fundus and its vasculature. The ONH neuroretinal rim and cup should be evaluated for evidence of thinning and enlargement, respec-

tively. The red‐free filter of the direct ophthalmoscope, which results in a green light source, permits examination of the RNFL for nerve fiber bundle defects, as well as examination of the neuroretinal rim. The myelinated axons of the canine ONH limit early detection of neuroretinal rim narrowing and cup enlargement in early POAG. The degree of optic nerve recession or cupping can be grossly evaluated by determining the variable diopter settings of the direct ophthalmoscope required to focus on the rim and the center of the optic cup. PACG glaucomas with abrupt bouts of marked elevations in IOP tend to produce progressive ONH degeneration along with generalized retinal degeneration, while slower and gradual elevations of IOP in POAG tend to produce optic disc cupping, gradual loss of myelin (the ONH becomes round), smaller pigmented optic discs with loss of the peripheral retinal vasculature and retinal degeneration, but preservation of the central retina and vasculature (and central vision). Generalized atrophy of the optic nerve, including loss of myelination, shrinking and darkening of the optic nerve, is common in all instances of glaucoma in the dog.

Ultrasonography and High-Resolution Imaging Advanced noninvasive imaging techniques that permit examination of the anterior chamber and outflow pathways can nearly approximate the resolution of routine histology and can be performed in the early stages of the disease (and before enucleation is usually justified). Routine 10–12 MHz ultrasonography has 300–400 μm resolution; HRUS 20 MHz and UBM 60 MHz resolutions approach 80 (HRUS) to 20 (UBM) μm, respectively (Bentley et  al., 2003; Gibson et  al., 1998; Miller et  al., 2004). OCT may be useful; its resolutions approach 10 μm (Leung et al., 2005). Both HRUS (20 MHz) and UBM (50–60 MHz) have been reported on in dogs, with both methods using sedation or general anesthesia. Amplitude scan (A‐scan) clinical ultrasonography (10–12 MHz) has been used to measure noninvasively the anteroposterior globe length, anterior chamber depth, lens thickness, and anteroposterior dimension of the vitreous body. Several reports of these ultrasonic measurements on the different parts of the canine eye have been published, although specific breed and age measurements are limited (Cottrill et al., 1989; Ekesten & Narfström, 1991; Gelatt et al., 1983; Schiffer et  al., 1982). Results of ultrasonic studies of PACG glaucoma in Samoyeds suggest a narrow‐ or closed‐ angle glaucoma pathogenesis with a narrowed anterior chamber, but increased thickness of the axial lens and vitreous body (Ekesten, 1993). These same findings also occur in PACG in people (Marchini et al., 1998). In early POAG of the Beagle, results of A‐scan ultrasonography indicate an enlarged anterior chamber and vitreous space, but a normal axial lens length and position (Gelatt et al., 1977b). The lens

thickness can increase as subluxation and tearing of the zonules occur (the lens less influenced by ciliary body contraction becomes somewhat more round in shape). Color Doppler imaging can noninvasively estimate blood flow parameters in the orbital and ocular tissues. These blood flow parameters have been reported in normal dogs, and reduced levels occur in POAG in the Beagle (Gelatt et  al., 2003; Gelatt‐Nicholson et al., 1999). The 20 MHz and 50 MHz models are the most versatile in a clinical setting and permit precise measurements of the anterior segment. They can image the ICA, pectinate ligaments, and sclerociliary cleft, and provide measurements of the entire depth and width of the ciliary cleft, anterior chamber depth, and relationships of the iris and pupil. These numeric measurements also permit statistical analysis of these observations and intraocular relationships. These imaging procedures are becoming commonplace in the clinical management of the canine glaucomas, and will refine our diagnostics, facilitate accurate determination of the type of glaucoma early in the disease process (open versus closed ICA, open versus closed ciliary cleft, other abnormalities), and increase our success rates in the preservation of vision and normal levels of IOP by permitting intervention in the earliest stages of the disease. UBM studies in Japan indicate that PACG eyes have reduced size in the opening and area of the ciliary clefts and scleral venous plexus. In those globes that responded to medical therapy, the size of the ciliary cleft and scleral venous plexus were increased (Hasegawa et  al., 2016). See Chapter  10, Parts 2 and 3, for further discussion of these imaging modalities.

Tonography Tonography is tonometry expanded over 2–4 minutes that permits quantification of the IOP‐sensitive component of the AH trabecular meshwork outflow. Tonography in humans has confirmed that nearly all the different types of human glaucoma (the sole exception being the very rare hypersecretion glaucoma) result from impairment of the AH outflow. In the dog, the prevailing assumption is that the different primary, secondary, and congenital glaucomas also result from impairment of the AH outflow, though tonographic documentation of the progressive obstruction of AH outflow has been obtained only for inherited POAG in the Beagle (Gelatt et  al., 1977, 1996; Spiess, 1995). Combined with fluorophotometry, tonography can differentiate, in relative terms, between the conventional (i.e., pressure‐sensitive corneoscleral– trabecular outflow) and unconventional (i.e., pressure‐insensitive uveoscleral outflow) pathways. In separate pneumatonographic studies, the mean ± standard deviation (SD) for the normal dog was 0.30 ± 0.15 μL/min/mmHg (Spiess, 1995), 0.28 ± 0.09 μL/min/ mmHg (Glover et  al., 1995b), and 0.35 ± 0.129 μL/min/ mmHg (Gelatt et  al., 1996; Fig.  20.4). In the POAGs, the

Schiøtz and pneumatonograph tonographic measurements gradually decline as the trabecular disease progresses (Gelatt et  al., 1977, 1996). Drugs such as parasympathomimetics that improve conventional AH outflow increase tonographic measurements in both normal dogs and dogs with POAG (Gum et al., 1993c; Spiess, 1995). Drugs that lower IOP by decreasing the rate of AH production or increasing the rate of uveoscleral (i.e., nonconventional) AH outflow do not cause significant changes in tonographic measurements. In genetic carriers of Beagle POAG mutation (heterozygous for G661R missense mutation in ADAMTS10), pneumatonographic measured AH outflow facilities (C) are slightly higher than in Beagles affected with early POAG (homozygous for G661R missense mutation in ADAMTS10), but below the normal wild‐type (control) Beagles (Gelatt et al., 1996). Hence, in the carriers of Beagle POAG ADAMTS 10 mutation, the facility of outflow values (C) were between the normal and glaucoma groups. Similarly, tonography in myocilin Thr377Met mutation carriers in humans demonstrated facilities of aqueous outflow that were intermediate to lower when compared to the noncarriers, but higher compared to the glaucoma groups (Wilkinson et al., 2003).

Pattern and Flash Electroretinography and Vision-Evoked Potentials The gold standard to assess vision in humans and to test for visual field loss in glaucoma is standard automated perimetry, which requires patient response and is impractical in veterinary medicine. Thus, the noninvasive electrophysiologic tests are most useful in research settings with animals and clinical veterinary medicine. The noninvasive electrophysiologic tests in humans with glaucoma that have been proven to be most useful are pattern electroretinography (PERG), multifocal, and flash electroretinography (fERG) with different colors of light stimuli, particularly blue (Graham & Fortune, 2009; Kanadani et al., 2014; Korth et al., 1994; Porciatti, 2015). PERG appears to originate from the RGCs of the inner retina, in contrast to fERG, in which the signals are primarily associated with the rod and cone photoreceptors and bipolar cells. Because POAG initially injures preferentially the peripheral RGCs, PERG has evolved as an important diagnostic tool to evaluate the inner retinal layers and assess the level of RGC damage (Ofri et al., 1993c). In contrast, fERG is most useful in PACG patients, where the marked elevations in IOP damage both the inner and outer retinal layers. Significant deterioration of short‐wavelength sensitivity (blue sensitive) in eyes with POAG occurs in humans (Graham & Fortune, 2009). The visual evoked potential (VEP) has been evaluated in normal, ocular hypertensive, and glaucomatous human patients. Blue‐on‐yellow VEP was recommended as a useful test in human glaucoma (Korth, 1997). Electrophysiology studies in the canine glaucomas are limited. PERGs are more difficult to obtain than fERGs.

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A

B Figure 20.4  Drawings and scanning electron micrographs (SEM) of the scleral lamina cribrosa in normal and glaucomatous eyes. A. From the normal pores in the normal eye, glaucoma causes pore misalignment and posterior movement or cupping of the lamina cribrosa (SEM, original magnification, X60). B. In the primary open-angle glaucomatous eye, optic nerve head demonstrates posterior displacement and loss of pore arrangement, which may impair axoplasmic and local capillary blood flow (SEM, original magnification, X60).

The major technical difficulties with PERGs are the light/ grating stimulator; the low amplitudes of the retinal response, which may require use of skeletal‐muscle‐paralysis anesthesia to reduce the interference from electromyographic activity; and the need for computer‐based recording instrumentation. There are reports of fERGs and PERGs from normal eyes with abruptly induced increased IOP (Brooks et al., 1992; Hamor et al., 2000; Korth, 1997) and POAG and normal control Beagles (Ofri et al., 1993c, 1994). PERGs in Beagles with POAG revealed differences between the central and peripheral retina, suggesting greater peripheral RGC damage, which is similar to events in humans that result in loss of the peripheral visual fields initially (Ofri et al., 1993a). In PERGs in normal and POAG Beagles, administration of sodium thiamylal induced significant amplitude increases in the PERGs of the peripheral retina using larger‐pattern gratings compared with those recorded from the central retina (Ofri et al., 1993b, 1994). These findings suggest that in Beagles with POAG, the peripheral (i.e., toroidal) retina and larger RGCs may be more sensitive to this drug and to elevations of IOP. The drug effects may

result from ischemic events or decreases in perfusion of the peripheral retina. The PERG is reduced in the Basset Hound with chronic angle‐closure glaucoma (Grozdanic et al., 2010). In normal dogs with acutely very high levels of IOP, the PERG waveforms were most sensitive to increases in IOP (Brooks et al., 1992; Grozdanic et  al., 2007). Outer retinal photoreceptor apoptosis was found in dogs with acute PACG, which could indicate that some refinement of fERG, to identify functional changes in the outer retina, might provide some predictive benefit for glaucoma therapy (Miller et  al., 1997). Increasing levels of experimentally induced IOP result in increased latency and reduced amplitude of the a‐ and b‐ waves and of the oscillatory potentials of the fERG (Hamor et al., 2000). In eyes with prolonged elevations of IOP, however, both the inner and outer retinal layers degenerate and fERG amplitudes decrease and often become nonrecordable (Plummer et al., 2013). Flash and pattern VEPs are measures of cortical visual activity and may have some benefit in evaluating glaucomatous eyes. Studies of VEPs in clinically normal dogs have

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Provocative Tests Provocative tests have been used to determine predisposition to both POAG and PACG. They may provide insight into the possible mechanism(s) for the increase in IOP. Tests for POAGs may include water provocative and steroid provocative tests. The provocative tests for narrow‐ and closed‐angle glaucomas include mydriatic drug and darkroom tests. These provocative tests have been used for several decades in humans to detect suspicious and borderline glaucomatous patients as well as to investigate the heredity of POAG. Water Provocative Test

The water provocative test has been reported on in normal dogs as well as in the POAG in Beagles, but is not routinely used by veterinary ophthalmologists (Gelatt et  al., 1976; Lovekin, 1971). The most useful water dosage for the water provocative test is 50–60 mL/kg, which is administered slowly and at body temperature by a stomach tube in an animal that has been fasted for 12 hours (Gelatt et al., 1976; Lovekin & Bellhorn, 1968). Cold water often results in vomiting. An IOP elevation in excess of 7–8 mmHg is abnormal, and may indicate trabecular dysfunction. In the POAG Beagle, the response to water loading becomes more exaggerated as the disease progresses in older dogs. The same effects have been observed in the glaucomatous Basset Hound. Corticosteroid Provocative Test

IOP elevations in humans with POAG have been associated with topical and systemic corticosteroids, and the same effects have been documented in the POAG Beagle. Topical 0.1% dexamethasone administered 4 times a day in normal dogs for 6 months increased IOP by approximately 3 mmHg (Gelatt & MacKay, 1998b). With inherited POAG in the Beagle, topical 0.1% dexamethasone instilled 4 times a day increased IOP by 4–5 mmHg within 2 weeks. Once topical dexamethasone therapy is discontinued in Beagles with POAG, the IOP returns to predrug levels within 7–10 days. Mydriatic or Darkroom Provocative Test

The mydriatic drug and darkroom tests are the classic procedures for PACG in humans. With parasympatholytic‐induced mydriasis or physiologically induced darkroom mydriasis, the dilated iris impairs further the outflow of AH, and the IOP becomes elevated acutely. If abrupt elevations in IOP (> 5 mmHg) occur within the first hour after onset of mydriasis, early PACG is suggested. The mydriatic test in early stages of POAG in Beagles is negative; however, more advanced cases may exhibit IOP elevations. In the PACG Basset Hound, both topical 1% tropicamide and 1% atropine

cause significant increases in IOP (35% and 50%, respectively; Grozdanic et al., 2010).

Structural and Functional Effects of Elevated Intraocular Pressure The canine glaucomas are diseases of constant and progressive change and consist of one or more of five features: (1) an abnormality of anatomy or function involving the AH outflow pathways; (2) physical changes causing AH outflow obstruction; (3) elevated IOP that is inconsistent with the health of the eye and impairs normal optic nerve axoplasmic flow and blood flow; (4) RGC dysfunction with resulting optic nerve degeneration and atrophy; and (5) visual field loss and blindness (Shields et al., 1996). The elevation of IOP in glaucoma patients, both human and canine, is responsible for considerable damage to the retina and optic nerve; however, IOP elevation is not the sole cause of ocular tissue damage. A variety of factors may accompany or be exacerbated by IOP elevations. Excitotoxic amino acids, defects in the ONH, changes in microcirculation, and ECM abnormalities may also contribute to damage in both canine and human glaucoma (Fechtner & Weinreb, 1994; Kondráromy et  al., 2019; Van Buskirk & Cioffi, 1992; Wilson, 1994). It is known that the changes experienced by the glaucomatous eye are dependent on the level of the IOP elevation, the duration of the elevation change, the onset of secondary effects (i.e., position of the lens, changes in the vitreous, secondary inflammation, etc.), changes in the circulation (some tissues have autoregulation and other ocular tissues do not), and other factors.

Extracellular Matrix–Aqueous Outflow Pathways and the Scleral Laminal Cribrosa Cellular and ECM abnormalities involving the AH outflow pathways, the peripapillary sclera, and the scleral laminal cribrosa coexist in human and dog eyes with POAG (Boote et al., 2016; Gottanka et al., 1997; Palko et al., 2013, 2016). The number of trabecular cells gradually declines as aging occurs; this loss of trabecular cells appears at a faster rate in human and Beagle POAG. The ADAMTS10 mutation in Beagles with POAG has been associated with a microfibril abnormality (Kuchtey et  al., 2011). A primary collagen defect has been proposed as a possible mechanism for the optic neuropathy of glaucoma. Abnormalities in the composition of collagen in the sclera, the lamina cribrosa, and the trabecular meshwork might be associated with altered pressure resistance in these regions (Boote et  al., 2016; Gelatt & Samuelson, 1986; Palko et  al., 2013, 2016; Rehnberg et al., 1987). This would suggest a more generalized ophthalmic disease in the primary glaucomas than just a local effect on the aqueous outflow pathways, and it

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been reported, but in glaucomatous canines studies are lacking (Strain et  al., 1990). See Chapter  10, Part 4 for further discussion of electrophysiologic diagnostics.

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might explain the different individual sensitivities of the ONH to different levels of IOP. ONH compliance in response to IOP elevations in eyes predisposed to primary glaucoma may be reduced, and the laminar tissue may be more rigid or stiff, and thus unable to protect the optic nerve axons from damage during IOP fluctuations (Zeimer & Ogura, 1989).

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Changes in Globe Size In contrast to adult humans, enlargement of the globe, which is also termed hydrophthalmos, buphthalmia, megaloglobus, or macrophthalmia, occurs in all animal species, including the dog, cat, horse, cow, rabbit, nonhuman primates, and also in the infant and young human. Globe enlargement in humans is rare today, but early in the 1900s it was not unusual, as IOP control was unusual. Somewhat correlated to the magnitude of the IOP elevation, globe enlargement may develop within several days, or it may develop very slowly over several months. Young puppies with acute glaucoma secondary to anterior uveitis often show marked and rapid increase in globe size. Assuming rapid reduction in the IOP, these globes may reduce to near‐ normal size. Buphthalmic globes of adult animals usually do not return to their normal, prehypertensive size; however, they may shrink in chronic stages when ocular hypotony (IOP < 5 mmHg) develops, resulting from reduced production of AH because of ciliary body atrophy. Most of the enlargement of the globe results from the expansive effects of IOP elevations on the elastic sclera rather than those on the more rigid cornea.

Corneal Changes The cornea in the canine glaucomas becomes thicker because of edema within the stroma. This edema is generalized throughout the stroma, and clinically may be concentrated immediately beneath the corneal epithelium initially. The extent of the corneal edema may somewhat parallel the elevation in IOP. When IOP approaches 40 mmHg in the absence of intraocular inflammation, the corneal endothelial “pump” mechanism begins to decompensate, stromal edema develops, and the cornea thickens. With sustained or marked elevations in IOP, corneal endothelial cell death occurs, and gaps in the posterior endothelial cell lining become evident with specular microscopy. The endothelial cell response is hypertrophy and sliding of existing cells to cover the area previously occupied by the lost cells. At specular microscopy, the endothelial cells become larger, lose their hexagonal appearance, and reduce in number. Because fewer cells are present to maintain corneal deturgescence, metabolic demands on each remaining cell are increased. When a critical endothelial cell density is lost, a gradual increase in the central corneal thickness occurs, followed

eventually by permanent corneal edema. The corneal thickness increases slightly in early glaucoma and considerably in advanced glaucoma, and this variable thickness with the presence of edema may render tonometry measurements less accurate. Peripheral corneal edema can also develop and is usually associated with the development of peripheral anterior synechiae. Corneal enlargement also occurs with elevations in IOP, and this enlargement can be appreciated by measuring the vertical and horizontal corneal diameter. Focal, linear breaks, or stretching of Descemet’s membrane (i.e., Haab’s striae) occur in enlarged corneas, thereby allowing minute amounts of AH direct access to the corneal posterior stroma. Striae may also be associated with acute IOP spikes. As the globe enlargement increases, exposure keratitis and corneal ulceration caused by lagophthalmia, impaired blink reflexes, corneal edema, and increased evaporation of the precorneal tear film may result. Pigmentary keratitis and corneal vascularization may occur with chronicity.

Changes to the Sclera With both abrupt and sustained elevations in IOP, the sclera is stretched and becomes thinner. The sclera is quite similar to the cornea but with dense, interlacing collagen lamellae and a larger concentration of elastic fibers. The predominant increase in globe size appears to relate mostly to scleral rather than corneal changes. Areas of sclera through which the nerves and blood vessels penetrate are particularly susceptible to thinning, with large staphylomas developing at the equator in some eyes. The scleral lamina cribrosa, where the optic nerve fibers exit the eye, is presented in “Retina and Optic Nerve Head.”

Changes of the Anterior Chamber Angle and Aqueous Humor Outflow Pathways The initial pathogenesis in the elevation in IOP in PACG and POAG appear quite different, but once IOP is elevated, the effects of this elevation eventually converge. The lamina cribrosa of the ONH and aqueous outflow pathways (AH) share many morphologic and physiologic similarities. However, the trabecular meshwork is unique to the regulation of aqueous outflow and IOP. As discussed in Chapters 2 and 3, the conventional outflow of AH in the canine eye through the ciliary cleft passes through the pectinate ligaments into the uveal trabecular meshwork, to the corneoscleral trabecular meshwork, the juxtacanalicular meshwork (probably the site of greatest resistance), and the angular aqueous plexus, to exit mostly into the intrascleral plexus. With normal IOP of about 15–20 mmHg, the total AH outflow resistance is produced by the combination of the corneoscleral trabecular meshwork (about 4–6 mmHg) and the angular aqueous plexus (about 10–12 mmHg). The pectinate ligaments seem

to have limited, if any, effect on AH outflow, except when extensive undifferentiated pectinate ligaments occur (PLD) and limit or decrease the opening of the ciliary cleft. Changes in the trabecular meshwork occur with aging, and in POAG and PACG. These changes involve the trabecular cells and the ECM of the trabecular meshwork, and affect both the conventional outflow pathways (pressure sensitive) and uveoscleral outflow pathways (pressure independent), involving the ICA as well as the ciliary or sclerociliary cleft. As the globe enlarges with persistent elevations in IOP in nonhuman species and young children, changes in these outflow pathways may represent a combination of early primary changes compounded by later secondary IOP‐related effects on both the morphology and the function of the ICA and ciliary cleft. Primary Open-Angle Glaucoma

POAG in dogs results from ECM changes in the AH outflow pathways and trabecular cells. These cells produce glycosaminoglycans (GAGs), extracellular glycoproteins, and fibrillar material (Acott, 1993; Lütjen‐Drecoll, 1993; Toris et al., 2008). Trabecular cells are highly phagocytic, resulting in a self‐cleaning filter for AH to traverse, removing particles, cellular debris, protein molecules, and the occasional pigment granules of different sizes, and even RBCs and experimentally introduced microspheres. Macrophages also wander throughout the trabecular meshwork assisting in the continuous “clean‐up” process. The ECM is the main site for AH resistance and a major contributor of IOP; it is also the pathologic site for increased AH resistance in POAG. The ECM comprises many different proteins, most of which are glycoproteins or proteoglycans. The GAGs isolated in both normal human and dog trabecular meshwork include hyaluronic acid, dermatan sulfate, chondroitin‐4‐sulfate, keratin sulfate, chondroitin‐6‐sulfate, and heparan sulfate (Gum et al., 1986). In studies investigating the different glycosaminoglycans within the trabecular meshwork of POAG in humans and the ADAMTS10‐mutant Beagle (Gum et al., 1993b; Knepper et al., 1996), hyaluronic acid declined, chrondroitin sulfate increased (humans) or decreased (dogs), and an undegradable, hyaluronidase‐ resistant GAG‐like material was identified in both species (Gum et al., 1986, 1987, 1993b). A study using human AH has indicated that the undegraded GAG‐like material was a small hyaluronic acid (McCarty et al., 2011). Hyaluronidase‐2 and hyaluronidase inhibitors are present in normal humans and those with POAG (McCarty et al., 2011). In the POAG eyes, hyaluronidase‐2 levels are increased and hyaluronidase inhibitors are decreased. Other important glycoproteins include laminin (a large basement membrane “glue”), fibronectin (another ECM “glue”), collagen (interstitial collagen; Type IV basement membrane collagen and Type V collagen), elastin (composed of fibrous protein elastin and formed around microfibrillar

protein fibrillin), myocilin (MacKay et  al., 2008a, 2008b; Samuelson et al., 2005) and CD44 proteins (Källberg et al., 2006). In POAG Beagles with the ADAMTS10 mutation, fibrillin, a 350 kDa protein containing glucosamine but not sulfated (10 nm diameter fibrils around amorphous cores of the elastic cores), is likely important to the pathogenesis of POAG and abnormalities are probably responsible for the increasing resistance for AH as it traverses the TM. The TM changes in human and dog POAG are quite similar. Observations from human glaucoma specimens generally include reduced numbers of trabecular cells (greater than by aging alone) with thicker basement membranes, and plaque formation in the corneoscleral beams and juxtacanalicular meshwork (thought to be derived from elastic‐like fibers that makeup the subendothelial tendon sheath). These thicker sheaths of the elastic fibers and connecting fibrils decrease the intertrabecular spaces and narrow AH flow pathways to the inner wall endothelium. Alterations of the ECM include collagen abnormalities (fragmentation, altered orientation, and abnormal spacing), fibronectin deposition in the subendothelium of Schlemm’s canal, and increased myocilin and αß‐crystalline levels (stress proteins). Clearly, the interactions of these proteins create complex changes within the trabecular meshwork and decrease AH flow through this entire area. Although different genes have been associated with POAG in humans, the ultrastructure of the trabecular meshwork has not been differentiated based on these specific genes and possible unique effects on the ECM. Among the different breeds of dogs with POAG, the Beagle glaucoma has the most documentation. The trabecular meshwork cells, like in humans, decline with aging, and more so in POAG. The ultrastructural changes of the AH outflow pathways of Beagle POAG have been reported at different phases of the disease (pre‐, early, moderate, and late; Samuelson et al., 1989). In the preglaucomatous dogs (1–11 months old), no abnormalities were present in the trabecular meshwork. In 12‐month‐old dogs, clustered basement membrane–like material was scattered throughout the corneoscleral trabecular meshwork. In the same region, elastin‐ like fibers appeared more numerous and were arranged less regularly. Occasional trabecular cells within the corneoscleral trabecular meshwork possessed small clusters of serrated opaque rods within their cytoplasm. In moderate to advanced POAG, these changes were more generalized and affected the entire corneoscleral trabecular meshwork. Narrowing developed with compression and less organization, with a concomitant build‐up of extracellular materials. Intertra­ becular spaces were markedly reduced in size in the uveal meshwork and to a lesser extent in the corneoscleral trabecular meshwork. A uniform layer of fibrils, 10–12 nm in diameter, and amorphous material coated most of the endothelial walls along the angular aqueous plexus. Elastin‐ like fibers frequently pressed against the endothelium of the angular aqueous plexus.

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Microfibrils are macromolecular aggregates located in the ECM of both elastic and nonelastic tissues that have essential functions in the formation of elastic fibers and control of signaling through the transforming growth factor beta (TGF‐β) family of cytokines. Microfibril defects could contribute to glaucoma through alterations in the biomechanical properties of tissue and/or through effects on signaling through TGF‐β, which is well established to be elevated in the AH of human and feline POAG patients. A role for microfibrils in glaucoma is suggested by the identification of risk alleles and mutations in the microfibril‐associated genes LOXL1 (for exfoliation glaucoma) and LTBP2 (for primary congenital glaucoma) in humans. Recent identification of a G661R missense mutation in the ADAMTS10 gene in the dog model of POAG naturally leads to a microfibril hypothesis of glaucoma, which in general states that defective microfibrils may be an underlying cause of glaucoma (Kuchtey & Kuchtey, 2014). Recent work has shown that diseases caused by microfibril defects are associated with increased concentrations of TGFβ protein and chronic activation of TGFβ‐mediated signal transduction in humans. Defective microfibrils could provide a mechanism for the elevation of TGF‐β2 in glaucomatous AH. However, a recent study in POAG dogs found that AH concentrations of active, latent, and total TGF‐β2 were not significantly increased in ADAMTS10‐mutant dogs compared to age‐matched controls. In contrast to reported findings in glaucomatous cats and humans, elevated levels of TGF‐β2 may not contribute to the development of open‐angle glaucoma in Beagles (Scott et  al., 2013c). Alternatively, TGF‐β2 may be bound within the ECM rather than free within AH in the anterior chamber. Preliminary immunohistochemical studies to evaluate the expression of TGF‐β2 in ocular tissues have characterized patterns of tissue distribution of TGF‐β2 in the eyes of dogs with open‐angle glaucoma and indicate that there is increased TGF‐β2 in the ciliary body epithelium, corneal epithelium, and optic nerve of affected dogs. Primary Narrow-Angle or Angle-Closure Glaucoma

While the primary mechanism for elevating IOP in POAG lies within the AH outflow pathways, the exact mechanism(s) involved in the genesis of PACG in the dog is poorly understood. Information on PACG in humans may provide some helpful clues. Pupillary block PACG is the most common cause of angle closure. Measurement of PACG in humans indicates smaller corneal diameter, smaller radius of anterior and posterior corneal curvatures, shallower anterior chamber, thicker lens, smaller radius of anterior lens curvature, more anterior lens position, and shorter axial length of the globe (Ritch & Lowe, 1996). Similar finding are reported in PACG in dogs. Hence, to help our understanding of canine PACG, UBM measurements of the anterior chamber angle and ciliary cleft, as well as the standard ultrasound measurements of

the entire axial globe length, anterior chapter depth, width of the lens, and size of the vitreous space, are invaluable. For those globes with PACG in which the AH outflow pathways are normal initially, narrowing of the anterior chamber and a forward displacement of the iris and lens may result in an unusually “tight” contact against the mid to central anterior lens surface. With the pupillary flow of AH somewhat impaired, the increase of only a few mmHg within the posterior chamber results in the forward displacement or “ballooning” of the basal iris, restricting AH access to the AH pathways and the opening of the ciliary cleft. With angle closure and collapse of the ciliary cleft in excess of 180°, formation of peripheral anterior synechiae begins to permanently impair AH outflow and IOP elevations commence. The more of the outflow pathways are apposed by synechiae, the higher the IOP elevates. In other PACG globes in which the trabecular meshwork or AH outflow pathways are abnormal (as with PLD/goniodysgenesis) and IOP gradually elevates, narrowing of the anterior chamber depth and forward displacement of the lens may occur as IOP insidiously increases. In the Basset Hound these changes appear continuous. Secondary changes in the ICA and ciliary cleft of the dog invariably involve progressive narrowing, and eventual closure, of the ICA and collapse of the ciliary cleft in moderate and advanced glaucoma. Mechanisms for these phenomena are still unclear, but some theories exist. Enlargement of the globe associated with the stretching of the sclera possibly distorts the ICA both anteroposteriorly and meridionally. The result is compaction of the corneoscleral trabecular meshwork and partial to complete collapse of the aqueous veins and intrascleral venous plexus. Also, the different components of the meshwork ECM, such as collagen, elastin, glycosaminoglycans, and glycoproteins, may become altered. Corneal endothelial cell proliferation and changes in Descemet’s membrane across the face of the ICA may develop and further compromise aqueous outflow. Peripheral anterior synechia can develop when the basal iris comes into direct contact with the compacted trabecular meshwork. The trabecular meshwork within the ciliary cleft may be subjected to abnormal stresses as the cleft collapses. Lens zonule disruption associated with lens subluxation and luxation may affect the mechanisms involved with trabecular opening and the overall size of the ciliary cleft space because of reduced tension from the zonules normally attached at the lens equator. Hence, with any form of glaucoma involving globe enlargement, secondary changes to the AH pathways may aggravate further clinical management of IOP control and prevention of additional optic nerve damage. Matrix Metalloproteinases

The matrix metalloproteinases (MMPs) also play a very important role in determining resistance to the AH outflow on AH within the ECM (Weinstein et al., 2007). The trabecu-

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Changes of the Iris Mydriasis is a consistent clinical finding in most types of glaucoma, except for those occurring secondary to anterior uveitis. Pupillary dilation in response to elevated IOP is a complex event. It may result from iris or optic nerve changes (or both). As the elevations in IOP increase, mydriasis is absolute, and pupillary changes after the instillation of diagnostic miotics are either limited or absent. This lack of response by the iridal sphincter muscle and, presumably, the longitudinal ciliary body musculature may be caused by impaired neural or vascular supply (or both) to the central iris. With time, the iridal stroma becomes thin, and the sphincter muscle atrophies. Hence, as the glaucoma progresses, pupillary dilation caused by limited response of the iridal sphincter musculature occurs. A lack of sensory input resulting from RGC dysfunction may also contribute to the mydriasis. The elevation in IOP may mechanically open the pupil to some extent. Pigment granules from the degenerating iridal melanocytes and the posterior pigmented iridal epithelia may be released into the AH and eventually lodge within the corneoscleral and uveal trabecular meshworks, or be phagocytized by the trabecular cells and macrophages.

Changes of the Ciliary Body The response of the ciliary body to elevated IOP is gradual degeneration with atrophy of the pars plicata and individual ciliary processes. The assumption, which has not yet been confirmed by results of fluorophotometry, is that the rate of AH formation is unchanged as the IOP is elevated until the perfusion pressure (i.e., mean arterial blood pressure minus IOP) approaches zero. With progressive deterioration of the ciliary body processes and nonpigmented ciliary body epithelia, the rate of AH formation probably decreases. With advanced ciliary body atrophy, profound ocular hypotony (< 5 mmHg) results. Corneal edema, cataract formation, retinal detachment, and intraocular hemorrhage often follow.

Changes of the Choroid and Tapetum Cellulosum The choroid is the primary vascular supply to the eye and particularly to the outer retinal layers. Short posterior ciliary arteries feed choroidal arteries, which form poorly anastomotic, choroidal circulatory lobules. The effect of elevated IOP on the choroid depends on rapidity of onset, duration, and level of the IOP elevation, as well as on the species involved (Yu et al., 1988). In the dog the tapetal retina seems less affected than the nontapetal zone. Once the ocular perfusion pressure (OPP) is reduced by increased IOP, the choroidal blood flow declines, because canine choroidal blood vessels poorly autoregulate in response to this dim­ini­shed blood flow. It appears the choroidal blood flow is most adversely reduced when IOP is markedly elevated (> 60 mmHg). Thus, both inner (RGCs) and outer (rod and cone photoreceptors and outer nuclear layer) retinal layers are affected at these high levels of IOP. Rabbit choroidal vessels, in contrast, vigorously autoregulate (Kiel & van Heuven, 1995; Whiteman et al., 2002). Reduced blood flow results in a hypoxic‐ischemic state, with various cytotoxic and vasoactive substances released that may accelerate local damage within the choroid and adjacent outer retina. After marked elevations of IOP in humans, poorly perfused “watershed zones” between adjacent choroidal lobules are markedly affected by the reduced perfusion. Watershed zones are the border areas between the territories of distribution from any two end‐ arteries. During a decrease in perfusion pressure in the vascular bed of one or more end artery, the watershed zone, being an area of comparatively poor vascularity, is the most vulnerable to ischemia. Accordingly, watershed zones have been shown to exist in the primate choroid between the distributions of the posterior ciliary arteries, the short posterior ciliary arteries, the short and long posterior ciliary arteries, the posterior and anterior ciliary arteries, the choriocapillaris lobules, and the vortex veins (Hayreh, 1990). This perfusion deficit results in focal areas of chorioretinal ischemia and degeneration in the ischemic zones. Ischemia associated with the nonperfusion of individual short posterior ciliary arteries also occurs in dogs with primary glaucomas, appearing as focal, fan‐shaped areas of chorioretinal degeneration radiating from the ONH. As in humans, these apparent watershed zone degenerations in the dog more often seem to follow abrupt and severe elevations in IOP (> 60 mmHg). In the POAG Beagle, both fluorescein and indocyanine green angiography demonstrated wedge‐ shaped areas of delayed choroidal filling, delayed superior retinal venule filling, and peripapillary and ONH hyperfluorescence. The abnormalities were more distinct with the fluorescein method (Burn et al., 2017). Changes in the tapetum cellulosum after sustained elevations of IOP include degeneration and thinning, though compared with the nontapetal fundus, the tapetal fundus

SECTION IIIA

lar meshwork cells can detect changes in IOP and respond by increasing levels of MMP. The metalloproteinases increase the ECM turnover rate, reduce the resistance to AH outflow though the trabecular meshwork, and lower the IOP. The latent form of MMP‐2 seems the most relevant MMP in the canine eye. The AH in glaucomatous dogs had elevated latent MMP‐2 compared to normal eyes (Weinstein et al., 2007). In the ICA tissues, the active form of MMP‐2 was significantly higher in glaucomatous eyes. Also, in dogs with primary and secondary glaucoma, there was a significant increase in latent MMP‐9 forms. ADAMTS10 and ADAMTS17 are members of the family of secreted metalloproteinases; mutations in these genes cause POAG (and primary lens luxation, PLL) in dogs (Kuchtey et al., 2010).

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appears somewhat spared initially. Histopathologic examinations of moderately advanced glaucomatous globes may reveal near‐complete loss of the RGCs in the nontapetal fundus, but a surprising, though reduced, number of normal‐ appearing RGCs remain in the tapetal fundus.

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Changes of the Lens Abrupt or sustained elevations in IOP may result in cataract formation and changes in the lens position within the patella fossa. The basis for cataract development is not understood, but it may occur secondary to changes in the composition and rate of AH formation, and perhaps changes in the nutrition and waste removal functions it serves, or due to toxic metabolites present as a result of the glaucoma pathogenesis. These cataractous changes initially affect the active areas of new lens‐fiber formation. Focal vacuoles can progress to complete cataract formation. Transposition of the canine lens from the patella fossa may result from primary zonular disease or be secondary to globe enlargement. In terrier breeds and Border Collies, the zonular defects appear to be primary and inherited (Curtis et al., 1983; Formston, 1945; Foster et al., 1986; Willis et al., 1979). In several breeds, including the Jack Russell Terrier, Parson Russell Terrier, Miniature Bull Terrier, Tibetan Terrier, Lancashire Heeler, Chinese Crested, Australian Cattle Dog, Jagd Terrier, Patterdale Terrier, Rat Terrier, Sealyham Terrier, Tenterfield Terrier, Toy Fox Terrier, Volpino Italiano, Welsh Terrier, Wirehaired Fox Terrier, and Yorkshire Terrier, PLL has been associated with the ADAMTS17 splice donor site mutation (Farias et  al., 2010; Gould et  al., 2011; Sargan et  al., 2007). The anomalous zonules break down, thereby resulting in subluxation that can progress to total luxation of the lens to the anterior or vitreal chamber. Luxations of the lens may cause pupillary block, which in turn results in acute elevations of IOP. Typically, the terrier breeds with PLL are between 1 and 4 years of age, and are usually distinct from older dogs (7–10 years old) with advanced cataractous formation, zonular degeneration, and lens luxations. Similar to human patients with Weill–Marchesani syndrome (WMS), dogs with ADAMTS10 and ADAMTS17 mutations exhibit zonular abnormalities concurrent to elevations in IOP, which follow the ECM abnormalities within both the lens zonules and the trabecular meshwork that accompany these defects (Dagoneau et  al., 2004; Gould et  al., 2011; Kutchey et  al., 2011). In these individuals, lens subluxations and luxations likely occur due to these zonular changes rather than buphthalmic globe stretching. In secondary lens luxation, globe enlargement appears to be important to its pathogenesis (Gwin, 1982). With globe enlargement, zonular tension appears to be significantly increased. If the zonules are intact, marked traction and elongation of the individual ciliary body processes may be

observed through a widely dilated pupil. Tearing of the zonules occurs most frequently near their insertions at the lens equatorial capsule; infrequently, the zonular transection may occur at the level of the ciliary body process, with a small section of the process remaining adherent to the zonule. Often with cataract hypermaturity zonular loss is present; these dogs are typically middle‐aged to older (5–8 years old). Lens luxations can markedly hamper clinical management of the canine glaucomas. A subluxated to totally luxated lens may result in abrupt elevations in IOP, and lens luxations can block the pupil and impair aqueous passage, especially if the pupil is miotic. Attachment of the vitreous to the posterior lens capsule and tearing of the anterior hyaloid face may also cause the cortical or formed vitreous to enter the pupil or anterior chamber (or both) and to impede AH outflow. A secondary iridocyclitis may develop from iridolenticular contact. The lack of zonular tension on the ciliary cleft may hasten its reduction and eventual collapse.

Changes of the Vitreous Abrupt and sustained elevations in IOP result in vitreal liquefaction and formation of vitreal cortical strands. Tearing of the anterior hyaloid membrane associated with lens subluxation, anterior lens luxation, and posterior (i.e., intravitreal) luxations may allow this liquefied vitreous direct access to the anterior chamber and the AH outflow pathways. The liquefied vitreous can permit a subluxated lens to eventually luxate posteriorly, then contact and even adhere to the ventral retinal surface. The liquefied vitreous may also alter physical support to the retina and predispose to retinal detachment. When high elevations in IOP occur, the posterior vitreous may be displaced into the anterior ONH (Schnabel’s cavernous atrophy).

Changes of the Retina, Scleral Lamina Cribrosa, and Optic Nerve Changes in IOP have profound effects on the retina and the ONH. Normally the scleral lamina cribrosa represents the exit of the RGC axons (with glia and blood vessels) at a pressure of about 10–18 mmHg, to become the intraorbital division of the optic nerve surrounded by cerebrospinal pressures of about 10 mmHg. When the IOP exceeds 30 or even 50 mmHg, the scleral lamina cribrosa faces a considerable pressure difference. Scleral Lamina Cribrosa

The scleral lamina cribrosa becomes distorted and compressed posteriorly by increases in IOP, thus affecting axoplasmic flow within the RGC axons and probably impairing blood supply to the ONH by compromising the blood vessels in the laminar trabeculae (Brooks et  al., 1989b; 1995a;

axons from acute, mechanical displacement of the ONH during increases in IOP, and changes occurring with age in human laminar ECM result in a reduced ability to respond to episodic IOP spikes (Hernandez, 1992). The cupping of the ONH associated with glaucoma results from optic nerve axonal death as well as from compression, stretching, and rearrangement of the connective tissues of the lamina cribrosa in response to altered IOP. ONH compliance in response to minor alterations in IOP diminishes as glaucomatous optic nerve damage progresses (Hernandez, 1992; Hernandez & Pena, 1997). A complex relationship exists between the astrocytic, neural, vascular, and fibrous elements of the scleral lamina cribrosa (Elkington et al., 1990; Hernandez & Ye, 1993). Glial cells, blood vessels, and collagen beams form a multilayered

Fig. 20.5). Both ischemic and mechanical effects to the lamina cribrosa interfere with optic nerve axoplasmic flow and lead to axonal and RGC death. These changes have been studied in normal dogs with experimentally, acutely elevated IOP, as well as in ADAMTS10‐mutant Beagles with inherited POAG in which IOP elevations were sustained for 6–36 months (Samuelson et al., 1983). The elevated IOP obstructs both orthograde and retrograde axoplasmic flow of the RGC axons at the scleral lamina cribrosa. Structural and biochemical abnormalities in the ECM of the lamina cribrosa may affect the progressive compression and remodeling of this connective tissue in primate (Zeimer & Ogura, 1989) and possibly in canine glaucoma. The lamina cribrosa from normal, young human eyes has the ECM of a compliant tissue, which may be able to respond and protect the optic nerve

A

B

C Figure 20.5  Optic nerve heads in three primary open-angle glaucomatous Beagles. A. Normal optic disc. B. Optic disc in early hypertension with electrophysiologic evidence of glaucoma. C. Optic disc in a moderate stage of primary open-angle glaucoma with enlargement of the optic cup.

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meshwork through which the optic nerve fibers are interwoven. Connective tissue in the lamina cribrosa provides biomechanical support to these axons, and the tensile strength and elasticity of this connective tissue mainly result from the presence of collagen and elastic fibers. Cross‐bridging between collagen fibers is most dense near the ECM of the collagenous laminar beams, and it is less dense toward the axons (Furuta et al., 1993). This organization may play a role in the smooth transfer from the axon to the laminar beam of tissue‐shear stresses associated with IOP. Elastin, which consists of a central core of α‐elastin and a microfibrillar sheath, is a major component of the ECM elastic fibers of the lamina cribrosa, and it is responsible for its elastic properties (Hernandez & Pena, 1997). Elastic fibers undergo marked changes, such as loss and fragmentation, in the lamina cribrosa of humans (Hernandez, 1992) and ADAMTS10‐mutant Beagles with POAG (Samuelson et  al., 1989). Changes occurring with age also affect the elastin of the lamina (Hernandez, 1992). No elastin is found in the ECM of fetal lamina cribrosa. Laminar tissues are undergoing elastogenesis in infant humans, and elastin is present in microfibrillar aggregates in the core of the laminar plates. Thin, elastic fibers run longitudinally in the core of the laminar plates in young adults. With age, elastic fibers become thicker, tubular, and surrounded by densely packed collagen fibers. In POAG Beagles with the ADAMTS10 mutation, collagen density was significantly reduced and collagen anisotropy was reduced in the mid‐posterior sclera (Boote et al., 2016). In humans with early POAG, tubular elastic fibers are absent, and fragments of elastic fibers and microfibrillar aggregates are found, thereby suggesting that new elastin synthesis is disorganized (Hernandez, 1992). In advanced POAG, masses of nonfibrillar, elastin‐positive material with a spotted appearance, proliferation of basement membranes, and bundles of elastin‐negative microfibrils are present. Glial hyperplasia, loss of collagen fibers, more severe disorganization and fragmentation of elastin fibers, and accumulation of nonfibrillar, elastic‐like material also occur (Hernandez, 1992). It appears that elastin continues to be synthesized. This biosynthesis may be abnormal, however, or there may be abnormal degradation. These changes may be induced by alterations in the ONH microenvironment caused by ischemia or mechanical changes to the lamina cribrosa. The progression of changes in elastic fibers and ECM disorganization is associated with progressive loss of optic nerve function. Abnormalities of collagen composition in both the lamina cribrosa and the trabecular meshwork may be associated in part with altered pressure resistance in these regions (Gelatt & Samuelson, 1986; Rehnberg et al., 1987). The precise distribution of collagen types and the amino acids associated with collagen, proline, hydroxyproline, and hydroxylysine have been studied immunohistochemically in the eyes of humans with healthy eyes and in humans with glaucoma, to

characterize the lamina cribrosa and trabecular meshwork and to determine if those areas are different from the surrounding sclera. Concentrations of the collagen‐specific amino acids proline, hydroxyproline, and hydroxylysine were increased in the lamina cribrosa of glaucomatous human eyes, but remained at normal levels in the sclera and trabecular meshwork. Collagen Types I, III, and IV were found in the lamina cribrosa, the trabecular meshwork (weak for Type I), and the retrolaminar optic nerve. Only Type I collagen was found in the sclera. Type IV collagen and laminin were found in the blood vessels and laminar beam margins (i.e., basement membrane components) of both infant and adult humans (Rehnberg et  al., 1987), and in another study (Morrison et al., 1989), heavy concentrations of Type I and III fibrillar collagen were found in the interstitium of the laminar beams of adults. Fibrillin, which is the microfibrillar portion of elastin, was also found in longitudinal bands in the laminar beams; neonatal laminas contained less interstitial collagen, with a predominance of Type III (Morrison et al., 1989). Type III collagen is more distensible, but has less tensile strength, than Type I (Elkington et al., 1990). This may be why optic discs found in congenital glaucoma among humans can display rather remarkable and reversible optic nerve cupping. Mutations recently reported in ADAMTS10 (POAG in Beagle, Norwegian Elkhound) and ADAMTS17 (POAG and PLL in over 20 canine breeds) have been associated with microfibrin abnormalities (Kuchtey et al., 2014). Functionally, elastic fibers and collagen act as parallel mechanical elements to applied stress or strain (Hernandez, 1992; Hernandez & Ye, 1993). Collagen fibers are extended easily at low stress levels, with most of the stress being borne by the elastic fibers. At high levels of strain, collagen fibers limit further laminar tissue distention, thereby providing strength and support to the tissue. The decrease in collagen density and the degenerative changes in elastic fibers of the lamina cribrosa observed in humans with POAG must alter the mechanical properties of the laminar tissue early in the disease process (Hernandez, 1992). It has been demonstrated that dogs with the G661R missense mutation in ADAMTS10 have an inherently weaker and biochemically distinct posterior sclera, with a reduction in fibrous collagen density even before clinical indications of optic nerve damage. However, it remains to be shown whether and how the altered scleral biomechanics may affect the rate of glaucoma progression following IOP elevation (Boote et al., 2016; Palko et al., 2013, 2016). Retina and Optic Nerve Head

In spontaneous (noninduced) glaucoma in the dog, elevations in IOP result in damage to RGCs initially, especially in the peripheral and inferior retina, followed by atrophy of the ONH (loss of myelin and RGC axons, changes in neuroretinal rim size and the cup‐to‐disc ratio) and then degeneration of the outer retinal layers and the retina as a whole. Clinically

affected animals will have loss of vision, which may be transient or permanent depending upon the degree and duration of IOP elevation, functional mydriasis, and impaired pupillary light reflexes, due to pressure‐induced damage. Other clinical signs that may result from IOP elevations include corneal edema, episcleral injection, and further structural and functional injury to the drainage apparatus. Regardless of the role elevations of IOP play in the glaucomas, these diseases are considered neurodegenerative diseases because they result initially in the death of a neural cell, the RGC. Decreased function of large‐diameter RGCs in the peripheral retina and decreased blood velocity of the ONH vasculature are present at normal IOP before increases of significant IOP in canine POAG (Gelatt et  al., 2003; Gelatt‐Nicholson et al., 1999; Ofri et al., 1993a, 1994), suggesting that the disease process has been set in motion prior to the elevation of IOP. There is partial to complete obstruction of axoplasmic flow at the scleral lamina cribrosa and elevated intravitreal glutamate in canine POAG (Brooks et al., 1997; Samuelson et al., 1983). RGC and photoreceptor apoptosis, in addition to intravitreal glutamate elevation, are present in canine PACG glaucoma (Brooks et al., 1997; Miller et al., 1997). All of these abnormalities suggest that for the canine glaucomas, the most accurate definition may be that they are the final common pathway of a group of diseases with increased IOP, decreased RGC sensitivity and function, RGC death, optic nerve axonal loss with concurrent ONH cup enlargement, incremental reduction in visual fields, and blindness. It remains unclear why elevated IOP tends to damage the RGCs and ONH and why, under certain conditions, similar damage occurs even at normal IOP. A recent study in normotensive dogs predisposed to glaucoma, those in which the fellow eye had already been diagnosed with primary glaucoma, revealed thinner retinas and RNFL as observed with OCT compared to normotensive eyes in controls (Graham et al., 2020). Is axoplasmic flow blocked by some mechanical effect on the axons associated with biomechanical dysfunction of the ONH, or is the blockage secondary to ischemia caused by ONH microcirculatory abnormalities? Both undoubtedly occur to some degree and may be influenced by the magnitude of the elevated IOP. These effects on the different tissues of the eye depend heavily on the IOP variables, which include, but are not restricted to, the magnitude and duration of the pressure elevation, the rate of the elevation (i.e., chronic versus abrupt), and the interrelationship of IOP with the perfusion pressure of the eye (i.e., the mean arterial blood pressure minus the IOP). High IOP, compromised vascular supply to the ONH and inner retinal vasculature, and weakened lamina cribrosa structural support all play a role in glaucomatous optic nerve damage in the dog. Although the endpoint is usually the same, there may be significant differences in the retina and ONH between POAG and PACG eyes in the early and middle stages. The retina and ONH in POAG are affected more slowly, with gradual

reduction in ONH size, loss of myelin and cupping (difficult to detect without serial photographs or high‐resolution imaging), and peripheral retinal vasculature (vessel size). POAG is characterized by maintenance of central vision until late in the disease process and relatively slower IOP elevation. The clinical picture is one of slow, peripheral retinal degeneration (initially the RGCs), vascular attenuation, and ONH degeneration. In PACG, the IOP elevations are acute and often very high (> 50 mmHg). ONH degeneration occurs much more quickly and all retinal layers are affected (hence the reduced fERG; Scott et  al., 2013a; Whiteman et al., 2002). In POAG eyes, the fERG is usually normal, but the PERG is changed, especially in the peripheral retina (Ofri et  al., 1994). Early microscopic examinations (within 24 hours) of PACG globes reveal marked RGC necrosis and mild neutrophil infiltration (Scott et  al., 2013a; Whiteman et  al., 2002). The entire retina is affected in PACG eyes. Necrosis of the RGCs with segmental nerve fiber layer rapidly progressed to involve all of the retinal layers within 1 day of onset of acute congestive PACG. Apoptosis of the RGCs and photoreceptor death was present within 1 day and prominent by 3 days (Scott et  al., 2013a; Whiteman et  al., 2002). The inner retinal layers, especially the RGC and RNFL as well as the ONH, appear to be most sensitive to changes in IOP, and elevations in IOP can produce a cascade of tissue and vascular events that eventually lead to cell death (Quigley, 1996). High IOP, compromised vascular supply to the ONH, and weakened ECM of the lamina cribrosa all play a role in glaucomatous optic nerve damage (Fick & Dubielzig, 2016; Hernandez & Pena, 1997; Spaeth, 1993). Local retinal amino acid excitotoxic injury, neurotropin deprivation to RGCs, and axoplasmic flow impairment at the prelaminar scleral cribrosa may contribute as well, both individually and collectively, to the optic nerve damage in the primary glaucomas, and perhaps in part to that in the secondary glaucomas (Brooks et al., 1997; Fechtner & Weinreb, 1994; Nickells, 1996; Samuelson et al., 1993). Large‐diameter optic nerve axons appear to be particularly sensitive to the elevated IOP that occurs during human, monkey, canine, and equine glaucoma (Brooks et al., 1995a, 1995b; Quigley et al., 1987). Axons of all diameters are subject to severe tissue‐ shearing forces at the lamina cribrosa resulting from the abrupt reduction in hydrostatic pressure (Holländer et  al., 1995; Morgan et  al., 1995). The large‐diameter axons were initially thought to be most susceptible to this sudden pressure transition because the critical collapsing pressure of axons is inversely proportional to the cube of the axon’s radius, but this hypothesis has recently become the subject of debate. Even small elevations in IOP may cause a reduction of axoplasmic flow and subsequent axon collapse, with axonal degeneration and atrophy. Sensitivity of the optic nerve to a particular level of IOP may change over time, based on biomechanical tissue properties, with progressive

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damage occurring at an IOP that was previously believed to be safe (Brubaker, 1996; Haefisa & Anderson, 1996). At every level of IOP there is a risk of glaucomatous damage, though the risk increases with increasing IOP. Damage can occur with extreme rapidity, as in angle‐closure glaucoma, or it may progress slowly, as in chronic POAG (Haefisa & Anderson 1996). IOP cannot be used by itself to determine whether glaucoma is present or whether optic nerve damage will occur or progress (Spaeth, 1993; Fig. 20.6 and Fig. 20.7). Deformation of the pores of the canine scleral lamina cribrosa occurs quite early in canine glaucomatous optic neuropathy during the POAGs (Brooks et  al., 1989a). This progressive, early deformation of the lamina cribrosa may not be detected ophthalmoscopically. OCT examination of the glaucomatous canine ONH reveals little change to the canine ONH at early to moderate stages of POAG, with sudden and dramatically increased optic disc cup depth and loss of neuroretinal rim at advanced stages of glaucoma (Dawson et al., 1995; Oh et al., 2013). Both elastin and collagen in the lamina cribrosa and trabecular meshwork are progressively disrupted as the disease progresses. The continued progression of ONH degeneration and deterioration of the animal’s vision despite lowering of IOP is classic evidence for the role of non‐IOP‐related factors in glaucomatous optic neuropathy. Acute and sustained elevated IOP in the rabbit with experimental chymotrypsin glaucoma, in the rabbit with congenital buphthalmia, in the nonhuman primate with laser‐induced experimental

Figure 20.6  Advanced optic disc atrophy in primary closed-angle glaucoma in an American Cocker Spaniel.

Figure 20.7  Chronic bilateral primary open-angle glaucoma in a Beagle dog. Note the buphthalmos, corneal edema, striae, and pigment, and mydriasis.

glaucoma, in humans with spontaneous glaucomas, and in primary glaucoma among several breeds of dog are associated with elevated intravitreal glutamate levels induced by retinal and ONH ischemia (Brooks et al., 1997; Dreyer et al., 1996). Among animals tested, intravitreal glutamate levels are much higher in the ACS with glaucoma than in Samoyed, Shar‐Pei, and Akita (Brooks et al., 1997). In all probability, the initial primary optic nerve injury from the elevated IOP induces RGC degeneration and apoptosis caused by glutamate excitotoxicity, neurotropin deprivation, accumulation of intraneuronal calcium, and formation of nitric oxide, proteases, and oxygen free radicals. The more severe the IOP‐ induced primary injury, the more dramatic the secondary effects; likewise, the less severe the primary IOP‐induced injury, the less severe the secondary degenerative effects to the RGCs. Failure of successful treatment of glaucoma relates not only to elevated IOP, but to the creation of a hostile retinal and ONH microenvironment that continues after the IOP has been normalized. There are several possible sources for the excess vitreal glutamate found in the glaucomas of different animal species. The loss of neurotrophic factor communication between axonal synaptic terminals and neuronal cell bodies when both orthograde and retrograde axoplasmic transport are obstructed at the lamina cribrosa in glaucoma may cause RGC death (Nickells, 1996). Dying RGCs could then release their intracellular stores of glutamate, which in turn results in further retinal cellular injury (Bito, 1977). A second source of increased vitreal glutamate levels could be the increased membrane permeability of diseased RGCs, which allows the release of intracellular glutaminase and conversion of extracellular glutamine to glutamate. Intracellular glutaminase is normally present in RGCs to convert glutamine to glutamate, and glutamine is normally found at high levels in the

vitreous (Ankarcona, 1995). A third source of glutamate may be disrupted removal of glutamate by the Müller cells (Silveira et al., 1994). Müller cells normally clear the synaptically released glutamate, but this ability may be impaired or overloaded under the ischemic conditions of high IOP (Huang et al., 1996). Under conditions of retinal ischemia, Müller cell transport systems that normally move glutamate into the cells may even actually work in reverse and deposit glutamate into the extracellular spaces (Otori et  al., 1995). The Müller cells of dogs with glaucoma are glial fibrillary acidic protein–positive, thus indicating an alteration in cellular physiology (Komáromy et al., 1997). A redistribution of glutamate was seen in the retinas of dogs with primary glaucoma (McIlnay et  al., 2004). Glutamate was lost from cell bodies in damaged areas of the inner and outer nuclear layer, whereas other cells, presumably Müller cells, contained an increased level of glutamate. Glutamine synthetase decreases in immunoreactivity with glutamate redistribution (Chen et  al., 2008). These decreases occurred in mildly damaged areas of the retina before overt retinal thinning. Reactive Müller cells occurred primarily in chronic primary glaucoma in severely damaged areas of the retina. The decreases in glutamine synthetase may potentiate ischemia‐induced early glutamine redistribution and neuron damage. Glutamate levels that are potentially toxic to RGCs are likely associated with the pathogenesis of primary glaucoma in the dog. Mean (± SD) vitreal glutamate concentrations were 31.7 ± 12.4 and 6.9 ± 6.3 mM in glaucomatous and normal eyes, respectively (Brooks et al., 1997). Other studies have found no increases in vitreal glutamate levels in animal models of glaucoma or in human patients with glaucoma (Levkovitch‐Verbin et  al., 2002; Wamsley et  al., 2005). The reason for the discrepancies in the interlaboratory results may be differences in experimental design, sample collection, or detection methods. However, local concentration of glutamate at the membrane receptors of RGCs is probably a more important issue than vitreal levels of glutamate. If retinal damage differs in intensity in focal areas, as shown in dogs, overall glutamate levels may be normal while there is a focal excess of glutamate in ischemic areas with affected glutamate reuptake (McIlnay et  al., 2004). Retrograde axonal transport obstruction of brain‐derived neurotrophic factor (BDNF) and its TrkB receptors in the retina and optic nerve have been demonstrated in the glaucomatous ACS (Iwabe et  al., 2007). Both BDNF and TrkB immunostaining was detected in a more intense pattern in glaucomatous eyes when compared to normal eyes. As demonstrated in the Beagle with POAG and acutely elevated IOP in normal dogs, in which there is obstruction of both orthograde and retrograde axoplasmic flow of the RGC axons at the scleral lamina cribrosa (Samuelson et al., 1983; Williams et al., 1983), BDNF retrograde axonal transport is also substantially inhibited by IOP elevation in the ACS. Differences

in the degree of IOP elevation and the retina–optic nerve perfusion pressures appear to directly influence the degree of impairment of these orthograde and retrograde axoplasmic flow markers. Alterations in the retinal levels of the stress‐inducible proteins glial fibrillary acidic protein (GFAP), heat shock protein 60, and hypoxia‐inducible factor‐1α (HIF‐1α) in rapidly progressive disease suggests a shift in cell regulation between acute (< 2 days) and chronic (> 7 days) glaucoma groups, and supports previous studies reporting that ischemia is a very important mechanism in this disease (Savagian et  al., 2008). This study also correlates with most clinical observations that acute primary glaucoma is a rapidly progressive degeneration involving all layers of the retina (both retinal and choroidal circulation are markedly affected) and a catastrophic event on vision. This study further correlates to clinical observations that differentiate PACG (which is also catastrophic) from the more common POAG in humans. Weibel‐Palade bodies are endothelial storage organelles of von Willebrand factor, which is a high‐molecular‐weight glycoprotein with a role in hemostasis and has been recently associated with the ADAMTS family of secreted metalloproteinases (Kuchtey et  al., 2011). These organelles are often associated with microcirculatory disorders such as diabetes and atherosclerosis in humans, but they are uncommonly found in the circulatory system of normal dogs. Weibel‐ Palade bodies are, however, found in the laminar capillaries of Beagles with hereditary glaucoma (Brooks, 1989b). The presence of Weibel‐Palade bodies in Beagles with hereditary glaucoma is highly suggestive of a primary or secondary ONH microcirculatory disorder. Changes of Ocular Perfusion Pressure

The concept of OPP is very important in understanding blood pressure and flow in the “pressurized” eye. OPP is equal to the external ophthalmic artery mean blood pressure minus the IOP. OPP is the driving force for blood entering the ocular circulation, and it exists as a range of values. In humans, the OPP is approximately 50 mmHg (Alm, 1983). Increasing the IOP decreases the OPP, as does lowering the blood pressure. In most vascular circulatory beds, blood flow is autoregulated, which means that moderate reductions in OPP induce a dilatation of the vessels and increase the blood flow. In equation form: Q

r4

blood velocity,



where Q is blood flow and r is the radius of the vessel. Blood flow may also be compared with the resistance of the vessels of the microcirculation. In equation form: Q where

P R,



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R 8l

n r4 ,

or

SECTION IIIA

Q

pnpr 4 8l ,



and Q is the blood flow, ΔP is the OPP, n is the number of vessels, r is the radius of the vessel, l is the length of the vessel, and η is the blood viscosity. Blood flow is directly proportional to the radius of the vessel to the fourth power. Thus, small alterations in arterial radius result in dramatic changes in vascular resistance and blood flow (Little & Little, 1989). Because of the autoregulation of retinal vascular resistance, blood flow remains largely unchanged within a wide range of OPPs (Orgül et al., 1995). When there is no autoregulation, each reduction in perfusion pressure is followed by a corresponding reduction in blood flow (Little & Little, 1989). Influencing stimuli include transmural pressures (i.e., the difference between intravascular and ocular tissue pressures), local accumulations of metabolites, and local anoxia. The retinal and ONH microcirculations are vigorously autoregulated in most species, but some evidence suggests the choroidal circulation has limited or no autoregulatory capability (Orgül et al., 1995). Both the retinal and ONH circulations can autoregulate their blood flow during reduced OPP caused by elevated IOP (Sossi & Anderson, 1983). Blood flow in the inner retina is practically unaffected by moderate changes in OPP. Blood flow and metabolism of the retina and prelaminar optic nerve are disturbed only at very high IOPs in the dog (Brooks, unpublished data, 1998). The short posterior ciliary arteries in dogs with acute (< 7 days) glaucoma demonstrated pathology with reduced luminal areas and fewer numbers of arteries, suggesting vascular pathology (Fick & Dubielzig, 2016). Changes in the different blood flow parameters, as measured by color Doppler imaging of both intraocular and orbital arteries and veins, have been reported in inherited POAG in Beagles (Gelatt et al., 2003; Gelatt‐Nicholson et al., 1999). Alterations in OPP may result in vascular insufficiency of the ONH if inherent compensatory autoregulatory mechanisms of the ONH are defective. Disease of the optic nerve vascular endothelial cells can result in decreased ability to produce nitric oxide, overproduction of endothelin (i.e., a potent vasoconstrictor), or both (Orgül et  al., 1995). Elevations of AH endothelin‐1 are found in POAG and normal tension glaucoma in humans and dogs with primary glaucoma (Källberg et al., 2002; Noske et al., 1997; Sugiyama et al., 1995; Tezel et al., 1997). In addition, endothelin‐1 levels were increased in the vitreous of glaucomatous dogs (Källberg, unpublished data, 2004). The apparent alterations in the circulation of the glaucomatous optic nerve implicate dysfunction of vascular regulatory mechanisms. Chronic ischemia of the anterior optic nerve has been induced in animal models, either by perineural infusion or intravitreal

injections of endothelin‐1 (Cioffi et al., 2004). These studies have resulted in glaucomatous‐like damage to the optic nerve. However, the elevated endothelin levels may not by themselves be responsible for the optic neuropathy seen in glaucomatous patients. Endothelin‐1 is even more highly elevated in a number of systemic diseases, but in these instances optic neuropathy seems not to occur more frequently than in the normal population. Glaucoma patients may have a primary vascular dysregulation, manifesting as an inappropriate arterial constriction or inadequate dilation.

Inflammatory Effects The role of inflammation before, during the elevation of IOP, and with prolonged periods of elevated IOP (< 50 mmHg) in primary and secondary glaucomas is poorly understood. Clinical observations suggest that anterior and posterior segment inflammations occur with many primary forms of canine primary glaucoma, especially when IOP is markedly elevated (> 50 mmHg). The classic example of concurrent inflammation and primary glaucoma (rather than primary uveitis and secondary glaucoma) is PACG in the Basset Hound, which may be accompanied by anterior uveitis when IOP elevations exceed 50 or 60 mmHg. Anterior segment inflammation concurrent with or following elevated IOP can worsen trabecular AH outflow directly with inflammatory cells and fibrin deposition, quickly followed by peripheral anterior synechia formation. When uveitis precedes and causes secondary glaucoma, the degree of inflammation is often more severe or is at least more long‐standing than the uveitis that is concurrent to primary glaucoma. In the study of goniodysgenesis‐related glaucoma, nearly all globes contained inflammation and pigment dispersion from either (1) segmental loss from the posterior iris epithelium epithelium; (2) clumping of the posterior iris pigment epithelium; (3) pigmented cells within the trabecular meshwork or anterior chamber; or (4) preferential settling of pigmented cells in the ventral ICA (Reilly et  al., 2005). Both neutrophils (early) as well as lymphoplasmacytic (later) inflammation were often present. These observations support the importance of inflammation in glaucomatous eyes, especially those with high IOP elevations. Although pupillary block associated with iris–lens touching and posterior iris pigment epithelium loss may be important in the genesis of this form of glaucoma, the presence of pigment cells (normally phagocytized by the trabecular cells) in the outflow pathways may further impair AH outflow. The origin of pigment cells may also suggest cell death and loss secondary to the high levels of IOP and local ischemia and the associated inflammation. Another report documented retinal pigment damage, breakdown of the blood–retinal barrier, and retinal inflammation in dogs with advanced primary glaucoma (Mangan

20: The Canine Glaucomas

(Pumphrey et  al., 2013a). Although it remains unclear whether these differences are part of the pathogenesis of disease or are sequelae to glaucomatous changes, these findings provide support for the hypothesis that immune‐mediated mechanisms play a role in the development or progression of GDRG.

Primary and Breed-Predisposed Canine Glaucomas The primary glaucomas in the dog are divided clinically into POAG and PACG. In the veterinary medical literature, the association of abnormalities of the pectinate ligaments (often termed goniodysgenesis or more precisely PLD) and angle‐closure glaucomas appears to be more than coincidence, and an important risk factor.

Pectinate Ligament Dysplasia Dysplasia of the pectinate ligaments (i.e., solid sheets of pectinate ligaments; initially termed mesodermal remnants) appears to be common in some breeds, but has not been directly related to an increased resistance to the outflow of AH (Rühli & Spiess, 1996). It would appear that glaucoma may develop in only the most severely affected forms of PLD (those with well in excess of 180° of the ICA involved). The pectinate ligaments appear to provide the basal support (i.e., anchor or pillar) for the iris to the posterior cornea and may affect the opening of the sclerociliary cleft. PLD in the dog is often localized to a few limited areas of the ICA, and it does not appear to increase resistance to AH outflow as measured by applanation tonometry or tonography (Rühli & Spiess, 1996). If PLD alone impairs AH access to the uveal and corneoscleral meshwork in some of these breed‐specific, narrow‐ or closed‐angle glaucomas, then goniotomy or transection of a significant circumference the pectinate ligaments of the filtration angle could offer both preventive and therapeutic benefits. It is important to differentiate the iridocorneal anomalies (e.g., persistent mesodermal bands, PLD) from any inflammatory‐associated changes (peripheral anterior synechiae). In some breeds, such as the Basset Hound and Flat‐Coated Retriever, the extent of the PLD can progress over time and predispose these dogs to glaucoma at later ages (Oliver et al., 2016; Pearl et al., 2015). This suggests that chronic or low‐grade anterior uveal inflammation may also be important in the genesis of glaucoma in these breeds and serial gonioscopy may be informative. Other breeds reported to have PLD include the Leonberger (Fricker et al., 2016), Golden Retriever, Border Collie, and Hungarian Vizsla (Oliver et al., 2017). The diagnosis of PLD is best achieved by a combination of both gonioscopy and biomicroscopy. Unfortunately, differentiation between dysplastic pectinate ligaments and peripheral

SECTION IIIA

et al., 2007). The globes were divided into 11 with acute glaucoma (within 5 days after the onset of acute glaucoma) and 13 with chronic glaucoma (beyond 5 days following onset). The affected dogs included 19 ACS, 3 Basset Hounds, and 1 Dachshund. All dogs had both primary glaucoma as well as goniodysgenesis. Various medical and laser treatments had been attempted in all dogs. Abnormal pigmented cells, including displaced retinal pigment epithelium (RPE) cells and macrophages (identified by lectin binding), were distributed throughout the neuroretinas and vitreous bodies. Both hypertrophy of the RPE cells and loss of RPE cell continuity occurred. The regions of the greater loss of neurons had greater displaced pigment. Signs of retinal inflammation included infiltration of leukocytes, retinal swelling, and albumin leakage from the retinal vessels. Perivascular CD3‐ positive T lymphocytes occurred in the glaucomatous retinas. In contrast to the acute glaucomatous globes, the globes with chronic glaucoma contained increased pigmentary changes, fewer neutrophils, and less retinal swelling. These posterior segment changes correlate with pigment dispersion and inflammatory changes reported in the anterior segment (Reilly et  al., 2005). It would appear that following elevated IOP there are considerable changes in the anterior and posterior segments related to local tissue ischemia and cell damage. Over time these changes in the posterior segment lead to exposure of the retinal auto‐antigens to the immune system, and contribute further to the intensity and duration of the retinal inflammation. The changes in the anterior segment could increase further the elevated IOP and directly damage the outflow pathways. In another study in the dog, retinas were obtained from advanced glaucoma globes and retinal RNA obtained (Jiang et  al., 2010). Global gene expression patterns were determined using oligonucleotide microarrays and confirmed by real‐time polymerase chain reaction. The presence of tumor necrosis factor and its receptors was identified by immunolabeling. At least 500 genes were detected with significant changes in expression level in the glaucomatous retinas. Decreased expression levels were detected for a large number of functional groups, including synapse and synaptic transmission, cell adhesion, and calcium metabolism. Genes with increased expression levels were mainly associated with inflammation, including antigen presentation, protein degradation, and innate immunity. Anti‐inflammatory mechanisms that protect the retina in early glaucoma may eventually fail and lead to the development of autoantibodies in many glaucomatous eyes. It is conceivable in advanced canine glaucoma that once the immune response develops, it may further accelerate vision loss by IOP‐independent mechanisms. Significant differences in serum autoantibodies against optic nerve antigens have been found in dogs with goniogenesis‐related glaucoma (GDRG) compared to normal dogs

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anterior synechiae in chronic glaucoma can be very difficult or even impossible (Bauer et al., 2016). In one report the histologic diagnosis of PLD in the presence of chronic secondary glaucoma was not possible (Bauer et  al., 2016). In some breeds, the extent of PLD increases with age, suggesting concurrent inflammation may assume a very important role.

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Effect of Gender The effect of gender appears important in humans with PACG, with the female affected much more frequently, especially in Asian populations (Foster, 2002). In contrast, POAGs are equally divided among men and women. Does the effect of gender also occur in the dog? Differences in the ratios of males to females for PACG by gender appear in the ACS, Basset Hound, Cairn Terrier, Chow Chow, English Cocker Spaniel, Samoyed, and perhaps the Siberian Husky. Magrane (1956) first reported more affected females than males in the ACS in his group of 25 affected animals that were presented with narrow‐angle glaucoma, and this also appears to be true in several other breeds. Whether this female predisposition is constant for the different breeds with PACG remains to be documented. From 1964 to 1973, the percentage ratios of male to females for most breeds were approximately equal. However, in the ACS, the females were affected more often than the males (percentage male : female 1 : 1.93). In the 1974–1983 interval, the percentage ratios of females to males were higher in the ACS (male : female 1 : 1.49), Basset Hound (1 : 1.65), English Cocker Spaniel (1 : 7.44), and Welsh Terrier (1 : 2.51). For 1984–1993, the percentage ratios of glaucomatous females to males were higher in the following breeds: ACS (male : female 1 : 1.76), American Eskimo (1 : 2.23), Basset Hound (1 : 1.48), and Samoyed (1 : 1.68). From 1994 to 2002, the ratios of females to males with glaucoma were higher in the ACS (1 : 1.31), Basset Hound (1 : 2.4), Cairn Terrier (1 : 2.42), Chow Chow (1 : 1.78), English Cocker Spaniel (1 : 7.14), Samoyed (1 : 2.23), and Siberian Husky (1 : 1.88). Recently, HRUS has suggested that the predisposition of the female PACG may be related to a reduced ICA opening (Tsai et al., 2012). One possible explanation is a smaller outflow pathway in females. Comparisons of normal Beagles by 20 MHz ultrasonography suggest that female Beagles have smaller angle opening distances and angle recess areas (Tsai et  al., 2012). The same study is yet to be performed in most of the PACG breeds.

Effect of Age Age appears to be an important risk factor and affects the time for presentation of the most of the glaucomas in the purebred dog. This finding may be misleading, as the onset of the disease and time of clinical presentation may be months to years different. In the Beagle with POAG, ocular hypertension starts in dogs between 12 and 18 months of

age, but overt clinical signs of glaucoma (i.e., early globe enlargement, mydriasis) and other signs are usually not detected and the dog not presented to the veterinarian until 4–6 years of age or even later. In those breeds with PACG, the time course appears abbreviated, but may span several months. In the majority of breeds, the primary glaucomas are presented most often in dogs at an average age of about 6+ years, except in the Siberian Husky, Samoyed, and Welsh Springer Spaniel, which are younger. A number of breeds, including the Basset Hound, Flat‐Coated Retriever, and Dandie Dinmont Terrier, have been identified as having a significant association between appearance and degree of PLD and age (Oliver et al., 2016).

Primary Glaucomas The discussions of breed‐related glaucomas in this section detail what is known or has been published to date. The reader will note that despite the length of this chapter, there is not very much known about the disease process, its etiology, pathogenesis, and treatment strategies. There is much yet to be elucidated. For some breeds, there is a clear understanding and characterization of the condition of the drainage angle (open versus narrow or closed); in others, that distinction has yet to be made. It is possible, or likely, that within each breed there are different forms and manifestation of this frustrating disease. Inherited/primary open‐ and narrow‐ or angle‐closure glaucomas occur bilaterally in purebred, and likely also in some mixed‐breed, dogs (see Fig.  20.2 and Fig.  20.7). Although the primary glaucomas have been reported in at least 45 breeds in the United States (see Table 20.1A), very few breeds have been thoroughly investigated to date. While much progress has been made in understanding the genetics of canine POAG, there is very limited information on the mode(s) of inheritance for most of the canine PACGs.

Genetics Based on the specific breed predilection of primary glaucomas, a genetic etiology is suspected to be responsible, and affected dogs should be excluded from breeding. Despite the high prevalence of primary glaucomas in dogs, genetic etiologies have been studied in only a relatively small number of breeds. Genetics of Canine Primary Angle-Closure Glaucoma

PACG is the most common form of primary, breed‐related canine glaucomas, suggesting a genetic etiology. Many breeds have been studied, with the highest prevalences documented in the ACS, Basset Hound, Chow Chow, Siberian Husky, Shiba Inu, Shih Tzu, Magyar Vizsla, and Newfoundland (Gelatt & MacKay, 2004a; Graham et  al., 2017b; Kato et  al.,

2006b; Komáromy & Petersen‐Jones, 2015; Slater & Erb, 1986; Strom et  al., 2011a). Because a simple mode of Mendelian inheritance could not be identified in most canine breeds studied, PACG appears to be a complex trait with multiple suspected genetic and environmental risk factors contributing to the disease (Graham et  al., 2017b; Komáromy & Petersen‐ Jones, 2015). The possible exceptions are the Welsh Springer Spaniel (Cottrell & Barnett, 1988) with a proposed autosomal dominant trait, as well as the Siberian Husky (Nell et  al., 1993), Basset Hound (Ahram et al., 2015), and Border Collie (Oliver et al., 2020; Pugh et al., 2019) with suggested autosomal recessive inheritance. PACG genetics has been investigated most extensively in the Basset Hound, thanks to the availability of a closed colony with informative pedigree (Ahram et al., 2014, 2015; Grozdanic et  al., 2010). Genome‐wide association study (GWAS) has revealed three genetic loci as possible contributors to the PACG phenotype in this breed with three positional candidate genes: COL1A2, RAB22A, and NEB (Ahram et al., 2014, 2015). All three have been shown to be expressed in the anterior segment of the eye, where they may play a role in AH outflow (Ahram et al., 2014, 2015). While COL1A2 (encoding the pro‐ alpha 2 chain of Type I collagen) is a promising PACG candidate gene due to the suspected involvement of collagen and other ECM components in the PACG pathogenesis (Vithana et al., 2011, 2012), subsequent studies have focused on NEB, which encodes for nebulin, a protein that that is expressed in the ciliary muscle where it may regulate muscle contractility (Ahram et al., 2015; McElhinny et al., 2003). It is possible that changes in nebulin and its function may alter muscle function and thereby contribute to PACG development (Ahram et al., 2015). The disease‐associated NEB allele is commonly found in the Basset Hound population: 88% of PACG‐affected Basset Hounds in the United States are homozygous for the NEB risk allele; the remaining 12% are heterozygous (Ahram et  al., 2015). Among PACG‐unaffected Basset Hounds, 33% and 44% are homozygous and heterozygous for the NEB risk allele, respectively, while 22% are homozygous for the nonrisk allele (Ahram et al., 2015). The identification of the NEB risk allele in the Basset Hound represents significant progress toward a better understanding of canine PACG; however, it remains a complex disease, since not all of the homo‐ and heterozygous animals develop glaucoma – additional genetic and environmental factors likely contribute. In fact, genome‐wide association sequencing in a cohort of European Bassett Hounds identified two novel loci associated with pectinate ligament abnormality and PACG. The results were confirmed in American Bassett Hounds, thereby failing to corroborate the associations previously identified in genetic testing of these dogs (COLIA2, RAB22A, and NEB; Oliver et  al, 2019). This supports the likely complex etiology of the condition in this breed. Progress in the understanding of canine PACG genetics has been made in other breeds as well, and investigations are

ongoing. In Shiba Inus and Shih Tzus, SRBD1 was identified as a PACG risk gene (Kanemaki et al., 2013). It encodes for S1 RNA‐binding domain and has been associated with human forms of primary glaucoma; however, its function remains unknown (Liu et  al., 2014; Mabuchi et  al., 2015; Writing Committee for the Normal Tension Glaucoma Genetic Study Group of Japan Glaucoma et al., 2010). In the Dandie Dinmont Terrier, a 9.5‐megabase region on canine chromosome 8 has been identified as a susceptibility locus for canine PACG; no specific disease gene has been identified yet (Ahonen et al., 2014). Most progress in the understanding of canine PACG genetics has been made in Border Collies, where PLD and PACG have been identified as a monogenic, autosomal recessive traits, caused by a missense mutation in the OLFML3 gene (Oliver et  al., 2020; Pugh et al., 2019). Genetics of Pectinate Ligament Dysplasia and Ciliary Cleft Opening in the Dog

Goniodysgenesis or PLD, combined with the narrowing of the ICA and ciliary cleft, is a well‐recognized risk factor of PACG (Bjerkås et al., 2002; Ekesten & Narfström, 1991; Kato et al., 2006a; Martin & Wyman, 1968; van der Linde‐Sipman, 1987; Wood et al., 1998, 2001). The inheritance of PLD and the width of the ciliary cleft have been studied in a number of dog breeds, such as the English Springer Spaniel (Bjerkås et al., 2002), Flat‐Coated Retriever (Read et al., 1998; Wood et  al., 1998), Great Dane (Wood et  al., 2001), Samoyed (Ekesten & Torrang, 1995), and Border Collie (Oliver et al., 2020; Pugh et  al., 2019). Quantitative polygenic traits are most likely, based on the observation that both the severity of PLD and the narrowing of the ciliary cleft worsen with the degree of kinship in PACG‐affected animals (Bjerkås et al., 2002; Ekesten & Torrang, 1995). Breeding of only animals with normal ICAs led to a reduction in the presence and degree of ICA abnormalities in the English Springer Spaniel (Bjerkås et  al., 2002). An autosomal recessive inheritance has been proposed for PLD in the Bouvier des Flandres (Rühli & Spiess, 1996) and confirmed in the Border Collie (Oliver et al., 2020; Pugh et al., 2019). Because much remains unknown about the link between the presence of PLD and glaucoma development and the genetics of PLD, there is no consensus between veterinary ophthalmology organizations regarding the inclusion of gonioscopy as part of routine genetic eye screening in order to provide breeding advice. Furthermore, without the additional assessment of the ciliary cleft width by HRUS or UBM, gonioscopy alone may not provide a full picture of the status of the AH outflow pathways (Grozdanic et  al., 2010; Tsai et al., 2012). While the ACVO has not issued recommendations against breeding of PLD‐affected dogs, the ECVO has adopted stricter rules with recommended gonioscopy for a number of breeds, including the ACS, all types of Bassets, Bouvier des Flandres, English Springer Spaniel, Flat‐Coated

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Retriever, Siberian Husky, and Samoyed (European College of Veterinary Ophthalmologists’ Hereditary Eye Disease Committee, 2013). While dogs with a mild degree of PLD (fibrae latae affecting less than 25% of the pectinate ligament circumference) are considered unaffected, a diagnosis of laminae and occlusio will result in a recommendation against breeding (European College of Veterinary Ophthalmologists’ Hereditary Eye Disease Committee, 2013; Spiess et al., 2014). Genetics of Canine Primary Open-Angle Glaucoma and Primary Lens Luxation

Thanks to the monogenic, autosomal recessive inheritance of all currently known forms of canine POAG and the availability of well‐established POAG Beagle colonies, great advances were made in recent years toward the better understanding of canine POAG genetics (Ahonen et  al., 2014; Forman et  al., 2015; Gelatt & Gum, 1981; Kuchtey et  al., 2013; Lazarus et al., 1998; Oliver et al., 2018). All currently known canine POAG‐causing mutations have been identified in two genes encoding for secreted matrix metalloproteinases: ADAMTS10 and ADAMTS17. The first mutations were identified in the ADAMTS10 gene of affected Beagles (p.G661R missense mutation with glycine to arginine change at position 661; Kuchtey et  al., 2013) and Norwegian Elkhounds (p.A387T missense mutation with alanine to threonine amino acid change at position 387; Ahonen et al., 2014), a gene that is strongly expressed in the trabecular meshwork. These findings were followed by the discovery of ADAMTS17 mutations in POAG‐affected Petit Basset Griffon Vendéen dogs (inversion in intron 12; Forman et al., 2015), Basset Hounds (19 base pair or bp deletion in exon 2; Oliver et  al., 2015), Basset Fauve de Bretagne dogs (p.G519S missense mutation with glycine to serine change at position 519; Oliver et al., 2015), and Chinese Shar‐Peis (6 bp deletion in exon 22; Oliver et al., 2018). Routine genetic testing for some of these mutations is available. The p.G661R ADAMTS10 missense mutation responsible for Beagle POAG was excluded as a cause of primary glaucoma in the ACS, Australian Cattle Dog, Chihuahua, Jack Russell Terrier, Jindo, Siberian Husky, Shiba Inu, Shih Tzu, and Yorkshire Terrier (Kuchtey et al., 2013). Despite the recent discovery of genetic defects responsible for canine POAG, the detailed molecular and cellular mechanisms resulting in the accumulation of extracellular trabecular meshwork plaques and increased trabecular outflow resistance remain unknown (Samuelson et  al., 1989). ADAMTS10 and ADAMTS17 are matrix metalloproteinases that play a role in fibrillin‐1 (FBN1) microfibril structure and function (Hubmacher & Apte, 2011). Canine POAGs are homologous to a group of human connective tissue disorders caused by abnormal microfibril formation: These microfibrillopathies include WMS and Marfan syndrome (MS), which are also caused by mutations in ADAMTS10

(WMS), ADAMTS17 (WMS), and FBN1 (MS and WMS; Dagoneau et al., 2004; Hubmacher & Apte, 2011; Kuchtey & Kuchtey, 2014; Kutz et al., 2008, 2011; Le Goff et al., 2011; Morales et  al., 2009). The ocular phenotype in affected human patients consists mainly of ectopia lentis/PLL combined with various degrees of open‐angle or angle‐closure glaucoma, the latter caused by shallow anterior chamber and pupillary block associated with the anterior dislocation of the lens (Chu, 2006; Dagoneau et al., 2004; Faivre et al., 2007; Hubmacher & Apte, 2011; Izquierdo et  al., 1992; Kuchtey & Kuchtey, 2014; Kutz et al., 2008; Morales et al., 2009; Wright & Chrousos, 1985). Like human WMS patients, zonular dysplasia and/or various degrees of PLL was reported in most POAG‐affected dog breeds, including the Beagle (Teixeira et  al., 2013), Petit Basset Griffon Vendéen (Bedford, 2016), and Chinese Shar‐Peis (Lazarus et al., 1998; Oliver et al., 2018), thereby closely linking canine POAG and PLL. In these dogs, zonular dysplasia and open‐angle glaucoma occur independently from each other, since IOP increases even without the dislocation or presence of a lens, as shown in the ADAMTS10‐mutant Beagles (Gelatt & Samuelson, 1988). It is likely that modifier genes are involved in determining if an ADAMTS10‐ or ADAMTS17‐mutant dog presents to the veterinary ophthalmologist because of PLL or primary glaucoma. In our clinical experience, even ADAMTS10‐mutant Beagles can present with limited PLL (Teixera et al., 2013). Based on these recent genetic discoveries, we think it is important for the clinician to consider a POAG component in “classic” PLL breeds, such as terriers (Alario et al., 2015; Curtis & Barnett, 1980; Gould et  al., 2011; Lazarus et  al., 1998; Morris & Dubielzig, 2005; Strom et  al., 2011a; Willis et al., 1979), because of their genetic defect in ADAMTS17 (splice donor site mutation: ADAMTS17c.1473+1 G>A; Farias et al., 2010; Gould et al. 2011). These canine patients may present with elevated IOP without lens displacement into the anterior chamber or pupillary block, but instead with lens subluxation or posterior lens luxation (Curtis et al., 1983; Glover et  al., 1995a). Furthermore, glaucoma often persists following surgical lens removal. In other words, glaucoma associated with PLL may not be entirely secondary to anterior lens dislocation and vitreous prolapse, as generally perceived (Gelatt & MacKay, 2004a); instead, there may be a POAG component. Like canine POAG, PLL also appears to be an autosomal recessive trait in most affect breeds (Curtis, 1990; Curtis et al., 1983; Ketteritzsch et al., 2004; Lazarus et  al. 1998; Willis et  al., 1979); hence, most heterozygous dogs that carry an ADAMTS17 mutation remain clinically unaffected (Farias et al., 2010; Gould et al., 2011). Interestingly, an estimated nearly 5% of heterozygous Miniature Bull Terriers, and a few heterozygous dogs of other breeds, such as the Parson Russell Terrier, Chinese Crested Dog, and Tenterfield Terrier, may develop PLL (Farias et  al., 2010; Gould et  al., 2011). This phenomenon

could be attributed to haploinsufficiency, a dominant negative effect of the mutant ADAMTS17 protein, or additional, still unknown mutations in ADAMTS17 or elsewhere in the genome (Farias et al., 2010; Gould et al., 2011). The Animal Health Trust recommends that carriers of ADAMTS17 mutations be regularly screened for signs of PLL. Diurnal IOP and/or tonography studies in dogs with DNA mutations may help separate those dogs with PLL (and secondary glaucoma) from those with a combination of PLL and primary glaucoma that may exhibit at different times. Because of their important function in microfibril formation, mutations in ADAMTS10 and ADAMTS17 not only result in an ocular phenotype with ectopia lentis/PLL and glaucoma in affected human WMS patients, but also short body stature, fingers, and toes (Faivre et al., 2007; Hubmacher & Apte, 2011; Khan et  al., 2012; Morales et  al., 2009; Robinson, 2006). Until recently, the canine disease phenotype appears to be limited to ocular symptoms. However, there have been speculations that PLL‐affected, ADAMTS17‐ mutant dogs may be slightly smaller than unaffected littermates, and that selection toward smaller body size may have contributed to the higher frequencies of the disease allele in affected breeds (Farias et al., 2010; Gould et al., 2011; Jeanes et al., 2019). Significant shorter body height has been confirmed in ADAMTS17‐mutant Petit Basset Griffon Vendéen and Shar‐Pei dogs (Jeanes et al., 2019).

Primary Open-Angle Glaucoma In the breeds with POAG, the increase in IOP is gradual and progressive, and the clinical signs develop from barely noticeable to advanced over a matter of years (usually 2–4; Miller, 2005). In the early and moderate stages of the disease, IOP is generally between 25 and 40 mmHg, and there is mydriasis, variable corneal edema, and episcleral congestion. Vision is present in these early stages. The dog’s eye is not appreciated as abnormal to the casual observer, and the dog is not usually presented to the veterinarian until the eyes are well advanced and enlarged. The descriptions below discuss breeds that have been confirmed to have POAG. Other breeds, even breeds that also have documented forms of PACG, likely have forms of POAG, possibly due to different genetic mutations, including the ACS, Basset Hound, Boston Terrier, Chow Chow, English Springer Spaniel, Miniature Schnauzer, Siberian Husky, and Poodle (Standard and Toy‐ Miniature breeds). Glaucoma in the Beagle

The Beagle breed is thought to be a very old breed (previously referred to as Begles), with its genesis in both England and France. Inherited glaucoma in Beagles was first reported in 1972 (Gelatt, 1972), and a colony of affected dogs was established shortly thereafter to permit long‐term investigation of this spontaneous disease (Gelatt et al., 1977b, 1981b).

POAG in the Beagle is the most well characterized of all spontaneous forms of canine glaucoma. The initial nine Beagles that presented with bilateral primary glaucoma had open ICAs initially in the early glaucoma eyes, and ICA closure and ciliary cleft collapse with enlargement of the globe in eyes with advanced glaucoma. During the past five decades, POAG in the Beagle has been investigated in considerable detail in the research setting and compared to the disease in Beagles and other breeds from the general population that present to the veterinary clinic. In the North American survey from 2004, glaucomatous Beagles were 6.24 ± 1.31 years of age when presented for first diagnosis (Gelatt & MacKay, 2004a). In the closed colony of glaucomatous Beagles, the ocular hypertension begins between 1 and 2 years of age, but becomes first noticeable by owners when secondary globe enlargement, mydriasis, and lens subluxation develop much later, usually at 4–6 years of age. The elevation in IOP becomes apparent with tonometry in Beagles between 8 and 16 months of age, but the clinical signs of glaucoma are delayed until 2–5 years old (Fig. 20.8). The increase in IOP and decline in outflow facility, as measured by Schiøtz tonography, pneumatonography, and constant‐pressure perfusion of the anterior chamber, develop slowly (Gelatt et al., 1977a, 1996; Peiffer & Gelatt, 1980). In affected dogs, the pneumatonographic outflow declines from 0.19 ± 0.07 μL/min/mmHg (3–6 months of age) to 0.07 ± 0.05 μL/min/mmHg (43–48 months of age). The pneumatonographic outflow measurements of genetic carrier (heterozygous) dogs are between those of affected and normal dogs. The mean episcleral venous pressure of both normal and glaucomatous dogs is 10–12 mmHg (Gelatt et al., 1982). The ICA and sclerociliary cleft are initially open and devoid of any abnormalities (Fig.  20.9). The IOP in early glaucomatous dogs slowly increases from the mean normal IOP of 16–18 mmHg. Animals 2–5 years of age have IOPs in the range of 25–40 mmHg. Diurnal IOP variations (8–12 mmHg) as well as IOP differences between fellow eyes of individual dogs are greater in affected dogs, with the highest IOP in the morning (Gelatt et al., 1981a). Results of serial A‐scan ultrasonography indicate that the increased IOP produces slight enlargement (1–2 mm) of the axial length of the globe, with concurrent lens subluxation and narrowing of the ICA and collapse of the sclerociliary cleft in dogs between 1 and 4 years. Lens removal at 6 months and prior to the onset of ocular hypertension in Beagles bred for POAG did not delay the onset of glaucoma (Fig.  20.10; Gelatt & Samuelson, 1988). Eventual ICA and sclerociliary cleft closure begins in animals 4–6 years of age and progresses. A few individuals maintain a gonioscopically open angle until as late as 8–10 years of age. POAG is inherited in Beagles as an autosomal recessive trait (Gelatt & Gum, 1981) and is associated with a G661R missense mutation in the ADAMTS10 gene, which is highly expressed in the trabecular meshwork (Kuchtey et al.,

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Section IIIA: Canine Ophthalmology

Lens position (Mean age)

1202

Gonioscopic findings Mackay-Marg Tonometric Results (mm Hg) Schiotz Tonographic Results (C) (ul/mmHg/min)

SECTION IIIA

Zonulary Disinsertion

In Situ

Narrow collapse of cleft

Normal

48 46 44 42 40 38 36 34 32 30 28 0.16 0.14 0.12 0.10 0.08 0.06 0.04

0

6

Subluxation/ luxation

12

18

24 30 Age in months

Narrow to closed

36

42

48

Figure 20.8  Progression of primary open-angle glaucoma in a Beagle with monitoring of intraocular pressure (applanation tonometry), aqueous humor resistance to outflow (C; tonography), position of the lens, appearance of the iridocorneal angle and ciliary cleft (gonioscopy), and amplitude scan ultrasonography (axial globe length). With globe enlargement, secondary iridocorneal angle and ciliary cleft closure as well as lens luxation with zonulary disinsertion occur.

2011). The ADAMTS10 mutation has not only been identified in this colony of glaucomatous Beagles, but also in clinical patients, and a second colony at Michigan State University. POAG in the Beagle, while generally following a slow, gradual, smoldering development (IOPs in mid‐30s persistently and maintenance of vision until 8–10 years of age or beyond), may in some individuals present more acutely (high IOP and vision loss by 4 years of age). The male : female ratio for POAG in the Beagle is 1 : 1. Interbreeding of the two different types of Beagles (13 and 15 inches) indicated onset of glaucoma was unaffected by body size. Before DNA testing was available, provocative tests were useful in differentiating early POAG Beagles or suspect clinical patients from normal animals. Oral administration of water and topical administration of corticosteroids produce abnormal increases in the IOP of glaucomatous Beagles. In normal dogs, oral administration of water (50 mL/kg) increased the IOP by 3.1–8.6 mmHg, whereas in glaucomatous Beagles the rise in IOP ranged from 7.3 to 19.9 mmHg (Gelatt et al., 1976). After 10–14 days of either unilateral or bilateral 0.1% dexamethasone administered 4 times a day in

glaucomatous Beagles, the IOP increases by approximately 5 mmHg (Gelatt & MacKay, 1998b). Elevated serum cortisone levels occur in glaucomatous Beagles, suggesting a chronic stress response to the disease and ocular hypertension, and appear to be cyclical with the diurnal IOP changes (Chen et al., 1980). Visual resolution as measured by PERG in both normal and glaucomatous Beagles has been compared (Ofri et  al., 1993a, 1993b, 1993c, 1994). The visual resolution limit of normal dogs was determined to be 6.9 ± 2.6 minutes of arc per phase in the central 15 degrees of the retina and 11.8 ± 2.3 minutes of arc per phase in the toroidal 15 degrees of the retina. In dogs with early glaucoma, the respective results were 7.8 ± 2.1 and 13.0 ± 3.1 minutes of arc per phase. For both groups, the resolution limit of the central 15 degrees was significantly higher (P < 0.0005) than that of the more peripheral, toroidal 15 degrees of the retina. There was no significant difference (P > 0.29) between the resolution limit of normal and that of early glaucomatous dogs for either the central or toroidal fields. Analyses of PERG results obtained 30 minutes and 2 hours after the injection of thiamylal sodium revealed that the second stimulation of the toroidal

Figure 20.9  Gonioscopic view of the iridocorneal angle and opening of the ciliary cleft in a Beagle with early primary open-angle glaucoma.

Intraocular Pressure (mmHg)

50 45 40 35 30 25 20 Phakic Aphakic

15 10

1

2

3 4 12 24 36 48 60 72 84 96 108 Surgery Weeks

Figure 20.10  Effect of unilateral lens removal in 6-month-old ADAMTS10 Beagles on the onset of ocular hypertension. Comparison of the intraocular pressure (IOP) results between the phakic and aphakic eyes did not prevent elevations in IOP bilaterally during the 2-year study.

15 degrees of the retina was remarkably larger than the first stimulation only in the glaucomatous dogs, and that it occurred with only the larger (> 48 minutes of arc per phase) gratings. Thiamylal sodium in a glaucomatous dog produced an initial 66% decline in signals from the central 30 degrees of the retina and an 88% decline in those from the more peripheral toroidal 15 degrees of the retina 30 minutes after the injection. Two hours after the injection, signals from the

peripheral 15 degrees of the retina again were increased above the first signal, with the central 15 degrees being unaffected. One possible explanation for this may be local effects from this barbiturate anesthetic on the larger RGCs within the less vascular toroidal retina. Barbiturates are known to increase retinal excitability, and perfusion deficits found in glaucoma might delay the drug reaching the retinal cells or prolong the presence of drug metabolites. This discovery supports the finding of initial peripheral retinal loss (similar to humans with POAG who first sustain peripheral field loss). A gradual decrease in amplitudes of the full‐field ERG photopic b‐wave and photopic negative response with POAG disease progression has been reported (Plummer et al. 2013). Results of preliminary studies using OCT of the superior and inferior neural rims of the ONHs in dogs indicated that the mean thickness of the RNFL ranged from 278 μm in one normal dog, to 361 μm in one dog with early glaucoma, and 161 ± 35 μm in six eyes with advanced glaucoma (Dawson et  al., 1995, 1996). Mean histopathologic RNFL measurements in similar dogs produced values of 242 ± 58 μm in eight normal eyes and 90.5 ± 59.0 μm in the glaucomatous dogs. One possible explanation for this increased peripapillary retinal thickness in dogs with the early glaucoma may be the presence of enlarged RGC axons from impaired axoplasmic flow. ONH cupping and neuroretinal rim loss have recently also been documented by OCT imaging in the POAG Beagles at Michigan State University (Oh et al., 2013). Results of color Doppler imaging of normal Beagles and those with inherited glaucoma in which the IOP was not medically controlled indicate significant differences in several specific blood flow parameters of many ophthalmic and orbital blood vessels (Gelatt et  al., 2003; Gelatt‐Nicholson et al., 1999). Differences in blood flow parameters on color Doppler imaging affected the exterior and internal ophthalmic arteries, anterior ciliary arteries, and short posterior ciliary arteries, all of which exhibited significant differences, but the parameters of the primary retinal arteries were not affected. Results of color Doppler imaging also demonstrate characteristic spectral waveforms for several of these blood vessels, as well as further differences when dogs with early, moderate, and advanced glaucoma are compared. Of interest is that initial changes in the color Doppler measurements of most of the orbital blood vessels in the glaucomatous dogs developed prior to the onset of ocular hypertension. Results of light microscopic examinations of the aqueous outflow indicate no abnormalities in early‐affected animals (Peiffer & Gelatt, 1980). By transmission‐electron microscopy (TEM), however, abnormalities were first detected in 12‐month‐old dogs (Samuelson et al., 1989). Clustered basement membrane–like material was scattered throughout the outer corneoscleral trabecular meshwork (Fig.  20.11). Elastin‐like fibers appeared to be more numerous and to be arranged less regularly than those in normal dogs, and small clusters of serrated, opaque rods were present within the

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AAP

SECTION IIIA

AAP

A

B

C

D

GM

F

Figure 20.11  Trabecular meshwork of glaucomatous Beagles at 12 months, 2 years, 3.5 years, and 5 years of age. A. In the 12-month-old glaucomatous Beagle, note the clustering of fibrils (arrows) along the inner face of the endothelium of the angular aqueous plexus (AAP; 12,000×). B. In the 2-year-old glaucomatous Beagle, note the fibrils, including those from elastic fibers (arrows), pressing against and within the vacuoles of the endothelium of the AAP (12,000×). C. In the 3.5-year-old moderately advanced glaucomatous Beagle, note the thickened band of granular material (GM) interspersed with fibrils (F) and basement membrane–like material (arrow; 40,000×). D. In the 5-year-old glaucomatous Beagle, note the closely packed trabeculae within the corneoscleral meshwork (4,000×). (Courtesy of Don Samuelson.)

cytoplasm of the trabecular cells within the corneoscleral meshwork. In the more advanced stages of the disease, these changes were more extensive and generalized within the corneoscleral meshwork. The trabeculae became more compressed and disorganized, with the concomitant accumulation of extracellular materials. Perfusion of the anterior chamber in normal dogs with bovine testicular hyaluronidase increases the constant‐pressure perfusion rate beyond that of control dogs (Gum et al., 1992; Samuelson et  al., 1987). Perfusion of glaucomatous dogs with hyaluronidase, however, did not increase the constant‐pressure perfusion rates. Histochemical localization of the glycosaminoglycans within the corneoscleral beams and

juxtacanalicular zone in normal dogs reveals that chondroitin sulfate is the major component, with lower amounts of hyaluronic acid, dermatan sulfate, and heparin sulfate (Gum et  al., 1986, 1993b). In glaucomatous dogs, the amount of chondroitin sulfate decreases as the disease advances, and a glycosaminoglycan hyaluronidase–resistant material develops. Even though the disease‐causing mutation has been identified in the ADAMTS10 gene (Kuchtey et  al., 2011), which is highly expressed within the trabecular meshwork, the molecular disease mechanisms that result in the excessive accumulation of ECM material are still unknown. Retinal and optic nerve changes in affected dogs have also been studied. Anterior movement of the scleral lamina cri-

brosa can initially be detected by scanning laser ophthalmoscopy, which is followed by posterior displacement of the multilayered lamina cribrosa (Brooks, 1996). Cupping of the canine ONH develops as the disease progresses. Such cupping is difficult to use as a clinical guide to glaucoma progression, however, because the rate of cup progression is variable. The retinal blood vessels, especially the small, peripapillary retinal arterioles and veins, gradually disappear. The optic discs become round with the loss of myelin, depressed, and atrophied. Results of short‐term studies measuring orthograde rapid axoplasmic flow with tritiated leucine in normal dogs at perfusion pressures of 12–100 mmHg (IOP 6–100 mmHg) revealed a pressure‐ related label accumulation at the scleral lamina cribrosa (Williams et al., 1983). The same effect also occurs in glaucomatous dogs (Samuelson et al., 1983). Trypsin and detergent digests reveal a well‐developed scleral lamina cribrosa in the dog (Brooks et al., 1998b). Slight posterior distortion or bowing of the scleral lamina cribrosa occurs before ophthalmoscopic changes to the optic disc can be observed. Posterior displacement and compression of the scleral lamina occur regularly in moderate stages of the disease. In advanced glaucomatous eyes, extreme posterior displacement of the scleral lamina, marked distortion of the lamina pore space, compression of the lamina, and disturbances of the congruent laminar pores are observed. Vascular casts of the optic nerve microcirculation did not reveal any differences between normal and glaucomatous Beagles (Brooks et al., 1989a). Results of ultrastructural examination of the optic nerve capillaries revealed many spherical, membrane‐bound, electron‐dense inclusions that closely resemble Weibel‐Palade bodies in the pericytes and endothelial cells of affected Beagles at all stages of the disease; the Weibel‐Palade bodies have been associated with microcirculatory abnormalities in both humans and diabetic dogs (Brooks et al., 1989a). The ultrastructural changes of the optic nerve axons at the ONH in glaucomatous dogs are prominent (Samuelson et  al., 1983). In dogs with early glaucoma, the optic nerve axons vary in diameter, are irregularly swollen, have various stages of demyelination, and contain occasional swollen mitochondria, dense bodies, and vesicles. Within most of the prelaminar, choroidal, and scleral lamina cribrosa, the axonal mitochondria frequently possess irregular, electron‐ dense bodies. In globes with moderate and advanced glaucoma, the optic nerve has more extensive pathologic changes. The myelinated axons are widely separated by demyelinated axons, hypertrophied or hyperplastic glial cells (i.e., astrocytes, oligodendrocytes, microglia), and edema. Dense, multilaminar myelin structures with shrunken, degenerated axons occur frequently within the prelaminar regions. Axons in the scleral lamina are extremely swollen with mitochondria and other cytoplasmic organelles, including various types of opaque inclusions and smooth‐surfaced vesicles.

Frequently, axoplasmic debris fills the spaces between the axons and the glial cells. Histomorphometry of the optic nerves in age‐matched normal and glaucomatous dogs indicate significant differences (Brooks et al., 1995). The mean total optic nerve axon count in normal dogs is nearly 150,000. The mean optic nerve axon diameters in normal, early glaucomatous, and advanced glaucomatous eyes are 1.53, 1.25, and 1.13 μm, respectively. The counts of optic nerve axons 2.0 μm or greater in diameter were reduced by up to 60% in the central regions of the optic nerves of affected dogs. These findings suggest that, as with POAG in humans and laser‐induced experimental glaucoma in nonhuman primates, the large‐ diameter optic nerve axons are more susceptible than the smaller‐diameter fibers to damage and disappear first in glaucomatous Beagles. Smaller‐diameter axons are extensively damaged later, such that only “resistant” ganglion cell axons are present late in the disease. The dog RGCs have been assigned to the morphologic classes α, β, and γ, which are equivalent to the neurophysiologically classified RGC types Y, X, and W reported in other species. The large RGCs have fast conduction velocities, large retinal receptive field surface areas, large‐diameter axons, and preferentially project to layers A and C (i.e., magnocellular layers) of the carnivore lateral geniculate body. An early focus of study involved the gene and protein myocilin, the first gene associated with several types of early‐ and late‐onset POAGs in humans. The protein myocilin, a secreted 55–57 kDa glycoprotein that forms dimers and multimers, was first reported in 1997 by Polansky and colleagues and termed trabecular meshwork‐induced glucocorticoid protein (TIGR; Polansky et  al., 1997). In the eye, myocilin is expressed in high amounts in the trabecular meshwork, sclera, ciliary body, and iris; low amounts have been detected in the retina and optic nerve in humans. One of the major characteristics of cultured trabecular meshwork cells is an increased secretion of myocilin following treatment with glucocorticoids (Clark et al., 2001). After myocilin was reported as a novel cytoskeletal protein in the retina and ONH, the term TIGR was replaced with myocilin (MYOC) for both the gene and the protein (Kubota et  al., 1997). All of the functions and effects of myocilin have not been determined, but MYOC mRNA is induced by stress, hydrogen peroxide, mechanical stretch, and steroid treatment. The gene myocilin was reported in the normal dog genome in the summer of 2003. In the same year, the protein myocilin was identified in the AH of normal laboratory‐quality Beagles, and in POAG in the Beagles, myocilin AH levels were increased (MacKay et  al., 2008b). As POAG progressed in these Beagles, the AH myocilin levels increased further. Myocilin was also localized in the normal and glaucomatous Beagle trabecular meshwork and nonpigmented ciliary body epithelium (Samuelson et  al., 2005). As with the aqueous myocilin levels, the glaucoma

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Section IIIA: Canine Ophthalmology

animals had increased amounts of myocilin in these tissues and it increased further in the older glaucomatous dogs. AH levels of myocilin of most primary glaucomas in purebred dogs and secondary glaucomas are also increased when compared to the AH from primary cataractous and diabetic cataracts of different breeds of a large number of dogs (MacKay et al., 2008b). CD‐44 is a cell‐surface glycoprotein that is involved with cell–cell interactions, cell adhesion, and cell migration, and is expressed in a large number of mammalian cell types. CD44 is also a receptor for hyaluronic acid, found in the AH outflow pathways. CD44 is increased in the AH as well as in several of the ocular tissues in POAG Beagles (Källberg et  al., 2006). These preliminary myocilin and CD44 studies suggest these changes are probably “downstream” and represent a common pathway in many primary glaucomas (rather than related to the causative genetic defect). Even though both the myocilin and CD44 proteins were elevated in AH, the trabecular meshwork, and nonpigmented ciliary body epithelium (Källberg et  al., 2006), no mutation was identified in the MYOC gene of Beagles with POAG (Gelatt & Wallace, unpublished data, 2004; Kato et al., 2009b; Storey et al., 2008). Similarly, although elevated AH and trabecular meshwork myocilin levels have been documented in a large number of breeds of dogs with the primary glaucomas, MYOC gene mutations could not be detected as a cause for primary narrow/angle‐closure glaucoma in the Shiba Inu (Gelatt & Wallace, unpublished data, 2004; Kato et al., 2006a, 2007, 2009; Storey et al., 2008). Another candidate gene, CYP1B1, was also excluded as the cause for Beagle POAG (Kato et al., 2009a). A mutation in the ADAMTS10 gene, caused by the substitution by glycine for arginine (gly661/arg) within a single 4Mb locus on the canine chromosome 20, was documented that is associated with POAG in the Beagle (Kuchtey et al., 2011). The ADAMTS family of proteins are matrix metalloproteinases that have important roles in microfibril formation and connective tissue organization. Despite the recent discovery of genetic defects responsible for Beagle POAG, the detailed molecular and cellular mechanisms resulting in the accumulation of extracellular trabecular meshwork plaques and increased trabecular outflow resistance remain unknown (Samuelson et al., 1989). Investigations of the posterior globe revealed that compared to wild‐type canine sclera, the ADAMTS10‐mutant tissue is biomechanically weaker and biochemically distinct, with decreased density and increased anisotropy of the collagen fibers, especially around the ONH (Boote et al., 2016; Palko et al., 2013). Age‐ associated scleral stiffening and loss of mechanical damping is comparable between wild‐type and ADAMTS10‐mutant dogs, regardless of chronic IOP elevation in affected animals (Palko et al., 2016). Because ADAMTS10 plays an important role in microfibril formation, which is a major component of the lens zonules, the G661R missense mutation in the Beagle

ADAMTS10 gene results in zonular dysplasia (Teixeira et al., 2013), which appears to be independent from the changes within the trabecular meshwork; IOP increases months to years before the dislocation or presence of a lens luxation (Gelatt & Samuelson, 1988). Nevertheless, in our clinical experience, ADAMTS10‐mutant Beagles can present with limited PLL, even though this has not been reported in the literature nor is a significant risk factor. Although Beagles are usually affected by POAG, there is a recent report of a purebred Beagle with PACG associated with goniodysgenesis (Park et al., 2019). This underscores the importance of a thorough examination and history in order to make the distinction and facilitate prognostication. Glaucoma in the Norwegian Elkhound

The prevalence of glaucoma in the Norwegian Elkhound has been decreasing in North America (1974–1983: 2.96%; 1984– 1993: 2.34%; 1994–2002: 1.98%). POAG was originally described in 29 Norwegian Elkhounds from Norway (Bjerkås et  al., 1994; Ekesten et  al., 1997). Glaucomatous dogs described in the original reports ranged in age from 3.9 to 13.0 years (median age 6.6 years). The male : female ratio of affected dogs is 1 : 1.3. Dogs in the North American survey were a mean of 6.9 ± 0.8 years at initial presentation (Gelatt & MacKay, 2004a). Applanation tonometric measurements ranged from 26 to 44 mmHg (median 35.5 mmHg) in the early cases and from 35 to 67 mmHg (median 52 mmHg) in dogs with advanced glaucoma. The ICA and ciliary cleft appeared normal in early‐affected dogs, with IOPs ranging from the upper 20s to the 30s. PLD was not observed, though occasional “stout” pectinate fibers were noted, with some narrowing of the ciliary cleft opening. The ciliary cleft gradually closes as the glaucoma advances and the IOP progressively increases. Synechial closure of the ciliary cleft occurred in the advanced cases. Lens subluxation and total lens luxation, buphthalmos and Haab’s striae, and ONH atrophy and retinal degeneration occurred late in the disease, with subsequent loss of vision. This breed is an excellent example of one in which individuals with IOPs in the mid‐30s mmHg and significant ONH pathology (cupping that involves the entire nerve head) maintain vision longer than expected. These dogs seem to tolerate fairly high IOP for months and can be quite buphthalmic, but can retain some functional vision. An additional retrospective histopathologic study of 9 clinically normal and 22 glaucoma eyes showed open‐angle and closed‐cleft glaucoma with PLD (2 normal and 18 glaucoma eyes), ciliary cleft abnormalities (hypoplasia or collapse), and linear deposition of PAS‐positive basement material within the uveal trabecular meshwork (in 19 glaucoma eyes). TEM demonstrated thickening of uveal trabecular beams by poorly staining large collagen fibrils and irregular deposition of excess basement material. Affected dogs presented between 5.5 and 8 years of age (Oshima et al., 2004).

A missense mutation in the exon 9 of the ADAMTS 10 gene appears to be the cause in the Norwegian Elkhound (Ahonen et al., 2014). The alanine to threonine substitution (different than the POAG Beagle) seems to affect the function of this protein on the ECM and microfibril composition (also possible defective structure of the lens zonules). This change occurs within the highly conserved functional metalloprotease domain of the protein. Presence of the zonulary defect (and possible weakness) could predispose to lens displacement, but its effect on the genesis of elevated IOP remained to be established. Glaucoma in the Petit Basset Griffon Vendéen

POAG was recently reported in the Petit Basset Griffon Vendéen in the United Kingdom based on the examination of 366 dogs over a 6‐year period (Bedford, 2016), with 38 dogs affected with POAG (prevalence 10.4%). Clinical signs developed after 3 years of age, with elevated IOP ranging between 34 and 48 mmHg at presentation. Initially the drainage angle appears open gonioscopically and the pectinate ligaments appear normal. In advanced POAG, globe enlargement, lens subluxation, ONH cupping, and impaired to complete loss of vision occurred. Lens subluxation was prominent in 10 dogs with phacodonesis and/or iridodonesis and aphakic crescents before subsequent elevation of IOP. An inversion mutation in intron 12 of ADAMTS17 was discovered as the cause for POAG (and PLL) in the affected Petit Basset Griffon Vendéen dogs (Forman et al., 2015). Primary Open-Angle Glaucoma and Primary Lens Luxation in other Canine Breeds

The division of canine primary glaucoma into POAG and PLL‐ PACG types is still unresolved. Some breeds may share both types of glaucoma (see “Genetics”). Unfortunately there are no detailed clinical descriptions for most of them, only reports of the genetic defect in ADAMTS17. In other words, glaucoma associated with PLL may not be entirely secondary to anterior lens dislocation and vitreous prolapse, as currently perceived (Gelatt et al., 2004); instead, there may be a POAG component. Tonography in some Wirehaired Fox Terriers presented with anterior lens luxations and glaucoma in one eye and the fellow eye with normal IOP and no evidence of lens luxations has suggested decreased aqueous outflow in the normotensive eye. The relationship between lens luxations and glaucoma is at best unsettled, and requires investigations. The discovery of ADAMTS17 mutations in POAG‐affected Basset Hounds (19 bp deletion in exon 2; Oliver et al., 2015), Basset Fauve de Bretagne dogs (p.G519S missense mutation with glycine to serine change at position 519; Oliver et al., 2015), and Chinese Shar‐Peis (6 bp deletion in exon 22; Oliver et al., 2018) means that It is important for the clinician to consider a POAG component in “classic” PLL breeds, such as terriers, (Alario et  al., 2015; Curtis & Barnett, 1980; Gould et  al., 2011;

Lazarus et al., 1998; Morris & Dubielzig, 2005; Strom et al., 2011a; Willis et al., 1979), because of their genetic defect in ADAMTS17 (splice donor site mutation: ADAMTS17c.1473+1 G>A; Farias et  al. 2010; Gould et  al., 2011). These canine patients may present with elevated IOP without lens displacement into the anterior chamber or pupillary block, but instead with lens subluxation or posterior lens luxation (Curtis et al., 1983; Glover et al., 1995a). Furthermore, glaucoma often persists following surgical lens removal. In other words, glaucoma associated with PLL may not be entirely secondary to anterior lens dislocation and vitreous prolapse, as generally perceived (Gelatt & MacKay, 2004b); instead, there may be a POAG component.

Primary Angle-Closure Glaucoma The clinical stages of PACG dogs are different from those in POAG and are characterized by abrupt increases in IOP, which are initially transient and self‐controlled (and unrecognized), but eventually the elevation in IOP persists and prompts presentation to the veterinarian. These abrupt IOP changes are apparently the result of pupillary blockage to AH from posterior chamber to anterior chamber, and the forward displacement of the basal iris with narrowing to closure of the ICA and cleft. These abrupt increases in IOP initially are in the 30+ mmHg range, but as the angle narrowing and closure advance, the increase can reach 50 mmHg or even higher and produce clinical signs that merit presentation to the veterinarian. Eventually (sometimes within days), this appositional narrowing and closure of the ICA and sclerociliary cleft develop peripheral anterior synechiae, “zipping” the outflow pathways closed, and rending the glaucoma refractory to pressure‐lowering drugs. During the next decade or so, the PACG breeds will hopefully be characterized further and the genesis of their glaucomas documented. Some breeds may also have both PACG and POAG forms (likely due to different genetic mutations), which further complicates accurate diagnosis. The increased occurrence of the PACG in females of many of these breeds will complicate the search for the mode of inheritance as well as the causative gene. The stages of canine PACG can be divided clinically into latent or prodromal, intermittent glaucoma, acute congestive or high‐pressure glaucoma, or postcongestive and chronic glaucoma, as proposed by Miller (2005; Table 20.3). The clinical types of PACG in humans are quite similar and have been divided into intermittent angle‐closure glaucoma, subacute angle‐closure glaucoma, acute angle‐closure glaucoma, and chronic angle‐closure glaucoma (Ritch & Lowe, 1996). Each stage of PACG has certain clinical characteristics that can aid in diagnosis and characterization and serve as a guide for therapy. Because the acute congestive stage of PACG is usually the first stage presented to the veterinarian, it is not surprising that nearly 50% of these eyes are blind

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Table 20.3  The different stages of primary angle-closure glaucoma in the dog.

Stage

History

Intraocular Pressure (IOP) at Exam

Latent

Breed-predisposed

Normal

Shallow

Intermittent (subacute)

Transient corneal edema

Normal

Congestive (acute)

Possible previous attacks

Postcongestive Chronic glaucoma

Angle-Closure Depth

Gonioscopy

High-Resolution Ultrasonography

Clinical Signs

Narrow

Sigmoidal iridal occludable

None; watch for configuration; progression; consider prophylactic therapy

Shallow

Narrow to closed/ appositional

Ciliary cleft narrow to closed

Bouts of partial mydriasis and corneal edema; other glaucoma signs variable Prophylactic therapy

Elevated; marked

Shallow

Closed Appositional to periodic acid-Schiff (PAS)

Cleft closed

High IOP with mydriasis; corneal edema; episcleral congestion; other signs

Glaucoma history

Normal

Shallow

Closed with PAS

Cleft closed

Normal to low IOP due to decrease aqueous humor production Signs of glaucoma

Glaucoma history

Increased

Shallow

Closed with PAS

Cleft closed

Buphthalmia; other signs of glaucoma; optic disc and retinal degeneration; blindness

and medical therapy at this stage has limited success that typically is only short‐lived. Glaucoma in the American Cocker Spaniel

In the United States, primary glaucoma in the ACS appears as a narrow‐angle or angle‐closure type, without significant amounts of PLD (Lovekin, 1964; Magrane, 1956, 1957). The prevalence of glaucoma in the ACS in North America has been increasing (1964–1973: 1.39%; 1974–1983: 2.07%; 1984– 1993: 3.95%; 1994–2002: 5.52%, the highest for any breed; Gelatt & MacKay, 2004a). In the first ACS report of 25 animals with glaucoma, 7 were males and 18 were females (1 : 2.6; Magrane, 1956, 1957). The mean age of affected animals at first presentation was 6.33 ± 1.46 years. Subsequent reports described glaucoma in the ACS in additional dogs in America and the Netherlands (Boevé & Stades, 1985; Lovekin, 1964; Lovekin & Bellhorn, 1968). In the North American survey of 1,982 glaucomatous cockers, 665 were males and 1,331 were females (1 : 2). The mean ± SD for affected animals was 6.72 ± 1.13 years. The presentation of primary glaucoma in the ACS is highest in middle‐aged to older dogs (1–2 years of age: 0.63%; 2–4 years of age: 1.07%; 4–7 years of age: 4.3%; 7–10 years of age: 7.03%; 10–15 years of age: 8.39%; 15+ years of age: 5.32%). Narrow‐angle glaucoma in the ACS continues to be the most frequent primary glaucoma presented to US veterinary ophthalmologists (Gelatt & MacKay, 2004a). This breed also continues to be one of the most popular in the United States. The usual history of PACG or narrow‐angle glaucoma in the ACS is unremarkable, with clinical signs unrecognized until an acute congestive crisis occurs; however, occasion-

ally there will be reports of conjunctival hyperemia and even transient corneal edema, both self‐limiting. Most affected dogs present with either classic clinical signs of unilateral, acute congestive glaucoma of a few days’ duration or with chronic, advanced glaucoma with buphthalmia, lens changes, retinal and ONH degeneration, and blindness (Fig.  20.12). Often, the condition becomes bilateral within several months. In Magrane’s series, the second eye was usually affected within 12 months. Both the history and clinical course suggest this glaucoma may be a series of acute IOP attacks, with the subsequent magnitude of the IOP elevation gradually increasing. Tonographic measurements are usually within normal limits in dogs with mild to moderately narrow ICAs, but they are lower than normal ( 0.10– 0.15 μL/min/mmHg) in dogs with very narrow and closed (due to synechiae formation) ICAs and clefts. Tonometry of the acute congestive glaucomas often yields IOPs as great as 50–70 mmHg. The corneal edema that parallels the elevation in IOP after approximately 40 mmHg usually prevents gonioscopy. Gonioscopy of the ACS with ocular hypertension generally reveals a narrow to closed ICA and reduced ciliary clefts; as the glaucoma progresses, angle closure and ciliary cleft collapse with peripheral anterior synechia formation are common. More recently, PLD in the ACS has also been reported, but it does not appear to occur commonly (Smith et al., 1993). Changes of the ocular fundus in the ACS may not correlate well with the duration and magnitude of the elevated IOP because of the wide range of IOP elevation. It is not unusual for an ACS to present with a very high IOP (70–80 mmHg) and a history of signs of glaucoma being present for less than 1

A

B

Figure 20.12  Narrow-angle and cleft glaucoma in an American Cocker Spaniel. A. Both corneal edema and striae are present, and the intraocular pressure is 52 mmHg. B. Gonioscopy reveals a closed iridocorneal angle and cleft.

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week, but not return of vision after the IOP is lowered below 20 mmHg. Ophthalmoscopically, the ocular fundus cannot be visualized until the IOP is lowered and the corneal edema reduced. The optic nerve and retina may initially appear to be normal, although some vascular attenuation may be present. With the IOP maintained within the normal range after these acute increases, additional retinal and ONH degeneration may become apparent within a few weeks. In some of these dogs, the retinal degeneration may affect only limited areas, appearing as radiating or fan‐shaped zones from the ONH and representing areas of retinal and choroidal degeneration caused by ischemia from the occlusion of individual short posterior ciliary arteries, apparently with high IOP levels. Because this breed often presents with its first affected eye with very high IOP and often irreversibly blind, prophylactic therapy of the fellow eye is very important. The p.G661R ADAMTS10 missense mutation responsible for Beagle POAG was excluded as a cause of primary glaucoma in the ACS (Kuchtey et al., 2013). Glaucoma in the Basset Hound

In the Basset Hound, reports detailing inherited glaucoma are limited and based on a relatively small number of animals (Bedford, 1975; Boevé & Stades, 1985; Martin & Wyman, 1968; Wyman & Ketring, 1976). PACG with PLD (i.e., mesodermal dysgenesis) was documented in Basset Hounds during the late 1960s and investigated during the early 1970s (Martin & Wyman, 1968; Wyman & Ketring, 1976). In these reports, 63% of Basset Hounds had some degree of PLD, but fewer than 3% had glaucoma. In the most recent North American survey, glaucoma occurred very frequently in the Basset Hound at a mean age of 6.3 ± 1.30

years at first presentation. Prevalence has been increasing (1964–1973: 3.08%; 1994–2002: 5.44%) and appears to increase with increasing age (Gelatt & MacKay, 2004a). The gender ratio reflects the greater prevalence of the disease in females (1 : 2.4). Unlike the simple autosomal recessive inheritance pattern in the Beagle and equal gender ratio, the heredity of Basset Hound glaucoma is likely more complex. More recently a colony of glaucomatous Basset Hounds was established and the glaucoma classified as chronic angle‐closure glaucoma with presumed autosomal recessive inheritance (Ahram et al., 2014, 2015; Grozdanic et al., 2010). Basset glaucoma usually presents clinically as either unilateral, acute, congestive PACG or as chronic PACG with buphthalmia and eventual blindness (Fig. 20.13). In a study using periodic tonometry, a gradual rise in IOP occurred in glaucomatous Basset Hounds starting at 14 mmHg (8‐ month‐old dogs), 15.5 mmHg (15‐month‐old animals), 17.5 mmHg (18‐month‐old dogs), 24 mmHg (24‐month‐old animals), and 36 mmHg (30‐month‐old dogs; Grozdanic et  al., 2010). This suggests that progressive changes in the AH outflow pathways, probably within the trabecular meshwork, develop before IOP exceeds normal levels. When glaucomatous Basset Hounds are provoked with mydriatics, affected dogs treated with topical 1% tropicamide or 1% atropine develop significant elevations in IOP (35% and 50%, respectively). Anterior uveitis, with at least some of the corneal edema related to this inflammation, is present, which is unusual among breed‐related canine glaucomas. It is not known at what point this inflammatory response develops or if the uveitis develops in response to the marked elevations in IOP and tissue damage. This inflammation complicates greatly the medical and surgical treatments of this form of

A

B

Figure 20.13  A. Basset Hound with bilateral advanced glaucoma. B. At gonioscopy, large, persistent mesodermal bands, rather than distinct, individual pectinate ligaments, are often visible. With extensive involvement, flow holes are present in these dysplastic pectinate ligaments. Because iridocyclitis is often present, these pectinate ligament anomalies must be differentiated from progressive, peripheral anterior synechiation of the aqueous outflow pathways in this type of glaucoma.

20: The Canine Glaucomas

tion in exon 2 of ADAMTS17 in Basset Hounds diagnosed with POAG in the United Kingdom (Oliver et al., 2015). The existence of different forms of glaucoma within a single breed confounds the study and expectations of the disease. Glaucoma in the Boston Terrier

The prevalence of glaucoma is also increasing in the Boston Terrier (1964–1973: 0.97%; 1974–1983: 1.82%; 1984–1993: 2.6%; 1994–2002: 2.88%; Gelatt & MacKay, 2004a). It also increases with age (2–6 months of age: 0.88%; 6–12 months: 0.52%; 1–2 years: 0%; 2–4 years: 1.116%; 4–7 years: 1.99%; 7–10 years: 4.08%; 10–15 years: 5.64%; and 15+ years: 12.5%). Glaucoma presents in the middle‐aged and aged Boston Terrier, with a mean age at initial presentation of 7.02 ± 1.24 years old. The male/female ratio is 1 : 1. There is no detailed report on glaucoma in this breed to date. Glaucoma in the Bouvier des Flandres

In the Bouvier des Flandres, two reports of PLD and narrow‐ angle glaucoma have been published (Boevé & Stades, 1985; van der Linde‐Sipman, 1987). Both reports were based on dogs in the Netherlands, where the breed is the most frequently affected purebred dog with glaucoma. In America, the Bouvier des Flandres is a relatively new breed of dog, and the number of glaucomatous animals in the survey report was limited to 23 animals (mean age of 5.43 ± 1.70 years old; Gelatt & MacKay, 2004a). The male : female ratio of affected dogs is 1 : 1. In addition to PLD and narrow ICA and ciliary cleft, histopathology of the affected secondary pectinate ligaments and trabecular meshwork contained significant amounts of PAS material, which may also affect AH outflow (van der Linde‐Sipman, 1987). Ciliary clefts measured in 98 dogs by HRUS and divided into open, narrow, or closed revealed that a narrow or closed ciliary cleft was associated with the development of PACG (Dubin et al., 2017). Nine of the dogs with narrowed or closed clefts went on to develop PACG (9.8%), suggesting association but not causation. In the Bouvier des Flandres a recessive inheritance of PLD has been proposed (Rühli & Spiess, 1996). Glaucoma in the Chow Chow

In the Chow Chow breed, the first report of glaucoma consisted of 18 glaucomatous animals (13 females and 5 males), with a mean age at initial presentation of 6.2 ± 2.2 years (Corcoran et al., 1994). That is similar to that noted in the North American prevalence survey, which reported a mean age of 6.45 ± 1.07 years on first presentation (Gelatt & MacKay, 2004a). The prevalence is increasing (1984–1993: 2.05%; 1994–2002: 4.70%) and the disease occurs more commonly in the aged animal (2–6 months of age: 0.46%; 6–12 months: 1.04%; 1–2 years: 0.35%; 2–4 years: 0.86%; 4–7 years: 5.92%; 7‐10 years: 9.69%; 10–15 years: 5.22%). The male : female ratio in primary glaucoma in this breed is approximately 1 : 2.

SECTION IIIA

glaucoma and requires concurrent anti‐inflammatory therapy. High‐frequency ultrasonography indicates complete collapse of the ICA in dogs about 20 months old (Grozdanic et al., 2010). In the opposite, normotensive eye, and in the affected eye, gonioscopy usually reveals a narrow to closed ICA, and the opening of the ciliary cleft is spanned by varying sizes and numbers of consolidated thickened pectinate ligaments or mesodermal remnants, with varying numbers of “flow holes.” There are usually some gaps in the regions of PLD, where the pectinate ligaments appear normal, and the gaps permit direct inspection of the trabecular meshwork and the ciliary cleft opening. Serial gonioscopy of some glaucomatous Basset Hounds suggests a gradual increase in the extent of the appearance of PLD with aging, suggesting possible formation of peripheral anterior synechiae with progressive narrowing of the ICA. Results of histopathologic examinations of these affected eyes mainly involved the advanced form of the glaucoma. Short, stout pectinate ligaments span the collapsed ciliary cleft and, in the advanced glaucomas, are often in direct contact with the peripheral cornea, with the opening to the ciliary cleft being collapsed. The termination of Descemet’s membrane in advanced cases is often enlarged, divided, and bulbous. Descemet’s membrane and corneal endothelial cells may extend posteriorly along the trabecular beams. Specific changes within the trabecular meshwork in the early stages of this disease are unknown. Schiøtz tonographic measurements of Basset Hounds with glaucoma revealed significantly impaired outflow (0.05 μL/ min/mm Hg; Helper et  al., 1974). In one of these Basset Hounds presenting with unilateral glaucoma, the flow rate in the affected eye was 0.03 μL/min/mmHg and 0.10 μL/ min/mm Hg in the “normal” fellow eye, which subsequently developed glaucoma 1 year later. While scotopic and photopic fERG does not reveal significant deficits in early‐affected Bassets, PERG indicated significantly reduced amplitudes. Reduced PERGs can occur in dogs as young as 18 months of age and gradually declined from 3.5 ± 0.42 μV (18‐month‐old dogs) to 1.84 ± 1 μV (30‐ month‐old dogs). There appeared to be a significant correlation between IOP levels and PERG amplitudes. This also suggests that functional vision deficits may precede significant elevations in IOP (Grozdanic et al., 2010). Medical treatment of Basset Hound glaucoma is difficult because of the often acute and very high elevations of IOP, and the clinical signs of combined angle‐closure glaucoma and iridocyclitis. Often the first presenting eye is moderately enlarged, the lens subluxated, the ONH cupped, and vision has been lost. Recent genetic reports on the Basset Hound are presented in “Genetics” in this chapter (Ahram et  al., 2015; Grozdanic et  al., 2010; Oliver et  al., 2015). Most instances of glaucoma in the Basset Hound are attributed to PACG; however, there has been a discovery of a 19 bp muta-

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Primary glaucoma in the Chow Chow has been associated with ICA closure and limited PLD (Corcoran et  al., 1994). Most animals presented with bilateral, acute congestive glaucoma. Results of gonioscopy, when possible, revealed narrow to closed ICAs, with short, stout pectinate ligaments. PLD, appearing as focal areas of solid pigmented sheets, was usually quite limited (< 1/16 the circumference of the angle). On the basis of clinical observations regarding the extent of PLD, the genesis of this form of primary glaucoma appears to be of the narrow‐ and closed‐angle type. Histopathologic results of a dog that had glaucoma for 18 months, as well as of four globes from three other Chow Chows with chronic glaucoma, revealed extensive retinal degeneration as well as deep cupping and gliosis of the optic discs. The pathology of the outflow pathways indicated collapse of the ciliary clefts and compression of the trabeculae. Endothelial cells and PAS‐positive basement membrane material spanned the pectinate ligaments and occurred within the trabecular meshwork. The termination of Descemet’s membrane had irregularities and nodular terminations. The Chow Chow is another breed with primary glaucoma that often retains functional vision until late in the disease, frequently despite elevated IOP, buphthalmia, and obvious, extensive ONH cupping and degeneration. Glaucoma in the English Cocker Spaniel

Glaucoma in the English Cocker Spaniel may be more common in the United Kingdom, and there is but a single report including 16 glaucomatous dogs with a mean age of 9.8 years old (Bedford, 1980a). The prevalence of glaucoma in the English Cocker Spaniel in North America is fairly constant (1.16‐1.35% between 1973 and 2002), and the disease primarily affects middle‐aged and older dogs (2–12 months: 0%; 1–2 years: 2%; 2–4 years: 0%; 4–7 years: 0.66%; 7–10 years: 1.44%; 10–15 years: 3.36%). The mean age of initial presentation and diagnosis of glaucoma in the English Cocker Spaniel was 6.83 ± 1.34 years old. The male : female ratio for this breed’s glaucoma is 1 : 2+. Bedford reported both narrow and closed ICAs and clefts as well as PLD in this breed (Bedford, 1977a). Breeding of only animals with normal ICAs led to a reduction in the presence and degree of ICA abnormalities in the English Springer Spaniel (Bjerkås et al., 2002). Glaucoma in the English Springer Spaniel

The prevalence of primary glaucoma in this breed in North America is low (0.48% in 1974–1983) and the age at diagnosis varies (2–4 years: 0.48%; 4–7 years: 0.28%; 7–10 years: 0.72%; 10–15 years: 1.4%; Gelatt & MacKay, 2004a). This glaucoma, characterized as narrow ICA and PLD, was reported in 14 (5 males and 9 females) of 279 English Springer Spaniels in Norway (Bjerkås et  al., 2002). While narrowing of the ICA in the hypertensive dogs seemed somewhat constant, the degree of PLD was more variable, with affected dogs generally more severely affected and more

frequently in older dogs. About 25.5% of the normotensive Springers had some degree of pectinate ligament abnormality. Degree of PLD in this breed is graded based on the percentage (1/16 wedges) of angle circumference involved with PLD. Normal (i.e., normotensive) dogs in a series have been graded as normal (74.5%), grade 1 (15.8%), 2 (6.8%), 3 (1.8%), or 4 (1.1%), but no correlation has been made between presence or grade of PLD and development of glaucoma in this breed. Some narrowing of the ICA was present in 17.9% of English Springer Spaniels. This breed‐related glaucoma appears to be inherited because related dogs were affected, and this possibility should be investigated more thoroughly. Glaucoma in the Flat-Coated Retriever

Primary glaucoma also affects Flat‐Coated Retrievers from the United Kingdom, but the condition has not been reported among those from the United States (Read et al., 1998; Wood et al., 1998). Flat‐Coated Retrievers with the more extensive forms of PLD are predisposed to glaucoma. In one study, 16 had glaucoma (62.5%–100.0% of the ICA circumference affected) and 11 were normotensive (62.5%–87.5% of the circumference affected); Read et al., 1998). The onset of glaucoma has been postulated to develop as corneal endothelial basement membrane deposition within the ciliary cleft, or as gradual closure of the compromised cleft from lenticular enlargement with aging occurs, but no histopathologic examination findings have been described. The possible relationship between the corneal endothelium and the trabecular meshwork endothelia within the ciliary cleft in the pathogenesis of this glaucoma is unclear, but intriguing. Repeated gonioscopic examinations of 96 dogs indicated that 39 (40.6%) developed progression in their PLD from the original observations (Pearl et al., 2015). Progression to the most severe form of PLD occurred in 12 (previously determined unaffected) of 96 dogs. Serial gonioscopic observations appear very important in this breed, particularly in older dogs. The role of secondary inflammation in the progression of these dysplastic pectinate ligaments over time and further closure of the opening of the iridociliary cleft is likely important. Glaucoma in the Great Dane

PACG as it occurs in Great Danes from the United Kingdom has been described (Barnett & Mason, 1993; Wood et  al., 2001). In that study 18 dogs were affected (11 females and 7 males), with an age range of 1–9 years (mean 4 years). Most dogs presented with unilateral acute congestive glaucoma, with 3‐ to 24‐month intervals before the fellow eye developed clinical signs. Gonioscopy of the initially affected eyes, as well as of the opposite, normotensive eyes, revealed narrow to closed ICAs with PLD. No tonographic or histopathologic examinations of affected eyes have been reported. A subsequent study of 180 Great Danes compared depth of anterior chamber, presence of goniodysgenesis (PLD), devel-

20: The Canine Glaucomas

Glaucoma in the Shiba Inu in Japan

The Shiba Inu is a relatively new breed in America, but its popularity is increasing. However, the Shiba Inu is a popular breed in Japan and demonstrates glaucoma with ICA narrowing and thickening of pectinate ligaments (Kato et  al., 2006a, 2006b, 2007). The thickened pectinate ligaments range from very broad strands to small sheets and broad solid sheets, with or without flow holes. Of the primary glaucoma dogs in Japan, the Shiba Inu breed has the highest incidence (Kato et al., 2006b). Most Shiba Inu patients present with acute high IOP elevations, mydriasis, corneal edema, scleroconjunctival congestion, pain, and often loss of vision. This breed, like the Basset Hound, has considerable concurrent uveitis as part of the disease process and can maintain sight for longer than expected. Affected individuals are reported to respond better to surgical implantation of a gonioshunt compared to medical therapy alone, with a mean duration of vision retention of 58 months into the postoperative period (Kubo & Ito, 2019; Saito et al., 2017). The genetics in this breed have been studied, but are not yet worked out. In a study involving glaucomatous, nonglaucomatous with open ICA, and nonglaucomatous with closed ICA Shiba Inu dogs, the exons of the canine MYOC gene were amplified and sequenced. A healthy Beagle dog was the control. Myocilin RNA was present in the ciliary body and trabecular meshwork, but the MYOC gene in this breed did not appear to be mutated (Kato et  al., 2007). The G661R ADAMTS10 missense mutation responsible for Beagle POAG has been excluded as a cause of primary glaucoma in the Shiba Inu (Kuchtey et  al., 2013). In Shiba Inus (and Shih Tzus), SRBD1 has been identified as a PACG risk gene (Kanemaki et  al., 2013). It encodes for S1 RNA‐binding domain and has been associated with human forms of primary glaucoma; however, its function remains unknown (Liu et al., 2014; Mabuchi et al., 2015; Writing Committee for the Normal Tension Glaucoma Genetic Study Group of Japan Glaucoma et al., 2010) Glaucoma in the Miniature and Toy Poodle

Although the prevalence of glaucoma in Miniature and Toy Poodles in North America is not high and is relatively stable (Miniature: 1.49–1.86%; Toy: 1.06–1.2%), the popularity of these breeds results in very large numbers of glaucomatous animals (Gelatt & MacKay, 2004a). Glaucoma in these breeds tends to occur in middle‐aged to older animals (Miniature Poodle: 2 months–4 years of age: 0%; 4–7 years: 0.42%; 7–10

years: 2.0%; 10–15 years: 2.37%; 15+ years: 3.78%; Toy Poodle: 2 months–4 years: 0%; 4–7 years: 1.07%; 7–10 years: 1.19%; 10–15 years: 1.79%; 15+ years: 2.34%). The mean age of initial presentation with glaucoma in Miniature Poodles was 7.31 ± 1.23 years. The affected male : female ratio for this breed is 1 : 1.4. Glaucoma in the Samoyed

The first report of PACG in the Samoyed was in Europe and included 12 glaucomatous animals (mean age 6.6 ± 2.8 years) and 179 normotensive dogs (Ekesten 1993; Ekesten & Narfström, 1991, 1992; Ekesten & Torrang, 1995). In the North American survey, there were 148 glaucomatous dogs with a mean age at first presentation of 6.16 ± 1.39 years (Gelatt & MacKay, 2004a). Prevalence in North America is relatively stable (1.43% in 1974–1983; 1.57% in 1984–1993; and 1.59% in 1994–2002). In the Samoyed breed, glaucoma is presented in middle‐aged and older dogs (2 months–4 years: 0%; 4–7 years: 3.15%; 7–10 years: 2.15%; 10–15 years: 0.61%), and the mean age of initial presentation with glaucoma was 6.16 ± 1.39 years. The ratio of males to females in the breed is 1 : 2.23. PACG in Samoyeds has been investigated clinically in Sweden (Ekesten, 1993; Ekesten & Narfström, 1991, 1992; Ekesten & Torrang, 1995). This breed is another excellent example of members that have elevated IOPs (mid‐30s mmHg) and advanced cupping of the ONH, but maintenance of vision. Results of gonioscopy indicated PLD to varying degrees in 47 of 210 eyes. The width (opening) of the ciliary cleft (as measured from goniophotographs) decreases with age. However, there was no significant correlation between IOP and degree of PLD of these animals. Interestingly, considerably narrower clefts were found in the eyes of dogs closely related to Samoyeds with angle‐closure glaucoma. The heritability of the relative depth of the ciliary cleft opening was estimated at 56%. In affected animals, age‐ related shallowing of anterior chamber depth, increased lens thickness, increased vitreal axial length, and increased axial length of the globe are present before the onset of clinically detectable increased IOP in the fellow eyes of unilaterally glaucomatous Samoyeds (Ekesten, 1993; Ekesten & Narfström, 1991, 1992). These are frequent observations for primary narrow‐ or closed‐angle glaucoma in humans as well (Ekesten, 1993). The glaucomatous eyes all had closed ICAs. Eyes with narrow ICAs had anteriorly positioned lenses and a longer vitreous body. The increase in globe axial length will increase the radial shearing forces at the scleral lamina cribrosa, to which the axons are exposed as they exit the globe, according to the equation S

DP * R

2h,



where S is the radial shearing forces, DP the translaminar pressure difference, R the radius of the globe, and h the scle-

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opment of glaucoma, and inheritance of goniodysgenesis (Wood et al., 2001). The estimated heritability of the degree of goniodysgenesis was 0.52, and there was a significant relationship between the angle abnormalities in the parents and their offspring. Anterior chamber depth of < 3.7 mm was a predictor of glaucoma. Shallow anterior chambers and extensive PLD appear to be risk factors in this breed.

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ral thickness at the lamina (Fechtner & Weinreb, 1994). Increased susceptibility of ONH axons to IOP is the result. The classic hypothesis concerning the pathogenesis of narrow‐angle glaucoma is a relative block of AH passage through the pupil, which is caused by the greater tension applied by the iris against the central lens or, in Samoyeds, by the more anteriorly positioned lens. Increased resistance to the escape of AH into the pupil from behind the iris results in the more forward displacement of the basal iris, which could be associated with a narrow opening of the ciliary cleft. Over time, the outflow pathways become progressively more compromised and eventually close. Glaucoma in the Shar-Pei

A relatively new breed to North America, the Shar‐Pei exhibits primary or breed‐related glaucoma with increasing frequency (1984–1993: 1.53%; 1994–2000: 4.40%) in later life (2 months–2 years: 0%; 2–4 years: 1.49%; 4–7 years: 7.58%; 7–10 years: 7.42%; 10–15 years: 3.17%; Gelatt & MacKay, 2004a). The breed has also been reported with hereditary lens luxation and POAG (Lazarus et al., 1998; Oliver et al., 2018), and how these two breed‐related diseases interrelate remains to be defined. In the glaucoma study, males and females were affected with similar frequency and a male : female ratio of 1 : 0.89. In the dogs with PLL, the mean age of affected animals was 4.9 years (range of 3–6 years). This breed is another example that retains vision in the face of IOPs in the mid‐30s mmHg and severe ONH cupping. A 6 bp deletion in exon 22 of the ADAMTS17 gene has been implicated in the development of POAG and PLL in this breed (Oliver et al., 2018). Glaucoma in the Siberian Husky

The prevalence of glaucoma in the Siberian Husky (1984– 1993: 1.13%; 1994–2002: 1.88%) reflects the increased popularity of the breed in North America. PLD and progressive narrowing of the ICA have been associated with this form of ocular hypertension. Nell and colleagues reported that PLD in this breed may be inherited via an autosomal recessive mode of inheritance. She also reported that PLD was observed more frequently in the female and in blue irides (Nell et al., 1993). In these normotensive dogs, there was no relationship between the amount of PLD and IOP. Glaucoma in this breed affects mainly young and middle‐aged dogs (2 weeks–2 months: 1.75%; 2–6 months: 1.24%; 6–12 months: 1.42%; 1–2 years: 1.0%; 2–4 years: 1.69%; 4–7 years: 2.59%; 7–10 years: 2.01%; 10–15 years: 0.86%). The mean ± SD age of initial presentation with glaucoma was 5.27 ± 1.64 years. In the Husky the ratio of affected males to females is 1 : 1.88. Glaucoma in the Welsh Springer Spaniel

In Welsh Springer Spaniels from the United Kingdom, 28 cases of PACG have been reported (Cottrell & Barnett, 1988). Females were affected more frequently than males (ratio 4.2 : 1). Age of onset ranged from 10 weeks to 10 years (mean

age 2.75 years). Four dogs were affected before 1 year of age. Time from the onset of glaucoma in the first eye to that in the second eye ranged from 6 days to 3 years. Clinical signs were either those of acute congestive glaucoma with pain, dilated and unresponsive pupils, episcleral congestion, corneal edema, and IOP as high as 80–100 mmHg, or those of chronic angle‐closure glaucoma with enlarged globes, Haab’s striae, lens subluxation and cataract formation, and advanced retinal and ONH degeneration. Gonioscopy of the affected dogs revealed eyes with regions of narrow and regions of closed ICAs and ciliary clefts, as well as other eyes with the angles totally closed. The Welsh Springer Spaniel has sparse and “wispy” pectinate ligaments. Scanning electron micrographs of the outflow pathways revealed closure of the ICA, complete absence of the pectinate ligaments, the iris root merging with the corneal endothelium, and partial collapse to complete closure of the ciliary cleft. This form of glaucoma was familial, and the mode of inheritance appeared to be dominant (Cottrell & Barnett, 1988). Selected matings, however, were not performed. The affected animals with partially open or narrow angles were thought to be heterozygous, and those whose eyes had completely closed angles were thought to be homozygous. The defect may show variable expression as well. Glaucoma in the Border Collie

Sudden‐onset glaucoma has been recognized in Border Collies since the 1990s. Breed enthusiasts soon thereafter started a database to track affected dogs and the results of gonioscopic examinations, but a definitive association between PLD, or pectinate ligament abnormality (PLA) as it is referred to in the breed, could not be established with this alone (Pugh et  al., 2019). Recent studies in Border Collies have identified and confirmed the association of a single variant in OLFML3 with PLD and PACG (Oliver et al., 2020; Pugh et al., 2019). This variant consists of a change of arginine to glutamine in the OLFML3 protein encoded on canine chromosome 17. PLD and PACG have previously been considered to be complex diseases caused by multiple genetic and environmental factors. The results of these studies, however, are consistent with PLD and PACG largely being a monogenic, autosomal recessive trait, at least in Border Collies. Other Breeds

Additional breeds also develop primary glaucomas (see Table 20.1A), but the specifics of the disease in most breeds have not been investigated. Primary narrow‐angle glaucoma occurs in Golden Retrievers from the United Kingdom, with angle closure, cleft collapse, and PLD observed. Studies in the Eurasier breed in France have been reported (Boillot et  al., 2014). Secondary glaucoma associated with pigmentary dispersion and anterior uveal cysts also occurs in this breed (see Chapter  21). Additional clinical studies using

20: The Canine Glaucomas

Secondary Glaucomas The secondary glaucomas consist of diseases with increased IOP, open to closed ICAs and ciliary clefts, and detectable impairment of AH outflow. Both the medical and surgical management of secondary glaucomas in the dog have been overshadowed by those of the primary glaucomas. Clinical management of the secondary glaucomas is often more clear‐cut, because the cause of the increased IOP can be ascertained (Table 20.4), and the prognosis for the glaucoma progression predicated. Medical or surgical treatment of the secondary glaucomas is directed toward removing the cause of the elevated IOP. There may be additional or secondary changes (e.g., peripheral anterior synechiae) that may require application of the standard glaucoma filtering or cyclodestructive procedures. The most frequent cause of glaucoma in the dog requiring surgery is lens displacement, which is demonstrated as subluxation, anterior luxation, or posterior luxation and cataract formation. Dogs with ADAMTS17 and ADAMTS10 mutations likely have a component of POAG that is exacerbated by the complications and sequelae associated with lens displacement. Uveitis and intraocular tumors are also associated with secondary glaucoma in the dog.

Risk Factors and Secondary Glaucoma in the Dog Lenses and the Glaucomas

Removal of the lens, though not commonly considered to be a surgical procedure for treatment of glaucoma, may be necessary in treatment of many of the canine lens‐induced glaucomas. Lens removal may be indicated for secondary glaucomas associated with lens‐induced uveitis and cataract resorption, intumescent cataracts, anterior and posterior lens luxations, and subluxations. When the lens is displaced from its patella fossa in a glaucomatous eye, maintenance of IOP within normal limits by surgical, medical, or some combination of these treatments may be impossible without lens removal. Lens removal has not been attempted in early PACG dogs to either prevent the onset and/or progression of angle closure or treat angle‐ closure eyes if IOP is already elevated. Lens luxations and

Table 20.4  Summary of treatments for the secondary glaucomas in the dog. Anterior Uveitis Peripheral anterior synechiae Pupillary obstruction Iris bombé Medical: Corticosteroids, Nonsteroidal anti-inflammatory agents, Mydriatics Surgical: Coreoplasty, Iridencleisis Lens-Associated Cataract Surgical: Lens removal Displacement (Anterior luxation, subluxation, posterior luxation) Surgical: Lens removal; other Intraocular Neoplasms Surgical: Iridocyclectomy; enucleation; laser Hyphema Surgical: Aspirate/tissue plasminogen activator Melanocytic (Dog Only) Surgical: Anterior chamber shunts; enucleation Aphakic/Pseudophakic (Angle/Pupil Obstruction) Surgical: Coreoplasty; Iridencleisis; anterior vitrectomy Malignant Surgical: Anterior vitrectomy Silicone Oil Surgical: Aspirate

cataract‐induced uveitis account for nearly 80% of all secondary glaucomas. Subluxated Lenses and Anterior and Posterior Lens Luxations

Lens luxations are the most common cause of secondary glaucoma in the dog, but they also can occur secondary to buphthalmia in primary glaucoma. It is important to recognize, however, that PLL and POAG may occur in combination in dogs with ADAMTS17 and ADAMTS10 mutations, which makes the designation of secondary glaucoma from a lens luxation complicated and potentially tenuous. Approximately 80% of all of the secondary glaucomas are associated with lens luxations in the dog. Most of the PLLs (presumed inherited) occur in younger dogs of the terrier breeds and occur bilaterally. Many breeds have glaucoma and lens luxations as inherited and concurrent traits. Lens luxations can also develop when the globe becomes enlarged, and the lens zonules become stretched and transected. Enlargement of the globe causes progressive stretching of the zonules, which eventually breaks their attachments to the equatorial lens capsule, or infrequently causes disinsertion of their attachments to the ciliary body. In the dog with bilateral buphthalmia and lens subluxation/luxation, it may be impossible to determine if the lens luxations are primary or secondary. The breed, age of onset, and presence or

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HRUS (20 MHz), UBM (50–60 MHz), OCT, ultrasound ocular measurements, and IOP diurnal recordings will hopefully document these glaucomas and their pathogenesis during the onset and early stages of these diseases. Once families of affected dogs are identified, DNA tests may reveal the causative gene defects. Accurate genetic testing may reveal potential glaucoma dogs before onset of the disease, enabling further documentation and classification of the disease (open/closed angle).

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absence of cataract development may aid in making this determination. Total luxation with normal‐sized globes is more common in primary luxation syndromes, with subluxations more commonly caused by the buphthalmia from glaucoma. Lens luxations in Terriers are common, especially in young dogs (3–5 years old; Table  20.5), and these dogs may present with either unilateral or bilateral and acute or chronic secondary glaucoma (Curtis, 1990). These younger dogs with PLL also have a higher rate of bilateral involvement (86% vs. 15% with secondary lens luxations; Betschart et al., 2014). In a study on the prevalence of primary or breed‐related and secondary glaucomas in the Wirehaired Fox Terrier, this breed was diagnosed with both the primary and secondary glaucoma types (Gelatt & MacKay, 2004a, 2004b). It is obvious that many veterinary ophthalmologists have difficulty establishing whether the initial ocular hypertension is primary or related to lens displacement in this breed. In the Wirehaired Fox Terrier, Formston first associated lens luxation to the glaucoma in 90 animals with a mean age of 4.96 ± 1.43 years. None of the dogs was less than 3 years old (Formston, 1945). In another study on lens luxation in dogs, Curtis and Barnett (1983; Curtis, 1990) reported that terrier breeds with PLL were relatively young (mean age 4.7 years), younger than dogs presenting with glaucoma without lens luxations. The PLL occurred in dogs between 3 and 5 years old, while the secondary lens luxations occurred in dogs over 8 years old (Curtis & Barnett, 1983). The secondary glaucoma associated with lens instability or dislocations may be the result of iridocyclitis from microTable 20.5  Inherited and breed predisposition to lens luxation in the dog. Inherited

Breed Predisposed

Border Collie

Australian Collie

Cairn Terrier

Basset Hound

Jack Russell Terrier

Beagle

Lakeland Terrier

Chihuahua

Manchester Terrier

German Shepherd

Miniature Bull Terrier

Greyhound

Norfolk Terrier

Miniature Poodle

Norwich Terrier

Miniature Schnauzer

Scottish Terrier

Norwegian Elkhound

Skye Terrier

Spaniel Breeds

Sealyham Terrier

Pembroke Welsh Corgi

Smoothhaired Fox Terrier

Welsh Terrier

West Highland White Terrier

Toy Poodle

Tibetan Terrier

Toy Terrier

Wirehaired Fox Terrier

trauma between the unstable lens and iris, with resultant increases of AH fibrin, proteins, and inflammatory cells, which can themselves interfere with aqueous drainage, and it also may aid in formation of preiridal fibrovascular pupillary membranes as well as anterior and posterior synechiae, which further compromise AH drainage (Fig.  20.14). Anterior lens movement can mechanically impair passage of AH through the pupil, thereby causing increased posterior chamber pressure, which in turn causes anterior ballooning of the peripheral iris and reduction in the area of the ICA outflow pathways. Such movement of the iris also contributes to the formation of permanent peripheral anterior synechiae, and posterior synechia that cause a condition known as iris bombé. Lens subluxation is first apparent with a variable‐size aphakic crescent (Fig. 20.15). With loss of the zonulary support, the lens becomes unstable (phacodonesis), as does the iris (iridodonesis). The vitreous may protrude through the aphakic crescent to variable amounts. Possible mechanisms by which these unstable lenses may produce ocular hypertension include microtrauma and iridocyclitis, peripheral anterior and posterior synechiae, formation of preiridal and ICA inflammatory membranes, pupillary blockage of AH flow, and vitreous pupillary blockage, among other factors. The completely luxated lens can remain in the patella fossa, luxate into the anterior chamber, or move posteriorly through the torn anterior vitreal face and into the vitreous (Fig.  20.16). One report suggests that ocular hypertension occurs in 73% of canine eyes with anterior lens luxations, in 43% of those with subluxations, and in 38% of those with posterior lens luxations (Glover et al., 1995a). With anterior displacement of the lens from the patella fossa, vitreous adhering to the posterior lens capsule may occlude the pupil, thereby preventing pupillary flow of AH and ballooning the base of the iris, which in turn causes ICA and sclerociliary cleft closure. This type of iris bombé often masks the basal iridal and filtration angle changes. With posterior or vitreal luxation of the lens, the torn anterior vitreal membrane allows both liquid and formed (i.e., gel) vitreous access into the pupil and the anterior chamber. Formed vitreous may cause pupillary blockage and secondary glaucoma. It can also adhere to the posterior cornea and ICA. Blockage of the ICA with formed vitreous sufficient to increase IOP is infrequent, but blockage of the pupil from vitreous sufficient to increase IOP occurs commonly. In POAG and PLL and associated with ADAMTS mutations, the defect can affect the AH outflow pathways as well as the zonules. These defects may occur together clinically, or one defect may be dominant. DNA studies have been reported in several breeds with lens luxations (Farias et  al., 2010; Gould et  al., 2011; Oberbauer et  al., 2008; Sargan et  al., 2007). A mutation located in a 6.3 Mbp region in the central part of the chromosome 3 (‐logP (max) = 6.4) was first reported in Miniature

A

B

Figure 20.14  A. Glaucoma secondary to zonular dysplasia and an anteriorly luxated lens. The lens has migrated into the anterior chamber and is in contact with the corneal endothelium. The pupil is mydriatic and there is an obvious aphakic crescent nasal to the dislocated lens. Note the episcleral injection. B. Anterior lens luxation of a complete cataract with concurrent glaucoma.

Bull Terriers, Lancashire Heelers, and Tibetan Terriers (Farias et al., 2010; Sargan et al., 2007). GWAS and fine mapping by homozygosity were used to demonstrate a GT‐>AT splice donor site mutation at the 5′end of intron 10 of the ADAMTS17 gene in Miniature Bull Terrier, Jack Russell Terrier, and Lancashire Heeler (Farias et  al., 2010). The predicted exon 10 skipping and resultant

Figure 20.15  In lens subluxation, the cause of the ocular hypertension is less obvious. Intermittent pupillary obstructions of aqueous humor passage by the unstable lens and formed anterior vitreous, chronic iridocyclitis, and progressive iridocorneal angle and ciliary cleft closure, however, appear to be important.

frame shift were confirmed with RNA derived from affected dogs. Subsequently, this c.147311G>A mutation in ADAMTS17 was found in PLL‐affected dogs of an additional 14 breeds, not all of them with terrier coancestry: Australian Cattle Dog, Chinese Crested Dog, Jagdterrier, Parson Russell Terrier, Patterdale Terrier, Rat Terrier, Sealyham Terrier, Tenterfield Terrier, Tibetan Terrier, Toy Fox Terrier, Volpino Italiano, Welsh Terrier, Wirehaired Fox Terrier, and Yorkshire Terrier (Gould et al., 2011). Genetic testing for this ADAMTS17 mutation is currently available for at least 26 breeds (Komáromy & Petersen‐Jones, 2015). ADAMTS17 is one of 19 known mammalian members of the ADAMTS family of genes that encode secreted metalloproteases that proteolytically modify

Figure 20.16  In posterior or vitreal lens luxation the lens often “falls” and lays on the floor of the vitreous body. Sometimes it adheres to the ventral retina. Often organized vitreous and even hemorrhage may be within the vitreous and its face.

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extracellular structural proteins. The exact mechanism(s) by which the ADAMTS17 mutation affects the lens zonules remains to be determined. The nonpigmented (inner) ciliary body epithelium produces and secretes fibrillin 1, which is the important component of the zonules.

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Cataractous versus “Clear” Lenses

Lens luxation may involve normal as well as cataractous lenses, but in most instances the mechanism for the zonular disinsertions differs. In terriers, Tibetan Terriers, and Border Collies, the zonules appear to possess structural malformations, and bilateral lenticular displacement occurs in dogs only a few years of age with clear lenses. IOP can remain normal or be associated with abrupt elevations (Curtis, 1990; Curtis & Barnett, 1983; Foster et al., 1986; Willis et al., 1979). In contrast, luxations of cataractous and often hypermature lenses tend to occur with inherited cataracts in older dogs (8–10 years old) of the nonterrier breeds. The zonular degenerations with advanced cataractous lenses appear to relate to the capsular and zonular changes associated with cataract hypermaturity and lens‐induced uveitis. With focal zonular degenerations, small aphakic crescents develop, and partially liquefied vitreous may protrude through a defect in the anterior hyaloid membrane and into the pupil. This vitreous may also display pigment spots. Early removal of displaced lenses, particularly in terriers, has the highest possibility of success for retention of vision and prevention of secondary glaucoma on top of POAG associated with ADAMTS10 and ADAMTS17 mutations. Delayed medical or surgical treatment of eyes with displaced lenses can result in secondary glaucoma. Surgical removal of subluxated lenses, anterior luxated lenses, and posterior luxated (i.e., intravitreal) lenses may be accomplished by extracapsular, phacoemulsification, or intracapsular techniques (Glover et al., 1995a; Nasisse & Glover, 1997; see Chapter 23). In contrast to the high success rate of cataract surgery in dogs by phacoemulsification, the en bloc removal of luxated lenses has a much higher risk of serious postoperative complications, including glaucoma and retinal detachment. If surgery is not possible, the medical approach to therapy typically involves chronic topical anti‐inflammatories and anti‐glaucoma medications and diligent monitoring of IOP for elevations. For eyes with posterior luxations, long‐term therapy with potent miotic agents is advocated by some to keep the luxated lens behind the iris and in the vitreal chamber (Binder et al., 2007. Zonular fiber morphology has been evaluated by light microscopy and special stains in dogs with glaucoma (Morris & Dubielzig, 2005). Zonular fibers are composed of microfibrils, whose primary components are the glycoproteins fibrillin‐1 and fibrillin‐2. In 63 dogs diagnosed with glaucoma secondary to lens luxation, two distinct forms of abnormal zonular fiber morphology were recognized and designated as zonular fiber dysplasia and zonular fiber collagenization. The dysplastic form had zonular protein tightly

adherent to the nonpigmented ciliary body epithelium, exhibiting a distinct lamellar and cross‐hatched pattern that was strongly positive to PAS and trichome stains, and staining negative to elastin stains. In the second form of zonular fiber collagenization, the abnormality was prevalent in the terrier and Shar‐Pei breeds, and characterized by excessive zonular fiber that stains positive with PAS, trichrome (blue for collagen), and elastin stains, but was not tightly adherent to the nonpigmented ciliary body epithelium. The age of onset of glaucoma in these dogs also varied, with the zonular fiber dysplasia individuals developing lens dislocation at a much younger age (mean 5.2 years) compared to zonular fiber collagenization individuals (mean 8.9 years), supporting the likelihood of heritability of zonular fiber dysplasia (which has since been confirmed; see Chapter 22). Phacomorphic Glaucoma and Intumescent Cataract

The intumescent (i.e., swollen) cataract has been associated with an acute pupillary block, phacomorphic glaucoma in the dog. This phenomenon occurs most frequently in the dog with diabetic cataracts, which may also develop anterior and equatorial capsular tears. The enlarged lens displaces the iris forward, thus increasing posterior chamber pressure and causing the base of the iris to shift forward. This in turn narrows the ICA and impinges on the ciliary cleft opening. If iridocyclitis is also present, peripheral anterior synechia may form. Treatment of this form of secondary glaucoma usually requires surgical extraction of the cataractous lens, usually by phacoemulsification, in addition to aggressive anti‐ inflammatory therapy. Phacolytic Glaucoma/Resorbing Hypermature Cataracts and  LensInduced Uveitis

Rupture of the lens capsule from ocular trauma and lens‐ induced uveitis from resorbing hypermature cataracts can cause the phacolytic form of open‐angle glaucoma in the dog (Davidson et al., 1991a; Rubin & Gelatt, 1968). If the lens‐ induced uveitis is not carefully monitored and controlled medically, the filtration angle can eventually become obstructed with inflammatory cells, protein‐rich AH, fibrin, and macrophages filled with lens‐like material (Fig.  20.17 and Fig.  20.18). With chronic lens‐induced uveitis, formation of anterior and posterior synechia, peripheral anterior synechia, and iris bombé may contribute to this phacolytic form of secondary glaucoma. The definitive treatment for phacolytic glaucoma is cataract extraction to eliminate the source of the lens protein obstructing the aqueous outflow pathways. Medical therapy with betablockers, carbonic anhydrase inhibitors (CAIs), and hyperosmotic agents is useful for reducing IOP in preparation for surgery. Aphakic/Pseudophakic Glaucomas

The frequency of aphakic and pseudophakic glaucomas in humans after cataract surgery has gradually declined as surgical techniques have improved. In the 1950s and 1960s, the

A

B

Figure 20.17  A. Glaucoma secondary to chronic lens-induced uveitis. Hypermature cataracts were present in both eyes, and the left eye has become buphthalmic and developed exposure keratitis. B. Glaucoma secondary to chronic lens-induced uveitis in a Labrador Retriever. The hypermature cataract is subluxated dorsally and a large aphakic crescent is evident. Note the mydriasis and episcleral injection.

Figure 20.18  Aphakic glaucoma may develop secondary to pupillary occlusion from annular posterior synechiae (iris to iris; iris to lens capsular/anterior vitreous adhesions or both), resulting in iris bombé.

incidence of these glaucomas in humans was reported to be from 0.7% to 7.0%, and even as high as 12%. In 1965, secondary glaucomas after cataract extraction were the most common cause for enucleation in humans (35% in 1954 and 31% in 1965; Tomey & Traverso, 1991). With the increased frequency of extracapsular and phacoemulsification cataract surgery and the intracapsular lensectomy for luxated lens in the dog, aphakic and pseudophakic glaucomas became more frequent as well (Biros et  al., 2000; Davidson et  al., 1991b; Lannek & Miller, 2001; Paulson et al., 1986). In one report, the incidence of aphakic glaucomas after cataract surgery was estimated to be 3% (Davidson et al., 1991b). In another study, in which extracapsular cataract extractions were used, aphakic glaucomas developed in 20% of the eyes (Paulson et al., 1986). Of these glaucomas, approximately 30% devel-

oped during the first 6 months after surgery; the remaining 70% developed later. Other studies have yielded a higher prevalence of secondary glaucoma after lens removal in dogs followed long term (Biros et al., 2000; Lannek & Miller, 2001). In a report involving 172 dogs following phacoemulsification, the frequency of glaucoma increased with time, but remained under 10% overall (Sigle & Nasisse, 2006). The Boston Terrier, ACS, Cocker Spaniel–Poodle crosses, and Shih Tzus had increased risks of developing glaucoma. These same breeds are also predisposed to primary glaucoma. Also eyes with hypermature cataracts and anterior uveitis were most likely to develop glaucoma. Another report indicated about 15.8% of phacoemulsification patients may develop anterior uveitis and glaucoma in the long‐term postoperative period (Johnsen et al., 2006). These studies suggest that periodic reexamination after cataract surgery is critically important to monitor for the presence and degree of uveitis and changes in IOP. It appears that glaucoma can occur at any time following cataract surgery and its incidence may vary with surgeon experience and skill. The incidence will vary as well with duration of follow‐ up, as it appears that the risk of glaucoma does not disappear at any point in the postoperative period. As patient follow‐ ups are extended over time, a considerable number of patients are lost for a variety of medical and nonmedical reasons. In a study involving 247 dogs with 420 eyes operated, only 290 eyes were available for follow‐up 3 months after surgery, 259 eyes 3–6 months after surgery, 200 eyes 6 months–1 year after surgery, 132 eyes 1–2 years after surgery, 80 eyes 2–3 years after surgery, 39 eyes 3–4 years after surgery, and 17 eyes 4 years or more after surgery (Sigle & Nasisse, 2006). This demonstrates the difficulty of conducting long‐term studies, and the variable incidences of glaucoma following cataract surgery in the dog.

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Aphakic and pseudophakic glaucomas probably develop from multiple etiologies, especially occlusion of the pupil from inflammatory membranes and closure of the ICA and ciliary cleft by the formation of preiridal fibrovascular membranes and peripheral anterior synechia (Scott et al., 2013b). The glaucomas that occur secondary to pupillary blockage in the dog are usually characterized by a small pupil that is either adhered to itself or is obstructed by a membrane consisting of organized fibrin, inflammatory cells and fibrous tissue, anterior capsule remnants, artificial intraocular lens, posterior capsule, the anterior vitreous, or any combination of these. There may be iris bombé as well. The occluded pupil may be depressed and sometimes barely visible because of the iris bombé that bulges into the central and peripheral anterior chamber. IOP as measured by applanation or rebound tonometry is usually elevated, but this may not accurately reflect the profound IOP elevation in the posterior chamber behind the iris due to impaired flow of AH into the anterior chamber. If the pupillary obstruction is acute (< 72 hours), intensive medical therapy consisting of potent mydriatics (such as 0.1% scopolamine, 10% phenylephrine), topical and systemic corticosteroids, topical and systemic nonsteroidal anti‐ inflammatory medications, and systemic CAIs can be attempted. Intravenous mannitol can be administered rapidly to reduce IOP, but its effects may be muted by the increased permeability of the blood–aqueous barrier due to iridocyclitis. Intracameral tissue plasminogen activator (tPA), 25–50 μg, can readily assist in the resolution of fibrin occlusion of the pupil of less than 2 weeks’ duration (Martin et al., 1993). If pupillary flow of AH is not possible, the occluded pupil can be opened by dissection with a sharp blade or hypodermic needle, laser iridotomy, iridectomy, or iridencleisis, but reformation of adhesions is common. Unsuccessful resolution of an occluded pupil and iris bombé results in chronic buphthalmia and blindness. Intraocular hemorrhage should be anticipated in these procedures, because the inflamed canine iris is highly vascular. During iridectomy, a radial (i.e., complete) or basal (i.e., peripheral) section of the iris is excised; unless they are large, these sites will eventually close, with iridal scarring and inflammatory membranes. The neodymium : yttrium‐aluminum‐garnet (Nd : YAG laser may be used to produce full‐thickness iris holes (i.e., laser iridotomy); unfortunately, these holes will usually close within a few days. Our impression is that aphakic glaucomas secondary to pupillary occlusion tend to occur early in the postoperative recovery period. The form of aphakic glaucoma characterized by angle closure, ciliary cleft collapse, and formation of peripheral anterior synechia develops in the dog several months or even years after successful cataract surgery. The onset of this glaucoma is usually slow and insidious, which is another reason for long‐term monitoring of these patients after cataract

surgery. Clinical signs may be either acute or chronic, but the elevation in IOP usually occurs over several weeks. Gonioscopic examination reveals large areas of peripheral anterior synechiae. Aggressive, long‐term anti‐inflammatory therapy may reduce the concurrent iridocyclitis and lower the IOP. Topical betablockers as well as topical and systemic CAIs can temporarily lower the IOP, but eventually an anti‐glaucoma surgical procedure will be necessary. Aphakic glaucomas caused by either of these mechanisms may be difficult to reverse with intensive medical therapy; more often, they will require further surgery to relieve the pupillary occlusion and angle blockade. Acute Postoperative Hypertension Following Cataract Surgery

Postoperative hypertension (POH) during the immediate postoperative period after cataract removal has been recognized for decades in both humans and dogs. In a report involving humans, the frequency of POH of > 30 mmHg 5 hours after surgery was 75%, and 21% for an IOP of 40 mmHg or greater (Vuori & Ali‐Melkkila, 1993). In a clinical study involving 88 dogs undergoing cataract surgery, the incidence of postoperative hypertension of 25 mmHg or greater was 49%, of 30 mmHg or greater 34%, of 40 mmHg or greater 20%, and of 50 mmHg or greater 6% (Smith et  al., 1996). Several studies have confirmed POH following lens removal; perhaps the most important variables are the times and frequencies of postoperative tonometry (Chahory et al., 2003; Miller et  al., 1997). The average onset for POH of 25 mmHg or greater was 4.9 hours. The incidence of POH was not affected by lens removal technique (extracapsular or phacoemulsification); however, those eyes receiving phacoemulsification demonstrated a more rapid increase in IOP (mean 3.9 hours) than eyes receiving extracapsular techniques (mean 8.4 hours). Tonometry performed 6–12 hours after cataract surgery will miss the majority of POH occurrences. Intraocular lens placement may also cause a more rapid increase in postoperative IOP. Both older dogs and longer phacoemulsification times increase the likelihood of POH. Factors not found to correlate with development of POH included sex, stage of cataract, type of surgical procedure used, intraocular lens placement, preoperative lens‐ induced uveitis, posterior capsular tears, and anterior vitrectomy (Biros et  al., 2000). Older Labrador Retrievers have a predisposition to both POH and subsequent glaucoma (Moeller et al., 2011). The cause of POH is not known, but it seems to result from obstruction of AH outflow pathways. It is also unknown if dogs that develop POH will, at a future date, develop glaucoma. In an experimental study of normal dogs that underwent phacoemulsification, IOP peaked at the third postoperative hour, with a mean IOP of 49.9 ± 5.0 mmHg (Miller et al., 1997). Use of a viscoelastic agent, 2% hydroxypropyl methylcellulose, did not affect the peak or duration of POH. Results of computer‐aided morphologic analysis indicated that increased IOP immediately after surgery may

20: The Canine Glaucomas

Malignant Glaucoma (Aqueous Misdirection)

Malignant glaucoma is a variation of pupillary block aphakic glaucoma, and it may develop after extracapsular extraction, phacoemulsification, or intracapsular extraction surgery (Denis, 2002; Strubbe, 2002). The pupil is usually of medium size and is obstructed with inflammatory membranes involving either the posterior lens capsule or the anterior vitreal face (with extracapsular extraction or phacoemulsification). The iris bombé may not be prominent centrally, but may place the peripheral iris in close proximity to the corneal endothelium. If the pupil is small, aqueous misdirection glaucoma may be detected by ultrasonography. Rather than remaining in the enlarged posterior chamber behind the iris bombé, the AH is either misdirected or redirected into the vitreous body through a tear in its anterior face. As AH formation continues and the IOP rises, the AH is now misdirected into the vitreous body, thereby pushing the organized or formed vitreous further into the occluded pupil. This is a surgical condition in which the impermeable pupillary membranes must be removed by incisions with iris scissors followed by anterior vitrectomy. Once these impediments are removed, pupillary flow of AH is reestablished. Because peripheral anterior synechia may develop quickly with this disorder; however, iridencleisis may be considered.

Traumatic Glaucomas

Traumatic glaucomas, which occur secondary to blunt and penetrating trauma, are infrequent in the dog. Complete acute hyphema in the dog is usually associated with uveal inflammation and low IOP; chronic or repeated intraocular hemorrhage in the dog is more apt to increase IOP. Direct damage to the trabecular meshwork and angle recession, which occurs in humans and results in glaucoma months to years after the traumatic incident, has not been reported in the dog. Traumatic glaucomas in the dog are usually associated with intense iridocyclitis and are best managed clinically with aggressive treatment of the inflammation, prevention of peripheral anterior synechia, and control of the IOP (with CAIs). If peripheral anterior synechia develops, medical therapy becomes ineffective, and some type of anti‐glaucoma surgical procedure is indicated. Intracameral tPA may be used to assist in resolution of anterior chamber fibrin following hyphema; however, recurrent hemorrhage can develop if tPA therapy is injected into eyes with acute (less than 7 days) or continuing/recurrent hemorrhages. Uveitic Glaucomas

The iridocyclitides are a common group of intraocular diseases in the dog, and development of secondary glaucomas with these conditions is a serious complication. The inflammatory glaucomas may develop either with acute intense iridocyclitis associated with pupillary occlusion and iris bombé, with obstruction of the filtration angle with inflammatory cells, fibrin, and cellular debris, or with chronic iridocyclitis, usually from peripheral anterior synechiae, but infrequently from annular posterior synechia and iris bombé (Fig. 20.19). The most frequent cause of secondary glaucoma in the dog in North America is associated with cataract‐ induced uveitis that becomes chronic (Gelatt & MacKay, 2004b). The iridocyclitides may be associated with localized ocular diseases (e.g., corneal perforation, iris prolapse, iris bombé) or systemic infectious or inflammatory diseases (see Chapter 21 and Chapter 37, Part 1). Vogt‐Koyanagi‐Harada‐ like syndrome, or uveodermatologic syndrome, occurs in several Arctic breeds of dogs, and a recently discovered pigmentary dispersion and cyst formation in Golden Retrievers and Great Danes can occur as chronic intraocular inflammations. Their serious long‐term complication is frequent cataract formation, which may further exacerbate secondary glaucoma (Deehr & Dubielzig, 1998; Holly et  al., 2016; Sapienza et al., 2000; Spiess et al., 1998). Several factors appear to be important in the pathogenesis of uveitic glaucomas (Moorthy et al., 1997). The trabecular meshwork may be plugged with inflammatory cells, fibrin, blood, and large molecular proteins, or it may be directly involved in the inflammation. The inflammatory cells within the trabecular meshwork may release cytotoxic substances such as arachidonic acid metabolites, cytokines, proteolytic enzymes, and oxygen metabolites (i.e., oxygen free radicals).

SECTION IIIA

result from a significant reduction in ciliary cleft cross‐sectional area and width. The results of both of these studies confirm the value of postoperative tonometric monitoring in dogs undergoing cataract and lens removal. If the IOP exceeds “safe limits,” topical or systemic CAIs (or both) or betablockers or some combination of these are recommended, because they reduce the rate of AH formation, but do not affect pupil size or increase the amount of iridocyclitis. Carbachol injected intracamerally during cataract surgery has been reported to prevent POH in dogs (Stuhr et al., 1998); however, the relative risk and benefits of a miotic agent to prevent this increase in IOP versus the intensification of postoperative uveitis must be weighted. Intracameral carbachol in Labrador Retrievers may exacerbate the incidence of POH and is not recommended for use in this breed (Moeller et al., 2011). When IOP exceeds 40 mmHg and is refractory to topical therapy and intravenous mannitol, anterior chamber paracentesis may be necessary. Prophylactic prevention of POH (IOP 20 mmHg or higher) in 52 dogs (88 eyes) was attempted using either latanoprost, dorzolamide, or dorzolamide and timolol (Dees et al., 2017). IOP was measured 4 hours, 24 hours, 7 days, and 14 days postoperatively. IOP of 20 mmHg was recorded in 38% of the 88 eyes; IOP of 25 mmHg or higher occurred in 26% of 86 eyes. Topical anti‐glaucoma medications did not change the frequency of POH significantly, but tPA administered intraoperatively appears to reduce the incidence of POH (Dees et al., 2017).

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A

B

Figure 20.19  A. Anterior uveitis has resulted in glaucoma. There is diffuse severe episcleral injection, perilimbal corneal vascularization, diffuse corneal edema, and a superficial corneal ulcer. The pupil is mid-range in size due to the opposing influences of uveitis and glaucoma. B. Slit-lamp photograph of an eye secondary to anterior uveitis. Note the forward bow of the central iris. The pupil margin is directed posteriorly toward the anterior lens capsule, to which it has synechiated, while the ciliary zone of the iris is pushed forward with iris bombé.

Endogenous prostaglandins (PGs) lower the IOP by increasing the uveoscleral outflow of AH through the ciliary cleft during the first hours of an intraocular inflammation, but the prostaglandin‐induced breakdown in the blood–aqueous barrier may briefly increase the IOP. Peripheral anterior synechiae may eventually occlude the filtration angle and the ciliary cleft. Posterior synechiae that encircle the pupil produce rapid development of iris bombé, which is caused by the lack of transpupillary AH flow, and increased IOP within the posterior chamber and segment. And lastly, chronic uveitis is very important risk factor. Clinical signs of uveitic glaucoma are a combination of those of iridocyclitis and either acute or chronic glaucoma. The pupil may be normal (mid‐range) in size, thus representing a balance between the effects of iridal inflammation and the IOP. Episcleral venous congestion, which is often present in the glaucoma, is partially masked by the conjunctival hyperemia (or ciliary flush) associated with the anterior segment inflammation. Likewise, corneal edema may represent a combination of the intensity of the iridocyclitis and the IOP elevation. Elevations in IOP may be acute or may gradually elevate over several weeks or months. Tonometry is an important diagnostic tool for uveitis. Most often, iridocyclitis causes decreased IOP; however, the onset of acute iridocyclitis, within the first hours, actually produces a transient elevation in IOP associated with the release of PGs from the iris. Clinical signs of iridocyclitis with a normal IOP may indicate the early development of secondary glaucoma. The treatment of uveitic glaucomas occurring in phakic eyes is targeted at the underlying uveitis and at controlling the IOP in order to minimize retinal and ONH damage and

prevent permanent intraocular inflammation‐induced adhesions. High concentrations and frequencies of topical and systemic corticosteroids and nonsteroidals are indicated. Because neither miosis nor mydriasis is desired, short‐term mydriatics may be used to intermittently move the inflamed iris and pupil, and to discourage the formation of posterior synechiae. Systemic antibiotics may also be indicated if an infectious process is present or suspected. Topical antibiotics are generally not indicated unless a corneal ulcer is present concurrently. Topical and systemic CAIs are administered to, hopefully, maintain the IOP within normal limits. Surgical treatments, such as laser cyclophotocoagulation and anterior chamber shunts, may also be attempted. As in humans, however, lower success rates in uveitic glaucomas versus other types of glaucoma occur in the dog because of the inflammation and protein‐rich AH. Ocular Melanosis and Melanocytic Glaucoma

Originally described as pigmentary glaucoma in the Cairn Terrier by Covitz and colleagues (Covitz et  al., 1984) and then by Petersen‐Jones (Petersen‐Jones, 1991; Petersen‐ Jones et  al., 2007, 2008), the preferred term melanocytic glaucoma now seems to be more appropriate than glaucoma associated with ocular melanosis. Pigmentary glaucoma or pigmentary dispersion glaucoma in humans is characterized by a 360°, dense band of pigmentation in the trabecular meshwork, slit‐like transillumination defects in the midperiphery of the iris, and a vertical band of pigment deposits on the central corneal endothelium (i.e., Kruckenberg spindle). In humans, the source of the pigment granules appears to be the posterior iris pigmented epithelium. In the dog, the pigmentation appears to relate primarily to the uveal melano-

cytes and melanophages, not the extracellular melanin granules. Melanosis (also called pigmentary glaucoma) of the globe has been associated with this form of secondary ocular hypertension in Cairn Terriers. Glaucoma in this breed in North America has a prevalence of 1.33% (1984– 1993) and 1.82% (1994–2002; Gelatt & MacKay, 2004b). This unique glaucoma affects middle‐aged to older Cairn Terriers, and it may affect one or both eyes (Fig. 20.20). It has also been reported in the Boxer and Labrador Retriever (Van de Sandt et  al., 2003). In these eyes, large aggregations of melanocytes and melanophages occur within the filtration angle, episcleral and subconjunctival tissues, tapetal ocular fundus, and even in the meninges about the ONH. What initiates the unchecked proliferations of these melanocytes is unknown, but the condition may represent a diffuse type of benign iris melanin cell proliferation. Reports focusing on ocular melanosis have provided insight (Petersen‐Jones et al., 2007, 2008). In these reports, 114 Cairn Terriers were described (44 males, 67 females, and 3 dogs with gender unknown). Age of onset was quite variable and the first noticeable clinical sign was a dark‐colored thickening of the basal iris. This was followed by the development of distinct episcleral and scleral pigment plaques, the release of pigment into the anterior chamber and AH, and the deposition of pigment into the AH outflow pathways (especially ventrally). Secondary glaucoma developed in the most severely affected dogs. A slow progression of pigmentation of the tapetal fundus occurred, probably from the posterior uveoscleral outflow of AH. In some dogs pigmentation adjacent to the ONH also developed. Pedigree analysis indicated a possible autosomal dominant mode of inheritance. Three affected Cairn Terriers eventually developed ocular melanomas and one mass metastasized widely. In the second report, 49 globes from Cairn Terriers with ocular mela-

nosis were examined histologically, some by immunohistochemistry, and others by TEM. Large round pigment‐laden cells were present within the anterior uvea, drainage angle, sclera, and episclera (Dawson‐Baglien et al., 2019). In 39 of the 49 globes (80%) the structures of the ICA were obliterated by the infiltrating pigment cells. Some of these cells were also noted within the posterior segment (78% of choroid samples and 28% of retinas), optic nerve meninges, and periphery of the ONH. The posterior iris epithelium was present and did not appear to be involved in the proliferative process. About 20% of the affected globes also had a lymphocytic‐plasmacytic infiltration of the anterior uvea and formation of preiridal fibrovascular membranes. Ultrastructurally, the pigment cells were mainly melanocytes with some macrophages. Many of the pigmented cells were immunoreactive to HMB45 (antibody for gp100 localized in stages II and III melanosomes), and some were MITF and vimnetin positive. Onset of chronic glaucoma appears to be slow and associated with the accumulation of pigmented cells within the filtration angle and scleral venous plexus. Some free melanin granules occur and are phagocytized by the wandering macrophages and trabecular endothelia within the outflow pathways. Medical and surgical treatment of this secondary glaucoma has not been successful in the long term, because the proliferating melanocytes and melanophages eventually completely obstruct any surgical anterior chamber bypass. Eleven potential candidate genes have been eliminated for ocular melanosis (Winkler et al., 2013). DNA studies to date have not identified the disease‐causing genetic mutation. A four‐stage grading system of ocular changes occurring in this condition has been developed (Petersen‐Jones et al., 2007). Stage 1 describes early‐affected animals with a characteristic dark‐colored, donut‐shaped thickening of the iris root. Stage 2 includes animals with iris thickening and small pigment plaques on the sclera. These spots are initially spicule shaped, but progress to circular foci. Stage 3 consists of more extensive scleral pigment plaques accompanying a “lumpy, bumpy” ciliary iris and thinning of the pupillary zone. Some pigment may be noted on the ventral pectinate ligaments, and in some instances on the corneal endothelium. Some animals will exhibit signs of anterior uveitis and may have periods of IOP elevation. Progression to Stage 4 involves the development of overt and chronic signs of glaucoma and further increase of pigment deposition in the ICA and in the sclera. Pigmentary Uveitis and Glaucoma in the Golden Retriever

Figure 20.20  Pigmentary glaucoma in the Cairn Terrier. Note the hyperpigmented uvea and pigment deposition in the sclera.

An angle‐closure/occlusion secondary glaucoma has been associated with pigment dispersion and iris and ciliary body cysts in Golden Retrievers (Deehr & Dubielzig, 1998; Esson et  al., 2009; Sapienza et  al., 2000). The mean age of the affected dogs is 7.6 years. Early in the disease, affected eyes demonstrate iridal hyperpigmentation, pigment deposition

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Figure 20.21  Glaucoma secondary to chronic pigmentary uveitis in a Golden Retriever. Note the multifocal posterior synechiae, pigment deposition on the anterior lens capsule, immature cataract, and corneal degeneration.

on the anterior lens capsule, cataract formation, and web‐ like strands of opaque material within the anterior chamber (Fig.  20.21). The clinical syndrome is characterized by the formation of thin‐walled membranes within the posterior chamber, proteinaceous exudation, and pigment dispersion, which appears to cause the glaucoma and cataract formation. These membranes are typically light brown or red; some appear as collapsed cysts within the posterior chamber. Pigment is deposited on the lenticular, iridal, and corneal endothelial surfaces. The time from diagnosis of the syndrome to the development of overt glaucoma is generally about 5 months. All affected globes have free pigment within the trabecular meshwork. In a study of 830 Golden Retrievers in western Canada, the prevalence of this disease was about 5% (iridociliary cysts in 4.8% and pigmentary uveitis in 5.9%). The incidence of pigmentary uveitis increased with age. Pigmentary/cystic glaucoma developed in 44.9% of the eyes with pigmentary uveitis. Pedigree analysis suggested an autosomal dominant mode of inheritance with incomplete penetrance (Holly et al., 2016). Histopathologic examination revealed that the anterior uveal cysts were lined by thin cuboidal or simple squamous epithelium, PAS‐positive basement membrane–like protein, and sometimes collagen or hyaluronic acid. Affected globes had little or no evidence of inflammation. Nearly all cysts remain in the posterior chamber. The thin cellular wall of the cysts stained positive with Vimentin, NSE, and S‐100 in all globes. This staining pattern is consistent with a ciliary body epithelial cell origin; however, one in three of the cysts also stained weakly positive for cytokeratin, which could out rule out an iridociliary epithelial origin. They may be stretched across of the anterior face of the vitreous and some were attached to the anterior lens capsule. Peripheral anterior synechiae formation occurred in about 30% of globes; posterior

synechiae were noted in about 50% of globes. Preiridal fibrovascular membranes were present in about 50% of globes. The pigment dispersion seems to cause the elevation in IOP. The cysts may compress focally the ICA and ciliary cleft, or release their own contents to cause angle closure by mechanical and inflammatory means. The toxic effects of the contents within the iridociliary cysts upon the trabecular meshwork is unknown. Medical and/or surgical treatment of this syndrome may lower IOP and prolong vision for a period of time, but eventually fails. A secondary glaucoma occurs in the Great Dane and the American Bulldog, and is similar but perhaps not identical to the disease in the Golden Retriever (Pumphrey et  al., 2013b; Spiess et  al., 1998). Additional information on this syndrome can be found in Chapter 21. It is important to recognize that not all Golden Retrievers that have anterior uveal cysts will develop or are at risk for the development of pigmentary uveitis. Many Golden Retrievers have anterior uveal cysts unrelated to this more serious condition. Careful examination looking for pigment sloughing and inappropriate pigment deposition is critical. Intraocular Neoplasms and Glaucoma

The most frequently occurring primary intraocular neoplasms in the dog are melanomas (Wilcock & Peiffer 1986), followed by adenomas and adenocarcinomas of the ciliary body and iris. Not infrequently, the presenting clinical signs of these anterior segment tumors are those associated with secondary glaucoma, iridocyclitis, hyphema, or some combination of these (Fig.  20.22). Metastatic intraocular neoplasms, often lymphoma or an adenocarcinoma, also frequently involve the iris and ciliary body. Glaucomas secondary to these neoplasms usually result from direct infiltration of the filtration angle, obstruction of the angle by tumor‐associated inflammatory products and peripheral anterior synechiae, or secondary preiridal membrane formation. Rapidly growing neoplasms often produce glaucoma, and tumor‐related necrosis may produce a secondary iridocyclitis. In the clinical management of these patients, gonioscopy, indirect ophthalmoscopy of the peripheral ocular fundus, and ultrasonography with color Doppler imaging are used to carefully define the borders of the neoplasm. A systemic medical workup is performed to look for the presence of preexisting metastases. Most of these tumor‐induced glaucomas are treated with enucleation, but local iridocyclectomy, either with or without scleral grafts, may successfully remove smaller neoplasms and preserve vision. Glaucomas Secondary to Silicone Oil and Rhegmatogenous Retinal Detachments

Glaucoma may be observed in the dog occurring secondary to silicone oil in the anterior chamber that has migrated following surgical reattachment of rhegmatogenous retinal detachments. Silicone oil is used in the repair to tamponade

A

B

Figure 20.22  A. Glaucoma secondary to an intraocular mass. Note the raised pigmented lesion posterior to the temporal iris that is displacing the lens. B. Glaucoma secondary to intraocular lymphoma. The iris is swollen with foci of hemorrhage and neovascularization. The dyscoria is suggestive of posterior synechiae. Diffuse corneal edema is also present.

the detached retina into contact with the RPE. Shifting of the oil from the vitreous into the anterior chamber, which occurs frequently in both aphakes and pseudophakes, increases the IOP by physically obstructing the aqueous outflow pathways. Treatment consists of removing the oil from the anterior chamber. The association between rhegmatogenous retinal detachments and elevated IOP in humans was described in 1972 (Netland et  al., 1994) and later reported in the dog (Smith et al., 1997). Nonrhegmatogenous retinal detachments in the dog are usually associated with normal or low IOP (i.e., ocular hypotony), presumably resulting from increased uveoscleral AH outflow. Canine rhegmatogenous detachments, however, especially in those dogs with giant retinal tears, may release rod and cone outer segment fragments into the subretinal fluids and vitreous, which eventually enter the anterior chamber. This cellular debris accumulates in the AH outflow pathways and elevates the IOP. Rod and cone outer segments may be demonstrated in the AH at the trabecular meshwork. Reattachment of these giant tears prevents further anterior movement of the outer segments and lowers the IOP; however, the risk of formation of preiridal fibrovascular membranes and subsequent secondary glaucoma remains high in these individuals.

enlargement (Fig.  20.23). This often severe buphthalmia occurs because of the abundance of elastin fibers within the immature sclera. If the IOP can be rapidly reduced to a normal level, the globe may return to near‐normal size. The longer the buphthalmia persists, however, the less likely it is that a return to approximately normal globe size will result. This rapid buphthalmia somewhat protects the ONH and retina against the elevated IOP, and vision may be maintained longer than expected. Histopathologic results of the few globes available with canine congenital glaucomas have revealed multiple anterior segment and AH pathology abnormalities, including within the trabecular meshwork (Smith et al., 1993; Strom et al., 2011a).

Congenital Glaucomas Extensive goniodysgenesis or trabecular maldevelopment is rare in the dog. When present, however, it may be unilateral or bilateral, and it occurs as an isolated defect or with other systemic anomalies. When present, elevations of IOP occur early in a puppy’s life (usually 3–6 months of age), and the primary complaint is one of rapid and often dramatic globe

Figure 20.23  Congenital glaucoma in a Parsons Russell Terrier puppy. Note the profoundly enlarged globe, episcleral injection, and keratitis. Young animals will often develop marked buphthalmia very quickly when intraocular pressure is elevated.

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Medical and Surgical Treatment of the Canine Glaucomas The optimal plan(s) for clinical management and preservation of vision for the different forms of the canine glaucomas have not been developed. Lowering IOP remains the only available treatment. In primary or breed‐related glaucomas, the genesis of the disease continues despite treatment, even in the face of control of IOP. Once medical control of IOP is achieved, there remains a great need for diligent regular monitoring, because these conditions do not remain static. The need to increase the frequency of medications or to institute combination therapy is expected. The choice of medical or surgical treatment, or most frequently a combination of both modalities, is based on the absence or presence of vision at initial presentation, the interest and ability of the owner to treat the glaucoma, the projected costs, and the temperament of the patient.

Target, Safe, and Diurnal Intraocular Pressure IOP has been firmly established as the primary, only treatable risk factor for the development of glaucomatous optic neuropathy. Other factors are also important, but the higher and/or longer the IOP elevation, the greater the risk and severity of optic nerve damage. Lowering the IOP is critical for maintaining both vision and quality of life. Establishing a “target” or “safe” IOP for each canine eye implies an IOP reduction to levels that reduce the RGC loss from glaucoma to normal, age‐related levels of RGC loss, and achieving an IOP that maintains the threshold number of RGCs necessary for vision (Jampel, 1997). Target IOP can be set by lowering the pressure to a given IOP, or it can be reduced by a given percentage. The greater the likelihood of future damage from glaucoma or the greater the amount of preexisting damage from glaucoma, the lower the target IOP should be set. The target IOP should relate to the maximum quality of life to be derived from preserving vision and comfort in the absence of side effects of therapy. A weakness of the target IOP concept is that because we are only able to obtain single, infrequent IOP tonometric measurements in the dog, we do not know the true IOP level. In the dog, setting the target IOP pressure at 20 mmHg or lower is reasonable, but if progressive loss of vision occurs it should be lowered, probably even lower than what is considered the normal range of IOP. A reasonable population distribution of IOP (mean ± 2 SD) in the normal dog based on the two largest studies is 8–30 mmHg and, on clinical experience, is 12–25 mmHg (Gelatt & MacKay, 1998a). The mean and SD of IOP in the normal dog represent the real variation in IOP, variations in tonometers, and daily (i.e., diurnal) variation. Previous results in normal dogs indicate that diurnal IOP fluctuates by 2–4 mmHg, with the higher IOP occurring in the morning and the lower IOP in the early evening; in dogs with POAG, however, these diurnal IOP variations

are greater, often ranging from 6 to 10 mmHg, even in dogs that have not yet expressed sustained IOP elevations in untreated eyes (Gelatt et al., 1981a). What Is a “Safe” IOP?

The scleral lamina cribrosa is a zone of pressure transition for the optic nerve axons. The IOP largely affects optic disc tissue pressure over the most anterior 100 μm of the ONH tissue. The axoplasmic flow of these axons is tenuous at even normal IOPs. The axons leave the eye under the influence of the IOP and pass through the decreasing tissue pressures of the lamina to come under the influence of the retrolaminar tissue pressure (RLTP). The RLTP (mean canine RLTP 7 mmHg) directly relates to the cerebrospinal fluid pressure in the dog (Morgan et al., 1995). The normal canine retina begins to show electrophysiologic evidence of effects from elevated IOP at 33 mmHg (under general anesthesia the baseline IOP is usually 10–12 mmHg; Hamor et al., 2000), and oscillatory potential parameters show changes in latency and amplitude at this IOP as well. Results of ONH autoradiography of normal dogs indicate that 10% of axons have mildly obstructed axoplasmic flow at an IOP of 25 mmHg (Williams et al., 1983), and this increases to near 100% at an IOP of 50 mmHg. Thus, the optic nerve axons are in a precarious functional state even at relatively normal IOPs in normal dogs. Beagles with hereditary glaucoma have mild to moderate obstruction of the axoplasmic flow of 87% of their optic nerve axons at an IOP of 30–35 mmHg (Samuelson et al., 1983). Settling for a goal of 30 mmHg in a glaucomatous eye will not often prevent damage to the optic nerve axons.

Medical Therapy for Intraocular Pressure Control Therapy for canine primary glaucomas is difficult to rationalize and apply when we do not yet understand the initiating events that result in compromised outflow of AH, the mechanisms by which these events lead to aqueous outflow obstruction, or even the nature of the obstruction itself. Thus, it follows that we have, at present, no means of detecting the initiating events in clinical patients, nor do we have treatments to prevent the outflow obstruction and optic nerve atrophy. Therefore, at present, there is no cure for the glaucomas. An ideal treatment or “cure” would require treatment of the optic nerve damage sustained in glaucoma, with subsequent reversal of visual field defects. This is currently not possible, so the aims of therapy are to slow the progress of the disease, maintain vision as long as possible, and keep the patient comfortable, as glaucoma can be a profoundly painful condition. Treatment of the different types of canine glaucoma has, as its paramount purpose, maintenance of vision and IOP within the normal range to prevent further damage to the

optic nerve and retina. Elevated IOP is the risk factor that is necessarily the only target of therapy. Unfortunately, most canine glaucomatous patients present with the condition at an advanced stage in at least the first eye, and the therapeutic goal may simply be a pain‐free eye that requires minimal medical care; the fellow eye may require the more intensive treatment regimen. No single treatment regimen for canine glaucoma is possible, because there are so many different types of glaucoma with different etiologies and stages of presentation (Table  20.6). In secondary glaucomas, the initiating cause must be identified and, if possible, either removed or suppressed. Medical treatment of canine glaucoma is a critical aspect, because surgical procedures often still require concurrent medical therapy. Medical therapy for narrow‐ and angle‐ closure glaucomas is usually short term when employed alone, because eventually the outflow becomes so impaired that drug‐associated changes in aqueous formation and outflow are inadequate. After anterior chamber bypass surgeries, however, some medical therapy may be necessary to maintain the IOP within a target zone. As with cataract surgery in the dog, results of some clinical studies suggest that the earlier in the glaucoma process the surgery is performed, the higher the long‐term success rate at controlling IOP and maintenance of vision (Jampel, 1997). Medical therapy for the glaucomas can Table 20.6  Treatment strategies for the canine glaucomas. Initial Medical Intraocular Pressure (IOP) Control: Is the eye blind or visual? Intravenous mannitol; anterior chamber paracentesis if mannitol fails Prostaglandins Miotics Adrenergics – beta-blockers Intravenous acetazolamide Corticosteroids possibly Neuroprotective drugs Short-Term IOP Control Prostaglandins Miotics Adrenergics – beta-blockers Carbonic anhydrase inhibitors (CAIs) – topical and parenteral Prostaglandins Neuroprotective drugs Surgery/laser Long-Term IOP Control Shunt surgery/laser cyclophotocoagulation Supplement with medical control: Miotics/prostaglandins Adrenergics CAIs – topical Neuroprotective drugs

also be quite expensive; additional information on these drugs may be found in Chapter 8, Part 5. The mainstay of medical therapy for glaucomas is the lowering of IOP by targeting AH dynamics, either by increasing outflow or by decreasing the production of AH. More specifically, the targets of medical therapy include (1) improving conventional AH outflow (through the corneoscleral trabeculae); (2) improving unconventional AH outflow through the uveoscleral outflow pathways; (3) decreasing active AH production (direct action on the nonpigmented ciliary body epithelium); (4) decreasing IOP by an osmotic imbalance between the intraocular tissues (mainly vitreous) and intraocular fluids and the circulatory system; (5) decreasing blood flow to the ciliary body processes; and combinations of these. Medical treatment of primary glaucomas often includes short‐term administration of a single drug, or combination of drugs, to maintain the IOP within normal limits (usually 20 mmHg or less) and the long‐term administration of combinations of drugs to supplement available filtering surgeries and cyclodestructive procedures. Prophylactic treatment of fellow eyes in dogs presenting with unilateral primary glaucoma appears to delay the onset of glaucoma in these eyes for several months or longer, and is highly recommended (Miller et al., 2000). Treatment of normotensive fellow eyes in dogs presenting with unilateral PACG using either topical 0.5% beta-blocker (betaxolol) or 0.25% demecarium bromide with a topical steroid resulted in a median time to development of clinical signs of 30 months in one study (Miller et al., 2000). In a smaller study, treatment of fellow eyes with topical CAIs did not appear to delay IOP elevation (Stavinohova et  al., 2015). While medical therapy of POAG in humans is generally quite successful, treatment of PACG in humans is less rewarding; vision is often impaired or lost on the initial presentation to the ophthalmologist (Aung et al., 2004). Outcomes in dogs are similar, although POAG canines have a greater risk of vision loss than do their human counterparts, due to delayed disease diagnosis and more rapid disease progression. PACG in the dog has a very poor prognosis for sight retention and IOP control overall. As glaucoma progresses, the intensity of medications will need to increase and eventually include a combination of drugs affecting different parts of the AH dynamics. Drugs to Increase Conventional Aqueous Humor Outflow

Therapy for glaucomas has gradually changed in both humans and dogs, as more effective drugs with fewer side effects have been introduced. Parasympathomimetics or miotics can be used in most types of canine glaucomas, except for those associated with severe inflammations of the anterior segment. They are frequently combined with CAIs and beta‐adrenergic antagonists in long‐term medical treatment of the primary glaucomas. Cholinergic miotics produce pupillary constriction, ciliary musculature contraction, and

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Section IIIA: Canine Ophthalmology

increased outflow facility of the AH through the trabecular meshwork. Miotics also produce vasodilation of the blood vessels of the conjunctiva, iris, intrascleral plexus, and aqueous veins. Miotics can reactivate latent iritis, intensify concurrent iritis, and increase the protein content of the AH. The two most frequently used miotics in the dog are currently pilocarpine and demecarium bromide. Pilocarpine has been used topically for the treatment of human glaucoma for more than a century, and in the 1950s through 1970s was the topical drug of choice. It was largely replaced by the introduction of beta-blockers in 1978–1979. Pilocarpine mimics acetylcholine at the iridal sphincter and ciliary body muscle end plates. The commercial solutions were available in many concentrations (0.25%–10%), even combined with 1% and 2% epinephrine, but are quite acidic (pH 4.0–5.5) and irritating, resulting in considerable blepharospasm, nictitans prolapse, and conjunctival hyperemia in the dog. The pH in the commercial solutions was used to prolong shelf life; pilocarpine solutions at pH 7 decrease IOP to a greater degree, but are not particularly stable (Carrier & Gum, 1989; Gelatt et  al., 1983; Gwin et  al., 1977; Whitley et al., 1980). Pilocarpine as sole therapy is no longer in favor nor recommended. Pilocarpine’s side effects in the dog made drug instillations progressively more difficult long term. Carbachol is similar to pilocarpine but less lipid soluble, and never became very popular for topical use. It was available in 0.75%–3% solutions, and acted similarly to pilocarpine in normal and glaucomatous dogs. Since about 2000, the PGs have largely replaced this group of drugs. Now topical pilocarpine is very limited in its availability and must usually be compounded (thereby greatly increasing its cost). Anticholinesterase miotics, such as demecarium bromide, inhibit the enzyme cholinesterase, thereby prolonging the action of locally produced acetylcholine at the motor end plates (Gum et  al., 1993a). Demecarium bromide 0.125%– 0.25% is a long‐acting anticholinesterase inhibitor, and has been used in dogs to control IOP in eyes with posterior lens luxations long term (Binder et al., 2007). It is not currently commercially available and must be compounded. Drugs to Reduce Aqueous Humor Formation

Adrenergics (beta-blockers and alpha‐agonists) lower IOP in the dog, but they must be combined with other drugs to achieve maximal effect. Epinephrine, an alpha‐ and beta‐adrenergic agonist, lowers IOP in normal as well as glaucomatous canine eyes when delivered as 1% or 2% solution (Gwin et al., 1978). Dipivalyl epinephrine, which is an epinephrine prodrug, is more lipophilic than epinephrine and possesses a greater ability to penetrate the cornea. Once in the cornea, dipivalyl epinephrine is converted to epinephrine and has both greater potency and less local toxicity than epinephrine. These agents are administered clinically 2–4 times daily and always combined with other topical drugs. Adrenergic agonists may produce local conjunctival irritation, as evidenced

by tearing, conjunctival hyperemia, and occasional chemosis. Since the introduction of PGs in the 1990s, use of these adrenergic agonists has become very limited. Topical beta‐antagonists such as timolol, betaxolol, and levobunolol were introduced in the late 1970s and they quickly became the first‐line therapy for the clinical management of POAG in humans. They are still used very frequently. In normotensive and glaucomatous Beagles, 0.5% timolol 2 times a day lowers IOP by approximately 5–7 mmHg (Gum et  al., 1991b; Wilkie & Latimer, 1991). Timolol can adversely affect the cardiac and respiratory systems, and should be used with care, especially in very small dogs and cats with asthma. Timolol is usually combined with other drugs, often dorzolamide (Plummer et  al., 2006), and instilled 2–3 times daily. Apraclonidine, an α2‐adrenergic agonist, in normal dogs produced mydriasis with inconsistent decreases in IOP and bradycardia (Miller et al., 1996). This agonist lowers IOP by reducing the formation of AH through reductions in cyclic adenosine monophosphate formation and reduced blood flow to the ciliary body, with no effect on outflow facility. Brimonidine tartrate (0.2%) is another α2‐agonist that lowers IOP by reducing AH formation and increasing uveoscleral outflow. In the dog, brimonidine lowers IOP only slightly and must be combined with other ocular hypotensive agents if used (Gelatt & MacKay, 2002a). Drugs to Increase Uveoscleral Aqueous Humor Outflow

PGs have been studied for nearly 30 years for their roles in ocular inflammation, but in the late 1980s it was discovered that very low concentrations of these drugs applied topically to the eye lowered IOP (Bito, 1986). Species differences in ocular hypotensive effects among humans, nonhuman primates, dog, cats, and other species have been demonstrated with topical PGA, PGE, and PGF and their analogues. PGF analogues are the most commonly employed topical anti‐ glaucoma drugs, and they are effective in both humans and dogs (Gum et al., 1991a). PGs seem to lower IOP by increasing the uveoscleral or unconventional AH outflow, although there is tonographic evidence that trabecular or conventional outflow may be also increased in some species (Toris & Camras, 1997). PGF also produces miosis in dogs that is of shorter duration than the decline in IOP, which may change the trabecular or conventional AH outflow and be responsible for the acute IOP‐lowering effect. Both PGA and PGF analogs can markedly lower IOP (decrease as high as 40–50%) in dogs (Gum et al., 1991a). With PGF2α the reduction in IOP in normal dogs was about 9 mmHg (Studer et al., 2000) and in glaucomatous dogs 19 mmHg (Gelatt & MacKay, 2001b). In glaucomatous Beagles, latanoprost, travoprost, bimatoprost, and unoprostone significantly lower IOP (Gelatt & MacKay 2001b, 2002b, 2004c; Ofri et  al., 2000). Recent investigations into this effective group of drugs have

resulted in additional topical PGs, including tafluprost (Alario et  al., 2015), PGE and PGA analogues, and latanoprostene bunod, a nitric oxide–releasing PG (Cavet & DeCory, 2018; Krauss et al., 2011). Ocular side effects after chronic administration of latanoprost in humans, nonhuman primates, and pigmented rabbits include increased iridal pigmentation, hypertrichosis, and pigmentation of the eyelashes. The hypertrichosis results in thicker and longer eyelashes and a separate commercially available preparation has been marketed for cosmetic purposes (Giannico et  al., 2013). As anti‐glaucoma therapy in the dog often requires multiple drugs to lower IOP to acceptable levels, PGs can be combined with topical beta‐antagonists and CAIs (both topical and systemic). Latanoprost seems to produce very few systemic effects, but is generally avoided in eyes with active anterior uveitis and anterior lens luxations. Drugs to Reduce Active Aqueous Humor Formation

Systemic and topical CAIs reduce active AH formation by inhibiting the carbonic anhydrase enzymatic processes within the nonpigmented ciliary body epithelium (Skorobohach et al., 2003). These drugs do not have an effect on outflow facility. In the dog, systemic and topical CAIs can reduce IOP by 20%–30% (Gelatt et al., 1979; King et al., 1991). The maximal effect usually occurs 4–8 hours after oral administration, and the ocular hypotensive effects of these drugs do not depend on diuresis. Systemic CAIs have been used in the treatment of all types of glaucoma in humans, but in the 1990s were nearly discontinued in humans because of serious side effects. The systemic preparations have been replaced by equally effective topical CAIs that have considerably fewer adverse effects, including dorzolamide and brinzolamide. Topical dorzolamide is usually administered every 8 hours or every 12 hours. As intraocular penetration is slow, the maximum reduction in IOP may not occur until after 4–5 days of instillation (King et al., 1991). Low doses of systemic CAI may be used to supplement topical instillations of dorzolamide to ensure maximum reductions of IOP (Gelatt & MacKay, 2001a). CAIs are useful for both short‐ and long‐term management of canine glaucomas and are generally added to the topical treatment regimen of PGs, timolol, pilocarpine, epinephrine, or anticholinesterase miotics. The combined effects of these agents are additive, and in some cases synergistic, and can usually maintain IOP within the safe range for a period of time (Plummer et al., 2006). There are few reports of corneal thickening in the dog, probably due to slight corneal edema from reduced corneal endothelial active transport of water from the cornea stroma (Beckwith‐Cohen et al., 2015). Drugs to Lower Intraocular Pressure by Osmotic Effects

Hyperosmotic agents are used systemically in the initial treatment of acute high‐pressure glaucoma in the dog to

lower IOP as rapidly as possible, and before surgical procedures for glaucoma to ensure a hypotonic globe. Systemic hyperosmotic agents commonly used include intravenous mannitol and oral glycerol (Lorimer et  al., 1989). With increased blood osmolarity, water is removed from the AH and the vitreous body, thus reducing the IOP and the volume of the vitreous body. Integrity of the blood–aqueous barrier is important for these drugs to be effective; presence of an iridocyclitis may reduce their ocular hypotensive effects. Ocular hypotension becomes evident within 30–60 minutes and lasts for at least 5 hours. The duration of effect relates to the rapidity of administration and the dose. These drugs are less commonly employed due to the rapidity of effect and ease of administration of topical PGs for acute congestive glaucoma. Other Drugs

An additional group of drugs, not currently available for practice, are those that act centrally (acting on the brain), like the cannabis derivatives. The exact mechanism by which IOP is lowered with such a substance is not known. A topical formulation of 2% delta‐9‐tetrahydrocannabinol (THC) has been shown to lower IOP in normal dogs by between 15% and 21%, suggesting that there are active cannabinoid receptors in the eye that may alter AH dynamics. It is likely that THC would lower IOP to a greater extent in glaucomatous animals; however, this is unlikely to be an improvement over existing IOP‐lowering medications (Fischer et al., 2013). Antifibrin and Cytotoxic Drugs

Intracameral injections of tPA, 25–50 μg, will quickly dissolve fibrin of less than 10–14 days’ duration within the anterior chamber and pupil (see Chapter  8, Part 4; Martin et al., 1993; Sidoti et al., 1995). The value of tPA in the different filtering and anterior chamber shunt surgeries for removing fibrin obstructions and postoperative ocular hypertension are unequaled, and tPA represents a major advance in the success of these surgeries. While AH outflow occurs, in part, through the posterior supraciliary and choroidal spaces and does not incite inflammation, once AH enters the subconjunctival and/or retrobulbar tissues, an inflammatory response occurs. Control of this persistent inflammatory response may greatly increase the success of surgical AH bypasses. Cytotoxic anti‐fibrosing drugs such as mitomycin‐C and 5‐fluorouracil may maintain the permeability and delay or prevent the scarring of subconjunctival aqueous outflow blebs adjacent to gonioimplants. Mitomycin, 0.2–0.4 mg/mL, is administered for 5 minutes intraoperatively to the episcleral surgical site via a surgical cellulose sponge, and then the area is profusely irrigated (Maggio & Bras, 2015; Tinsley et al., 1995). The conjunctival edges of the surgical wounds should not be touched with mitomycin, and high doses of mitomycin may diffuse through the sclera and lower the rate of AH formation by

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affecting the ciliary body. The loss of function of postsurgical gonioshunt blebs long term remains a major problem in the dog and requires further investigation. Control of this persistent inflammatory response may greatly increase the success of surgical AH bypasses.

SECTION IIIA

Surgical Therapy for Intraocular Pressure Control Surgical procedures for treatment of the primary glaucomas in the dog are divided into two types: those that construct alternate pathways of drainage within or to the outside of the eye, and those that decrease the formation rate of AH by destroying part of the ciliary body (Gelatt & Gelatt, 2011). Procedures to increase AH outflow include iridencleisis, corneoscleral trephination, cyclodialysis, combined iridencleisis and cyclodialysis, posterior sclerectomy, and anterior chamber shunts (i.e., gonioimplants). Techniques to reduce AH formation by partial destruction of the ciliary body include cyclocryothermy, cyclodiathermy, and transscleral or endoscopic cyclophotocoagulation. The most frequently used and effective procedures are anterior chamber shunts (i.e., gonioimplants) without or combined with destruction of the ciliary body processes by some form of laser cyclophotocoagulation (Bentley et  al., 1999; Bras & Maggio, 2015; Cook, 1997; Garcia et al., 1998; Graham et al., 2017a, 2018; Maggio & Bras, 2015; Sapienza & van der Woerdt, 2005; Westermeyer et  al., 2011). Other surgical techniques have fallen out of favor because of poor results. However, there is no gold standard surgical option that will be effective for all cases. Hence, the treatment strategy for canine glaucomas is constantly evolving. All postoperative cases, regardless of the technique used, will require supplemental postoperative medical therapy. Anterior chamber shunts are usually reserved for glaucomatous eyes that are visual or have the potential for vision and are often combined with laser therapy. Laser cyclophotocoagulation may be performed via the transcleral route or the endoscopic approach. The transcleral approach is considerably less invasive, but also less precise. The endoscopic approach generally requires removal of the lens, cataractous or not, via phacoemulsification. Laser cyclophotocoagulation may be used in visual or blind glaucomatous eyes to reduce or eliminate the need for topical and systemic medications and to prevent pain, but the endoscopic route is usually reserved for visual globes or eyes with cataract that are considered high risk for the development of glaucoma in the postoperative period. The optimal canine candidates for anti‐glaucoma surgery are visual patients with early glaucoma, no iridocyclitis or lens subluxation, and normal‐ appearing optic discs. Patients with vision and with IOP that is increasing despite maximum levels of medical therapy are also good candidates. Surgical treatments for advanced glaucomas not under adequate medical control and often with-

out the possibility of restoration of vision require different strategies. For enlarged blind and buphthalmic glaucomatous eyes, salvage procedures such as evisceration with placement of an intraocular prosthesis, chemical ablation with either gentamicin or cidofovir, or enucleation are recommended. Globes with exposure keratitis and corneal ulcerations should be enucleated, as they tend not to heal well following placement of an intraocular prosthesis. Reasons to Operate Early

Higher success rates may result when filtering techniques and gonioimplants for the canine glaucomas are employed early in the disease process. Reasons for this apparently higher success rate include the following: ●● ●●

●●

●●

●●

Some AH outflow still remains. Damage to the retina and ONH is not advanced, and vision is present. The likelihood of lens subluxation, buphthalmia, peripheral anterior synechiae, and ciliary cleft collapse is reduced. The incidence of the complications of concurrent iridocyclitis, preiridal rubeosis, and vitreous within the posterior or anterior chamber (or both) is reduced. There is preliminary evidence that surgical treatment of early glaucomatous globes is more successful than for the advanced stages.

In addition, the AH of humans with primary glaucoma, as well as of those with uveitic glaucoma, seems to stimulate proliferation of the subconjunctival and sub‐Tenon’s fibroblasts more than normal AH does. This may relate to higher levels of growth factors and glycoproteins/glycosaminoglycans in chronically affected and perhaps inflamed eyes. Preoperative Treatment

Preoperative considerations in treatment of the primary glaucomas include: ●●

●●

●● ●●

Preoperative control of IOP to a near‐normal level, if possible. Suppression of any concurrent anterior segment inflammation with corticosteroids and nonsteroidal agents. Maintenance of desired pupil size. Dehydration and reduction in size of the vitreous with osmotic agents.

IOP should be reduced to the low–normal range in patients before glaucoma surgery. Medical therapy and paracentesis may be necessary to lower the IOP to between 10 and 20 mmHg. If the IOP is 30 mmHg or greater after intensive anti‐glaucoma medical therapy, anterior chamber paracentesis is recommended to prevent further damage to the ocular tissues (Fig.  20.24). Surgical procedures that abruptly lower the IOP can be associated with acute

Figure 20.24  Anterior chamber paracentesis may be necessary as part of the initial medical therapy for refractory high intraocular pressure (IOP). It is indicated when IOP remains unchanged after a few hours of intense topical and intravenous osmotic therapy.

intraocular hemorrhage, exacerbated uveitis, and even retinal detachment. Many types of canine glaucoma also exhibit concurrent iridocyclitis, which may also be a primary factor or secondary factor in the genesis of the glaucoma. Both topical and systemic corticosteroids and nonsteroidal anti‐inflammatory agents are indicated to suppress inflammation and to reduce the levels of inflammatory cells and proteins in the AH. This inflammatory debris may compromise both short‐ and long‐ term, existing AH outflow pathways as well as the new surgical site. Anterior Chamber Shunts (Gonioimplants)

The first report of anterior chamber shunts or gonioimplants in the dog was published in 1942, when the lacrimal canaliculi were transposed into the limbus of normal dogs as a new

exit for AH from the anterior chamber (Gibson, 1942). In 1970, insertion of a silastic dacron tube through the limbus was attempted in normal dogs (Pritchard & Hamlet, 1970). In the early 1980s, the original Krupin–Denver valve was evaluated in normal Beagles as well as in Beagles with inherited glaucoma (Gum et  al., 1981; Gelatt et  al., 1987). This small scleral implant consisted of a small tube placed in the anterior chamber, a valve mechanism, and a short tube that extended only a few millimeters into the subconjunctival spaces. Without a broad area for reabsorption of the AH to occur, the exit of this implant became scarred and occluded in 50% of the dogs within 6 months. A modified (i.e., nonvalved) Joseph implant was evaluated in 15 dogs (21 eyes) with primary glaucoma, and encouraging results were reported (Bedford, 1988, 1989). Additional reports have evaluated Ahmed, Baerveldt, and other anterior chamber shunts in limited numbers of normal dogs as well as in dogs with primary glaucomas (Gelatt & Gelatt, 2011; Glover et al., 1995b; Graham et al., 2017a. Recent reports with higher success rates evaluated alternate drainage sites (Håkanson, 1996) as well as combined gonioshunts and either diode laser cyclophotocoagulation or cryothermy (Bentley et  al., 1999; Bras & Maggio, 2015; Cullen et al., 1998; Graham et al., 2018; Maggio & Bras, 2015; Sapienza et al., 2005). Gonioimplants are divided into those with unidirectional valved systems, which are designed to permit passage of AH at approximately 10–12 mmHg, and those with bidirectional nonvalved systems, which have no pressure‐regulatory devices except for the limited resistance in the shunt’s tubing (Table 20.7; Gelatt & Gelatt, 2011; Gelatt et al., 1992; Hong et al., 2005). Typically, with the valved implants IOP immediately after surgery is about 10–12 mmHg; with the nonvalved implants, IOP is often below 5 mmHg. With fibrosis around the implant, which develops approximately 3–6 weeks postoperatively, the resistance for aqueous outflow with both types of implants is the same. The Ahmed valve,

Table 20.7  Anterior shunts reported in the dog. Implant Anterior Chamber Tubing

Scleral Explant

Nonvalved “T” implant

Silicone ID 0.3 mm OD 0.6 mm

Baerveldt Silicone

Silicone 7 × 30 mm 420 mm2 250/350/500 mm2

Valved Ahmed

Silicone ID 0.3 mm Valve opens/closes –8–10 mmHg 5-sided polypropylene-with silicone base – 500 mm2

Joseph

Silicone ID 0.3 mm OD 0.64 mm Valve slit (side) 4–20 mmHg

Silicone strap 1 × 9 mm 8.5 cm long < 1600 mm2

Krupin

Silastic explant OD 0.64 mm Valve slit opens/closes 9–11 mmHg

Later #220 episcleral

OD 0.6 mm

ID 0.3 mm180–360 mm long

Note: Implant dimensions are calculated for the entire surface area of each implant. ID, inner dimensions; OD, outer dimensions.

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Section IIIA: Canine Ophthalmology

which is much larger than a slit‐shape valve, has been evaluated in an in vitro system at flows approximating the rate of aqueous turnover in the dog (Strubbe et  al., 1997). IOP < 5 mmHg postoperatively in the dog can result in excessive fibrin in the anterior chamber, occasional hemorrhage, and even retinal detachments. To limit postoperative hypotony and shallow anterior chambers in the nonvalve systems, the anterior chamber tubing can be temporarily occluded intraoperatively with a nonabsorbable suture inside the tubing, a ligature (either absorbable or nonabsorbable suture) around the tube, or other techniques. Often, postoperative fibrosis around the shunt necessitates revision of the bleb and removal of scar tissue to allow continued drainage and resorption of the aqueous by the conjunctival vasculature. Surgical Procedure for Anterior Chamber Shunts  The surgical

procedure for gonioimplants is similar for most of the episcleral devices. A 120–140°, fornix‐based, dorsal bulbar conjunctival flap is created approximately 5 mm posterior to the limbus to leave some bulbar conjunctiva with which to manipulate the globe (Fig. 20.25). Once the site is prepared, many advocate the use of topical mitomycin‐C prior to placement and securing of the implant, in hopes of preventing the development of fibrotic capsules around the shunt that constrict the bleb (Westermeyer et  al., 2011). The implant is usually positioned at or just posterior to the equator, with its rostral end approximately 8–12 mm from the limbus. The anterior border of the implant should be posterior to the extraocular muscle insertions. All anterior chamber shunts are checked before placement for both function and patency. A 25‐ to 27‐gauge hypodermic needle is cannulated into the end of the anterior chamber tubing, and sterile balanced salt, lactated Ringer’s solution, or tPA is injected to prime the tubing. Once the device is properly positioned, it is secured to the sclera and Tenon’s capsule with 2–4 nonabsorbable 7‐0 to 9‐0 sutures, which are usually placed at the anterior border and near the extraocular muscle insertions. In some dogs with glaucoma, the sclera may be very thin in this area, and sutures with good holding abilities may be difficult to achieve. The overall length of the anterior chamber silicone tubing is carefully estimated by laying the tubing directly onto the cornea. Once in the anterior chamber, the tubing should not touch either the iris or the cornea, and it should avoid crossing the center of the pupillary axis. The tip is usually cut in a slightly beveled position to facilitate insertion into the anterior chamber. A beveled opening may be less subject to plugging with fibrin postoperatively as well. When the tubing end is beveled at 45° or less, however, it may be more easily plugged if contact with the corneal endothelium occurs. A limbal‐based, partial‐thickness scleral hinge of 5 × 8 mm or a beveled hypodermic tunnel into the anterior chamber is prepared for the tubing to be inserted into the anterior chamber. The bend of the tubing as it enters the anterior chamber

should be angled in the scleral tunnel or covered with a scleral allograft to prevent its erosion through the bulbar conjunctiva in dogs with “tight eyelids.” Once the tubing is positioned in the anterior chamber, AH will generally be noted flowing through the device. The conjunctival flap wound is apposed using several simple interrupted or a continuous 6‐0 to 7‐0 absorbable suture. To treat any fibrin both in the AH and within the implant intraoperatively, tPA may be injected into the anterior chamber at the limbus. Postoperative Management  General postoperative manage-

ment includes the following:

●●

●●

●●

●●

●●

●●

●●

●●

Tonometry is used to evaluate the implant’s function for the next several days postoperatively. Control and resolution of the iridocyclitis with use of topical and systemic corticosteroids and nonsteroidal anti‐ inflammatory agents are critical to success. Moderate pupillary dilation and encouragement of pupil movement with careful use of mydriatics (e.g., 1% tropicamide). Prevention of infection with use of topical and systemic antibiotics. Maintenance of normal IOP levels using CAIs and, if necessary, beta-blocker adrenergics (miotics and PGs may be counterindicated because of their effects on the episcleral fibroblasts and increased AH flare). The bleb and the gonioimplant can be imaged with ultrasonography, and the blebs characterized as small, medium, and large (Lloyd et  al., 1993). The AH within the bleb appears as an echolucent area and the gonioplate appear as an echodense area. Although bleb size does not necessarily correlate with the level of IOP control, it does confirm that the implant’s tube is patent. Continued topical medications that may lower IOP as well as control inflammation may be important postoperatively. Prednisolone acetate (1%) was recommended in one clinical series to reduce any inflammation and control the fibroblasts within the bleb surrounding the extrascleral implant (Westermeyer et al., 2011). Analgesics should be used in the immediate postoperative period and the surgical site should be protected from self‐trauma.

Successful anterior chamber shunts will provide an IOP immediately after surgery of approximately 5 mmHg with nonvalved systems and of 10–12 mmHg with valved systems (Fig. 20.26). Occasional spikes of 5 or 10 mmHg may develop in the first few weeks if the shunt is temporarily plugged with fibrin. With development of a fibrous capsule about the base of the shunt, IOP will gradually increase to 12–20 mmHg several weeks later. Ultrasonography through the upper eyelid over the area of the shunt can demonstrate no surrounding AH “pool” if the tube or valve is occluded (Lloyd et al., 1993), or a very large bleb if the fibrosis around the implant

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A

B

C

D

E Figure 20.25  Surgical placement is similar for all the various anterior chamber shunts. A. Either the dorsolateral or dorsolateral quadrant is approached by scissor dissection under a fornix-based conjunctival flap. A space adequate to accommodate the episcleral base of the shunt between the dorsal rectus muscle and either the medial or lateral rectus muscle is prepared. B. The anterior chamber shunt must be primed with balanced salt solution before implantation. C. The anterior chamber shunt is positioned between the adjacent rectus muscles and, with some implants, under the rectus muscles. It is secured with simple interrupted, nonabsorbable sutures. D. After limbal puncture with a 20- to 22-gauge hypodermic needle and creation of the proper length and beveled end for the tube, the silicone tubing is inserted into the anterior chamber. The scleral aspect of this tube should be covered with either autogenous or homologous sclera to protect the overlying bulbar conjunctiva. E. Sagittal, postoperative view shows the proper position of the anterior chamber shunt, with its leading edge approximately 10–14 mm posterior of the limbus. (Modified with permission from Gelatt, K.N. & Gelatt, J.P. (2011) Surgical procedures for treatment of the glaucomas. In: Veterinary Ophthalmic Surgery (eds. Gelatt, K.N. & Gelatt, J.P.), pp. 263–303. Edinburgh: Elsevier-Saunders.)

Section IIIA: Canine Ophthalmology

SECTION IIIA

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Figure 20.26  Ahmed gonioshunt in place in an eye with primary glaucoma. The shunt tubing is entering the anterior chamber at the 1 o’clock position.

has become resistant to aqueous exit. Topical corticosteroids (e.g., 1% prednisolone) are recommended postoperatively for several months to impede capsule formation about the base of the anterior chamber shunt. Needling or partial excision of the dorsal fibrotic capsule as well as the injection of 5‐ fluorouracil are used to address implant failure several months postoperatively (Sherwood 1990). Complications of Anterior Chamber Shunts  Failures of ante-

rior chamber shunts may be grouped into three types (Sherwood, 1990). The immediate postoperative iridocyclitis can usually be controlled by routine anti‐inflammatory medications. Any fibrin or blood in the anterior chamber that may occlude the tubing or valve usually resolves with one or two injections of tPA. Long‐term failure of anterior chamber shunts is usually associated with development of an impermeable capsule about the episcleral base of the device. More effective anti‐ fibrosis drugs are needed to markedly impede or totally prevent capsule formation about the extrascleral base of these implants long term. These drugs may be injected or inserted as time‐release medications into the retrobulbar space either intraoperatively or 1–2 months postoperatively, after some capsule has formed about the implant and healing is complete. The Labrador Retriever seems to develop these fibrotic capsules very early (Moeller et al., 2011). Further improvements are necessary to minimize this complication.

Surgical Results  Strategies for placing anterior chamber shunts in the dog are still evolving. The current anterior chamber shunts drain AH into the subconjunctival and retrobulbar spaces, but alternate sites, including the frontal sinus and other areas, have been attempted in the dog (Cullen et al., 1998; Gelatt & Gelatt, 2011; Håkanson, 1996).

The success rate for anterior chamber shunts has progressively improved with the refinement in the gonioimplant device, surgical procedure, and postoperative clinical management. In 1989, in a report involving 21 eyes in 15 dogs with the primary glaucomas that received the modified Joseph shunt, 20 eyes were normotensive at 4 weeks, and 17 eyes were still normotensive at 9–15 months (Bedford, 1989), with about 50% of these eyes receiving oral dichlorphenamide daily. Of the 9 eyes with vision preoperatively, 8 were still visual at 9 months. A larger series of studies in 1993, 1995, and 1998, involving 83 eyes in 65 dogs, compared three different anterior chamber shunts for treatment of primary glaucoma (Garcia et  al., 1993, 1995, 1998). The criteria for success were maintenance of vision and IOP levels of 20 mmHg or less. The median time at which the IOP began to increase postoperatively depended on the shunt and ranged from 4 to 10–15 months. The median time for vision loss to develop postoperatively again varied by shunt and ranged from 4 to 6–9 months. At 1 year, 15 of the 22 eyes with an IOP of 20 mmHg or less were still visual. The most promising shunt was the large Ahmed shunt attached to a silicone band. More recent reports have combined the gonioimplant with cyclophotocoagulation or cryotherapy. Bentley and coworkers reported on 18 glaucomatous dogs (19 eyes) treated with cycloablation and Ahmed gonioimplantation (7 eyes were treated with a diode laser and 12 were treated with cyclocryoablation; Bentley et al., 1996). One year after surgery, 11 of 19 eyes (60%) had vision and 14 of 19 eyes had IOP lower than 25 mmHg. The implant can prevent the IOP spikes that follow the cycloablation, as well as reduce the amount of energy or freezing for cryoablation. Sapienza and van der Woerdt (2005) reported their results using a combined diode laser cycloablation and the Ahmed gonioimplant in 48 dogs (51 eyes). Good control of IOP was achieved in 39/51 (76%) of the eyes, and IOP was poor or uncontrolled in 12/51 (24%) of the eyes. After 6 months 20 of 41 (49%) eyes maintained vision, and after 12 months 12/29 (41%) of eyes had vision. In another series, temporalis muscle fascia or porcine intestinal submucosa grafts were used to cover the tube from the implant’s base to the limbus, and topical 1% prednisolone acetate was instilled daily to control any intraocular inflammation, as well as to submit fibroblastic activity within the bleb’s walls (Westermeyer et al., 2011). Mitomycin (0.25–0.50 mg) was administered by a trimmed cellulose sponge in the operative pocket for 5 minutes before implant insertion. The sides of the overlying conjunctival incision were not touched with the mitomycin solution‐soaked sponge, and the entire area was rinsed with copious amounts of balanced solution for 5 minutes. Bleb revision was occasionally necessary and was performed by an incision on the top of the bleb. The fibrous tissue was excised and AH flow immediately returned. The bleb was then again treated with mitomycin using the same protocol. As an alternate

20: The Canine Glaucomas

Cyclodestructive Techniques  Several noninvasive cyclode-

structive procedures have been developed to treat glaucomas in small animals by decreasing AH formation through partial destruction of the ciliary body processes. Excessive heat, as with diathermy or lasers, or extreme cold, as with cryotherapy, is directed through the overlying sclera to the ciliary body processes. Proper positioning of the cryo and laser probes is critical; these probes must be directly over the ciliary body processes. In the dog, this area is approximately 5 mm from the limbus in the dorsal aspects of the globe. With globe enlargement, the ciliary processes of the pars plicata may shift an additional 0.5–1.0 mm posteriorly. Cyclodestructive procedures require some functional AH outflow to have an optimal IOP‐reducing effect, because only partial destruction of the ciliary body will allow some level of minimal AH formation, which will continue to result in normal to subnormal IOP. Traditional cyclodestructive procedures can be refined only so much, in part because of the less than predictable regeneration of the ciliary body epithelium. Excessive application of these energies results in phthisis bulbi, with irreversible destruction of the ciliary body and permanent ocular hypotony.

Cyclocryothermy  Cyclocryothermy is employed primarily in advanced glaucomatous eyes to reduce IOP in the presence of persistent pain or to induce phthisis bulbi, which may be more cosmetically acceptable than a buphthalmic eye (Merideth & Gelatt, 1980). This technique is also used in permanently blind glaucomatous eyes that are nonresponsive to intensive medical treatments. Cyclocryothermy is used infrequently in visual eyes, because prolonged periods of elevated IOP may follow the procedure. The nitrous oxide or liquid nitrogen, 2.0–3.0 mm cryoprobe is applied 5 mm from the limbus directly onto the dorsal bulbar conjunctiva. Four to eight sites in the dorsal half of the eye are frozen for 120 seconds, each with the temperature of the cryoprobe reaching ‐60° to ‐80° C. The 3 and

9’clock positions are avoided to prevent direct damage to the long posterior ciliary arteries (Brightman et al., 1982). Transscleral Laser Photocoagulation  Transscleral cyclopho-

tocoagulation uses energy developed by different types of lasers to destroy the ciliary body and to reduce AH formation. Both noncontact and contact Nd : YAG and diode lasers have been used in different animal species and, though costly, are promising treatments of canine glaucoma. Laser cyclophotocoagulation has been evaluated in the normal dog using the Nd : YAG and diode lasers (Nadelstein et al., 1997; Nasisse et al., 1988; Quinn et al., 1994; Sapienza et al., 1992). Using a noncontact Nd : YAG laser in 25 normal dogs, either 100 J or 238 J was delivered 5 mm posterior to the limbus to the canine ciliary body. In the 100 J group, IOP declined by 6 mmHg, but returned to prelaser levels within 7 days (Nadelstein et al., 1997). In the 238 J group, IOP declined by 10 mmHg throughout the 7 and 28 days of observation. Seven days after laser treatment, ciliary hemorrhage and ciliary necrosis were prominent; 28 days after treatment, ciliary atrophy and fibrosis were the primary histopathologic findings, though one eye developed extensive intraocular hemorrhage and phthisis bulbus. With the total pulse energy delivered 5 mm posterior to the limbus and varied at 126, 154, and 212 J, contact Nd : YAG laser cyclophotocoagulation in normal dogs produced a 1‐month decline in IOP, except in the high‐energy group, in which ocular hypertension developed 5–10 days after treatment (Sapienza et al., 1992). As the energy dose increased, the intensity of iridocyclitis and the possibility of acute iatrogenic glaucoma also increased. Focal cataract formation occurred in 75% of laser‐treated eyes. The diode laser was evaluated in a study of five normal dogs undergoing contact transscleral cyclophotocoagulation 3 mm posterior to the limbus (Nadelstein et  al., 1997). The energy was delivered to 35 spots using 1.5 W at a duration of 1.5 seconds (i.e., 78.7 J per eye at 2.25 J/spot) and avoiding the 9 and 3 o’clock positions. Clinically, aqueous flare, conjunctival hyperemia, fibrin in the aqueous, miosis, limited hyphema, and in one dog intravitreal hemorrhage developed. IOP declined within 12–24 hours after treatment and remained low for the 28 days of observation. One dog’s IOP spiked a single reading of 30 mmHg 1 hour after laser treatment. One hour after laser treatment, the treated areas in the dog appeared as white, blisterlike lesions, with adjacent hemorrhage, fibrin strands, and inflammatory debris. By 28 days, these areas appeared depigmented and slightly atrophied. In another study, thermography was compared using the Nd : YAG and semiconductor diode laser among in vitro, normal canine eyes (Quinn et al., 1994). Histopathologic findings at the treated areas included a poorly demarcated, circular, hypereosinophilic focus of tissue coagulation that straddled the scleral–ciliary body interface. In this study, the Nd : YAG and diode lasers produced similar cyclodestructive effects.

SECTION IIIA

approach, 5‐fluorouracil (5 mg) was injected directly into the bleb twice at a 2‐week interval. At 12 months postoperatively, 8 of the 9 dogs were still visual. The 350 mm2 Baerveldt nonvalve device was evaluated in both primary glaucoma (9 eyes, 7 dogs) and secondary glaucoma (23 eyes, 21 dogs). IOP was maintained under 20 mmHg in 24 of the 32 eyes (75%), with 43.8% receiving no additional therapy and vision retained in 18 of the 27 eyes with vision prior to surgery, with an average follow‐up of 361 days. Postoperative complications were hypotony (81%), ocular hypertension (75%), and fibrin formation in the anterior chamber (63%; Graham et al., 2017a). When combined with transscleral cyclophotocoagulation, implantation of a Baerveldt drainage device resulted in greater control of IOP and vision retension than either transscleral cyclophotocoagulation or shunt placement alone (Graham et al., 2018).

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In a study using the noncontact Nd : YAG laser in 56 eyes of 37 dogs with glaucoma, promising results were obtained (Nasisse et al., 1990). Of these, 44 eyes had preexisting glaucoma, and 12 fellow eyes were treated prophylactically. The mean number of laser‐treated spots were 35 ± 10. The mean energy per burst was 7.1 ± 2.6 J, and the mean total energy delivered to each eye was 228 ± 81 J. Treatment success was defined as an IOP of 25 mmHg or less. Information on vision was not reported. In the 44 treated glaucoma eyes, IOP was reduced to 25 mmHg or less in 83%. Three of the four failures were eyes devoid of uveal pigmentation (Nasisse et al., 1990). In lightly or nonpigmented eyes, such as those in the Siberian Husky or Old English Sheepdog, laser cyclophotocoagulation was not nearly as successful. Hyphema developed in 16% of those eyes, but it resolved without complications in all but 2. Cataract formation occurred in approximately 37% of treated dogs (i.e., 12 of 32 eyes; Nasisse et al., 1990). A larger study using diode laser transscleral cyclophotocoagulation evaluated 176 eyes in 144 dogs with clinical primary glaucoma (Cook, 1997). The different breeds with these primary glaucomas were not analyzed separately, but approximately 50% were ACS. Laser treatments were administered 3–4 mm posterior to the limbus at 30–40 sites, for a mean dose of 85 J per eye. An immediate post‐treatment IOP elevation of 11.3 ± 7.8 mmHg occurred (pretreatment IOP 45 ± 10 mmHg) and was treated by anterior chamber paracentesis. This immediate spike in IOP in 4 eyes was associated with loss of vision. An IOP of 30 mmHg or less occurred in 110 of 136 eyes at 8 weeks, 69 of 106 eyes at 6 months, and 45 of 88 eyes at 1 year following the procedure. Major complications included corneal ulcerations, cataract formation, intraocular hemorrhage, retinal detachments, and phthisis bulbi. Using the menace response as a test of vision, positive results were obtained in 21 of 37 eyes (57%) at 8 weeks, 11 of 30 eyes (37%) at 6 months, and 11 of 19 eyes (53%) at 1 year. Of the 45 eyes that tested positive with the menace test before laser therapy, only 10 (5.5%) were still evaluated as being visual at 12 months. The results of this study suggest that diode laser cyclophotocoagulation may be effective at lowering IOP for as long as 1 year (50% of the eyes), but is less effective at maintaining vision (22%). In two studies from Australia, transscleral cyclophotocoagulation with the diode laser was evaluated in dogs with glaucoma following intracapsular lens extraction for displaced lenses and for the primary glaucomas (Hardman et al., 2001; O’Reilly et al., 2003). Approximately 16% of 99 patients with intracapsular lens removal for displaced lenses developed glaucoma. The diode laser probe with a spot size of 600 μm was applied perpendicularly (causing slight scleral indentation) to the globe in 20–25 sites 4 mm posterior to the limbus. A power of 1000 mW for 5000 ms delivered an average of 125 J per eye. Diode laser cyclophotocoagulation produced adequate control of IOP in 15 of 20 eyes (75%) without medications at 1 month post‐therapy. After 12 months, 8 of

15 eyes (53%) had vision and 7 of 15 eyes (47%) were nonvisual. A common protocol for visual eyes receiving contact diode laser cyclophotocoagulation is 1.2 W per site at a duration of 1.2 seconds with 35 sites (20 dorsal and 15 ventral), for a total of 50 J per eye (Fig. 20.27). The energy is delivered 3–4 mm posterior to the limbus. More energy can be delivered in eyes that are permanently blind. Medical treatment of glaucoma and anti‐inflammatory therapy for post‐treatment iridocyclitis should continue until the IOP is reduced and the inflammation subsides. It may take 3–4 weeks for the endpoint result (early postoperative IOP) of these surgical procedures to be known. The newer micropulse transscleral cyclophotocoagulation (MP‐TSCPC) seems to provide about a 70% success rate in IOP control, less postlaser inflammation, and fewer complications in humans, and shows early promise in its application in veterinary ophthalmology (Bras & Maggio, 2015; Sapienza et al., 2017; Sebbag et al., 2019a). The success rate of this modality at lowering IOP ranges from 50% to 65% depending upon the timeframe examined, with cases of primary glaucoma responding more favorably than those of secondary glaucoma (Sapienza et al., 2018). In dogs, corneal hypoesthesia is a common complication of MP‐TSCPC and can be associated with qualitative and quantitative tear film deficiencies and neurotrophic corneal ulcers (Sebbag et al., 2019b).

Figure 20.27  Multiple sites of transcleral cyclophotocoagulation in a dog. With the contact diode laser, transcleral cyclophotocoagulation was 1.2 w per site for 1.2 seconds, with 35 sites treated (20 dorsal and 15 ventral) for a total of 50 J per eye.

Diode Endoscopic Cyclophotocoagulation  Endoscopic cyclophotocoagulation (ECPC) with a diode laser has been reported for therapy of the canine glaucomas (Bras & Maggio, 2015; Bras et al., 2005), and offers the advantage of highly selective laser ablation of the pigmented ciliary body epithelium while under direct observation. The microendoscope has three divisions: (1) wide cone viewing light; (2) image 10,000 pixel fiber bundle with 110° field of view; and (3) diode laser (810 nm) within 20‐gauge diameter fiber bundle (30° curved or straight). The available integrated ophthalmic endoscopy systems provide both viewing and illumination (E4 and E2 consoles, Endo Optiks, Little Silver, NJ, USA) and include the video camera, light source, and video monitor. The surgical approach is either limbal for phakic, aphakic, and pseudophakic eyes using a 30° curved probe for as much as 300° from a single incision, or pars plana for phakic eyes treating 90–100° from a single incision (Fig.  20.28). During endolasering the ciliary process tissue quickly blanches (from black to light gray or white) and shrinks. Any tissue explosion (popping or bubble formation) is avoided. The ablation area is usually approximately 270° to achieve optimal ocular hypotensive effects. In phakic eyes, ECPC often affects the periphery of the lens and produces cataract formation, so most advocate concurrent removal of the lens via phacoemulsification followed by placement of an artificial intraocular lens. The limbal approach is generally used when concurrent phacoemulsification is performed. Overapplication of ECPC is associated with higher rates of complications. Color dilute breeds

Figure 20.28  Intraoperative image demonstrating blanching of the ciliary body processes during endoscopic laser cyclophotocoagulation. The red focus is the sight for the laser. The iris leaflet is located above the ciliary body in this image.

(Siberian Husky, Australian Shepherd, etc.) require higher levels of ECPC energy as the less pigmented ciliary body processes absorb less energy. ECPC therapy in glaucoma patients is encouraging, but patient follow‐ups are limited in both time and animal numbers. Studies to date report long‐term IOP control and reduced need for topical glaucoma drugs in about 80% of treated cases for 12 postoperative months and maintenance of vision (of animals sighted at the time of surgery) in about 70% of cases. Three‐year postoperative success rates decrease to about 50% with controlled IOP and sight (Lutz et al., 2013). Treatment of End-Stage Primary Glaucomas

Because of the limited success of both medical and surgical therapies for glaucoma in the dog, salvage procedures to prevent ocular pain, to reduce the enlarged and blind globe to near‐normal size to reduce corneal exposure, and to provide a cosmetically acceptable eye may be necessary. These procedures include pharmacologic destruction of the ciliary body with intravitreal injection of gentamicin or cidofivir, evisceration of the intraocular contents, followed by placement of an intrascleral or intraocular prosthesis and enucleation (i.e., surgical removal of the globe). Sometimes enucleation is the only viable option for certain patients and can even be used bilaterally to provide a happy pain‐free companion animal (Fig. 20.29). Pharmacologic destruction of the ciliary body with intraocular injections of gentamicin is a salvage procedure for advanced and blind canine glaucomatous eyes (Bingaman et al., 1994; Vainisi et al., 1983). Gentamicin is cytotoxic to the ciliary body epithelium and retina, thereby markedly reducing or even eliminating AH formation. In the original technique, 0.5–0.6 mL of liquefied vitreous was aspirated, and 25 mg of gentamicin sulfate and 1 mg of dexamethasone were injected into the vitreous space (Vainisi et  al., 1983). Pharmacologic ablation of the ciliary body was successful in lowering the IOP in 65% of patients for treatment of absolute glaucoma in early studies. Of eyes that do not respond to the first injection of gentamicin, 50% fail again to respond after the second injection, and approximately 10% of the eyes will

Figure 20.29  Postoperative appearance of bilateral intraocular prostheses following evisceration of the globes one year after the procedure.

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be phthisical after this method. This technique seems to work best when the preinjection IOP levels are less than 20 mmHg. In another study, both anterior chamber and intravitreal injections were attempted (Bingaman et al., 1994), although a variety of protocols and dosages exist. The dose of gentamicin should not exceed the patient’s total daily dose for this drug, and it has been reported to be absorbed systemically following intraocular injection (Rankin et  al., 2016). The most recent report used between 25 and 40 mg of gentamicin per eye and had a success rate of approximately 86% (Rankin et al., 2016). Eyes treated with doses of gentamicin higher than 20 mg had a significantly lower IOP after injection. Post-injection inflammation is common, as is cataract formation in phakic eyes. There have been reports of intraocular sarcoma development in glaucomatous eyes of both cats and dogs following gentamicin ablation (Duke et al., 2013). Recent reports of the use of the antiviral agent cidofivir have shown promise with successful lowering of IOP in 85% of cases and describe less postoperative inflammation and cataract development (Low et al., 2014). Evisceration and intrascleral prosthesis form another salvage procedure that may provide the most cosmetically acceptable result (see Chapter 14). This procedure treats the pain associated with absolute glaucoma, limits the corneal exposure from enlarged globes, and eliminates the need for anti‐glaucoma treatments. The overall result is more predictable, and phthisis bulbus is not possible. Some corneal edema, fibrosis, and pigmentation occur postoperatively. Healing is prolonged in these eyes, likely because the large incision that must be made in the sclera to accommodate the intraocular prosthesis compromises the innervation to the fibrous tunic and the vascular supply to the interior of the globe is eliminated. The most serious short‐term complications are the development of central corneal ulcerations and infections postoperatively. The most common long‐term complication is the development of keratoconjunctivitis sicca (Lin et al., 2007). As these dogs often do not blink well in the immediate postoperative period, a temporary tarsorrhaphy is recommended for 10–14 days in all patients. If corneal ulceration occurs, a pedicle conjunctival graft can also be applied, because the corneal healing in these patients is slow. The overall success rate with intrascleral prosthesis is approximately 85%–95%.

New Developments in Glaucoma Therapy Despite recent advances in the treatment of canine glaucoma, most affected dogs still go blind. There is no cure for glaucoma, but many forms of primary human glaucomas have become preventable with early diagnosis and intervention. Therefore, it is crucial that we gain a better understand-

ing of canine glaucoma risk factors and disease mechanisms, which will allow earlier diagnosis and more effective, targeted treatment to prevent continued RGC loss and blindness (Komáromy et al., 2019). Recent and ongoing advances in canine genetics and ophthalmic diagnostic technologies, including high‐resolution imaging and home monitoring of IOP, provide the necessary tools to aid in these efforts. Lowering IOP remains the main focus of glaucoma therapy, but other treatment options to protect and regenerate RGCs and their axons will hopefully become available in the foreseeable future.

Intraocular Pressure Control Novel Medical Therapies to Lower Intraocular Pressure

Recent advances in IOP control of human patients include novel drugs and drug implants. More effective IOP control may be achieved by introducing novel, mechanistic‐based medical therapies. Two newly approved topical IOP‐lowering medications are latanoprostene bunod (Vyzulta™, Bausch & Lomb, Bridgewater, NJ, USA) and netarsudil (Rhopressa™, Aerie Pharmaceuticals, Bridgewater, NJ, USA and Research Triangle Park, NC, USA). Latanoprostene bunod is a nitric oxide–donating PG F2α agonist that showed improved pressure‐lowering effect compared to latanoprost in glaucomatous Beagles (Borghi et al., 2010; Impagnatiello et al., 2011; Krauss et al., 2011). Compared to traditional PG analogues, latanoprostene bunod has a stronger therapeutic effect on the conventional outflow through the trabecular meshwork, in addition to an increase of uveoscleral outflow (Cavet & DeCory, 2018). Netarsudil is a Rho‐Kinase (ROCK) and norepinephrine transporter (NET) inhibitor. ROCK inhibition reduces cell contraction and cell stiffness, and decreases expression of fibrosis‐related proteins, resulting in increased trabecular outflow facility (Lin et  al., 2018; Rao et al., 2017; Wang & Chang, 2014). Netarsudil’s NET‐inhibitory activity is likely responsible for the documented reduction of AH production and decrease in episcleral venous pressure, further contributing to the lowering of IOP (Kiel & Kopczynski, 2015; Lin et al., 2018; Rao et al., 2001). Netarsudil results in great reductions in IOP in rabbits and monkeys (Lin et al., 2018). Unfortunately, in clinical investigations to date in normotensive and glaucomatous dogs with ADAMTS10 open‐angle glaucoma, netardusil administrered topically twice daily has only demonstrated small, clinically unimportant reduction in IOPs (Leary et  al., 2019; Yang et al., 2020). One major factor responsible for the progression of glaucomatous optic neuropathy in human patients is poor adherence to eye‐drop administration. It has been estimated that only 60%–70% of prescribed doses of eye drops for patients with glaucoma are taken (Friedman et al., 2007) and ~50% of patients have been found not to be adherent to their medica-

20: The Canine Glaucomas

Novel Surgical Therapies to Lower Intraocular Pressure

Because newly developed glaucoma medications are emerging at a very slow rate and are generally optimized for the human rather than canine eye, a continued focus on improved surgical therapies is important. Improvement of surgical therapies includes the continued optimizing of current techniques, such as more effective inhibition of scarring to prolong goniomplant bleb function (Martorana et  al., 2015; Saito et al., 2017; Yu‐Wai‐Man et al., 2017). A promising novel technique of cyclophotocoagulation uses a micropulse laser (MicroPulse® Cyclo G6, Iridex, Mountain View, CA, USA) for TSCP and will soon also become available for ECPC (Lee et al., 2017; Sapienza et al., 2017; Sebbag et al., 2019a, 2019b). The most dramatic recent changes in the surgical treatment of primary glaucoma in humans are represented in the development of microinvasive glaucoma surgeries (MIGS). Because of their effectiveness and minimal invasiveness, these AH‐draining techniques represent an attractive alternative to medical therapy for early stages of glaucoma (Fingeret et  al., 2018). While these procedures are being developed for human patients, with some of them specifically targeting species‐specific anatomic structures such as Schlemm’s canal, selective MIGS may be applicable to dogs and have even been tested informally by veterinary ophthalmologists. Among the most commonly used MIGS are EX‐ PRESS® Mini Glaucoma Shunt (Alcon, Fort Worth, TX, USA), SOLX® Gold Shunt (Solx, Waltham, MA, USA), InnFocus MicroShunt® (InnFocus, Miami, FL, USA), iStent® (Glaukos), and gonioscopy‐assisted transluminal trabeculotomy (GATT). Another subconjunctival MIGS drainage device, the XEN® Gel Stent (Allergan), was successfully tested for safety in normal Beagles (Shute et al., 2016).

Novel Gene and Stem Cell Therapies to Lower Intraocular Pressure

The field of ocular gene therapy has enjoyed several recent successes, with treatments for retinal and optic nerve diseases being translated into clinical applications for human patients (Bennett, 2017; Campochiaro et al., 2017; Guy et al., 2017). These advances will likely also benefit human and animal patients with glaucoma – for the treatment of both the anterior and posterior segments of the eye. As we gain a better understanding of glaucoma genetics and the molecular disease mechanisms within the AH outflow pathways, gene therapies will allow us to specifically address and correct the pathogenesis for more effective, long‐term IOP control. Targeting of transgene expression to trabecular meshwork has been successfully achieved in several animal species, including the dog, following intracameral injection of adenovirus, lentivirus, and adeno‐associated virus (AAV) gene therapy vectors (Bogner et al., 2015; Buie et al., 2010; Dang et  al., 2017; Oh et  al., 2014; Wang et  al., 2017). The recent expansion of the AAV vector toolkit combined with its excellent safety and efficacy record for use within the eye makes the AAV gene therapy vector a very attractive option for treatment of the trabecular meshwork and achieving long‐term IOP control in open‐angle glaucomas (Asokan et al., 2012; Bogner et al., 2015; Oh et al., 2014; Wang et al., 2017). Other tissues of the anterior segment, such as the ciliary muscle, may need to be targeted to address the disease mechanisms leading to PACG. Recently, proof of concept has been provided that the trabecular meshwork can be regenerated in advanced stages of disease and trabecular outflow restored: trabecular meshwork–like cells were induced from induced pluripotent stem cells and injected into the anterior chamber of transgenic, MYOC‐mutant mice (Zhu et al., 2016, 2017). As a result, the conventional outflow pathway was replenished with new cells, which resulted in improved outflow facility, IOP control, and halted RGC loss (Zhu et al., 2016, 2017). This type of stem cell–based therapy may become a promising possibility for long‐term IOP control in dogs with primary glaucoma.

Neuroprotection and Neuroregeneration One of the major challenges of treating glaucoma patients is the continued loss of RGCs and their axons despite effective IOP control. Considerable efforts have been made toward a better understanding of these IOP‐independent disease mechanisms and the development of neuroprotective treatments to address them and prevent further RGC death. Some of these mechanisms that may or may not be triggered by an increase in IOP have been discussed earlier in this chapter: excitotoxicity caused by excessive excitatory amino acid release, such as glutamate and aspartate (Brooks et al., 1997; Seki & Lipton, 2008); neurotrophin deprivation due to blockage of retrograde

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tion over 75% of the time (Okeke et al., 2009). Because of this poor adherence, several drug companies have developed devices for long‐term, sustained drug release, either onto the corneal surface or into the anterior chamber. Most of these implants release PG analogues, and some have already moved from preclinical testing into clinical application in human patients. Externally placed devices include the Helios™ bimatoprost periocular ring (Allergan, Dublin, Ireland) for placement into the conjunctival fornix (Brandt et  al., 2017) and OTX‐TP travoprost punctal plugs (Ocular Therapeutix, Bedford, MA, USA; Aref, 2017). Intracameral implants include Bimatoprost SR (Durysta, Allergan; Lee et  al., 2018), ENV515 travoprost (Envisia Therapeutics, Durham, NC, USA; Aref, 2017), OTX‐TIC travoprost (Ocular Therapeutix), and iDose travoprost (Glaukos, San Clemente, CA, USA; Aref, 2017). Intracameral, biodegradable latanoprost‐, bimatoprost‐, and travoprost‐releasing devices have recently been tested in dogs (Komáromy et  al., 2017; Lee et al., 2018; Navratil et al., 2015).

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axonal transport (Fahy et  al., 2016; Knox et  al., 2007; Pease et al., 2000; Salinas‐Navarro et al., 2010); excessive intracellular calcium (Ward et al., 2014); compromised blood flow to the ONH and retina (Agarwal et  al., 2009; Brooks et  al., 1989a; Chung et al., 1999; Flammer et al., 1999; Gelatt et al., 2003; Gelatt‐Nicholson et al., 1999; Michelson et al., 1998); oxidative stress (Liu et al., 2007; Mozaffarieh et al., 2008); inflammation and autoimmunity against retinal and optic nerve antigens (Bell et al., 2013; Pumphrey et al., 2013a; Wax & Tezel, 2009); and reactive gliosis (Bringmann et al., 2006; Inman & Horner, 2007, Neufeld & Liu, 2003; Son et al., 2010). A large number of compounds have been shown to address these disease mechanisms and protect RGCs effectively in experimental animal models of glaucoma, many of them being routinely used in the clinic for unrelated indications. Unfortunately, none of these drugs has been successfully moved into clinical application for glaucoma therapy. The two neuroprotective therapies that have gone through clinical trial for glaucoma are memantine, given by oral route, and ciliary neurotrophic factor (CNTF), continuously released into the vitreous. Memantine, an N­methyl‐ D­aspartate receptor antagonist, is used for the treatment of Alzheimer’s disease, and has been shown to reduce RGC death and functional loss by suppressing excitotoxicity in experimental glaucoma in rats and primates (Hare et  al., 2004a, 2004b; Wolde‐Mussie et  al., 2002). Unfortunately, Phase 3 trials have failed to demonstrate protection of visual function by memantine in human glaucoma patients (Weinreb et al., 2018). The continuous release of CNTF by intravitreal encapsulated cell therapy has recently been

tested in Phase 1 clinical trials in patients with POAG (ClinicalTrials.gov NCT01408472) and ischemic optic neuropathy (NCT01411657), but results have not yet been published. CNTF has previously been shown to slow RGC death in experimental glaucoma in rats (Pease et al., 2009). Because of its documented beneficial effect on ocular blood flow and its potential neuroprotective effect, the calcium channel blocker amlodipine is used systemically by some veterinary ophthalmologists on selected canine glaucoma patients (Källberg et al., 2003). The pursuit of neuroprotective therapy for glaucoma continues, including by gene and stem cell therapy (Jutley et al., 2017). In addition to neuroprotection, the replacement of lost RGCs and the regeneration of RGC axons are high priorities in glaucoma research. For example, the National Eye Institute, which is part of the National Institutes of Health, predicts that these goals should be achievable within 10–15 years with adequate funding (Goldberg et al., 2016). Retinal and optic nerve regeneration is naturally possible in fish and amphibians, but not in mammals. However, several animal studies have shown that under the right circumstances, mammalian RGCs are able to regenerate their axons and connect to the appropriate target areas in the brain, resulting in visual recovery (Benowitz et al., 2017; Laha et al., 2017). Furthermore, transplantation of RGCs by intravitreal injection is one method that is being worked on to replace lost RGCs (Tanaka et al., 2015). Ultimately, even transplantation of whole eyes may become a realistic option with improvements in optic nerve regeneration.

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Bentley, E., Nasisse, M.P., Glover, T., et al. (1996) Implantation of filtering devices in dogs with glaucoma: Preliminary results in 13 eyes. Veterinary & Comparative Ophthalmology, 6, 243–246. Betschart, S., Hässig, M., & Spiess, B. (2014) Lens luxation in dogs: A retrospective study of 134 dogs (2000–2011). Schweizer Archiv für Tierheilkunde, 156, 125–131. Binder, D.R., Herring, I.P., & Gerhard, T. (2007) Outcomes on nonsurgical management and efficacy of demecarium bromide treatment for primary lens instability in dogs: 34 cases (1990–2004). Journal of the American Veterinary Medical Association, 231, 89–93. Bingaman, D.P., Lindley, D.M., Glickman, N.W., et al. (1994) Intraocular gentamicin and glaucoma: A retrospective study of 60 dog and cat eyes (1985–1993). Veterinary & Comparative Ophthalmology, 4, 113–119. Biros, D.J., Gelatt, K.N., Brooks, D.E., et al. (2000) Development of glaucoma after cataract surgery in dogs: 220 cases (1987–1998). Journal of the American Veterinary Medical Association, 216, 1780–1786. Bito, L.Z. (1977) The physiology and pathophysiology of intraocular fluids. In: The Ocular and Cerebrospinal Fluids (eds. Bito, L.Z., Davson, H., & Fenstermacher, J.D.), pp. 273–289. New York: Academic Press. Bito, L.Z. (1986) Prostaglandins and other eicosanoids: Their ocular transport, pharmacokinetics and therapeutic effects. Transactions of the Ophthalmological Society of the United Kingdom, 105, 162–170. Bjerkås, E., Ekesten, B., & Farstad, W. (2002) Pectinate ligament dysplasia and narrowing of the iridocorneal angle associated with glaucoma in the English Springer Spaniel. Veterinary Ophthalmology, 5, 49–54. Bjerkås, E., Peiffer, R.L., & Ekesten, B. (1994) Primary glaucoma in the Norwegian Elkhound (abstract). Transactions of the American College of Veterinary Ophthalmology, 25, 74. Boevé, M.H. & Stades, F.C. (1985) Glaucoom bij hond en kat. Overzicht en retrospectievr evaluatie van 321 patienten. 1. Pathobiologishe achtergronden, indelingen en ras‐ predisposities. 2. Klinische aspecten. Tijdschrift voor Diergeneeskunde, 110, 219–236. Bogner, B., Boye, S.L., Min, S.H., et al. (2015) Capsid mutated adeno‐associated virus delivered to the anterior chamber results in efficient transduction of trabecular meshwork in mouse and rat. PLoS One, 10, e0128759. Boillot, T., Rosolen, S.G., Dulaurent, T., et al. (2014) Determination of morphological, biometric and biochemical susceptibilities in healthy Eurasier dogs with suspected inherited glaucoma. PLoS One, 9(11), e111873. Boote, C., Palko, J.R., Sorensen, T., et al. (2016) Changes in posterior scleral collagen microstructure in canine eyes with an ADAMTS 10 mutation. Molecular Vision, 22, 503–517. Borghi, V., Bastia. E., Guzzetta, M., et al. (2010) A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of

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intravitreal gentamicin. Veterinary Ophthalmology, 16(Suppl. 1), 188–190. Ekesten, B. (1993) Correlation of intraocular distances to the iridocorneal angle in Samoyeds with special reference to angle‐closure glaucoma. Progress in Veterinary & Comparative Ophthalmology, 3, 67–73. Ekesten, B., Bjerkås, E., Kongsengen, K., et al. (1997) Primary glaucoma in the Norwegian Elkhound. Veterinary & Comparative Ophthalmology, 7, 14–18. Ekesten, B. & Narfström, K. (1991) Correlation of morphologic features of the iridocorneal angle to intraocular pressure in Samoyed. American Journal of Veterinary Research, 52, 1875–1878. Ekesten, B. & Narfström, K. (1992) Age‐related changes in intraocular pressure and iridocorneal angle in Samoyeds. Progress in Veterinary & Comparative Ophthalmology, 2, 37–40. Ekesten, B. & Torrang, I. (1995) Heritability of the depth of the opening of the ciliary cleft in Samoyeds. American Journal of Veterinary Research, 56, 1138–1143. Elkington, A.R., Inman, C.B.E., Steart, P.V., et al. (1990) The structure of the lamina cribrosa of the human eye: An immunocytochemical and electron microscopical study. Eye, 4, 42–57. Esson, D., Armour, M., Mundy, P., et al. (2009) The histopathogical and immunohistochemical characteristics of pigmentary and cystic glaucoma in the Golden Retriever. Veterinary Ophthalmology, 12, 361–368. European College of Veterinary Ophthalmologists’ Hereditary Eye Disease Committee (2013) Manual for Presumed Inherited Eye Diseases in Dogs and Cats. Utrecht: ECVO. Fahy, E.T., Chrysostomou, V., & Crowston, J.G. (2016) Mini‐ review: Impaired axonal transport and glaucoma. Current Eye Research, 41, 273–283. Faivre, L., Collod‐Beroud, G., Loeys, B.L., et al. (2007) Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations:An international study. American Journal of Human Genetics, 81(3), 454–466. Farias, F.H., Johnson, G.S., Taylor, J.F., et al. (2010) An ADAMTS17 splice donor site mutation in dogs with primary lens luxation. Investigative Ophthalmology & Visual Science, 51, 4716–2721. Fechtner, R.D. & Weinreb, R.N. (1994) Mechanisms of optic nerve damage in primary open angle glaucoma. Survey of Ophthalmology, 39, 23–42. Fick, C.M. & Dubielzig, R.R. (2016) Short posterior ciliary artery anatomy in normal and acutely glaucomatous dogs. Veterinary Ophthalmology, 19, 43–49. Fingeret, M. & Dickerson, J.E, Jr. (2018) The role of minimally invasive glaucoma surgery devices in the management of glaucoma. Optometry and Vision Science, 95, 155–162. Fischer, K.M., Ward, D.A., & Hendrix, D.V. (2013) Effects of a topically applied 2% delta‐9‐tetrahydrocannabinol ophthalmic solution on intraocular pressure and aqueous humor flow rate in clinically normal dogs. American Journal of Veterinary Research, 74(2), 275–280.

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Gelatt, K.N. & Gum, G.G. (1981) Inheritance of primary glaucoma in the Beagle. American Journal of Veterinary Research, 42, 1691–1693. Gelatt, K.N., Gum, G.G., Barrie, K.P., et al. (1981a) Diurnal variations in intraocular pressure in normotensive and glaucomatous Beagles. Glaucoma, 3, 121–124. Gelatt, K.N., Gum, G.G., Brooks, D.E., et al. (1983) Dose response of topical pilocarpine‐epinephrine combinations in normotensive and glaucomatous Beagles. American Journal of Veterinary Research, 44, 2018–2027. Gelatt, K.N., Gum, G.G., Gwin, R.M., et al. (1981b) Primary open angle glaucoma: Inherited primary open angle glaucoma in the Beagle. American Journal of Pathology, 102, 292–295. Gelatt, K.N., Gum, G.G., Mackay, E.O., et al. (1996) Estimations of aqueous humor outflow facility by pneumatonography in normal, genetic carrier and glaucomatous Beagles. Veterinary & Comparative Ophthalmology, 6, 148–151. Gelatt, K.N., Gum, G.G., Merideth, R.E., et al. (1982) Episcleral venous pressure in normotensive and glaucomatous Beagles. Investigative Ophthalmology & Visual Science, 23, 131–135. Gelatt, K.N., Gum, G.G., Samuelson, D.A., et al. (1987) Evaluation of the Krupin‐Denver implant in normotensive and glaucomatous Beagles. Journal of the American Veterinary Medical Association, 191, 1404–1409. Gelatt, K.N., Gum, G.G., Williams, L.W., et al. (1979) Ocular hypotensive effects of carbonic anhydrase inhibitors in normotensive and glaucomatous beagles. American Journal of Veterinary Research, 40, 334–345. Gelatt, K.N., Gwin, R.M., Peiffer, R.L., et al. (1977a) Tonography in the normal and glaucomatous Beagle. American Journal of Veterinary Research, 38, 515–520. Gelatt, K.N. & MacKay, E.O. (1998a) Distribution of intraocular pressure in dogs. Veterinary Ophthalmology, 1, 109–114. Gelatt, K.N., MacKay, E.O. (1998b) The ocular hypertensive effects of topical 0.1% dexamethasone in Beagles with inherited glaucoma. Journal of Ocular Pharmacology and Therapeutics, 14, 57–66. Gelatt, K.N. & MacKay, E.O. (2001a) Changes in intraocular pressure associated with topical dorzolamide and oral methazolamide in glaucomatous dogs. Veterinary Ophthalmology, 4, 61–67. Gelatt, K.N. & MacKay, E.O. (2001b) Effects of different dose schedules of latanoprost on intraocular pressure and pupil size in the glaucomatous beagle. Veterinary Ophthalmology, 4, 283–288. Gelatt, K.N. & MacKay, E.O. (2002a) Effects of single and multiple doses of 0.2% brimonidine tartrate in the glaucomatous beagle. Veterinary Ophthalmology, 5, 253–262. Gelatt, K.N. & MacKay, E.O. (2002b) Effects of different dose schedules of bimatoprost on intraocular pressure and pupil size in the glaucomatous beagle. Journal of Ocular Pharmacology and Therapeutics, 18, 525–534. Gelatt, K.N. & MacKay, E.O. (2004a) Prevalence of the breed‐related glaucomas in pure‐bred dogs in North America. Veterinary Ophthalmology, 7, 97–111.

Gelatt, K.N. & MacKay, E.O. (2004b) Secondary glaucomas in the dog in North America. Veterinary Ophthalmology, 7, 245–259. Gelatt, K.N. & MacKay, E.O. (2004c) Effect of different dose schedules of travoprost on intraocular pressure and pupil size in the glaucomatous Beagle. Veterinary Ophthalmology, 7, 53–57. Gelatt, K.N., MacKay, E.O., Dashiell, T., et al. (2004) Effect of different dose schedules of 0.15% unoprostone isopropyl on intraocular pressure and pupil size in the glaucomatous Beagle. Journal of Ocular Pharmacology Therapeutics, 20, 411–420. Gelatt, K.N., Miyabayashi, T., Gelatt‐Nicholson, K.J., et al. (2003) Progressive changes in ophthalmic blood velocities in Beagles with primary open angle glaucoma. Veterinary Ophthalmology, 6, 77–84. Gelatt, K.N., Peiffer, R.L., Gwin, R.M., et al. (1977b) Clinical manifestations of inherited glaucoma in the Beagle. Investigative Ophthalmology & Visual Science, 16, 1135–1148. Gelatt, K.N., Peiffer, R.L., Jessen, C.R., et al. (1976) Consecutive water provocative tests in normal and glaucomatous Beagles. American Journal of Veterinary Research, 37, 269–273. Gelatt, K.N. & Samuelson, D.A. (1986) Collagen fiber organization in the iridocorneal angle of Beagles with inherited glaucoma (abstract). Investigative Ophthalmology & Visual Science, 27, 164. Gelatt, K.N. & Samuelson, D. (1988) The role of lens luxation in inherited glaucoma in the Beagle. Animal Eye Research, 17, 1–8. Gelatt‐Nicholson, K.J., Gelatt, K.N., MacKay, E.O., et al. (1999) Comparative Doppler imaging of the ophthalmic vasculature in normal Beagles and Beagles with inherited primary open‐angle glaucoma. Veterinary Ophthalmology, 2, 97–105. Giannico, A.T., Lima, L., Russ, H.H., et al. (2013) Eyelash growth induced by topical prostaglandin analogues, bimatoprost, tafluprost, travoprost, and latanoprost in rabbits. Journal of Ocular Pharmacology and Therapeutics, 29, 817–820. doi: 10.1089/jop.2013.0075. Gibson, G.G. (1942) Transscleral lacrimal canaliculus transplants. Transactions of the American Ophthalmology Society, 40, 499–515. Gibson, T.E., Roberts, S.M., Severin, G.A., et al. (1998) Comparison of gonioscopy and ultrasound biomicroscopy for evaluating the iridocorneal angle in dogs. Journal of the American Veterinary Medical Association, 213, 635–638. Glover, T.L., Davidson, M.G., Nasisse, M.P., et al. (1995a) The intracapsular extraction of displaced lenses in dogs: A retrospective study of 57 cases (1984–1990). Journal of the American Animal Hospital Association, 31, 77–81. Glover, T.L., Nasisse, M.P., & Davidson, M.G. (1995b) Effects of topically applied mitomycin‐C on intraocular pressure, facility of outflow, and fibrosis after glaucoma filtration surgery in clinically normal dogs. American Journal of Veterinary Research, 56, 936–940.

Goldberg, J.L., Guido, W., & Agi Workshop Participants (2016) Report on the National Eye Institute Audacious Goals Initiative: Regenerating the optic nerve. Investigative Ophthalmology & Visual Science, 57, 1271–1275. Gottanka, J., Johnson, D.H., Martus, P., et al. (1997) Severity of optic nerve damage in eyes with POAG is correlated with changes in the trabecular meshwork. Journal of Glaucoma, 6, 123–132. Gould, D., Pettit, L., McLaughlin, B., et al. (2011) ADAMTS17 mutation associated with primary lens luxation is widespread among breeds. Veterinary Ophthalmology, 14(6), 378–284. Graham, K.L., Donaldson, D., Billson, F.A., et al. (2017a) Use of a 350‐mm Baerveldt glaucoma drainage device to maintain vision and control intraocular pressure in dogs with glaucoma. Veterinary Ophthalmology, 20(5), 427–434. doi: 10.1111/vop.12443. Graham, K.L., Hall, E.J.S., Caraguel, C., et al. (2018) Comparison of diode laser trans‐scleral cyclophotocoagulation versus implantation of a 350‐mm2 Baerveldt glaucoma drainage device for the treatment of glaucoma in dogs (a retrospective study: 2010–2016). Veterinary Ophthalmology, 21, 487–497. Graham K.L., McCowan, C.I., Caruso, K., et al. (2020) Optical coherence tomography of the retina, nerve fiber layer, and optic nerve head in dogs with glaucoma. Veterinary Ophthalmology, 23, 97–112. Graham, K.L., McCowan, C., & White, A. (2017b) Genetic and biochemical biomarkers in canine glaucoma. Veterinary Pathology, 54, 194–203. Graham, S. & Fortune, B. (2009) Electrophysiology in glaucoma assessment. In: Glaucoma. Vol. 1: Medical Diagnosis and Therapy (eds. Shaarawy, T.M., Sherwood, M.B., Hitchings, R.A., & Crowston, J.G.), pp. 151–171. Philadelphia, PA: Saunders. Grozdanic, S.D., Kecova, H., Harper, M.M., et al. (2010) Functional and structural changes in a canine model of hereditary primary angle‐closure glaucoma. Investigative Ophthalmology & Visual Science, 51, 255–263. Grozdanic, S.D., Matic, M., Betts, D.M., et al. (2007) Recovery of canine retina and optic nerve function after acute elevation of intraocular pressure: Implications for canine glaucoma treatment. Veterinary Ophthalmology, 10(Suppl. 1), 101–107. Gum, G.G., Gelatt, K.N., Gelatt, J.K., et al. (1993a) Effect of topically applied demecarium bromide and echothiophate iodide on intraocular pressure and pupil size in Beagles with normotensive eyes and Beagles with inherited glaucoma. American Journal of Veterinary Research, 54, 287–293. Gum, G.G., Gelatt, K.N., & Knepper, P.A. (1993b) Histochemical localization of glycosaminoglycans in the aqueous outflow pathways in normal Beagles and Beagles with inherited glaucoma. Veterinary & Comparative Ophthalmology, 3, 52–57. Gum, G.G., Gelatt, K.N., Samuelson, D.A., et al. (1981) Evaluation of the Krupin‐Denver valve implant in

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normotensive and glaucomatous Beagles (abstract). Investigative Ophthalmology & Visual Science, 20, 24. Gum, G.G., Kingsbury, S., & Whitley, R.D. (1991a) Effect of topical prostaglandin PGA2, PGA2 isopropyl ester, and PGF2α isopropyl ester on intraocular pressure in normotensive and glaucomatous canine eyes. Journal of Ocular Pharmacology, 7, 107–116. Gum, G.G., Knepper, P.A., Collins, J.A., et al. (1986) Analysis of glycosaminoglycans in the trabecular meshwork of glaucoma and normal canine eyes. Investigative Ophthalmology & Visual Science, 27, 164. Gum, G.G., Larocca, R.D., Gelatt, K.N., et al. (1991b) The effect of topical timolol maleate on intraocular pressure in normal beagles and beagles with inherited glaucoma. Progress in Veterinary & Comparative Ophthalmology, 1, 141–150. Gum, G.G., Metzger, K.J., & Gelatt, K.N. (1993c) The tonographic effects of pilocarpine and pilocarpine‐ epinephrine in normal Beagles and Beagles with inherited glaucoma. Journal of Small Animal Practice, 34, 112–116. Gum, G.G., Samuelson, D.A., & Gelatt, K.N. (1992) Effect of hyaluronidase on aqueous outflow resistance in normotensive and glaucomatous eyes of dogs. American Journal of Veterinary Research, 53, 767–770. Guy, J., Feuer, W.J., Davis, J.L., et al. (2017) Gene therapy for Leber hereditary optic neuropathy: Low‐ and medium‐dose visual results. Ophthalmology, 124, 1621–1634. Gwin, R.M. (1982) Primary lens luxation in the dog: Associated with lenticular zonule degeneration and its relationship to glaucoma. Journal of the American Animal Hospital Association, 18, 485–491. Gwin, R.M., Gelatt, K.N., Gum, G.G., et al. (1977) The effect of topical pilocarpine on intraocular pressure and pupil size in the normotensive and glaucomatous beagle. Investigative Ophthalmology & Visual Science, 16, 1143–1148. Gwin, R.M., Gelatt, K.N., Gum, G.G., et al. (1978) Effects of topical 1‐epinephrine and dipivalyl epinephrine on intraocular pressure and pupil size in the normotensive and glaucomatous beagle. American Journal of Veterinary Research, 39, 83–86. Haefisa, I.O. & Anderson, D.R. (1996) Blood flow regulation in the optic nerve head. In: The Glaucomas: Basic Sciences (eds. Kitch, R, Shields, M.B., & Krupin, T.), 2nd ed., pp. 189–197. St. Louis, MO: Mosby. Håkanson, N.W. (1996) Extraorbital diversion of aqueous in the treatment of glaucoma in the dog: A pilot study including two recipient sites. Veterinary & Comparative Ophthalmology, 6, 82–90. Hamor, R.E., Gerding, P.A., Ramsey, D.T., et al. (2000) Evaluation of short‐term increased intraocular pressure on flash‐ and pattern‐generated electroretinograms of dogs. American Journal of Veterinary Research, 61, 1087–1091. Hardman, C. & Stanley, R.G. (2001) Diode laser transscleral cyclophotocoagulation for the treatment of primary glaucoma in 18 dogs: A retrospective study. Veterinary Ophthalmology, 4, 209– 215.

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Inman, D.M. & Horner, P.J. (2007) Reactive nonproliferative gliosis predominates in a chronic mouse model of glaucoma. Glia, 55, 942–953. Iwabe, S., Moreno‐Mendoza, N.A., Trigo‐Tavera, F., et al. (2007) Retrograde axonal transport obstruction of brain‐ derived neurotrophic factor (BDNF) and its TrkB receptor in the retina and optic nerve of American Cocker Spaniel dogs with spontaneous glaucoma. Veterinary Ophthalmology, 10(Suppl. 1), 12–19. Izquierdo, N.J., Traboulsi, E.I., Enger, C., & Maumenee, I.H. (1992) Glaucoma in the Marfan syndrome. Trans American Ophthalmological Society, 90, 111–117. Jampel, H.D. (1997) Target pressure in glaucoma therapy. Journal of Glaucoma, 6, 133–138. Jeanes, E.C., Oliver, J.A.C., Ricketts, S.L., et al. (2019) Glaucoma‐causing ADAMTS17 mutations are also reproducibly associated with height in two domestic dog breeds: Selection for short stature may have contributed to increased prevalence of glaucoma. Canine Genetic Epidemiology, 6, 5. Jiang, B., Harper, M.M., Kecova, H., et al. (2010) Neuroinflammation in advanced canine glaucoma. Molecular Vision, 16, 2092–2108. Johnsen, D.A.J., Maggs, D.J., & Kass, P.H. (2006) Evaluation of risk factors for development of secondary glaucoma in dogs: 156 cases (1999–2004). Journal of the American Veterinary Medical Association, 229, 1270–1274. Jutley, G., Luk, S.M., Dehabadi, M.H., et al. (2017) Management of glaucoma as a neurodegenerative disease. Neurodegenerative Disease Management, 7, 157–172. Källberg, M.E., Brooks, D.E., Garcia‐Sanchez, G.A., et al. (2002) Endothelin 1 levels in the aqueous humor of dogs with glaucoma. Journal of Glaucoma, 11, 105–109. Källberg, M.E., Brooks, D.E, Komáromy, A.M., et al. (2003) The effect of an L‐type calcium channel blocker on the hemodynamics of orbital arteries in dogs. Veterinary Ophthalmology, 6, 141–146. Källberg, M.E., MacKay, E.O., Rinkoski, T.A., et al. (2006) Aqueous humor myocilin and CD44 in dogs with glaucoma and cataracts (abstract). Investigative Ophthalmology & Visual Science, 47, 3385. Kanadani, F.N., Mello, P.A., Dorairaj, S.K., & Kanadani, T.C. (2014) Frequency‐doubling technology perimetry and multifocal visual evoked potential in glaucoma, suspected glaucoma, and control patients. Clinical Ophthalmology, 14(8), 1323–1330. Kanemaki, N., Tchedre, K.T., Imayasu, M., et al. (2013) Dogs and humans share a common susceptibility gene SRBD1 for glaucoma risk. PLoS One, 8(9), e74372. Kato, K., Kamida, A., Sasaki, N., et al. (2009a) Evaluation of the CYP1B1 gene as a candidate gene in beagles with primary open‐angle glaucoma (POAG). Molecular Vision, 15, 2470–2474. Kato, K., Sasaki, N., Gelatt, K.N., et al. (2009b) Autosomal recessive primary open angle glaucoma (POAG) in beagles is not associated with mutations in the myocilin (MYOC) gene.

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Oberbauer, A.M., Hollingsworth, S.R., Belanger, J.M., et al. (2008) Inheritance of cataracts and primary lens luxation in Jack Russell Terriers. American Journal of Veterinary Research, 69, 222–227. Ofri, R., Dawson, W.W., Foli, K., et al. (1993a) Chronic ocular hypertension alters local retinal responsiveness. British Journal of Ophthalmology, 77, 502–508. Ofri, R., Dawson, W.W., Foli, K., et al. (1993b) Primary open‐angle glaucoma alters retinal recovery from a thiobarbiturate: Spatial frequency dependence. Experimental Eye Research, 56, 481–488. Ofri, R., Dawson, W.W., & Gelatt, K.N. (1993c) Visual resolution in normal and glaucomatous dogs determined by pattern electroretinogram. Veterinary and Comparative Ophthalmology, 3: 111–116. Ofri, R., Raz, D., Kass, P.H., et al. (2000) The effect of 0.12% unoprostone isopropyl (Rescula) on intraocular pressure in normotensive dogs. Journal of Veterinary Medical Science, 62, 1313–1315. Ofri, R., Samuelson, D.A., Strubbe, D.T., et al. (1994) Altered retinal recovery and optic nerve fiber loss in primary open‐ angle glaucoma in the Beagle. Experimental Eye Research, 58, 245–248. Oh, A., Harman, C., Koehl, K.L., et al. (2013) Spectral‐domain optical coherence tomography of the optic nerve head in a canine model of primary open‐angle glaucoma (abstract). Investigative Ophthalmology & Visual Science, 54, 4893. Oh, A., Harman, C.D., Koehl, K., et al. (2014) Targeting of gene expression to the wildtype and ADAMTS10‐mutant canine trabecular meshwork by non‐self‐complementary AAV2 (abstract). Investigative Ophthalmology & Visual Science, 55, 5669. Okeke, C.O., Quigley, H.A., Jampel, H.D., et al. (2009) Adherence with topical glaucoma medication monitored electronically: The Travatan Dosing Aid study. Ophthalmology, 116, 191–199. Oliver, J.A., Ekiri, A., & Mellersh, C.S. (2016) Prevalence of pectinate ligament dysplasia and associations with age, sex and intraocular pressure in the Basset Hound, Flatcoated Retriever and Dandie Dinmont Terrier. Canine Genetics Epidemiology, 3, 1. doi: 10.1186/s40516‐016‐0033‐1. Oliver, J.A., Ekiri, A.B., & Mellersh, C.S. (2017) Pectinate ligament dysplasia in the Border Collie, Hungarian Vizsla and Golden Retriever. The Veterinary Record, 180(11), 279. Oliver, J.A., Forman, O.P., Pettitt, L., et al. (2015) Two independent mutations in ADAMTS17 are associated with primary open angle glaucoma in the Basset Hound and Basset Fauve de Bretagne breeds of dog. PLoS One, 10(10), e0140436. Oliver, J.A.C., Ricketts, S.L., Kuehn, M.H., & Mellersh, C.S. (2019). Primary closed angle glaucoma in the Basset Hound: Genetic investigations using genome‐wide association and RNA sequencing strategies. Molecular Vision, 25, 93–105. Oliver, J.A.C., Rustidge, S., Pettitt, L., et al. (2018) Evaluation of ADAMTS17 in Chinese Shar‐Pei with primary open‐angle

glaucoma, primary lens luxation, or both. American Journal of Veterinary Research, 79(1), 98–106. Oliver, J.A.C., Wright, H., Massidda, P.A., et al. (2020) A variant in OLFML3 is associated with pectinate ligament abnormality and primary closed‐angle glaucoma in Border Collies from the United Kingdom. Veterinary Ophthalmology, 23, 25–36. O’Reilly, A., Hardman, C., & Stanley, R.C. (2003) The use of transscleral cyclophotocoagulation with a diode laser for the treatment of glaucoma occurring post intracapsular extraction of displaced lenses: A retrospective study of 15 dogs (1995–2000). Veterinary Ophthalmology, 6, 113–119. Orgül, S., Meyer, P., & Cioffi, G.A. (1995) Physiology of blood flow regulation and mechanisms involved in optic nerve perfusion. Journal of Glaucoma, 4, 427–443. Oshima, Y., Bjerkås, E., & Peiffer, R.L. (2004) Ocular histopathologic observations in Norwegian Elkhounds with primary open‐angle closed cleft glaucoma. Veterinary Ophthalmology, 7, 185–188. Otori, Y., Shimada, S., Tanaka, K., et al. (1995) Changes of glutamate aspartate transporter (glast glut1) mRNA and its protein in rats following transient retinal ischemia (abstract). Investigative Ophthalmology & Visual Science, 36, 119. Palko, J.R., Iwabe, S., Pan, X., et al. (2013) Biomechanical properties and correlation with collagen solubility profile in the posterior sclera of canine eyes with an ADAMTS10 mutation. Investigative Ophthalmology & Visual Science, 54(4), 2685–2695. Palko, J.R., Morris, H.J., Pan, X., et al. (2016) Influence of age on ocular biomechanical properties in a canine glaucoma model with ADAMTS10 mutation. PLoS One, 11(6), e0156466. Park, S.A., Sledge, D., Monahan, C., et al. (2019) Primary angle‐closure glaucoma with goniodysgenesis in a Beagle dog. BMC Veterinary Research, 15, 75–82. Paulson, M.E., Lavach, J.D., & Severin, G.A. (1986) The effect of lens‐induced uveitis on success of extracapsular cataract extraction: A respective study of 65 lens removal in dogs. Journal of the American Animal Hospital Association, 22, 49–56. Pearl, R., Gould, D., & Spiess, B. (2015) Progression of pectinate ligament dysplasia over time in two populations of Flat‐Coated Retrievers. Veterinary Ophthalmology, 18, 6–12. Pease, M.E., McKinnon, S.J., Quigley, H.A., et al. (2000) Obstructed axonal transport of BDNF and its receptor TrkB in experimental glaucoma. Investigative Ophthalmology & Visual Science, 41, 764–774. Pease, M.E., Zack, D.J., Berlinicke, C., et al. (2009) Effect of CNTF on retinal ganglion cell survival in experimental glaucoma. Investigative Ophthalmology & Visual Sciences, 50(5), 2194–2200. Peiffer, R.L. & Gelatt, K.N. (1980) Aqueous humor outflow in Beagles with inherited glaucoma: Gross and light microscopic observations of the iridocorneal angle. American Journal of Veterinary Research, 41, 861–867.

Peiffer, R.L., Gum, G.G, Grimson, R.C., et al. (1980) Aqueous humor outflow in Beagles with inherited glaucoma: Constant pressure perfusion. American Journal of Veterinary Research, 41, 1808–1813. Petersen‐Jones, S.M. (1991) Abnormal ocular pigment deposition associated with glaucoma in the Cairn Terrier. Journal of Small Animal Practice, 32, 19–22. Petersen‐Jones, S.M., Forcier, J., & Mentzer, A.L. (2007) Ocular melanosis in the Cairn Terrier: Clinical description and investigation of mode of inheritance. Veterinary Ophthalmology, 10(Suppl. 1), 63–69. Petersen‐Jones, S.M, Mentzer, A.L., Dubielzig, R.R., et al. (2008) Ocular melanosis in the Cairn Terrier: Histopathological description of the condition, and immunohistological and ultrastructural characterization of the characteristic pigment‐laden cells. Veterinary Ophthalmology, 11, 260–268. Plummer, C.E., Koehl, K., Nussdorfer, F.D., et al. (2013) Assessment of retinal function loss in Beagles with inherited POAG using the photopic full‐field ERG. Proceedings of the 44th Annual Meeting of the American College of Veterinary Ophthalmologists, Rio Grande, Puerto Rico, November. Plummer, C.E., MacKay, E.O., & Gelatt, K.N. (2006) Comparison of the effects of topical administration of a fixed combination of dorzolamide‐timolol to monotherapy with timolol or dorzolamide on IOP, pupil size, and heart rate in glaucomatous dogs. Veterinary Ophthalmology, 9, 245–249. Polansky, J.R., Fauss, D.J., Chen, P. et al. (1997) Cellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response (TIGR) gene product. Ophthalmology, 211, 126–139. Porciatti, V. (2015) Electrophysiological assessment of retinal ganglion cell function. Experimental Eye Research, 141, 164–170. Pritchard, D.L. & Hamlet, M.P. (1970) A silastic‐dacron implant for the treatment of glaucoma. Veterinary Medicine, 65, 1191–1194. Pugh, C.A., Farrell, L.L., Carlisle, A.J., et al. (2019) Arginine to glutamine variant in olfactomedin like 3 (OLFML3) is a candidate for severe goniodysgenesis and glaucoma in the Border Collie dog breed. Genes, Genomes, Genetics, 9, 943–954. Pumphrey, S.A., Pizzirani, S., Pirie C.G., et al. (2013a) Western blot patterns of serum autoantibodies against optic nerve antigens in dogs with goniodysgenesis‐related glaucoma. American Journal of Veterinary Research, 74(4), 621–628. Pumphrey, S.A., Pizzirani, S., Pirie, C.G., et al. (2013b) Glaucoma associated with uveal cysts and goniodysgenesis in American Bulldogs: A case series. Veterinary Ophthalmology, 16, 377–385. Quigley, H.A. (1996) Neuronal death in glaucoma. Progress in Retinal and Eye Research, 18, 39–57. Quigley, H., Sanchez, R., & Dunkelberger, G., (1987) Chronic glaucoma selectively damages large optic nerve fibers. Investigative Ophthalmology & Visual Science, 28, 913–920.

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Section IIIA: Canine Ophthalmology

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Wilcock, B.P. & Peiffer, P.L. (1986) Morphology and behavior of primary ocular melanomas in 91 dogs. Veterinary Pathology, 23, 418–424. Wilkie, D.A. & Latimer, C.A. (1991) Effects of topical administration of timolol maleate on intraocular pressure and pupil size in dogs. American Journal of Veterinary Research, 52, 432–435. Wilkinson, C.H., van der Straaten, D., Craig, J.E., et al. (2003) Tonography demonstrates reduced facility of outflow of aqueous humor in myocilin mutation carriers. Journal of Glaucoma, 12, 237–242. Williams, L.W., Gelatt, K.N., Gum, G.G., et al. (1983) Orthograde rapid axoplasmic transport and ultrastructural changes of the optic nerve. Part I. Normotensive and acute ocular hypertensive Beagles. Glaucoma, 5, 117–128. Willis, M.B., Barnett, K.C., & Tempest, W.M. (1979) Genetic aspects of lens luxation in the Tibetan Terrier. Veterinary Record, 104, 409–412. Wilson, M.R. (1994) Glaucoma: The common pathway to blindness. Journal of Glaucoma, 3, 165–183. Winkler, P.A., Bartoe, J.T., Quinones, C.R., et al. (2013) Exclusion of eleven candidate genes for ocular melanosis. Journal of Negative Results in Medicine, 12, 6. Wolde‐Mussie, E., Yoles, E., Schwartz, M., et al. (2002) Neuroprotective effect of memantine in different retinal injury models in rats. Journal of Glaucoma, 11, 474–480. Wood, J.L.N., Lakhanim, K.H., Mason, I.K., et al. (2001) Relationship of the degree of goniodysgenesis and other ocular measurements to glaucoma in Great Danes. American Journal of Veterinary Research, 62, 1493–1499. Wood, J.L.N., Lakkhani, K.H., & Read, R.A. (1998) Pectinate ligament dysplasia and glaucoma in Flat Coated Retrievers. II. Assessment of prevalence and heritability. Veterinary Ophthalmology, 1, 91–99. Wright, K.W. & Chrousos, G.A. (1985) Weill‐Marchesani syndrome with bilateral angle‐closure glaucoma. Journal of Paedeatric Ophthamology and Strabismus, 22(4), 129–132.

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SECTION IIIA

20: The Canine Glaucomas

i1

Index Page locators in bold indicate tables. Page locators in italics indicate figures. This index uses letter‐by‐letter alphabetization. 1–2–3 snip technique  995, 996 180‐degree conjunctival flap see hood conjunctival flap 180‐degree graft see advancement graft 360‐degree conjunctival flap see total conjunctival flap 360‐degree graft see complete bulbar graft AAP see angular aqueous plexus ABC see ATP‐binding cassette aberrant dermis  1056–1057 ABK see acute bullous keratopathy abscesses canine corneal diseases  1127–1128 canine orbital diseases  887, 892–896, 894–897 computed tomography  671 diagnostic ultrasound  747, 753 equine ophthalmology  1904–1910, 1905, 1907–1910 exotic mammals  2220 food animal neuro‐ophthalmic diseases  2305 food animal systemic disease with ocular manifestations  2559 New World camelid ophthalmology  2095 ocular pathology  504–505 rabbit  2139 reptiles  2212–2214 ACAID see anterior chamber‐associated immune deviation Acanthamoeba spp.  692 accommodation avian ophthalmology  2056–2057 equine ophthalmology  1843 optics and physiology of vision  175–178, 175, 177 reptiles  2209–2210 retinoscopy  598 static accommodation  183–184, 183 under water  187–188, 187–189 visual acuity  244–246

acellular subepithelial stromal layer (ASL)  509, 509 acepromazine  565–566 acetazolamide  458–459 acetylcholine  134, 208 achiasmatic optic nerve canine neuro‐ophthalmic diseases  2274–2276, 2276 canine optic nerve diseases  1639 feline neuro‐ophthalmic diseases  2295 achromatopsia  1477, 1499, 1521–1522 acid burns  1121 acid‐fast granulomatous keratitis  1722 Acinebacter spp.  316 acquired disorders bovine ophthalmology  2014, 2014–2015 canine nasolacrimal diseases  1000–1003, 1001–1003 canine neuro‐ophthalmic diseases  2279–2288, 2280–2281, 2284 canine optic nerve diseases  1641–1655, 1642, 1643–1644, 1645–1646, 1648–1655 canine orbital diseases  892–905 canine vitreous diseases  1466–1472, 1469–1471 choroidal disorders  521–522, 522 conjunctival disorders  506–508, 507–508 corneal disorders  508–513, 509–513 equine neuro‐ophthalmic diseases  2299–2304, 2302 equine ophthalmology  1946–1947 equine systemic disease with ocular manifestations  2499–2520, 2501–2503, 2509–2510, 2515, 2518 feline anterior uvea diseases  1736–1738, 1736–1737 feline neuro‐ophthalmic diseases  2290–2296, 2294–2295, 2297 feline optic nerve and CNS diseases  1788–1790, 1790

feline orbital diseases  1791–1794, 1791–1794 feline posterior segment diseases  1774 feline systemic disease with ocular manifestations  2428–2469 food animal neuro‐ophthalmic diseases  2305–2310 food animal systemic disease with ocular manifestations  2540–2559, 2543, 2545, 2547–2549, 2551–2552, 2554–2556, 2558 glaucoma  525–530, 527, 528, 529 infectious inflammatory ocular disease  531, 531–532, 532 lacrimal gland disorders  506, 506 lens luxation/subluxation  525, 525 lenticular disorders  522–525, 524 metabolic diseases that affect the eye  530, 530 New World camelid ophthalmology  2093–2094, 2098, 2101–2102 noninfectious inflammatory ocular disease  503–506, 503, 504–505 ocular pathology  502–552 ovine and caprine ophthalmology  2030 porcine ophthalmology  2035–2036 retinal disorders  517–520, 518–520 scleral and episcleral disorders  513–514, 513–514 storage disorders, amino acid, and lipid peroxidation disorders  522, 523 uveal disorders  514–517, 514–518 vitreous disorders  518–522, 521 see also individual disorders; neoplasia Acremonium spp. canine ocular fundus diseases  1532 canine systemic disease with ocular manifestations  2359 feline ocular surface disease  1722–1723 acridine orange  706 ACTH see adrenocorticotropic hormone acupuncture  1028

i2

Index

acute bullous keratopathy (ABK)  1728–1729, 1728 acute fluid misdirection syndrome  1406 acute intraoperative rock‐hard eye syndrome  1406 acyclovir  403–404, 1709 ADAM9 mutations  1512 ADAMTS2 mutations  2536 ADAMTS10 mutations canine glaucomas  1183–1192, 1200–1207, 1213, 1215–1218 canine optic nerve diseases  1624–1625 ADAMTS17 mutations canine glaucomas  1189–1192, 1200–1201, 1207, 1211, 1214–1215 canine lens diseases and cataract formation  1353–1354, 1355–1356 surgical procedures on the canine lens  1431 adaptive/antigen‐specific immune response immunogenetics  268 manipulating the response  269–270 nature of the antigen  268 ocular immunology  263–264, 266–270 ocular surface adaptive immune response  271–272, 272 other immune reactions  268 ramping up the response  268–269 shutting down the response  269 T‐helper subsets  267–268 tissue where response initiates  268 adaptive optics (AO)  696–697 adenocarcinoma bovine ophthalmology  1986 canine anterior uvea diseases  1299 canine corneal diseases  1150 canine eyelid disorders  973, 974 canine lacrimal secretory system diseases  1034–1035 canine nictitating membrane diseases  1068 canine orbital diseases  890 diagnostic ultrasound  747 feline anterior uvea diseases  1763–1764, 1763 feline nictitating membrane diseases  1689 feline ocular surface disease  1700, 1700 ocular pathology  533, 548–549, 549 adenoma canine anterior uvea diseases  1295–1296, 1295 canine conjunctival diseases  1053 canine eyelid disorders  973, 974 canine lacrimal secretory system diseases  1034–1035 canine nictitating membrane diseases  1068, 1068 canine orbital diseases  902

diagnostic ultrasound  752 ocular pathology  487, 534–535, 536, 548–549, 549 adhesions  491, 492 Adies pupil  2286 adnexa general ocular examination  574–577, 576 laboratory sampling  610 miniature pig  2140–2141 nonhuman primates  2143 photography  852, 854 rabbit  2136 slit‐lamp biomicroscopy  583 adrenoceptors  454–457 adrenocorticotropic hormone (ACTH)  128, 2346–2347 advancement graft  1061 AEV see avian encephalomyelitis virus AFM see atomic force microscopy African horse sickness virus (AHSV)  305, 2513–2514 African swine fever (ASF)  2549 agar‐disk‐diffusion test  310, 311 agar‐gel immunodiffusion (AGID)  2360, 2364 age and aging canine anterior uvea diseases  1263–1264, 1264 canine glaucomas  1198 canine lens diseases and cataract formation  1318–1319, 1328, 1328–1330, 1339, 1339, 1354–1356, 1354 canine optic nerve diseases  1624–1625 canine orbital diseases  880, 882 canine vitreous diseases  1460 equine ophthalmology  1960–1961 ocular physiology  150–151 ophthalmic anatomy  78–79, 106 specular microscopy  689 tonometry  628 age‐related cataracts (ARC)  1339, 1339, 1348, 1946 age‐related macular degeneration (AMD)  285, 2144, 2150–2151, 2155 age‐related retinal degeneration  2125 AGID see agar‐gel immunodiffusion AH see aqueous humor AHSV see African horse sickness virus AIR see autoimmune retinopathies akinesia  567–568, 567, 1382 albinism avian ophthalmology  2059 bovine ophthalmology  2012, 2016, 2016 canine systemic disease with ocular manifestations  2330–2331 equine systemic disease with ocular manifestations  2495 feline anterior uvea diseases  1734

feline neuro‐ophthalmic diseases  2288–2289, 2288 feline systemic disease with ocular manifestations  2421–2422 food animal systemic disease with ocular manifestations  2535 ovine and caprine ophthalmology  2031 albuminoids  1330 alcelaphine herpesvirus‐1 (AlHV‐1)  306 aldose reductase inhibitors (ARI)  1348 algal diseases see fungal and algal diseases AlHV‐1 see alcelaphine herpesvirus‐1 alkaline injuries  1121 alkaloid toxicity  494 allergic blepharitis canine eyelid disorders  971–972, 972 equine ophthalmology  1874 feline eyelid diseases  1676–1678, 1677 allergic conjunctivitis anti‐inflammatory agents  422 canine conjunctival diseases  1049, 1049 feline ocular surface disease  1697–1698 food animal systemic disease with ocular manifestations  2541 allergic dermatitis  2348 alloimmune hemolytic anemia of foals  2500 α2‐adrenergic agonists  454–455, 1228 Alternaria spp.  322–323 alternative splicing  780 amacrine cells ophthalmic anatomy  101–102, 102 optics and physiology of vision  201, 201–202, 208 amaurosis  2104 amblyopia  239, 2278 AMD see age‐related macular degeneration ametropia  178–182, 178, 243–244 amikacin  391 amino acid disorders  522, 523, 2335 aminoglycosides  390–391 amiodarone toxicity  1142–1143, 2390 amlodipine  1240, 1786 amniotic membrane transplantation (AMT)  844, 1901–1902 amoxicillin  386–387 amphibians exotic animal ophthalmology  2206–2209 ocular disorders and lesions  2207–2209, 2208 ophthalmic anatomy  2206–2207, 2206–2207 ophthalmic examination  2207 amphotericin B  396–397, 2363 ampicillin  386–387 AMT see amniotic membrane transplantation ANA see antinuclear antibodies

Index

analgesia anti‐inflammatory agents  422 general ocular examination  568–571, 569 surgical procedures on the canine lens  1382 anangiotic retina  2193–2194, 2194 Anaplasma spp. canine ocular fundus diseases  1530–1531 canine systemic disease with ocular manifestations  2373 clinical microbiology and parasitology  318 equine systemic disease with ocular manifestations  2513 Ancylostoma spp.  330, 2366–2367 androgen deficiency  1010–1011 anemia canine conjunctival diseases  1057–1058 canine systemic disease with ocular manifestations  2342 equine systemic disease with ocular manifestations  2500 feline neuro‐ophthalmic diseases  2292 feline systemic disease with ocular manifestations  2429–2430 food animal systemic disease with ocular manifestations  2540 anemic retinopathy  301, 1786 anesthesia canine eyelid disorders  926 canine orbital diseases  905–907, 906 clinical pharmacology and therapeutics  438–441 examination after topical anesthetic application  610, 611 general ocular examination  565–566, 568–571, 569 microsurgery  794–795 nasolacrimal flush  636 paracentesis  638 surgical procedures on the canine lens  1382 tear tests  609 tonography  630 tonometry  627 angiography canine ocular fundus diseases  1479, 1480 canine optic nerve diseases  1632–1633 laboratory animal ophthalmology  2149–2150 New World camelid ophthalmology  2088 angioinvasive pulmonary carcinoma  707 angiokeratoma  1052 Angiostrongylus spp. canine ocular fundus diseases  1538

canine systemic disease with ocular manifestations  2365 clinical microbiology and parasitology  328 angular aqueous plexus (AAP) equine ophthalmology  1937–1938 ocular physiology  142–143 ophthalmic anatomy  61, 61, 76–77 anidulafungin  402 aniridia canine anterior uvea diseases  1262, 1262 equine ophthalmology  1851 anisocoria general ocular examination  572, 572 neuro‐ophthalmology  2250–2254, 2253, 2271–2272, 2273–2275 anisometropia  177, 599 ankyloblepharon canine eyelid disorders  929–930, 931 feline eyelid diseases  1666 anophthalmos canine orbital diseases  888 exotic mammals  2219 feline neuro‐ophthalmic diseases  2294 guinea pig  2128–2130, 2190 mouse and rat  2118–2119 ocular embryology and congenital malformations  20–22, 20, 21, 22 ocular pathology  493 reptiles  2211–2212 anorexia  2360 anterior blind spot  237 anterior capsular fibrosis  1406 anterior capsular tears  1406–1407, 1407 anterior capsular wrinkling  1372, 1396–1397, 1401 anterior capsulotomy  850 anterior chamber (AC) canine glaucomas  1186–1189, 1204, 1231–1235, 1231, 1233–1234 diagnostic ultrasound  748, 749 general ocular examination  576 indirect ophthalmoscopy  596 laboratory animal ophthalmology  2112–2113, 2113 ocular drug delivery  360 ocular embryology and congenital malformations  15, 16 ocular pathology  491 ocular physiology  145–146 photography  839, 841 slit‐lamp biomicroscopy  583–584, 585 surgical procedures on the canine lens  1372, 1405–1406 anterior chamber‐associated immune deviation (ACAID) afferent and efferent T regulatory cells produced  276–277 canine lens diseases and cataract formation  1350

characteristics  274–275 corneal transplantation  278–279 limited lymphatic drainage and tight vascular junctions  275 molecular and physiological basis  275 ocular APC traffic to thymus and spleen  276 ocular immunology  268, 273–279 ocular pathology  488 ocular tissues influence resident APCs  275–276, 276 anterior epithelium  85–86, 86 anterior segment confocal scanning laser ophthalmoscopy  696–697, 697 diagnostic ultrasound  741 exotic mammals  2219 fluorescein angiography  707–708, 709–711 general ocular examination  577 miniature pig  2140–2141 New World camelid ophthalmology  2097–2098, 2097, 2098–2099 nonhuman primates  2143–2144 optical coherence tomography  697– 704, 699–701, 703 photography  847 rabbit  2134 scanning laser polarimetry  697, 697 slit‐lamp biomicroscopy  581, 586 anterior segment dysgenesis (ASD) canine anterior uvea diseases  1263 equine ophthalmology  1853, 1854 feline anterior uvea diseases  1735 ocular embryology and congenital malformations  11, 21, 23–26, 25–28 ocular pathology  482, 484, 497–498, 497, 501, 502 anterior stromal puncture (ASP)  1101, 1103 anterior uvea avian ophthalmology  2069–2071, 2070–2071 bovine ophthalmology  2011–2013, 2012 feline anterior uvea diseases  1732–1764 mouse and rat  2122 porcine ophthalmology  2035, 2035 rabbit  2137 anterior uveitis canine systemic disease with ocular manifestations  2370, 2370 causes of feline uveitis  1740–1755, 1740–1741, 1742–1746, 1748, 1751–1752 classification of uveitis  1739 clinical features of feline uveitis  1738– 1739, 1739 clinical microbiology and parasitology  300

i3

i4

Index

anterior uveitis (cont’d) equine ophthalmology  1891, 1903, 1925, 1926 feline anterior uvea diseases  1738–1756 feline glaucomas  1766, 1767 New World camelid ophthalmology  2098, 2099 photography  841, 843, 848 slit‐lamp biomicroscopy  581, 583 systemic evaluation  1739–1740 treatment  1755–1756 anterior vitrectomy  1463–1464 antibacterial agents alteration of folate metabolism  393–394 bactericidal/bacteriostatic classification  385, 386 canine corneal diseases  1119–1120 canine lacrimal secretory system diseases  1026–1027 clinical microbiology and parasitology  309 clinical pharmacology and therapeutics  385–396 disruption of cell membrane  388–390 general principles of therapy  385 inhibition of cell wall synthesis  386–388, 389 interruption of DNA synthesis  394–396 interruption of protein synthesis  390–393 antibiotics/antimicrobials antimicrobial peptides  271 antimicrobial susceptibility tests  310–311 bovine ophthalmology  1998–2000 canine systemic disease with ocular manifestations  2356–2358, 2388–2389 equine ophthalmology  1860–1862, 1890–1891 feline ocular surface disease  1720–1721 feline systemic disease with ocular manifestations  2466–2468, 2467 food animal systemic disease with ocular manifestations  2556 surgical procedures on the canine lens  1381, 1382, 1421 anticoagulant rodenticide toxicity  2392–2393, 2392 antifibrin drugs  1229–1230 antifungal agents azoles  399–402 canine anterior uvea diseases  1280 canine corneal diseases  1120–1121 canine lens diseases and cataract formation  1340 clinical pharmacology and therapeutics  396–402

general principles of therapy  396 medications used to treat keratomycosis  398 polyenes  396–397 pyrimidines  397 antigen‐presenting cells (APC)  264–282, 276 antihypertensive drugs  1340 anti‐inflammatory agents canine anterior uvea diseases  1274–1276 canine lacrimal secretory system diseases  1027 clinical pharmacology and therapeutics  417–425 corticosteroids  417–421, 418 feline anterior uvea diseases  1752, 1755–1756 feline glaucomas  1768–1769 feline ocular surface disease  1715 nonsteroidal anti‐inflammatory drugs  421–425 surgical procedures on the canine lens  1377, 1380–1381, 1419 antimetabolite therapy  270–271 antimitotic therapy  270 antinuclear antibodies (ANA)  2348, 2434–2435 antioxidants  1347–1348 antiviral agents clinical pharmacology and therapeutics  402–405 feline ocular surface disease  1706–1711, 1708, 1710, 1756 general principles of therapy  402 APC see antigen‐presenting cells aperture  816–817, 816, 823–826, 830 aphakia canine glaucomas  1218–1220, 1219 canine lens diseases and cataract formation  1320 ocular pathology  501–502, 502 optics and physiology of vision  180–182, 181 retinoscopy  599 aplasia  482–483, 484, 500 aplasia palpebrae  930–931 apoptosis  484–485, 487 apraclonidine  455, 1228 aquaporins  149 aqueous flare  1270–1271, 1271 aqueous humor (AH) canine anterior uvea diseases  1270–1272, 1271–1272 canine glaucomas  1173, 1185–1190, 1196, 1202, 1205–1206, 1210, 1214–1216, 1220–1230 composition  140–141 equine ophthalmology  1883, 1886, 1936–1937, 1937–1942 fluid dynamics  143–146, 143, 145 formation  139, 140

intraocular pressure  138–139, 143–148, 147–148 measurement of aqueous dynamics  145–146, 145 New World camelid ophthalmology  2097 ocular physiology  130–131, 138–148 ocular rigidity  146 ophthalmic anatomy  70–71, 76–77, 77 outflow  142, 142, 143, 144 regulation  141–142, 144 structural and biomechanical attributes  142–143 aqueous misdirection  1221 aqueous outflow  2134 aqueous paracentesis  637–639, 639 arachidonic acid derivatives  1268 ARC see age‐related cataracts arcus lipoides corneae  1730 area centralis  190, 248 ARI see aldose reductase inhibitors arsanilic acid  2556 arthritis  2356 artifacts diagnostic ultrasound  738, 738 optics and physiology of vision  179 artifactual consensual response  2058 ascorbic acid  149–150 ASD see anterior segment dysgenesis ASF see African swine fever ASL see acellular subepithelial stromal layer ASP see anterior stromal puncture Aspergillus spp. antifungal agents  396–397, 399–402 bovine ophthalmology  1993 canine anterior uvea diseases  1281 canine lens diseases and cataract formation  1345 canine ocular fundus diseases  1532 canine systemic disease with ocular manifestations  2359 clinical microbiology and parasitology  322–323 equine systemic disease with ocular manifestations  2507 feline systemic disease with ocular manifestations  2441, 2441 in vivo confocal microscopy  693 New World camelid ophthalmology  2101 asteroid hyalosis canine vitreous diseases  1462, 1469, 1469 diagnostic ultrasound  744 ocular pathology  520–521, 521 astigmatism optics and physiology of vision  182–183, 182 retinoscopy  599 surgical procedures on the canine lens  1410–1411, 1411

Index

astrocytes  104, 106–107 astrocytoma  550–551, 550, 1553 atmospheric perspective  1842 atomic force microscopy (AFM)  131, 133 atonic pupil  1431 ATP‐binding cassette subfamily A4 (ABCA4)  196, 1521 ATP‐binding cassette subfamily G2 (ABCG2) transporter  352, 2467 atropine canine anterior uvea diseases  1276, 1280, 1291 canine lacrimal secretory system diseases  1014–1015 clinical pharmacology and therapeutics  437 feline anterior uvea diseases  1756 tear tests  607–608 atypical uveal melanoma  1759, 1759 Aujeszky’s disease canine systemic disease with ocular manifestations  2378 food animal neuro‐ophthalmic diseases  2308–2309 food animal systemic disease with ocular manifestations  2552 auriculopalpebral nerve block clinical pharmacology and therapeutics  440 equine ophthalmology  1845–1846, 1845 general ocular examination  567–568, 567 autofluorescence (AF)  1523 autogenous lamellar corneal grafts  1113–1115, 1114 autoimmune disease equine ophthalmology  1929 ocular immunology  270, 280–285 autoimmune retinopathies (AIR)  284 autologous serum  442 autorefractors  179–180 autosomal chromosomes  778 autosomal dominant inheritance  781–782 autosomal recessive inheritance  781, 785 avian encephalomyelitis virus (AEV)  308 avian influenza virus (H5N1/2)  1048 avian ophthalmology  2055–2084 anterior uvea  2069–2071, 2070–2071 bony orbit  2065 cataracts  2059, 2062–2064, 2063, 2071 conjunctiva  2056, 2068, 2068 cornea  2056, 2068–2069, 2069–2070 degenerative diseases  2063–2064, 2063 developmental malformations  2059, 2066, 2067 enucleation and evisceration  2073 eyelids  2055, 2067–2068 eyes of raptors  2066 glands of the raptor orbit  2065

inflammation and infections  2059– 2063, 2060–2061 lens  2056–2057, 2071 neoplasia  2064, 2071 nonraptor species  2057–2065 ophthalmic anatomy  2055–2057, 2056–2057 ophthalmic examination and normative values  2057–2059, 2065 posterior segment  2058, 2071–2073, 2072–2073 raptors  2065–2074 release recommendations  2073–2074 restraint  2065 tear quantification  2059, 2067 tonometry and glaucoma  2058–2059, 2066–2067 traumatic injury  2065, 2067, 2071 vitamin A deficiency  2064 avian poxvirus  308 avulsion trauma  1648–1649 axial cataracts  1946 azalide  1542 azathioprine  1154 azithromycin  392–393 azoles  399–402 BAB see blood–aqueous barrier Babesia spp. canine conjunctival diseases  1057 clinical microbiology and parasitology  327 equine systemic disease with ocular manifestations  2511–2512 Bacillus Calmette–Guérin (BCG)  1877, 1879, 2010 bacitracin  388, 389 bacterial infections amphibians  2207 anti‐inflammatory agents  420 avian ophthalmology  2060–2061, 2067–2068 bovine ophthalmology  1988 canine anterior uvea diseases  1284–1285 canine conjunctival diseases  1047, 1047, 1057 canine corneal diseases  1088, 1088, 1117–1118, 1119, 1129–1131, 1129–1130, 1141, 1141 canine eyelid disorders  968–969, 969 canine ocular fundus diseases  1530–1532 canine systemic disease with ocular manifestations  2355–2359, 2355, 2357 classification and mechanism of injury  308–309 clinical microbiology and parasitology  308–319 commensal ocular surface flora  311, 312

diagnostic methods  309–311, 309–311 equine ophthalmology  1859–1860, 1887–1893, 1897, 1900 equine systemic disease with ocular manifestations  2504–2507 exotic mammals  2220–2221 feline anterior uvea diseases  1749–1751 feline eyelid diseases  1666, 1676, 1678 feline ocular surface disease  1718–1722 feline orbital diseases  1791, 1791 feline posterior segment diseases  1783 feline systemic disease with ocular manifestations  2435–2440, 2437, 2439–2440 fish  2204 fluorescein angiography  712 food animal systemic disease with ocular manifestations  2542–2545, 2543, 2545 laboratory sampling  612, 615 New World camelid ophthalmology  2092–2094 ocular immunology  279–280 ovine and caprine ophthalmology  2024 pathogenic anaerobic bacteria  319 pathogenic gram‐negative aerobic bacteria  314–316 pathogenic gram‐positive aerobic bacteria  313–314 pathogenic obligate intracellular bacteria  316–319, 317 reptiles  2212–2214, 2213–2214 small mammal ophthalmology  2180–2182 surgical procedures on the canine lens  1381, 1418–1421 see also antibacterial agents; individual bacteria/diseases bacteriostatic preservatives  353 BAER see brainstem auditory‐evoked response band keratopathy  1137, 1137 Barraquer fine/microneedle holders  802, 810 Barraquer wire eyelid speculums  800 barrier retinopexy  1586–1588, 1587 Bartonella spp. antibacterial agents  392–393 canine anterior uvea diseases  1285 canine ocular fundus diseases  1531 canine systemic disease with ocular manifestations  2355, 2355 clinical microbiology and parasitology  315 feline anterior uvea diseases  1749–1750 feline systemic disease with ocular manifestations  2435–2436 basal cell carcinoma  1683

i5

i6

Index

basal cells  55, 56 Baum’s bumps  738 BBS4 mutations  1509 BCG see Bacillus Calmette–Guérin BCSE see bilateral convergent strabismus with exophthalmos Bdellovibrio bacteriovorus therapy  2000–2001 BDNF see brain‐derived neurotrophic factor behavioral testing  1477, 1502 Bennett’s cilia forceps  611 bent cartilage  1064, 1064 Berger’s space  92 Besnoitia spp.  2547, 2547–2548 BEST1 mutations  1497–1498 beta‐blockers canine glaucomas  1228 clinical pharmacology and therapeutics  455–457 feline glaucomas  1769 surgical procedures on the canine lens  1415 BHV‐1 see bovine herpesvirus type‐1 BHV‐4 see bovine herpesvirus type‐4 Bigelback procedure  954, 958 bilateral convergent strabismus with exophthalmos (BCSE)  1985, 2304–2305, 2304 bilateral granulomatous anterior uveitis  2291–2292 bilateral optic nerve atrophy (BOA)  2144 biliary fever  2511–2512 bimanual microincisional phacoemulsification (B‐MICS)  1398 bimatoprost  461–466, 462 binocular vision avian ophthalmology  2066 equine ophthalmology  1841–1842 fish  2201 fundamentals of animal vision  235, 237 New World camelid ophthalmology  2086 bioadhesion  365 biomaterial grafts  1721, 1722 biometry  735–736 biomicroscopy canine lens diseases and cataract formation  1317, 1319, 1321, 1339, 1345–1346, 1351 surgical procedures on the canine lens  1377 see also slit‐lamp biomicroscopy biopsy canine conjunctival diseases  1058 canine lacrimal secretory system diseases  1021 canine orbital diseases  888, 900 computed tomography  670–671 ocular pathology  482, 507

bipolar cells ophthalmic anatomy  101–102 optics and physiology of vision  196–201, 199–201, 206–208 birth trauma bovine ophthalmology  1991, 1991 equine ophthalmology  1862, 1863 Bishop‐Harmon forceps  811–812 Blaskovics K‐S modification  949–951, 951–952 blastocyst  3, 6 Blastomyces spp. antifungal agents  401 canine anterior uvea diseases  1279–1280, 1280 canine ocular fundus diseases  1532–1533, 1532 canine orbital diseases  891, 895 canine systemic disease with ocular manifestations  2359–2361 clinical microbiology and parasitology  323 diagnostic ultrasound  746 feline systemic disease with ocular manifestations  2441–2442 blepharitis allergic blepharitis  1676–1678, 1677 avian ophthalmology  2067 bacterial blepharitis  1676 bovine ophthalmology  1988 canine eyelid disorders  968–972, 969–972 equine ophthalmology  1857, 1859, 1872–1874, 1874 feline eyelid diseases  1671–1678, 1672, 1673–1674, 1677–1678 fungal blepharitis  1671–1673, 1673 immune‐mediated blepharitis  1676, 1677 miscellaneous blepharitis  1678, 1678 New World camelid ophthalmology  2091 nonhuman primates  2143 ovine and caprine ophthalmology  2024–2025 parasitic blepharitis  1673–1675, 1673 porcine ophthalmology  2035 protozoal blepharitis  1675–1676 rabbit  2135, 2182, 2183 slit‐lamp biomicroscopy  581 viral blepharitis  1674, 1675 blepharitis adenomatosa  971 blepharoconjunctivitis  2060, 2060 blepharophimosis  956, 959–960 blepharostenosis  956, 959–960 blind spots  1841 blind staggers  2519 blink reflex avian ophthalmology  2058, 2067 canine ocular fundus diseases  1478 corneal esthesiometry  600

feline eyelid diseases  1665 general ocular examination  573 general ocular features, lesions and diseases  2134 neuro‐ophthalmology  2257–2258 ocular drug delivery  355 ocular physiology  124–125, 125–126, 129, 131–132 tear film imaging  682 blood–aqueous barrier (BAB) canine anterior uvea diseases  1259, 1266–1271, 1273–1275, 1277 clinical pharmacology and therapeutics  453–454, 466–467 laser fluorophotometry and laser flare cell meters  704–705 ocular drug delivery  350–352, 351, 373 ocular physiology  138, 140–141, 145 blood flow  1195–1196 blood–retinal barrier (BRB) ocular drug delivery  350–352, 351, 373 ocular physiology  138 blood‐staining method  940, 940 blood–vitreous barrier (BVB)  152 blue eye  2379, 2552 bluetongue virus bovine ophthalmology  1985 clinical microbiology and parasitology  307 food animal systemic disease with ocular manifestations  2549 ovine and caprine ophthalmology  2024 blunt trauma avian ophthalmology  2071, 2072 canine anterior uvea diseases  1288 canine lens diseases and cataract formation  1345–1346 canine vitreous diseases  1468 feline anterior uvea diseases  1751–1752, 1752 BLV see bovine leukemia virus B‐MICS see bimanual microincisional phacoemulsification body/head position  627–628 body length  629 bone lysis  669, 670 bony orbit  2065, 2090, 2090 bony spicules  2193, 2193 Bordetella spp.  1696–1697 Borna disease clinical microbiology and parasitology  305 equine neuro‐ophthalmic diseases  2299 equine systemic disease with ocular manifestations  2514 Borrelia spp. antibacterial agents  388, 391 canine ocular fundus diseases  1531 canine systemic disease with ocular manifestations  2355–2356

Index

clinical microbiology and parasitology  316 equine systemic disease with ocular manifestations  2504 Borzoi chorioretinopathy  521, 522 botulism canine systemic disease with ocular manifestations  2356 clinical microbiology and parasitology  319 equine systemic disease with ocular manifestations  2504–2505 food animal systemic disease with ocular manifestations  2542 bovine herpesvirus type‐1 (BHV‐1)  306 bovine herpesvirus type‐4 (BHV‐4)  2549–2550 bovine leukemia virus (BLV)  307, 2550 bovine malignant catarrhal fever  515, 515 bovine ophthalmology  1983–2021 conjunctiva and cornea  1990–2010, 1990–1991, 1993, 1995–1996, 1998–1999, 2004–2008 eyelids  1987–1989, 1988–1989, 2008 glaucoma  1999, 2010–2011, 2011–2012 lens  2013–2015, 2013–2015 nasolacrimal system  1989–1990, 1990 neoplasia  1986–1987, 1989, 1989, 2002–2010, 2004–2008, 2013 ocular examination and ophthalmic parameters  1983, 1984 ocular fundus  2015–2020, 2015–2020 optic nerve  2020–2021, 2021 orbit and globe  1983–1987, 1984–1987 uveal tract  2011–2013, 2012 bovine papillomavirus (BPV)  307, 2004 bovine parturient paresis  2306, 2553 bovine‐specific ophthalmia  2541 bovine viral diarrhea (BVD)  307, 2305, 2550 Bowman’s layer  59, 59 BPV see bovine papillomavirus brachytherapy  1875–1877 bracken fern poisoning  2305–2306, 2557–2558, 2558 brain  2238–2240, 2239–2245, 2246–2247 brain abscess  2305, 2559 brain‐derived neurotrophic factor (BDNF)  1195 brainstem auditory‐evoked response (BAER)  2086 Branhamella spp.  316, 2028 Braund’s syndromes  2265–2268, 2265, 2266–2269 BRB see blood–retinal barrier breeding programs see selective breeding breed‐related multifocal chorioretinitis  1538–1539, 1539 bridge graft  1061 bright blindness  2305–2306, 2557–2558, 2558

brimonidine tartrate  455, 1228 brinzolamide  459–461 brow‐sling procedure  965, 966 Brucella spp. canine anterior uvea diseases  1284–1285 canine ocular fundus diseases  1531–1532 canine systemic disease with ocular manifestations  2356–2358, 2357 clinical microbiology and parasitology  316 bulbar pedical graft  1060, 1060–1061 bullous emphyema  2306, 2559 bullous keratopathy canine corneal diseases  1138–1139, 1138 equine ophthalmology  1920–1921, 1921 ocular pathology  511 bullous pemphigus  2503 buphthalmic glaucoma  601 buphthalmos  2011, 2208 bupivacaine  569–570, 906–907 butorphanol  566 BVB see blood–vitreous barrier BVD see bovine viral diarrhea C2orf71 mutations  1509–1510 CA see carbonic anhydrase CAI see carbonic anhydrase inhibitors calcific band keratopathy  1919–1920, 1920 calcific degeneration  509, 511, 1135–1136, 1136 calcineurin inhibitors  442–443 calcitonin gene‐related peptide (CGRP)  134, 277 calcium channel blockers (CCB)  466–467 CALT see conjunctiva‐associated lymphoid tissue camelids see New World camelid ophthalmology cAMP see cyclic adenosine monophosphate canalicular atresia  995–997, 998 canalicular misplacement  997, 999 canalicular obstruction  998 canal of Schlemm  76–77, 142–143 cancer‐associated retinopathy (CAR)  1549 Candida spp. antifungal agents  396–397, 399–402 avian ophthalmology  2061, 2061 feline systemic disease with ocular manifestations  2442 ocular pathology  532 canine adenovirus type‐1 (CAV‐1) canine anterior uvea diseases  1284 canine systemic disease with ocular manifestations  2378–2380, 2379 clinical microbiology and parasitology  304

canine adenovirus type‐2 (CAV‐2)  304–305, 1284 canine anterior uvea diseases  1259–1316 algal diseases  1285, 1285 aniridia and iris hypoplasia  1262, 1262 bacterial diseases  1284–1285 color variants  1259–1260, 1260 congenital disorders  1261–1263 degenerative iridal changes  1263–1265 developmental disorders  1259–1263, 1260–1262 ehrlichiosis  1283–1284 hyperlipidemia  1285–1286 hyperviscosity syndrome  1287 hyphema  1272, 1272, 1291–1292, 1298 inflammation/uveitis  1264–1285, 1266–1267, 1269, 1270–1273, 1300 lens‐induced uveitis  1277–1278, 1277 manifestations of selected diseases  1277–1287 mycoses‐associated uveitis  1279–1281, 1280 neoplasia  1293–1299, 1294–1295, 1298 non‐neoplastic iridal proliferations  1292–1293, 1292–1293 parasitic diseases  1282 persistent pupillary membranes  1260–1262, 1261 Peters anomaly  1262 pigmentary and cystic glaucoma  1286–1287, 1286 protozoal diseases  1282–1283 Rocky Mountain spotted fever  1284 secondary iris atrophy  1264 secondary to corneal, scleral, and periocular disease  1278 senile iris atrophy  1263–1264, 1264 solid intraocular xanthogranuloma in Miniature Schnauzer  1287 sulfonamide hypersensitivity  1287 surgical procedures  1299–1303, 1301–1302 trauma  1277–1278, 1287–1290, 1289 uveal cysts  1263–1265, 1264–1265 uveodermatologic syndrome  1278– 1279, 1278 viral diseases  1284 canine conjunctival diseases  1045–1062 anatomic abnormalities  1056–1057 conjunctival and subconjunctival hemorrhage  1055, 1055 conjunctivitis associated with tear deficiencies  1050–1051 cysts  1055 dermoids  1053–1054, 1054 effects of radiation therapy  1058, 1058 foreign bodies  1055, 1056 functional anatomy and physiology  1045 general response to disease  1046–1047

i7

i8

Index

canine conjunctival diseases (cont’d) infectious conjunctivitis  1047–1049, 1047–1048 inflammatory masses  1053, 1053–1054 ligneous conjunctivitis  1051, 1051 microscopic anatomy  1045–1046 neoplasia  1051–1053, 1051–1052, 1058 noninfectious conjunctivitis  1049–1050, 1049–1050 nonneoplastic conjunctival masses  1053–1055, 1053–1054 normal bacterial and fungal flora  1046 normal cytology  1046 orbital disease  1056, 1056 parasitic granulomas  1054–1055 pharmacologic research  1058 subconjunctival fat prolapse  1054, 1054 surgical procedures  1058–1062, 1059–1062 systemic disease  1057–1058, 1057 vascular supply and innervation  1046 canine corneal diseases  1082–1153 anatomy and pathophysiology  1082–1091 corneal clarity/transparency  1085 corneal edema  1090–1091, 1090 corneal opacities  1094–1096, 1095, 1131–1148, 1132, 1133–1147 corneal pigmentation  1089–1090, 1089–1090 corneal vascularization  1091, 1092, 1098, 1100, 1101 corneoscleral masses and neoplasms  1148–1153, 1148–1152 crystalline corneal opacities  1131–1137, 1132, 1133–1137 dermoids  1092–1094, 1093–1095 developmental and congenital disorders  1091–1096, 1093–1095 inflammatory keratopathies  1096–1131 limbal colobomas and staphylomas  1096 megalocornea  1092 metabolic and connective tissue disorders  1096 microcornea  1091–1092 non‐crystalline corneal opacities  1137–1143, 1137–1143 non‐inflammatory keratopathies  1131–1143 nonulcerative keratitis  1123–1131, 1124–1125, 1128–1131 review of corneal anatomy  1082–1085, 1083–1084, 1084 scleral diseases  1153–1155, 1153–1155 surgery for corneal opacities  1143–1148, 1144–1147 ulcerative keratitis  1096–1123, 1097–1099, 1101–1110, 1112–1121, 1123 wound healing  1085–1089, 1088

canine cyclic thrombocytopenia  2373 canine distemper virus (CDV) canine conjunctival diseases  1048 canine neuro‐ophthalmic diseases  2279–2280, 2280 canine ocular fundus diseases  1528–1530 canine systemic disease with ocular manifestations  2375–2377, 2376–2377 clinical microbiology and parasitology  303–304 canine eyelid disorders  923–987 ankylohlepharon  929–930, 931 congenital and presumed inherited disorders  929–965 dermoids and dysplasia palpebrae  931–932, 932 distichiasis and conjunctival ectopic cilia  932–935, 933–934 ectropion and oversized palpebral fissure  946–956, 948–959 entropion  935–945, 936–946 eyelid coloboma or aplasia  930–931 inflammation  968–971, 969–971 inflammatory masses  972 lagophthalmos  968 lid trauma  965–968 microblepharon, blepharophimosis, or blepharostenosis  942, 956, 959–960 miscellaneous eyelid procedures  977–980 neoplasia  972–974, 973, 974 osteoma cutis  931 other eyelid diseases  971–972, 972 permanent tarsorrhaphy  978, 982 postoperative care  929, 943–944, 956, 968, 979–980 principles of lid surgery  925–929, 926–931 ptosis  968 reconstructive blepharoplasty  974–977, 975–981 redundant skin folds around the eye  964–965 structure and function of the eyelid  923–925, 924 temporary tarsorrhaphy  977–978 trichiasis  956–964, 960–965 trichomegaly  964 canine glaucomas  1173–1255 anterior chamber angle  1186–1189 choroid and tapetum cellulosum  1189–1190 ciliary body  1189 ciliary cleft  1199–1200, 1211 classification of the glaucomas  1177–1178, 1177 clinical signs  1178–1179, 1179 congenital glaucomas  1225, 1225 cornea  1186 definition of glaucoma  1173

diagnostic procedures  1177–1178, 1179–1185 ECM–AH outflow pathways  1185–1190 electroretinography and visual‐evoked potentials  1183–1185 epidemiology and signalment  1174–1176, 1174–1176, 1197–1215 American Cocker Spaniel  1209–1210, 1209 Basset Hound  1210–1211, 1210 Beagle  1201–1206, 1202–1204 Border Collie  1214 Boston Terrier  1211 Bouvier des Flandres  1211 Cairn Terrier  1222–1223, 1223 Chow  1211–1212 English Cocker Spaniel  1212 English Springer Spaniel  1212 Flat‐coated Retriever  1212 Golden Retriever  1223–1224, 1224 Great Dane  1212–1213 Miniature and Toy Poodle  1213 Norwegian Elkhound  1206–1207 other breeds  1207, 1214–1215 Petit Basset Griffon Vendéen  1207 Samoyed  1213–1214 Shar‐Pei  1214 Shiba Inu  1213 Siberian Husky  1214 Welsh Springer Spaniel  1214 gene and stem cell therapy  1239 genetics  1183, 1185, 1187–1190, 1198–1201 globe size  1186 gonioscopy  1177–1178, 1181–1182, 1181, 1203, 1209–1210 high‐resolution ultrasonography and ultrasound biomicroscopy  1177–1179, 1182–1183, 1188, 1211, 1215 inflammation  1196–1197 intraocular neoplasms  1224, 1225 iris  1189 lens  1190, 1200–1201, 1206–1207, 1214–1220 medical therapy for IOP control  1226–1230, 1227, 1238–1239 neuroprotection and neuroregeneration  1239–1240 new developments in glaucoma therapy  1238–1240 ocular perfusion pressure  1189, 1195–1196 ophthalmoscopy  1182 optic nerve head  1173, 1179, 1182, 1186, 1189–1196, 1191, 1194 pectinate ligament dysplasia  1177–1178, 1181–1182, 1187, 1197–1198 primary glaucomas  1174–1215, 1174–1176

Index

progression of primary open‐angle glaucoma  1202 provocative tests  1185 retina  1192–1197, 1194 sclera  1186 scleral laminal cribrosa  1185–1186, 1190–1192, 1191 secondary glaucomas  1174–1176, 1215–1225, 1215–1216, 1217 staging of primary angle‐closure glaucoma  1207–1209, 1208 structural and functional effects of elevated IOP  1185–1197 surgical therapy for IOP control  1230–1238, 1231, 1231, 1233–1234, 1236–1237, 1239 target, safe, and diurnal IOP  1226 tonography  1183, 1184, 1211 tonometry  1177–1178, 1180–1181 vitreous  1190 canine heartworm disease  2365 canine herpesvirus (CHV) antiviral agents  402–403 canine conjunctival diseases  1047–1048, 1048 canine corneal diseases  1118–1120, 1120 canine ocular fundus diseases  1530 canine systemic disease with ocular manifestations  2377–2378 clinical microbiology and parasitology  302–303 canine idiopathic granulomatous disease  2345 canine lacrimal secretory system diseases  1008–1044 cysts, foreign bodies, and neoplasia  1033–1035, 1034 formation and dynamics of tear components  1008–1013, 1009–1013 keratoconjunctivitis sicca  1013–1019, 1014, 1015–1016, 1017–1018, 1022, 1027–1033 medical treatment of tear film deficiencies  1021–1029, 1022–1024, 1025–1026, 1027–1028 pathogenesis of tear film disease  1013–1014 qualitative tear abnormalities  1019– 1021, 1020–1021, 1027–1029 surgical treatment of tear film deficiencies  1029–1033, 1029, 1030–1031, 1033 canine lens diseases and cataract formation  1317–1370 acquired lens abnormalities  1328– 1347, 1328–1332, 1334–1336, 1339, 1342, 1344 anatomy and physiology  1317 aphakia  1320

classification of canine cataracts  1328, 1328–1330 colobomas  1320–1321, 1321 complications of untreated cataracts  1349–1351, 1351 congenital lens abnormalities  1319– 1328, 1320–1321, 1323, 1324, 1325 dietary deficiencies  1345 embryonic vascular abnormalities  1322–1326, 1323, 1324, 1325 epidemiology and signalment  1322–1327, 1323, 1325, 1333–1339, 1334–1336, 1353–1354, 1355–1356 histopathologic changes and cataract formation  1331–1332, 1331–1332 infectious diseases  1345 intraocular diseases  1341–1342 lens‐induced uveitis  1349–1350 lens luxation/subluxation  1326, 1341–1342, 1351–1358, 1352–1354, 1355–1356 lenticonus/lentiglobus  1321–1322, 1321 medical treatment of cataracts  1347–1349 medications, toxic substances, and external agents  1340–1341 microphakia and spherophakia  1320, 1320, 1324 normal findings according to age  1318–1319 nuclear sclerosis  1350–1351, 1351 pathophysiological changes and cataract formation  1328–1331 primary acquired cataracts  1333–1339, 1334–1336, 1339 primary congenital cataracts  1326–1327 secondary acquired cataracts  1340– 1347, 1342, 1344 secondary congenital cataracts  1328 special techniques for lens examination  1317–1318, 1318–1319 systemic ion disturbances  1342, 1342 systemic metabolic diseases  1342– 1345, 1344 trauma  1345–1347 visual consequences of cataracts  1349 see also surgical procedures on the canine lens canine multifocal retinopathy (CMR)  1497–1498, 1497–1498 canine nasolacrimal diseases  988–1007 acquired diseases  1000–1003, 1001–1003 anatomy  988, 989 atresia of the canaliculus, nasolacrimal sac, and nasolacrimal duct  995–997, 998

canaliculi obstruction  998 clinical manifestations  990, 990 congenital diseases  994–1000, 995–1000 dacryocystitis and foreign bodies  990, 990, 1001–1002, 1002 dacryolithiasis  1002–1003 developmental disorders  998–1000, 1000 diagnostic procedures  990–994, 991–993 embryology  988, 989 lacerations  1000–1001, 1001 micropunctum  995, 996–997 nasolacrimal duct obstruction  998 neoplasia of the nasolacrimal duct  1003, 1003 physiology  988–990 puncta and canaliculi misplacement  997, 999 punctal atresia  994–995, 995–996 canine neuro‐ophthalmic diseases  2274–2288 acquired disorders  2279–2288, 2280–2281, 2284 congenital disorders  2274–2278, 2276–2277 developmental disorders  2278–2279 canine nictitating membrane diseases  1062–1071 anatomy, histology, and function  1062– 1063, 1063 anomalous, congenital, and developmental disorders  1064, 1064 bent cartilage  1064, 1064 inflammatory conditions  1068–1070, 1070 miscellaneous diseases  1070 neoplasia  1051–1052, 1068, 1068–1069 prolapse of the nictitans gland  1064– 1067, 1065–1067 protrusion of the nictitating membrane  1067–1068 surgical procedures  1070–1071, 1071 surgical repositioning  1065–1067, 1066–1067 trauma, reconstruction, and foreign bodies  1070 canine ocular fundus diseases  1477–1574 algal diseases  1536, 1536 bacterial diseases  1530–1532 behavioral testing  1477 developmental disorders  1485–1498 development/maturation of the canine fundus  1485, 1485 examination methods  1477–1482 functional testing of the retina  1479–1482, 1481 fungal diseases  1532–1535, 1532, 1534 immunologic disease  1549

i9

i10

Index

canine ocular fundus diseases (cont’d) inflammation and infections affecting the ocular fundus  1527–1528, 1528–1529 inherited retinal degenerations  1498–1519, 1500–1502, 1504–1506, 1507–1509, 1511, 1514–1518 lysosomal storage diseases  1525–1527, 1526 nontapetal fundus  1483–1484, 1500 normal ocular fundus  1482–1485, 1483–1485 nutritional retinopathies and supplementation  1545–1547, 1546 optic nerve head  1478–1479, 1482, 1484, 1484 other retinal dystrophies  1519–1525, 1520, 1523–1524 parasitic diseases  1537–1538 peripheral cystoid retinal degeneration  1552, 1552 proliferative and neoplastic conditions  1552–1556, 1553–1555 protozoal diseases  1536–1537 reflexes and responses  1477–1478 retinal toxicities  1542–1545, 1543–1544 retinal vasculature  1484–1485 retinoschisis  1552 secondary retinal degeneration  1549– 1552, 1550–1552 specific retinopathies  1538–1542, 1539, 1541–1542 structural visualization of the fundus  1478–1479, 1479–1480 tapetal fundus  1482–1483, 1499–1500 vascular disease  1547–1549, 1547–1548 viral diseases  1528–1530 canine ocular gliovascular syndrome (COGS)  744, 1651–1652 canine optic nerve diseases  1622–1661 acquired disorders  1641–1655, 1642, 1643–1644, 1645–1646, 1648–1655 clinical examination of the optic nerve  1628–1633, 1629–1635 congenital disorders  1637–1640, 1638–1641 diagnostic imaging  1633–1637, 1636–1637 intracanalicular optic nerve  1628 intracranial optic nerve and optic chiasm  1628 intraocular optic nerve  1623–1626, 1623–1626 intraorbital optic nerve  1627–1628, 1628 structure and function of the optic nerve  1622–1628, 1623–1626, 1628 canine orbital diseases  879–922 acquired orbital diseases  892–905 ancillary diagnostic tests  880–888, 893 anophthalmos  888

clinical signs/examination  879–880, 881–883 computed tomography  883–888, 884, 889, 893–905, 894–895, 898, 905 congenital anomalies of the orbit and globe  888–892 cystic eye, microphthalmia, and nanophthalmia  889–890 diagnostic ultrasound  882–883, 884–888, 894–896, 894–895, 899 fine needle aspiration and tissue biopsy  882, 888, 900 inflammatory lesions: cellulitis/ abscess  892–896, 894–897 magnetic resonance imaging  883–888, 886–887, 890, 893–905 miscellaneous lesions  904–905 myositis  897–900, 897–900 neoplasia  883, 888, 888–890, 900–902, 901, 911–914 ophthalmic anatomy  879, 880 orbital cysts  891–892 radiography  884 salivary retention cysts and mucoceles/ sialoceles  896–897 surgery of the globe and the orbit  905–914, 906, 908–915 traumatic lesions  902–904, 903–904 vascular anomalies  890–891, 892 canine papillomavirus (CPV)  305, 2380 canine posterior segment surgery  1575–1621 anatomic considerations  1575–1578, 1576–1578 demarcation and barrier retinopexy  1586–1588, 1587 endoscopic pars plana vitrectomy  1608–1609, 1609 factors responsible for retinal detachment  1578–1583, 1579–1580, 1582 pneumatic retinopexy  1585–1586 prophylactic retinopexy  1583–1585, 1584–1585 retinal prosthesis  1611–1612, 1613 subretinal injection  1612–1614, 1613–1614 success of retinal detachment repair  1610–1611, 1611 surgical equipment  1590–1591, 1591–1596 transconjunctival sutureless vitrectomy  1605–1608 types of retinal detachment  1578 vitrectomy for giant retinal tears  1588–1589, 1589–1590 vitreoretinal surgical (23‐gauge) technique  1599–1605, 1600–1605 vitreous substitutes  1591–1599, 1597–1598, 1601–1604, 1604–1605, 1606–1609, 1609

canine systemic disease with ocular manifestations  2330–2420 acquired disorders  2341–2393 algal diseases  2353–2354, 2354 bacterial infections  2355–2359, 2355, 2357 cardiovascular diseases  2341–2342, 2341 hematologic diseases  2342–2345, 2344 idiopathic systemic diseases  2345–2347 immune‐mediated diseases  2347–2353, 2348–2349, 2352–2353 metabolic diseases  2380–2385, 2382–2383 mycotic diseases  2359–2364, 2363–2364 neoplasia  2385–2386, 2386 nutritional disorders  2386–2388, 2387–2388 parasitic diseases  2364–2372, 2366, 2370 Rickettsial diseases  2372–2375, 2374–2375 toxicities  2388–2393, 2389–2390, 2392 viral infections  2375–2380, 2376–2377, 2379, 2381 congenital disorders  2330–2334 coat color‐related diseases/conditions  2330–2331 dwarfism  2331–2332, 2332 Ehlers–Danlos syndrome  2332–2333 hydrocephalus  2333, 2333 keratoconjunctivitis sicca and ichthyosiform dermatosis  2333–2334, 2334 quadriplegia and amblyopia  2334 developmental disorders  2334–2340 amino acid disorders  2335 fucosidosis  2335–2337 galactocerebrosidosis  2337–2338 GM1‐/GM2‐gangliosidosis  2338 inborn errors of metabolism  2334–2335 lysosomal storage diseases  2335, 2336–2337 mucopolysaccharidosis  2339 neuronal ceroid lipofuscinosis  2339–2340, 2340 canine vitreous diseases  1459–1476 acquired disorders  1466–1472, 1469–1471 aging  1460 degenerative disorders  1468 developmental disorders  1464–1466, 1464–1466, 1467 development and anatomy  1459–1460 diagnostic procedures  1460–1463, 1461–1463 medical treatment  1463

Index

other ophthalmic disorders  1462, 1472, 1472 physiology  1460 surgical treatment  1463–1464 cannabis derivatives  1229 cannulation nasolacrimal flush  636, 636 small mammal ophthalmology  2181, 2182 canthus  925 capecitabine  1143 capsular tension ring (CTR)  1409, 1426–1428, 1432–1435, 1434, 1434 capsulorhexis/capsulectomy equine ophthalmology  1949 surgical procedures on the canine lens  1372, 1394–1397, 1395–1397, 1402, 1402, 1406–1408 CAR see cancer‐associated retinopathy carbachol  452, 1228 carbamate inhibitors  452–453 carbamate insecticides  2557 carbohydrate metabolism  524 carbonic anhydrase (CA)  139 carbonic anhydrase inhibitors (CAI) adverse effects  460–461 canine glaucomas  1218–1222, 1227–1229 clinical pharmacology and therapeutics  457–461 clinical use  460 feline glaucomas  1769 mechanism of action  457–458, 458 surgical procedures on the canine lens  1415–1416 systemic administration  458–459 topical administration  459–460 carbopols  365 carcinoma fluorescein angiography  707 magnetic resonance imaging  678–679, 679 see also individual types carcinoma in situ  2004, 2005, 2006 cardiovascular diseases canine systemic disease with ocular manifestations  2341–2342, 2341 feline systemic disease with ocular manifestations  2428–2429, 2428–2429 carnitine  150 carotenoids  1348, 1546–1547 Carter sphere introducer  800 cartilage eversion  1688 caruncular trichiasis  962, 964, 1056–1057 caspofungin  401–402 Castroviejo calipers  800 cataracts acquired or secondary cataracts  1946–1947 age‐related cataracts  1946

amphibians  2208 anti‐inflammatory agents  420 avian ophthalmology  2059, 2062–2064, 2063, 2071 bovine ophthalmology  2013–2015, 2013–2015 canine anterior uvea diseases  1260–1262, 1274, 1277 canine glaucomas  1218–1221, 1219 canine lens diseases and cataract formation  1317–1318, 1326–1351, 1357 canine ocular fundus diseases  1495, 1500–1501, 1502 canine posterior segment surgery  1579, 1600 canine systemic disease with ocular manifestations  2383, 2383 canine vitreous diseases  1461 classification of canine cataracts  1328, 1328–1330 clinical classification  1945 complications of untreated cataracts  1349–1351, 1351 degu  2196, 2197 developmental cataracts  1944–1946 diagnostic ultrasound  742, 742–743 dietary deficiencies  1345 equine ophthalmology  1850, 1854– 1855, 1856, 1943, 1944–1951, 1945, 1950, 1961 equine systemic disease with ocular manifestations  2518–2519 exotic mammals  2220, 2222–2223, 2222 feline lens diseases and cataract formation  1770–1773, 1770–1772 feline systemic disease with ocular manifestations  2461–2463, 2462 ferret  2195, 2195 fish  2203–2205 general ocular examination  577 general ocular features, lesions and diseases  2138 guinea pig  2132, 2190–2191, 2191, 2193, 2194 heritability of equine cataracts  1946 histopathologic changes and cataract formation  1331–1332, 1331–1332 infectious diseases  1345 intraocular diseases  1341–1342 lens luxation  1357 medical treatment  1347–1349 medications, toxic substances, and external agents  1340–1341 microsurgery  799 mouse and rat  2123 New World camelid ophthalmology  2100, 2103 nonhuman primates  2143–2144

ocular embryology and congenital malformations  26, 29–30 ocular pathology  486, 491, 500, 501, 523–525, 524 optics and physiology of vision  180–181 ovine and caprine ophthalmology  2030 pathophysiological changes and cataract formation  1328–1331 photography  840, 842, 858 porcine ophthalmology  2036 prepurchase ophthalmic examination  1961 primary acquired cataracts  1333–1339, 1334–1336, 1339 primary congenital cataracts  1326–1327, 1850, 1854–1855, 1856 rabbit  2186–2188, 2188 reptiles  2215–2216, 2215 secondary acquired cataracts  1340–1347, 1342, 1344 secondary congenital cataracts  1328 slit‐lamp biomicroscopy  585, 587, 588, 589–590 special techniques for lens examination  1317–1318, 1318–1319 specular microscopy  689 systemic ion disturbances  1342, 1342 systemic metabolic diseases  1342– 1345, 1344 trauma  1345–1347 visual consequences  1349 cataract surgery equine ophthalmology  1947–1951, 1950 feline lens diseases and cataract formation  1773 long‐term results  1951 patient positioning  1948 patient selection  1947–1948 postoperative considerations  1951 preoperative preparation  1948 surgical preparation  1949 techniques and surgical approach  1948, 1949–1951, 1950 see also phacoemulsification; surgical procedures on the canine lens cat bags  565 caterpillar trauma  966 cats see feline CAV‐1 see canine adenovirus type‐1 CAV‐2 see canine adenovirus type‐2 cavernous sinus syndrome  2269, 2272, 2385 cavitation bubbles  1410, 1410 CBM see ciliary body musculature CC see congenital cataracts CCB see calcium channel blockers CCC see continuous curvilinear capsulorhexis/capsulotomy CCD see charge‐couple devices

i11

i12

Index

CCDC66 mutations  1510 CCDD see congenital cranial dysinnervation disorder CCT see central corneal thickness CD44  1206 CDV see canine distemper virus CEA see Collie eye anomaly cellular retinaldehyde‐binding protein (CRALBP)  1929 cellulitis canine conjunctival diseases  1056 canine orbital diseases  883, 892–896, 894–897 canine systemic disease with ocular manifestations  2348, 2348 diagnostic ultrasound  744 equine ophthalmology  1868–1869, 1868 ocular pathology  504–505 reptiles  2213 Celsus–Hotz procedure  933, 935, 938–939, 939, 942–943, 943–946 central blindness feline optic nerve and CNS diseases  1790 food animal systemic disease with ocular manifestations  2559 ovine and caprine ophthalmology  2033 central corneal thickness (CCT) canine corneal diseases  1082–1084 optical coherence tomography  696 pachymetry  685–686 central nervous system (CNS) canine optic nerve diseases  1629–1630, 1653–1654 canine systemic disease with ocular manifestations  2350, 2355, 2361–2363, 2385 equine systemic disease with ocular manifestations  2517 feline optic nerve and CNS diseases  1788–1790, 1790 feline systemic disease with ocular manifestations  2463 neuro‐ophthalmology  2237–2238, 2238, 2262, 2285, 2295, 2300–2301, 2307 cephalosporins  387–388 cerebellar syndrome  2267–2268, 2268 cerebral hemorrhagic infarcts  675, 675 cerebral hypoxia  2294 cerebral syndrome  2266, 2266 cerebrocortical necrosis  2307, 2553–2554 cerebrospinal fluid (CSF) canine optic nerve diseases  1626, 1628, 1643–1644, 1647, 1653–1654 canine systemic disease with ocular manifestations  2333, 2333, 2350, 2363–2364, 2371–2372 clinical microbiology and parasitology  304

magnetic resonance imaging  674–676, 677 neuro‐ophthalmology  2239–2240, 2240 cerebrovascular accidents (CVA)  2280, 2341 ceroid lipofuscinosis  2538 cervical syndrome  2268, 2269 cervicothoracic syndrome  2268, 2269 CEUS see contrast‐enhanced ultrasonography CF see complement‐fixation CFF see critical flicker frequency cGMP see cyclic guanosine monophosphate CGRP see calcitonin gene‐related peptide chalazion  971 charge‐couple devices (CCD)  821, 823–824 Chédiak–Higashi syndrome (CHS) feline anterior uvea diseases  1733, 1733 feline neuro‐ophthalmic diseases  2290 feline systemic disease with ocular manifestations  2421 food animal systemic disease with ocular manifestations  2535–2536, 2536 chemical cautery  1901 chemical keratitis canine corneal diseases  1121–1122, 1121 equine ophthalmology  1893–1894 chemical trauma  965–966 chemokines  267 chemosis  1049, 1049 chemotherapy canine anterior uvea diseases  1299 canine corneal diseases  1149–1150 canine systemic disease with ocular manifestations  2372 equine ophthalmology  1877, 1879 feline eyelid diseases  1683 cherry eye  1064–1065, 1065–1067 chiggers  2509 chinchilla  2193–2194 chip and flip technique  1400 Chlamydia spp. bovine ophthalmology  1993–1994 clinical microbiology and parasitology  316–318, 317 exotic mammals  2220 feline eyelid diseases  1666 feline ocular surface disease  1689–1694, 1691 feline systemic disease with ocular manifestations  2436–2438, 2437 food animal systemic disease with ocular manifestations  2542–2543, 2543 ovine and caprine ophthalmology  2025–2026

Chlamydophila spp. antibacterial agents  391–393 bovine ophthalmology  1993–1994 clinical microbiology and parasitology  316–318, 317 ovine and caprine ophthalmology  2025–2026 chloramphenicol  393, 1276 chlorhexidine  1421 chloroquine  1544 chlorpromazine  1091 cholesterolosis bulbi  521 cholesteryl esters  126–127 cholinergic agonists (miotics) adverse effects  453–454 canine glaucomas  1227–1228 canine lacrimal secretory system diseases  1021–1022, 1022 clinical pharmacology and therapeutics  451–454 clinical use  453 direct‐acting parasympathomimetics  452 indirect‐acting parasympathomimetics  452–453 mechanism of action  451–453 cholinergic antagonists  435–436 chondroitin sulfates  58–59, 92 choriocapillaris  83, 84–85, 84 choriocapillary atrophy  708 chorioretinal colobomas  714 chorioretinitis canine ocular fundus diseases  1527–1528, 1528–1529, 1531–1532, 1538–1539, 1539 clinical microbiology and parasitology  303, 305 diagnostic ultrasound  744, 746 equine ophthalmology  1862, 1954–1955, 1954–1955 feline posterior segment diseases  1782–1783, 1782 fluorescein angiography  708 chorioretinopathy  1955–1956, 1955 choristoma  23, 25 see also dermoids choroid canine glaucomas  1189–1190 choriocapillaris  83, 84–85, 84 diagnostic ultrasound  741, 743, 746, 747–748, 748, 751 feline posterior segment diseases  1774–1788, 1774–1777, 1779–1782, 1784–1785, 1787–1788 fish  2201–2203 large‐vessel layer  80–81, 81, 109–110 medium‐sized vessel and tapetum layer  81–84, 82–84, 83 ocular drug delivery  360, 369 ocular embryology and congenital malformations  18

Index

ocular pathology  521–522, 522 ocular physiology  137 ophthalmic anatomy  79–85, 80–84, 83 optics and physiology of vision  177 suprachoroidea  79–80, 79–80 choroidal hypoplasia canine ocular fundus diseases  1486–1487, 1487 ocular embryology and congenital malformations  22, 24 ocular pathology  498 choroidal melanoma  1554, 1554–1555 choroidal neoplasia  544, 546 choroidal neovascularization (CNV)  2151, 2155, 2155–2156 choroiditis  487, 1528 chromatic aberrations  185–187, 186, 1843 chromatic defocus  1843 chromodacryorrhea  2120 chromophores  193, 205–206, 205–206 chronic keratitis  427 chronic lymphoplasmacytic uveitis  491 chronic stromal keratitis  297 chronic superficial keratitis (CSK) canine corneal diseases  1088, 1125–1127, 1125 cause  1126 diagnosis and differential diagnosis  1126 epidemiology and signalment  1125–1126 histopathologic features  1126 ocular pathology  513, 513 treatment  1126–1127 chronic uveitis  1357 CHS see Chédiak–Higashi syndrome CHV see canine herpesvirus CIC see corneal incision contracture cicatrization  1020 cidofovir  403, 1707–1709 cilia canine eyelid disorders  924, 932–935, 933–935 canine ocular fundus diseases  1509–1512, 1511 feline eyelid diseases  1670, 1671 ocular pathology  498–500 ciliary adenoma  487 ciliary body canine anterior uvea diseases  1259, 1295–1296, 1295 canine glaucomas  1189 equine ophthalmology  1942 fish  2201–2202 New World camelid ophthalmology  2097 ocular drug delivery  350, 357, 359 ocular embryology and congenital malformations  13–14, 16–17 ophthalmic anatomy  67–72, 67–73 vasculature  72, 73

ciliary body musculature (CBM) ophthalmic anatomy  70–78, 70–72 optics and physiology of vision  175–177, 175 ciliary body neoplasia feline anterior uvea diseases  1764 magnetic resonance imaging  678, 678 ocular pathology  548–549, 549 ciliary cleft (CC) canine glaucomas  1199–1200, 1211 equine ophthalmology  1937–1938 general ocular examination  576 gonioscopy  630–636, 631–635 ocular pathology  525–527 ophthalmic anatomy  70, 71 slit‐lamp biomicroscopy  588–589 ciliary flush  1269 ciliary hypoplasia  484, 501–502 ciliary neurotrophic factor (CNTF)  1240, 1522 circadian rhythm  629 cisplatin  1877, 1879 Cladosporium spp.  322–323 clarithromycin  393 clindamycin  393 clinical microbiology and parasitology  293–348 bacteriology  308–319 fungal and algal diseases  319–324 parasitic diseases  327–330 protozoal diseases  324–327 virology  293–308 clinical pharmacology and therapeutics antibacterial agents  385–396 antifungal agents  396–402 anti‐inflammatory agents  417–425, 418 antiviral agents  402–405 calcium channel blockers  466–467 carbonic anhydrase inhibitors  457–461, 458 cholinergic agonists (miotics)  451–454 drugs acting on adrenoceptors  454–457 immunosuppressant drugs  425–427 local anesthetics  438–441 medical therapy for glaucoma  451–478 mydriatics/cyclopegics  435–438, 436 new directions  469–470 ocular drug delivery  349–384 ocular inflammation  417 osmotic agents  467–469 prostaglandin analogues  461–466, 462, 464, 469–470 tear substitutes and stimulators  441–444 closantel  1542 Clostridium spp. antibacterial agents  388 canine systemic disease with ocular manifestations  2356, 2358–2359

clinical microbiology and parasitology  319 equine systemic disease with ocular manifestations  2504–2505, 2507 feline systemic disease with ocular manifestations  2439–2440 food animal systemic disease with ocular manifestations  2542, 2545 CMOS see complementary metal oxide semiconductor CMR see canine multifocal retinopathy CNGA1 mutations  1507–1508, 1509 CNGA3 mutations  1521–1522 CNGB1 mutations  1507–1508, 1509 CNGB3 mutations  1521–1522 CNTF see ciliary neurotrophic factor Coccidioides spp. antifungal agents  401 canine anterior uvea diseases  1280–1281 canine systemic disease with ocular manifestations  2361–2362 clinical microbiology and parasitology  323 feline systemic disease with ocular manifestations  2442–2443, 2444 Cochet–Bonnet esthesiometer  599–600, 600 COGS see canine ocular gliovascular syndrome COL1A2 mutations  1199 COL2A1 mutations  1468 COL9A2 mutations  1494–1496 COL9A3 mutations  1494–1496 COL11A1 mutations  1468 Colibri utility forceps  811–812 collagen canine glaucomas  1192 ocular physiology  129, 131, 132, 148, 151 ophthalmic anatomy  56–59, 57, 107–108 collagen cross‐linking (CXL)  374, 1122–1123, 1721, 1901 collagen fibrils  1085 collagenolysis equine ophthalmology  1891–1892 ocular pathology  509, 510, 520, 521 collagen shields  366 Collie eye anomaly (CEA) canine ocular fundus diseases  1485–1489, 1487–1489 canine optic nerve diseases  1639–1640, 1640–1641 canine posterior segment surgery  1581–1582, 1582 canine vitreous diseases  1466 ocular embryology and congenital malformations  22, 24–25, 25 ocular pathology  498

i13

i14

Index

colobomas bovine ophthalmology  2016–2017, 2017 canine anterior uvea diseases  1260, 1260, 1262 canine corneal diseases  1096 canine eyelid disorders  930–931 canine lens diseases and cataract formation  1320–1321, 1321 canine ocular fundus diseases  1487, 1488, 1489 canine optic nerve diseases  1639–1640, 1640–1641 equine ophthalmology  1852–1853, 1853, 1855, 1857, 1857 exotic mammals  2219–2220 feline anterior uvea diseases  1735–1736, 1736 feline optic nerve and CNS diseases  1788, 1790 fluorescein angiography  714 mouse and rat  2119 New World camelid ophthalmology  2100–2101 ocular embryology and congenital malformations  22, 22–25, 25, 33, 33 ocular pathology  483, 484, 494–495, 496, 501–502 ovine and caprine ophthalmology  2024, 2024 porcine ophthalmology  2036 colobomatous syndrome  1774, 1774 color Doppler optical coherence tomography  704 color opponent cells  240–241 color space  822 color vision equine ophthalmology  1843–1844, 1843 fundamentals of animal vision  239–241, 239, 240, 241 complement  269 complementary metal oxide semiconductor (CMOS) sensors  821, 823 complement‐fixation (CF) test  321 complete bulbar graft  1061–1062, 1062 complete congenital cataracts  1946 complete incision superficial keratectomy  1093, 1094 complete/total retinal dysplasia  1493–1494 complex traits  782 computed tomography (CT)  665–671 basic principles and physics  665–666 canine nasolacrimal diseases  993–994, 993 canine optic nerve diseases  1633–1635, 1636–1637 canine orbital diseases  883–888, 884, 889, 893–905, 894–895, 898, 905 canine vitreous diseases  1461

contrast studies  666–667 dacrycystorhinography  665, 670, 673 equine ophthalmology  1852, 1865– 1867, 1865–1866, 1869 feline systemic disease with ocular manifestations  2441 neuro‐ophthalmology  2250–2253 orbital CT  667–670, 668, 670–672 percutaneous biopsy guidance  670–671 three‐dimensional CT  667, 667 concentric cortical lamination  1942 confocal microscopy  2151 confocal photomicrography  1130 confocal scanning laser ophthalmoscopy (cSLO) anterior segment and retinal imaging  696–697, 697 canine optic nerve diseases  1632, 1633 fluorescein angiography  714 future directions  716 congenital blindness  1984, 2019, 2034 congenital cataracts (CC) bovine ophthalmology  2013–2014 canine lens diseases and cataract formation  1326–1328 equine ophthalmology  1854–1855, 1856 exotic mammals  2220, 2222, 2222 New World camelid ophthalmology  2103 ovine and caprine ophthalmology  2030 porcine ophthalmology  2036 congenital cranial dysinnervation disorder (CCDD)  2276–2277 congenital deafness  2276, 2422 congenital disorders avian ophthalmology  2059 bovine ophthalmology  1983–1985, 1984, 1990–1991, 1990–1991, 2011–2013, 2012, 2016–2018 canine anterior uvea diseases  1261–1263 canine corneal diseases  1091–1096, 1093–1095 canine eyelid disorders  929–965 canine glaucomas  1225, 1225 canine lens diseases and cataract formation  1319–1328, 1320–1321, 1323, 1324, 1325 canine nasolacrimal diseases  994–1000, 995–1000 canine neuro‐ophthalmic diseases  2274–2278, 2276–2277 canine nictitating membrane diseases  1064 canine optic nerve diseases  1637–1640, 1638–1641 canine orbital diseases  888–892 canine systemic disease with ocular manifestations  2330–2334, 2332–2334

canine vitreous diseases  1461 defective organogenesis  493–495, 494–496 defective tissue differentiation  495–502, 496–497, 499–502 equine neuro‐ophthalmic diseases  2296–2299, 2298 equine ophthalmology  1849–1857, 1849–1854, 1856–1857 equine systemic disease with ocular manifestations  2495–2499, 2496–2499 feline anterior uvea diseases  1734–1736, 1735–1736 feline eyelid diseases  1665–1668, 1666–1668 feline glaucomas  1764–1765, 1765 feline lens diseases and cataract formation  1770–1771, 1770 feline neuro‐ophthalmic diseases  2288–2290, 2288–2290 feline optic nerve and CNS diseases  1788, 1790 feline orbital diseases  1791 feline posterior segment diseases  1774 feline systemic disease with ocular manifestations  2421–2423 ferret  2195 food animal neuro‐ophthalmic diseases  2304 food animal systemic disease with ocular manifestations  2535–2538, 2536–2537 general ocular features, lesions and diseases  2135 guinea pig  2128–2130, 2190–2191 miniature pig  2140 mouse and rat  2118–2119 New World camelid ophthalmology  2091, 2093, 2097, 2098, 2099–2100 ocular pathology  493–502 ovine and caprine ophthalmology  2022 porcine ophthalmology  2034–2036 see also individual disorders; ocular embryology and congenital malformations congenital stationary night blindness (CSNB) canine ocular fundus diseases  1522 equine ophthalmology  1850, 1857, 1956 equine systemic disease with ocular manifestations  2495, 2496 neuro‐ophthalmology  2296–2298, 2298 ocular pathology  519 conjunctiva avian ophthalmology  2056, 2068, 2068 bovine ophthalmology  1990–2010, 1990–1991, 1993, 1995–1996, 1998–1999, 2004–2008

Index

canine conjunctival diseases  1045–1062 general ocular examination  574 guinea pig  2130–2131 histology  615–616 New World camelid ophthalmology  2092–2094, 2093 ocular drug delivery  350, 356–357, 367–368, 367 ophthalmic anatomy  48–49, 48 ovine and caprine ophthalmology  2025–2029, 2026–2027 conjunctiva‐associated lymphoid tissue (CALT) canine conjunctival diseases  1045 canine lacrimal secretory system diseases  1012–1013, 1012–1013 canine nictitating membrane diseases  1063 ocular immunology  271 ophthalmic anatomy  48 conjunctival cysts  2093 conjunctival defects  1059 conjunctival ectopic cilia  932–935, 933–934 conjunctival erosions  2451–2452, 2452 conjunctival goblet cells canine conjunctival diseases  1045–1046, 1051 canine lacrimal secretory system diseases  1012, 1020–1021, 1028 conjunctival grafts  1901 conjunctival neoplasia equine ophthalmology  1881, 1882 feline ocular surface disease  1698–1700, 1699–1700 ocular pathology  534–541, 535, 536–541 conjunctival overgrowth ocular pathology  507–508, 508 rabbit  2184, 2184 conjunctival rhinostomy  996–997, 998 conjunctival sequestrae  507–508 conjunctival surface adenocarcinoma  1700, 1700 conjunctivitis avian ophthalmology  2060–2061, 2061, 2068, 2068 canine nasolacrimal diseases  990, 990 canine systemic disease with ocular manifestations  2370, 2370 clinical microbiology and parasitology  297, 300, 303 equine ophthalmology  1858, 1881 feline ocular surface disease  1690–1698 guinea pig  2130, 2191, 2191 mouse and rat  2119–2120 New World camelid ophthalmology  2091, 2093–2094, 2093

nonhuman primates  2143 ocular pathology  489, 489, 506, 507 rabbit  2135, 2182, 2182–2183 slit‐lamp biomicroscopy  581 connective tissue disorders  1096 contact hypersensitivity  1050 contagious ophthalmia see infectious bovine keratoconjunctivitis continuous curvilinear capsulorhexis/ capsulotomy (CCC) equine ophthalmology  1949 surgical procedures on the canine lens  1372, 1394–1397, 1395–1397, 1402, 1402, 1406–1408 continuous infusion  362–363 contrast  251, 251 contrast‐enhanced ultrasonography (CEUS)  742–743, 750–753, 752 conus papillaris  136 cornea acquired/inherited disorders  508–513, 509–513 anti‐inflammatory agents  420, 423–424 avian ophthalmology  2056, 2068–2069, 2069–2070 biomechanics  131, 132, 133 bovine ophthalmology  1990–2010, 1990–1991, 1993, 1995–1996, 1998–1999, 2004–2008 Bowman’s layer  59, 59 canine anterior uvea diseases  1290 canine corneal diseases  1082–1153 canine glaucomas  1186 clarity/transparency  54, 129–130, 130, 1085 cloudiness  1730 congenital disorders  500 Descemet’s membrane  59–60 diagnostic ultrasound  747–748, 748 electroretinography  759–760 equine ophthalmology  1851, 1883–1922 feline ocular surface disease  1717–1732 fish  2201 general ocular examination  575–576, 575 glycans and collagen types  56–59, 57 guinea pig  2128, 2131 honeycomb appearance  580, 587 innervation  54, 54, 132–134, 133, 692–693 in vivo confocal microscopy  690–695, 691–696 metabolism  130–131 microsurgery  799, 805–806, 807–809 New World camelid ophthalmology  2094–2097, 2095–2096 nonhuman primates  2143 ocular drug delivery  349–350, 355–356, 355, 359–362, 362

ocular embryology and congenital malformations  15, 16 ocular imaging  682–696, 684, 686–688, 690–696 ocular pathology  479, 482 ocular physiology  129–134, 130, 132–133, 133, 1718 ophthalmic anatomy  53–61, 53–60, 53, 57, 1717–1718 optical coherence tomography  695–696 optics and physiology of vision  172– 173, 174, 182–185, 184, 189 ovine and caprine ophthalmology  2025–2029, 2026–2027 photography  839–842, 852–855, 854–856 physical characteristics  53–54, 53, 53 rabbit  2134 sensitivity  131–132 slit‐lamp biomicroscopy  579–587, 582–588 stroma  56–59, 56–59 surgical procedures on the canine lens  1393–1394, 1393–1394, 1405, 1410–1413, 1419 corneal collagen cross‐linking (CXL)  374, 1721, 1901 corneal confocal microscopy  2151 corneal degeneration avian ophthalmology  2063, 2069, 2070 canine corneal diseases  1135–1137, 1136 exotic mammals  2222 fish  2205 New World camelid ophthalmology  2096 corneal dystrophy canine corneal diseases  1131–1134, 1133–1134 equine ophthalmology  1918–1919 feline ocular surface disease  1729–1730, 1730 mouse and rat  2120–2121, 2121 New World camelid ophthalmology  2096 ocular pathology  483, 485, 511–513, 512 corneal edema avian ophthalmology  2069 bovine ophthalmology  1991, 1993 canine anterior uvea diseases  1270, 1270 canine corneal diseases  1090–1091, 1090, 1153, 1155 canine systemic disease with ocular manifestations  2379–2380, 2379 exotic mammals  2221 photography  845 slit‐lamp biomicroscopy  582 surgical procedures on the canine lens  1411–1413, 1412

i15

i16

Index

corneal endothelial dystrophy  1137– 1140, 1137–1139 corneal endothelial toxicity  1381 corneal endothelium canine corneal diseases  1086–1087 in vivo confocal microscopy  692 ocular physiology  130 ophthalmic anatomy  60–61, 60 rabbit  2134 slit‐lamp biomicroscopy  579–580, 585–586, 587 specular microscopy  686–690, 687–688, 690 corneal epithelial inclusion cysts  1148–1149, 1148–1149 corneal epithelium canine corneal diseases  1082–1083, 1083, 1085–1087, 1097–1099, 1098 ocular physiology  130–131, 132 ophthalmic anatomy  54–56, 54–56 slit‐lamp biomicroscopy  579–580, 585 corneal esthesiometry  599–601, 600 corneal incision contracture (CIC)  1405 corneal incision dehiscence  1410, 1437, 1437 corneal mineralization  1919–1920, 1920 corneal neoplasia and nodules equine ophthalmology  1922, 1922 feline ocular surface disease  1731– 1732, 1732 ocular pathology  541–542 corneal opacities amphibians  2208 band keratopathy  1137, 1137 canine corneal diseases  1094–1096, 1095, 1131–1148 corneal degeneration  1135–1137, 1136 corneal dystrophy  1131–1134, 1133–1134 corneal endothelial dystrophy  1137–1140, 1137–1139 crystalline corneal opacities  1131–1137, 1132, 1133–1137 exotic mammals  2219 Florida keratopathy  1140–1141, 1141 intracorneal stromal hemorrhage  1141–1142, 1142 lipid keratopathy  1135, 1135 mouse and rat  2120 non‐crystalline corneal opacities  1137–1143, 1137–1143 pharmaceutical deposits  1142–1143, 1143 posterior polymorphous dystrophy  1140, 1140 rabbit  2136–2137 surgery for corneal opacities  1143–1148, 1144–1147 corneal pigmentation  1089–1090, 1089–1090

corneal reflex corneal esthesiometry  599–601, 600 general ocular examination  573, 574 neuro‐ophthalmology  2258–2259 ocular physiology  124–125, 125 corneal sensitivity avian ophthalmology  2068–2069 canine corneal diseases  1084 surgical procedures on the canine lens  1431 corneal sequestrae equine ophthalmology  1919 feline ocular surface disease  1724–1728, 1725, 1727 feline systemic disease with ocular manifestations  2454–2458, 2455 ocular pathology  510–511, 511 corneal stromal abscesses canine corneal diseases  1127–1128 equine ophthalmology  1904–1910, 1905, 1907–1910 ovine and caprine ophthalmology  2027 corneal stromal ulcers  1437, 1437 corneal thickness canine corneal diseases  1082–1084 exotic mammals  2219 fish  2201 in vivo confocal microscopy  693 ocular physiology  131 ophthalmic anatomy  53–54, 53 optical coherence tomography  696 pachymetry  682–686, 684, 686 specular microscopy  687 tonometry  628 corneal touch threshold (CTT)  600, 2258–2259 corneal transplantation  278–279 corneal ulceration see ulcerative keratitis corneal vascularization bovine ophthalmology  1998, 1998 canine corneal diseases  1091, 1092, 1098, 1100, 1101 corneoconjunctival culture  611–612, 612 corneoconjunctival cytology  612–615, 613–614 corneoconjunctival transposition canine conjunctival diseases  1062 canine corneal diseases  1112, 1113 photography  834 corneoscleral masses  1148–1149, 1148 corneoscleral trabecular meshwork (CSTM) equine ophthalmology  1937–1938 ophthalmic anatomy  75–79, 75–76 corneoscleral transposition  1112, 1113 corpora nigra bovine ophthalmology  1983, 1984 equine ophthalmology  1922–1923, 1923 ovine and caprine ophthalmology  2021, 2021

corticosteroid provocative test  1185 corticosteroids canine anterior uvea diseases  1274–1275, 1280 canine corneal diseases  1100, 1125–1126, 1136, 1142 canine lacrimal secretory system diseases  1028 clinical pharmacology and therapeutics  417–421 equine ophthalmology  1892, 1932 feline anterior uvea diseases  1755–1756 feline eyelid diseases  1674–1675, 1674 feline glaucomas  1769 indications for ocular disease  419 mechanism of action  417–418 New World camelid ophthalmology  2102 ophthalmic corticosteroids and their side effects  419–421 routes of administration  418–419, 418 viral infections  303 cortisol  128 Corynebacterium spp.  313–314 coumarin poisoning  2558–2559 cowpox virus  1675 cows see bovine ophthalmology COX see cyclooxygenase CPC see cyclophotocoagulation cpd see cycles per degree CPRA  1546 CPV see canine papillomavirus crack and flip technique  1400 CRALBP see cellular retinaldehyde‐ binding protein cranial dysinnervation disorder  2276–2277 cranial nerves  882 see also neuro‐ophthalmology craniomandibular osteopathy  904–905, 905 critical flicker frequency (CFF)  232–233, 233 cryodestructive techniques  1235 cryopreservation  1115, 1115, 1152 cryoprobe method  1433 cryosurgery canine eyelid disorders  928–929, 933 equine ophthalmology  1877 cryotherapy bovine ophthalmology  2008–2009 canine corneal diseases  1151–1152 canine posterior segment surgery  1583–1584, 1584 equine ophthalmology  1875–1877, 1879 Cryptococcus spp. antifungal agents  396–397, 399–400 canine anterior uvea diseases  1281 canine ocular fundus diseases  1533–1535, 1534

Index

canine systemic disease with ocular manifestations  2362–2363, 2363 clinical microbiology and parasitology  323–324 equine systemic disease with ocular manifestations  2507–2508 feline anterior uvea diseases  1747–1748, 1748 feline systemic disease with ocular manifestations  2443–2444, 2444 cryptophthalmos  2059 crystallins canine lens diseases and cataract formation  1317, 1330–1331, 1350 ocular immunology  280–281 ocular physiology  148–149, 151 CsA see cyclosporine A CSF see cerebrospinal fluid CSK see chronic superficial keratitis cSLO see confocal scanning laser ophthalmoscopy CSNB see congenital stationary night blindness CSTM see corneoscleral trabecular meshwork CT see computed tomography CTL see cytotoxic T lymphocytes CTR see capsular tension ring CTT see corneal touch threshold culture bacterial infections  310, 311 canine nasolacrimal diseases  991 corneoconjunctival culture  611–612, 612 equine ophthalmology  1888–1893, 1904–1905 fungal and algal diseases  320–321 paracentesis  640–641, 640 protozoal diseases  324 curcumin  1347 Cushing’s syndrome  2384 cutaneous asthenia  2536 cutaneous vasculitis  2503 Cuterebra spp. clinical microbiology and parasitology  330 feline anterior uvea diseases  1751, 1751 feline eyelid diseases  1674 feline ocular surface disease  1698 feline systemic disease with ocular manifestations  2446, 2446–2447 CVA see cerebrovascular accidents CXL see collagen cross‐linking cyanoacrylate tissue adhesive  1102, 1103, 1104 cycles per degree (cpd)  242, 243 cyclic adenosine monophosphate (cAMP)  454–456 cyclic guanosine monophosphate (cGMP)  193–195, 231–232

cyclocryothermy  1235 cyclodextrin complexation  361 cyclooxygenase (COX) canine anterior uvea diseases  1268 clinical pharmacology and therapeutics  417, 421–422, 424–425 cyclopegics see mydriatics/cyclopegics cyclopentolate  437 cyclophotocoagulation (CPC) feline glaucomas  1769–1770 optics and physiology of vision  171 surgical procedures on the canine lens  1438 cyclopia ocular embryology and congenital malformations  20, 20 ocular pathology  494, 495 cyclosporine A (CsA) canine anterior uvea diseases  1276 canine corneal diseases  1125–1127 canine lacrimal secretory system diseases  1022–1024, 1023–1024, 1027–1028, 1027–1028 clinical pharmacology and therapeutics  425–427, 442–443 equine ophthalmology  1933–1934, 1933 surgical procedures on the canine lens  1426 Cylindrocarpon spp.  696 Cysticercus spp.  330, 2546–2547 cysts canine anterior uvea diseases  1263–1265, 1264–1265, 1286–1287, 1286 canine conjunctival diseases  1055 canine corneal diseases  1148–1149, 1148–1149 canine lacrimal secretory system diseases  1033–1034, 1034 canine orbital diseases  889–890, 891–892 canine vitreous diseases  1471, 1471 diagnostic ultrasound  744–745, 748, 749 equine ophthalmology  1855, 1869, 1922–1923, 1923 feline anterior uvea diseases  1735, 1737–1738, 1737 feline eyelid diseases  1680–1681 New World camelid ophthalmology  2093 ocular pathology  493, 505, 505, 509, 510, 516–517 surgical procedures on the canine lens  1379–1380, 1379 Cytauxzoon spp.  1747 cytobrush  613–614, 613 cytokeratins  56 cytokines  264, 267, 270

cytology bovine ophthalmology  1994–1996, 1995, 2004–2006 canine anterior uvea diseases  1274, 1280, 1298–1299 canine conjunctival diseases  1046 canine nasolacrimal diseases  991 corneoconjunctival cytology  612–615, 613–614 equine ophthalmology  1888–1893, 1904–1905 feline ocular surface disease  1704–1705 feline systemic disease with ocular manifestations  2437–2440, 2437, 2440 paracentesis  640–641, 640 photography  834 cytotoxic drugs  1229–1230 cytotoxic T lymphocytes (CTL)  268–269, 270, 272, 275–280 cytotoxin  1997–1998 dacryocystitis canine nasolacrimal diseases  990, 990, 1001–1002, 1002 contrast radiography  665, 673 equine ophthalmology  1858 New World camelid ophthalmology  2091 rabbit  2136, 2180–2182, 2180–2181 dacryocystorhinography (DCRG)  664–665, 664, 670, 673 avian ophthalmology  2057 canine nasolacrimal diseases  992–994 equine ophthalmology  1852, 1882 New World camelid ophthalmology  2088, 2088 dacryolithiasis  1002–1003 dacryops  500, 500 DAM see digital asset management damaged‐associated molecular pattern molecules (DAMP)  264, 265 dark adaptation  230–231, 231, 248–250, 764–765, 764 darkroom test  1185 day blindness see achromatopsia dazzle reflex general ocular examination  573 neuro‐ophthalmology  2256, 2256 ocular physiology  124–125, 125 DCRG see dacrycystorhinography deafness  2276, 2422 DED see dry eye disease deep lamellar endothelial keratoplasty (DLEK)  1909–1910, 1910 deep stromal abscesses (DSA)  1904–1910, 1905, 1907–1910 degenerative disorders avian ophthalmology  2063–2064, 2063 bovine ophthalmology  2018–2020, 2019–2020

i17

i18

Index

degenerative disorders (cont’d) canine vitreous diseases  1468 corneal disorders  509 lenticular disorders  522–525 ocular pathology  505, 509, 516, 522–525, 529–530 optic nerve degeneration  529–530 orbital disorders  505 ovine and caprine ophthalmology  2031 porcine ophthalmology  2037 uveal disorders  516 see also individual disorders degu  2196, 2197 dehydration  1772 delayed type hypersensitivity (DTH)  269, 274–277, 280 demarcation retinopexy  1586–1588, 1587 Demarres chalazion clamp  800 demecarium bromide  452–453 Demodex spp. bovine ophthalmology  1988 canine systemic disease with ocular manifestations  2368 clinical microbiology and parasitology  328 equine systemic disease with ocular manifestations  2508–2509 feline eyelid diseases  1673, 1673 feline systemic disease with ocular manifestations  2447 food animal systemic disease with ocular manifestations  2547 ovine and caprine ophthalmology  2024–2025 dendritic corneal ulceration  297 depth of field (DOF)  818–819, 818, 823–826, 852–859 depth perception see stereopsis dermatan sulfate  58–59 dermatologic diseases canine systemic disease with ocular manifestations  2347–2348 equine systemic disease with ocular manifestations  2502–2503, 2503 feline systemic disease with ocular manifestations  2433–2434 dermatomyositis  2351 Dermatophilus spp.  1988 dermatophytosis canine systemic disease with ocular manifestations  2363 clinical microbiology and parasitology  322 equine systemic disease with ocular manifestations  2508 feline systemic disease with ocular manifestations  2444, 2444 food animal systemic disease with ocular manifestations  2546 dermatosparaxis  2536

dermoids avian ophthalmology  2059 bovine ophthalmology  1990, 1990–1991 canine conjunctival diseases  1053–1054, 1054 canine corneal diseases  1092–1094, 1093–1095 canine eyelid disorders  931–932, 932 equine ophthalmology  1850, 1851 feline eyelid diseases  1671 feline ocular surface disease  1730–1731 guinea pig  2130, 2191, 2191 New World camelid ophthalmology  2093 ocular embryology and congenital malformations  22–23, 25 ocular pathology  500, 501 rabbit  2136 descemetoceles  584, 1109–1111, 1112 Descemet’s membrane canine corneal diseases  1143 canine glaucomas  1188 diagnostic ultrasound  749 ophthalmic anatomy  59–60 slit‐lamp biomicroscopy  584, 585–587 Descemet’s membrane detachment (DMD)  1921–1922 developmental disorders avian ophthalmology  2059, 2066, 2067 bovine ophthalmology  1989–1990, 1990, 2013–2014 canine anterior uvea diseases  1259– 1263, 1260–1262 canine corneal diseases  1091–1096, 1093–1095 canine lens diseases and cataract formation  1333–1339, 1334–1336, 1339 canine nasolacrimal diseases  998–1000, 1000 canine neuro‐ophthalmic diseases  2278–2279 canine nictitating membrane diseases  1064 canine ocular fundus diseases  1485–1498 canine systemic disease with ocular manifestations  2334–2340, 2336–2337, 2340 canine vitreous diseases  1464–1466, 1464–1466, 1467 equine ophthalmology  1944–1946 equine systemic disease with ocular manifestations  2499 feline anterior uvea diseases  1733–1736, 1733–1736 feline neuro‐ophthalmic diseases  2290 feline optic nerve and CNS diseases  1788, 1790

feline orbital diseases  1791 feline posterior segment diseases  1774 feline systemic disease with ocular manifestations  2423–2428, 2425, 2427 food animal neuro‐ophthalmic diseases  2304–2305, 2305 food animal systemic disease with ocular manifestations  2538–2540 guinea pig  2128–2130 miniature pig  2140 mouse and rat  2118–2119 rabbit  2135 dexamethasone  418–421, 1142, 1291 DHA see docosahexanoic acid diabetes mellitus canine lens diseases and cataract formation  1343–1344, 1344 canine systemic disease with ocular manifestations  2380–2383, 2382–2383 diagnostic ultrasound  742, 742 feline lens diseases and cataract formation  1772 feline systemic disease with ocular manifestations  2461–2463, 2462 fluorescein angiography  712–713 New World camelid ophthalmology  2103 ocular pathology  530 slit‐lamp biomicroscopy  585 small mammal ophthalmology  2193, 2194, 2196 specular microscopy  689 surgical procedures on the canine lens  1376, 1378, 1430–1431 diabetic retinopathy (DR) canine ocular fundus diseases  1547– 1549, 1548 canine systemic disease with ocular manifestations  2382–2383 feline posterior segment diseases  1786 feline systemic disease with ocular manifestations  2463 laboratory animal ophthalmology  2150–2151, 2155 diagnostic ultrasound  733–756 anterior chamber  748, 749 artifacts  738, 738 A‐scan modality  734, 735–736, 736–737 avian ophthalmology  2066 basic principles and physics  733–734 Baum’s bumps  738 B‐scan modality  734, 736–741, 736–748, 751, 753 canine anterior uvea diseases  1294 canine lens diseases and cataract formation  1321, 1321 canine nasolacrimal diseases  993

Index

canine ocular fundus diseases  1478–1479, 1495 canine optic nerve diseases  1635–1636 canine orbital diseases  882–883, 884–888, 894–900, 894–895, 899 canine posterior segment surgery  1584 canine vitreous diseases  1461, 1461–1462 choroid  743, 746 contrast‐enhanced ultrasonography/ Doppler  742–743, 750–753, 752, 1203 cornea  747–748, 748 equine ophthalmology  1866–1867 general ocular examination  576 high‐resolution ultrasound/ultrasound biomicroscopy  745–750, 748–751 instrumentation and processing  734–735, 735 iridocorneal angle and uveal drainage system  750, 751 lens  742, 742, 750 New World camelid ophthalmology  2088 normal ultrasonographic anatomy  741 ocular and orbital abnormalities  742– 745, 742–747 orbit  743–744, 747 retina  743, 746 routine globe evaluation with B‐ scans  738–741, 739–741 sclera  743, 746, 747–748, 748 surgical procedures on the canine lens  1374–1375, 1374–1375 technique  747, 748 three‐dimensional ultrasound  753–754, 753 transducer positioning  739–741, 740–741 uvea  748–750, 748–750 vitreous  742–743, 744–745 diazepam  565 dichlorophenamide  459 dichromatic vision  240, 241 diclofenac  422–424 diencephalic syndrome  2266, 2266 diet and nutrition bovine ophthalmology  2004 canine lens diseases and cataract formation  1345, 1347–1348 canine ocular fundus diseases  1523, 1545–1547, 1546 canine systemic disease with ocular manifestations  2386–2388, 2387–2388 equine systemic disease with ocular manifestations  2517–2518 exotic mammals  2222, 2223–2224 feline eyelid diseases  1677–1678 feline lens diseases and cataract formation  1772

feline posterior segment diseases  1775–1777, 1776 feline systemic disease with ocular manifestations  2464–2466, 2465 fish  2204–2205, 2204 food animal systemic disease with ocular manifestations  2553–2556, 2554–2556 nutritional retinal degeneration  1775–1777, 1776 ocular pathology  524–525 supplementation  1546–1547 see also individual nutrient deficiencies diffuse corneal edema  1137, 1137 diffuse illumination  837, 838 diffuse iris melanoma  585 diffuse ulcerative conjunctival disease  1020 digital asset management (DAM)  860–864, 862 digital photography see photography digoxin  1542 dilated pupil syndrome  2290–2291, 2432–2433 dimethyl sulfoxide (DMSO)  1340 diode endoscopic cyclophotocoagulation  1237, 1237 diosmin  1347 diphenythiocarbazone  1544 dipivefrin  454 diplopia  237, 237 Dipteric larvae canine ocular fundus diseases  1538 canine systemic disease with ocular manifestations  2364–2365 feline systemic disease with ocular manifestations  2446, 2446–2447 direct focal illumination  838–839, 839–842 direction‐selective ganglion cells (DSGC)  202–204, 203–204 Dirofilaria spp.  328–329, 2509, 2509, 2365 discoid lupus erythematosus  2347–2348 disophenol toxicity  2389 displaced/dislocated lens fragments  1408–1409 disseminated Rhizopus  2546 distemper see canine distemper virus distichiasis canine eyelid disorders  932–935, 933–934 equine ophthalmology  1880, 1881 feline eyelid diseases  1670, 1671 diurnal rhythm  607 divide‐and‐conquer technique  1399, 1399 DLEK see deep lamellar endothelial keratoplasty DMD see Descemet’s membrane detachment DMSO see dimethyl sulfoxide

DNA testing see genetics and DNA testing docosahexanoic acid (DHA)  1546 DOF see depth of field dogs see canine dominant white gene/locus  2422 dopamine  208 dorzolamide  459–461 double‐cone photoreceptors  99, 99, 240 doxycycline canine corneal diseases  1100 clinical pharmacology and therapeutics  391–392 feline anterior uvea diseases  1750 feline ocular surface disease  1692–1693, 1695 DR see diabetic retinopathy draping  926 Draschia spp.  2509–2510 dropped nuclear fragments  1582–1583 Drualt’s bundle  18 drug efflux transporters see efflux transporters drug‐induced blepharitis  1676–1678, 1677 drug‐induced retinotoxicity  1542–1544, 1543, 1780–1782, 1780 drug‐related uveitis  1753 dry eye disease (DED) laboratory animal ophthalmology  2147–2148, 2157 ocular drug delivery  352–353 ocular immunology  277–278 Dryopteris poisoning  2558 DSA see deep stromal abscesses DSGC see direction‐selective ganglion cells DTH see delayed type hypersensitivity dwarfism canine ocular fundus diseases  1494–1496, 1495–1496 canine systemic disease with ocular manifestations  2331–2332, 2332 dysautonomia canine neuro‐ophthalmic diseases  2281 canine systemic disease with ocular manifestations  2345–2346 equine neuro‐ophthalmic diseases  2299 equine systemic disease with ocular manifestations  2500–2501 feline neuro‐ophthalmic diseases  2290–2291 feline systemic disease with ocular manifestations  2432–2433 dyscoria  1263 dysplasia  483, 485, 495–496, 496, 498–502, 499–502 see also individual locations dysplasia palpebrae  931–932, 932 dysplastic lacrimal puncta  1990 dystocia  2499–2500 dystrophy  483, 485, 511–513, 512 see also individual locations

i19

i20

Index

EALT see eye‐associated lymphoid tissue EAPTT see endodontic absorbent paper point test Eastern equine encephalitis (EEE)  306 EAU see experimental autoimmune uveitis Echidnophaga spp.  1674 echinocandins  401–402 Echinococcus spp.  330, 2512–2513 echothiophate iodide  453 ECM see extracellular matrix ECP see endoscopic cyclophotocoagulation ectoderm  3–11, 7, 12 ectopia lentis  1855 ectopic cilia canine eyelid disorders  932–935, 933–935 equine ophthalmology  1881 ectropion Bigelback procedure  954, 958 Blaskovics K‐S modification  949–951, 951–952 bovine ophthalmology  1987 canine corneal diseases  1124–1125 canine eyelid disorders  946–956, 948–959 cicatricial pure ectropion  948, 949 clinical signs  946–947, 948, 949 epidemiology and signalment  946 equine ophthalmology  1857–1858, 1859–1860 feline eyelid diseases  1670, 1670 Fuchs procedure  953–954, 955 Grussendorf procedure  955–956, 959 Helmbold procedure  951, 952 homologous and prosthetic lateral canthal ligament construction  947–948 Kuhnt–Szymanowski procedure  947, 949–951, 950–952, 954, 957 lateral eyelid wedge excision  949, 950 lower lid position in primary ectropion  947, 948 modified Roberts–Jensen pocket procedure  953–954, 955 notch deformation  950, 951 ovine and caprine ophthalmology  2023–2024 postoperative care  956 prognosis and prevention  956 shortening the lower lid margin  948–952, 950–952 shortening the upper lid length  951–952 simple, permanent tarsorrhaphy  952–953, 953–954 stabilizing the lateral canthus  954 Stades procedure  955, 958 surgical procedures  947–956, 948–959 therapy  947 Wyman and Kaswan method  954, 956 EEE see Eastern equine encephalitis

efflux transporters  352 effusive retinal detachment  1581 Ehlers–Danlos syndrome (EDS) canine lens diseases and cataract formation  1343, 1357 canine systemic disease with ocular manifestations  2332–2333 feline systemic disease with ocular manifestations  2422 food animal systemic disease with ocular manifestations  2536 Ehrlichia spp. canine anterior uvea diseases  1283–1284 canine ocular fundus diseases  1530–1531 canine systemic disease with ocular manifestations  2373–2374, 2374–2375 clinical microbiology and parasitology  318 EHV‐1 see equine herpesvirus‐1 EHV‐2 see equine herpesvirus‐2 EIA see equine infectious anemia EK see eosinophilic keratitis EL see equine leukoencephalomalacia Elaeophora spp.  2025, 2221 elastin, canine glaucomas  1192 electricity‐induced cataracts  1341 electrocautery  933–934, 945 electrocution canine systemic disease with ocular manifestations  2391 equine neuro‐ophthalmic diseases  2299–2300 equine systemic disease with ocular manifestations  2518–2519 food animal neuro‐ophthalmic diseases  2306 food animal systemic disease with ocular manifestations  2556 electrodiagnostic tests  757–777 electro‐oculogram  774 full field electroretinography  757–771 multifocal electroretinography  774, 774 pattern electroretinography  773, 773 visual‐evoked potentials  772–773, 773 electromagnetic spectrum  168–169, 169 electron microscopy  1520 electro‐oculogram (EOG)  774 electrophysiology, 757‐777 electroretinography (ERG) canine glaucomas  1183–1185, 1193, 1202–1203, 1211 canine neuro‐ophthalmic diseases  2287 canine ocular fundus diseases  1479– 1482, 1481, 1501–1502, 1509, 1513–1522, 1525, 1541, 1549–1550 canine optic nerve diseases  1636–1637

canine posterior segment surgery  1588 canine systemic disease with ocular manifestations  2347 diagnostic technique 757‐777 equine ophthalmology  1958 exotic animal ophthalmology  2219 focal and multifocal electroretinography  774, 774, 1183–1185, 1482 fundamentals of animal vision  231, 231 New World camelid ophthalmology  2104 optics and physiology of vision  170, 194 photography  835 surgical procedures on the canine lens  1375 visual‐evoked potentials  1183–1185, 1481–1482, 1636–1637 see also flash electroretinography; full field electroretinography; pattern electroretinography electrothermal therapy  2009 ELISA see enzyme‐linked immunosorbent assay embryonic nuclear cataracts  1945 emmetropia optics and physiology of vision  178–182, 178 retinoscopy  597–599 under water  187–188, 187–189 EMND see equine motor neuron disease EMUE see eosinophilic meningoencephalitis of unknown etiology Encephalitozoon spp. canine anterior uvea diseases  1283 canine lens diseases and cataract formation  1345 clinical microbiology and parasitology  327 exotic mammals  2221 feline lens diseases and cataract formation  1771–1772, 1772 feline ocular surface disease  1720 small mammal ophthalmology  2187–2189, 2188 endocyclophotocoagulation  1609 endoderm  3 endodontic absorbent paper point test (EAPTT)  601, 605–610 avian species  606–607 domesticated animals  602–603 fish, reptiles, and amphibians  608 nondomesticated animals  604–605 endophthalmitis canine posterior segment surgery  1581 surgical procedures on the canine lens  1381–1382, 1404, 1407–1408, 1410, 1416–1421 endoscopic cyclophotocoagulation (ECP) canine glaucomas  1237, 1237 equine ophthalmology  1941

Index

endoscopy canine nasolacrimal diseases  994 pars plana vitrectomy  1608–1609, 1609 endothelial cell density in vivo confocal microscopy  692 pachymetry  685–686 specular microscopy  687–689 endothelial decompensation  1411–1413, 1412 endothelial dystrophy  512, 512, 693 endothelial wound healing  1886 endotheliitis  848 endothelin‐1  1196 end‐stage primary glaucomas  1237–1238, 1237 enophthalmos canine orbital diseases  879–880, 882 equine ophthalmology  1864–1865, 1865 enrofloxacin feline posterior segment diseases  1780–1782, 1780–1781 feline systemic disease with ocular manifestations  2466–2468, 2467 small mammal ophthalmology  2181–2182 entropion bovine ophthalmology  1987 canine corneal diseases  1124–1125 canine eyelid disorders  935–945, 936–946 central entropion  941–942, 941–942 clinical signs  936–937 complications  944–945 diagnosis  937 epidemiology and signalment  936, 937 equine ophthalmology  1857–1858, 1859, 1871–1872 feline eyelid diseases  1668–1670, 1669 lateral canthal entropion  942–943, 943–946 macro‐ and microblepharon  942 medial entropion  942 New World camelid ophthalmology  2091 other surgical and nonsurgical methods  945 ovine and caprine ophthalmology  2023, 2023 porcine ophthalmology  2034, 2034 postoperative care  943–944 prognosis and prevention  945 Quickert–Rathbun procedure  938, 938 severity of the condition  935–936, 936 shortening of the lower lid  943, 945–946 surgical procedures  938–943, 939–946 tacking lids or stay sutures  937–938, 938 therapy  937

enucleation avian ophthalmology  2073 canine orbital diseases  907–908, 908 equine ophthalmology  1867–1869, 1942 feline orbital diseases  1794 rabbit  2189–2190 environmental irritants  1050 enzyme‐linked immunosorbent assay (ELISA) canine systemic disease with ocular manifestations  2357–2358, 2369–2372 feline anterior uvea diseases  1742 feline ocular surface disease  1692 feline systemic disease with ocular manifestations  2441 fungal and algal diseases  322 protozoal diseases  325 viral infections  294–295, 295, 299 EOG see electro‐oculogram EOM see extraocular muscles eosinophilic conjunctivitis  1697, 1697 eosinophilic keratitis (EK) equine ophthalmology  1917–1918, 1918 feline ocular surface disease  1714–1716, 1714 laboratory sampling  614 eosinophilic keratoconjunctivitis  506 eosinophilic meningoencephalitis of unknown etiology (EMUE)  2283, 2349 eosinophilic myositis  505–506 eosinophils  489, 489 epinephrine canine glaucomas  1228 clinical pharmacology and therapeutics  438, 454 neuro‐ophthalmology  2265 epiphora canine nasolacrimal diseases  990, 990 equine ophthalmology  1961 feline nasolacrimal system diseases  1685, 1685 New World camelid ophthalmology  2091 rabbit  2180–2182, 2180–2181 episclera  62, 513–514, 513–514 episcleral anesthesia see sub‐Tenon’s anesthesia episcleral hemorrhage  1858 episcleral prolapse  1987 episcleritis  513, 513, 1153 epithelial debridement  1101, 1101–1102 epithelial wound healing  1885 epitheliotropic mastocytic conjunctivitis  1698 epitope spreading  1929 epizootic lymphangitis  2508 EPM see equine protozoal myeloencephalitis

equatorial cataracts  1946 equine adenovirus‐1  306, 2513 equine babesiosis  2511–2512 equine encephalomyelitis viruses  306 equine granulocytic anaplasmosis  2513 equine grass sickness  2299, 2500–2501 equine herpesvirus‐1 (EHV‐1) clinical microbiology and parasitology  305 equine ophthalmology  1955–1956 equine systemic disease with ocular manifestations  2514 New World camelid ophthalmology  2098, 2101 equine herpesvirus‐2 (EHV‐2) antiviral agents  402–403 clinical microbiology and parasitology  305 equine ophthalmology  1912 equine systemic disease with ocular manifestations  2514 equine infectious anemia (EIA)  305, 2514 equine leukoencephalomalacia (EL)  2519 equine motor neuron disease (EMND)  1956–1957, 1956, 2501–2502, 2501 equine neuro‐ophthalmic diseases  2296–2304 acquired disorders  2299–2304, 2302 congenital disorders  2296–2299, 2298 equine ophthalmology  1841–1982 acquired ocular and adnexal problems in the foal  1857–1862, 1859–1863 aqueous humor dynamics and glaucoma  1937–1942 anatomy and physiology  1937–1939 clinical features of equine glaucoma  1936–1937, 1939 diagnosis of equine glaucoma  1939–1940 risk factors for equine glaucoma  1939 treatment of equine glaucoma  1940–1942 breed‐related conditions  1961, 1962 clinical assessment of vision in horses  1844 color vision  1843–1844, 1843 congenital disorders  1849–1857, 1849–1854, 1856–1857 conjunctival diseases  1881, 1882 corneal diseases  1883–1922 anatomy  1883–1884 bacterial keratitis  1897, 1900 corneal dystrophy  1918–1919 corneal neoplasia  1922, 1922 corneal perforation/laceration  1897–1899 corneal sequestrae  1919 corneal stromal abscesses  1904–1910, 1905, 1907–1910 Descemet’s membrane detachment  1921–1922

i21

i22

Index

equine ophthalmology (cont’d) eosinophilic keratitis  1917–1918, 1918 foals  1858–1862, 1861 foreign bodies  1894, 1894 fungal/mycotic keratitis  1894–1897, 1895, 1897, 1898–1899 hereditary equine regional dermal asthenia  1919 idiopathic primary edema/bullous keratopathy  1920–1921, 1921 immune‐mediated keratitis  1913–1917, 1914–1915 infection  1887–1888 inflammation/keratitis  1886 keratoconjunctivitis sicca  1912–1913 limbal keratopathy  1918 linear keratopathy  1921 mineralization and calcific band keratopathy  1919–1920, 1920 non‐ulcerative corneal diseases  1904–1922 parasitic keratitis  1918 pectinate ligament avulsion  1921 perforating corneal injury  1886–1887 radiation‐induced keratopathy  1919 superficial punctate keratitis  1904, 1904 surgical therapy  1899–1904, 1903 ulcerative keratitis  1888–1904 viral keratitis  1910–1912, 1911 wound healing  1884–1886 electroretinography  1958 examination of the equine eye  1844–1849, 1845, 1847 eyelid diseases  1870–1881 blepharitis  1872–1874, 1874 entropion  1871–1872 eyelashes  1846, 1847, 1880–1881, 1881 lacerations  1872, 1873 neoplasia  1874–1880, 1875–1876, 1876, 1878, 1879, 1880–1881 geriatric eye problems  1960–1961 lens diseases  1942–1951 cataracts  1850, 1854–1855, 1856, 1943, 1944–1951, 1945, 1950 concentric cortical lamination  1942 lens colobomas  1855 lens luxation/subluxation  1854– 1855, 1942–1944 nuclear sclerosis  1942 monocular vision cues  1842–1843 nasolacrimal disease  1882–1883 neonatal ocular problems  1848–1849 nictitating membrane diseases  1881–1882 optic nerve diseases  1958–1960, 1959–1960 orbital diseases in adults  1862–1870

anatomy and physiology  1862–1865, 1864–1865 diagnostic procedures  1865–1867, 1865–1866 fractures and trauma  1869–1870, 1870 inflammation and cellulitis  1868–1869, 1868 neoplasia  1870, 1871 orbital fat prolapse  1870, 1871 paranasal sinuses  1868 retrobulbar nerve blocks  1867 surgical techniques  1867–1868 posterior segment diseases  1951–1958 chorioretinitis  1954–1955, 1954–1955 chorioretinopathy  1955–1956, 1955 congenital disorders  1855–1857, 1857 congenital stationary night blindness  1956 equine motor neurone disease  1956–1957, 1956 foals  1862 retinal detachment/ degeneration  1957–1958, 1957 vitreous  1952–1954, 1953 prepurchase ophthalmic examination  1961–1963 restraint and nerve blocks  1845–1846, 1845 systemic disease  1961 uveal diseases  1922–1937 equine recurrent uveitis  1925–1935, 1927, 1933 heterochromic iridocyclitis with secondary keratitis  1935–1937, 1936 uveal cysts  1922–1923, 1923 uveal neoplasia  1923–1924, 1924 uveitis  1924–1925, 1926 vision in horses  1841–1844 equine protozoal myeloencephalitis (EPM)  2300, 2511 equine recurrent uveitis (ERU)  1925–1935 breed susceptibility  1931–1932 chorioretinitis  1954–1955, 1955 clinical signs and syndromes  1926–1928, 1927 equine systemic disease with ocular manifestations  2505 histologic features  1931 immunosuppressant drugs  426 leptospirosis and ERU  1928–1929, 1930–1931 long‐term management and prognosis  1935 medical therapy  1932–1934, 1933 ocular drug delivery  369, 373 ocular immunology  282–283

ocular pathology  514–515, 514 pathogenesis  1928–1930 prepurchase ophthalmic examination  1961 secondary cataracts  1946–1947 surgical treatment  1934–1935 equine systemic disease with ocular manifestations  2495–2534 acquired disorders  2499–2520 bacterial infections  2504–2507 dystocia  2499–2500 hematologic diseases  2500 idiopathic systemic diseases  2500–2502, 2501–2502 immune‐mediated diseases  2502–2503, 2503 metabolic diseases  2516–2517 miscellaneous diseases  2519–2520 mycotic diseases  2507–2508 neoplasia  2517, 2518 nutritional disorders  2517–2518 parasitic diseases  2508–2513, 2509–2510 Rickettsial diseases  2513 toxicities  2518–2519 viral infections  2513–2516, 2515 congenital disorders  2495–2499 coat color‐related diseases/ conditions  2495–2497, 2496–2499 developmental disorders  2499 equine viral arteritis (EVA)  305, 2514, 2515 equine viral encephalitis  2515 equine viral encephalomyelitis  2300 ERG see electroretinography ERU see equine recurrent uveitis erythema  1046–1047 erythromycin  392, 1721 esotropia canine orbital diseases  899, 900 feline anterior uvea diseases  1734, 1734 feline neuro‐ophthalmic diseases  2288, 2288 ethambutol  1542 ethics  873–874 ethmoid hematomas  1869 ethylene glycol toxicity  2468 etodolac toxicity  2392 Eurotium spp.  400–401 euryblepharon  946–956, 948–959 EVA see equine viral arteritis evisceration avian ophthalmology  2073 canine orbital diseases  909–911, 910 exenteration canine orbital diseases  909, 909 equine ophthalmology  1867 feline orbital diseases  1794 ocular pathology  479, 481

Index

exophthalmos bovine ophthalmology  1985–1987, 1986–1987 canine orbital diseases  879–880, 882–884, 890–891, 890, 892, 894–895 equine ophthalmology  1864–1865, 1865 fish  2203–2205 guinea pig  2130 rabbit  2138–2139, 2138, 2184, 2185–2186 reptiles  2212 exotic animal ophthalmology  2200–2236 amphibians  2206–2209, 2206–2208 fish  2201–2206, 2202, 2204 mammals  2217–2224 cataracts  2220, 2222–2223, 2222 comparative anatomy, biometry, physiology, and normative test values  2217–2219 corneal degenerations and keratopathies  2222 inflammation and infections  2220–2222 neoplasia  2223 nutritional disorders  2223–2224 ocular fundus diseases  2223 ophthalmic malformations  2219–2220 population surveys  2219 traumatic injury  2224, 2224 ophthalmic examination  2200–2201, 2203, 2207, 2217–2219 reptiles  2209–2217, 2210–2217 expanding vitreous syndrome  1409 experimental autoimmune uveitis (EAU)  282 exposure  815–817, 823–824, 829–830 external hordoleum  971 external ophthalmic dyes  616–620 fluorescein dye  616–619, 616–619 other ophthalmic dyes  620 Rose Bengal  619–620, 620 extracapsular cataract extraction (ECCE)  1393, 1411 extracellular matrix (ECM) canine corneal diseases  1086–1088 canine glaucomas  1177–1178, 1185–1191 canine optic nerve diseases  1624–1625, 1633 clinical pharmacology and therapeutics  462 equine ophthalmology  1885–1887, 1930, 1938 ocular embryology and congenital malformations  3, 17 ocular physiology  142–143 extraocular muscles (EOM) amphibians  2206 diagnostic ultrasound  745

fish  2201 magnetic resonance imaging  676 neuro‐ophthalmology  2248–2250, 2248–2253, 2249 ocular embryology and congenital malformations  19–20 ocular physiology  136–137, 153–154 ophthalmic anatomy  42–46, 44–45, 46 extraocular myositis/polymyositis canine neuro‐ophthalmic diseases  2282–2283 canine orbital diseases  899–900, 899 canine systemic disease with ocular manifestations  2351–2352, 2352 ocular pathology  505–506 extrascleral prosthesis  911, 911 exudates  742–743, 746 exudative optic neuritis  1959 eye‐associated lymphoid tissue (EALT)  271–272, 1012 eye drops conventional eye drops  352–353 drug disposition after eye drop application  353–361, 353 factors affecting corneal absorption  355–356 nasolacrimal drainage and tear washout  354–355 penetration across the cornea  355, 355 penetration via conjunctival/scleral route  356–357 pharmacokinetics of conventional eye drops  358–361, 358 specular microscopy  689–690 systemic absorption  357–358, 357 eyelashes  1846, 1847, 1880–1881, 1881 eyelid agenesis  1666–1668, 1667–1668 eyelid colobomas ocular embryology and congenital malformations  33, 33 ovine and caprine ophthalmology  2024, 2024 eyelid neoplasia equine ophthalmology  1874–1880, 1875–1876, 1876, 1878, 1879, 1880–1881 feline eyelid diseases  1681–1684, 1682, 1682, 1684–1685 ocular pathology  534–541, 535, 536–541 eyelids avian ophthalmology  2055, 2067–2068 bovine ophthalmology  1987–1989, 1988–1989, 2008 canine eyelid disorders  923–987 canine lacrimal secretory system diseases  1012 equine ophthalmology  1845–1846, 1858, 1860, 1870–1881, 1873–1876, 1876, 1878, 1879, 1880–1881

feline eyelid diseases  1665–1684 general ocular examination  574 guinea pig  2130–2131 microsurgery  809 New World camelid ophthalmology  2090–2092, 2092 nonhuman primates  2143 ocular embryology and congenital malformations  18–19, 19 ocular physiology  124–126, 125–126 ophthalmic anatomy  46–48, 46–48, 923–925, 924 ovine and caprine ophthalmology  2023–2025, 2023–2024 porcine ophthalmology  2034–2035, 2034 reflexes involving the blink response  124–126, 125–126, 129 reptiles  2209 FA see fluorescein angiography; fluorescent antibody facial dysplasia syndrome  2536 facial nerve  925 FAE see follicle‐associated epithelium FAF see fundus autofluorescence FAHMS see feline aqueous humor misdirection syndrome FAM161A mutations  1510 famciclovir  404, 1709–1711, 1710 fat suppression  675–676, 675–676 fatty eye  2192, 2192 FCoV see feline coronavirus FCRD see feline central retinal degeneration FCV see feline calcivirus FDIM see feline diffuse iris melanoma feline anterior uvea diseases  1732–1764 acquired iris abnormalities  1736–1738, 1736–1737 anterior uveitis  1738–1756, 1739, 1740–1741, 1742–1746, 1748, 1751–1752 developmental or structural disorders  1733–1736, 1733–1736 neoplasia  1756–1764, 1757, 1759–1763 ophthalmic anatomy  1732 feline aqueous humor misdirection syndrome (FAHMS)  1767–1768, 1768 feline calcivirus (FCV) clinical microbiology and parasitology  298 feline ocular surface disease  1695–1696 feline systemic disease with ocular manifestations  2451–2452, 2452 feline central retinal degeneration (FCRD)  1775–1777, 1776, 2464–2466, 2465

i23

i24

Index

feline coronavirus (FCoV) clinical microbiology and parasitology  298–299 feline anterior uvea diseases  1742–1743 feline neuro‐ophthalmic diseases  2291–2292 feline systemic disease with ocular manifestations  2452–2454 feline diffuse iris melanoma (FDIM)  1756–1759, 1757 feline eyelid diseases  1665–1684 blepharitis  1671–1678, 1672, 1673–1674, 1677–1678 congenital eyelid abnormalities  1665–1668, 1666–1668 eyelid agenesis  1666–1668, 1667–1668 eyelid cysts and nodules  1680–1681 eyelid neoplasia  1681–1684, 1682, 1682, 1684–1685 eyelid opening abnormalities  1665– 1666, 1666 meibomian gland disorders  1678– 1680, 1679–1680 pigmentary disorders  1678, 1679 structural eyelid abnormalities  1668–1671, 1669–1671 feline glaucomas  1764–1770 causes and types  1764–1768, 1764 clinical signs and IOP measurement  1768, 1768 treatment  1768–1770 feline herpesvirus‐1 (FHV‐1) anti‐inflammatory agents  420 antiviral agents  402–405 clinical microbiology and parasitology  296–298 clinical signs  1702–1703, 1703–1704 diagnosis  1703–1705, 1704–1705 external ophthalmic dyes  618, 620 feline anterior uvea diseases  1744 feline eyelid diseases  1666, 1675 feline ocular surface disease  1689– 1693, 1701–1712, 1715, 1718–1719, 1725–1726, 1730 feline systemic disease with ocular manifestations  2436, 2454–2458, 2455 ocular drug delivery  368 pathogenesis  1701, 1702 treatment  1706–1712, 1706, 1708, 1710 feline immunodeficiency virus (FIV) clinical microbiology and parasitology  299–301 feline anterior uvea diseases  1739– 1740, 1742, 1743 feline systemic disease with ocular manifestations  2436, 2444, 2458–2459 feline infectious peritonitis (FIP) clinical microbiology and parasitology  298–299

feline anterior uvea diseases  1739, 1742–1744, 1744 feline neuro‐ophthalmic diseases  2291–2292 feline systemic disease with ocular manifestations  2452–2454 paracentesis  641 feline lens diseases and cataract formation  1770–1773 cataract surgery and lensectomy  1773 congenital cataracts and lens anomalies  1770–1771, 1770 lens luxation/subluxation  1772–1773 primary and secondary cataract formation  1771–1772, 1771–1772 feline leukemia virus (FeLV) clinical microbiology and parasitology  301–302 feline anterior uvea diseases  1739–1742, 1742 feline neuro‐ophthalmic diseases  2292–2293 feline ocular surface disease  1718 feline systemic disease with ocular manifestations  2430, 2444, 2459–2460, 2459–2460 feline lymphocytic uveitis  514–515 feline lymphoplasmacytic uveitis  515 feline nasolacrimal system diseases  1684–1686, 1685 feline neuro‐ophthalmic diseases  2288–2296 acquired disorders  2290–2296, 2294–2295, 2297 congenital disorders  2288–2290, 2288–2290 developmental disorders  2290 feline nictitating membrane diseases  1686–1689 cartilage eversion  1688 Horner’s syndrome  1686–1687, 1686, 1687 idiopathic third eyelid protrusion  1687 neoplasia  1688–1689 prolapsed nictitans gland  1688, 1688 feline ocular post‐traumatic sarcoma (FOPTS)  1759–1761, 1760–1761 feline ocular surface disease  1689–1732, 1690 allergic conjunctivitis  1697–1698 Bordetella bronchiseptica  1696–1697 Chlamydia felis  1689–1694, 1691 conjunctival disease  1690–1698 conjunctival neoplasia  1698–1700, 1699–1700 corneal dermoids  1730–1731 corneal disease  1717–1732 corneal dystrophies and degenerations  1729–1730, 1730 corneal neoplasia and nodules  1731–1732, 1732

dry eye disease syndromes  1716–1717, 1717, 1717 eosinophilic conjunctivitis  1697, 1697 eosinophilic keratitis/proliferative keratoconjunctivitis  1714–1716, 1714 epitheliotropic mastocytic conjunctivitis  1698 feline calcivirus  1695–1696 feline herpesvirus type 1  1689–1693, 1701–1712, 1715, 1718–1719, 1725–1726, 1730 keratoconjunctival disease  1701–1717 miscellaneous corneal infections  1722–1729, 1723, 1725, 1727–1728 mycoplasma‐associated ulcerative keratitis  1712 Mycoplasma felis  1694–1695, 1694 neonatal conjunctivitis  1697 parasitic conjunctivitis  1698 symblepharon  1712–1714, 1713 ulcerative keratitis  1718–1721, 1720, 1722 feline optic nerve and CNS diseases  1788–1790, 1790 feline orbital diseases  1791–1794 congenital and developmental disorders  1791 feline restrictive orbital myofibroblastic sarcoma  1792–1793, 1792 inflammation and infections  1791–1792, 1791 neoplasia  1793–1794, 1793–1794 traumatic proptosis  1791, 1791 feline panleukopenia virus (FPV)  302, 2451–2452, 2460 feline posterior segment diseases  1773–1788 acquired disorders  1774 congenital and developmental disorders  1774 neoplasia  1788 ophthalmic anatomy  1773–1774, 1773 retina and choroid  1774–1788, 1774–1777, 1779–1782, 1784–1785, 1787–1788 vitreous  1774 feline recurrent uveitis  283–284 feline restrictive orbital myofibroblastic sarcoma (FROMS)  1792–1793, 1792 feline retinal reattachment surgery  1608 feline sarcoma virus (FeSV) clinical microbiology and parasitology  302 feline anterior uvea diseases  1744–1745 feline systemic disease with ocular manifestations  2460–2461 feline spongiform encephalopathy (FSE)  2451

Index

feline systemic disease with ocular manifestations  2421–2494 acquired disorders  2428–2469 bacterial infections  2435–2440, 2437, 2439–2440 cardiovascular diseases  2428–2429, 2428–2429 hematologic diseases  2429–2432 idiopathic systemic diseases  2432– 2433, 2433 immune‐mediated diseases  2433–2435 metabolic diseases  2461–2463, 2462 mycotic infections  2441–2446, 2441, 2443–2444 neoplasia  2459–2460, 2463–2464 nutritional disorders  2464–2466, 2465 parasitic diseases  2446–2451, 2446–2450 prions  2451 toxicities  2466–2469, 2467, 2469 viral infections  2451–2461, 2452, 2455, 2459–2460 congenital disorders  2421–2423 coat color‐related diseases/conditions  2421–2422 developmental disorders  2423–2428, 2425, 2427 globoid cell leukodystrophy  2424 GM1‐/GM2‐gangliosidosis  2424–2425 lysosomal storage diseases  2423–2428 α‐mannosidosis  2423–2424 mucolipidosis type II  2425–2426, 2425 mucopolysaccharidosis  2426, 2427 sphingomyelin lipidosis  2426–2428 FeLV see feline leukemia virus fERG see flash electroretinography; full field electroretinography ferret  2194–2196, 2195–2196 ferritins  151 FeSV see feline sarcoma virus fetal nuclear cataracts  1945 FHV‐1 see feline herpesvirus‐1 fiber baskets  98–99, 99 fibrae latae  634, 634 fibril  1460–1461 fibrillin  1192, 1200 fibrin  1405, 1417–1418, 1756 fibrinous aqueous  1271, 1272 fibrinous membranes  1470, 1471 fibrinous uveitis  1862, 1862 fibroblasts  1086, 1087 fibroma  973 fibrosarcoma canine eyelid disorders  973 feline anterior uvea diseases  1764 feline eyelid diseases  1683

feline nictitating membrane diseases  1689 feline ocular surface disease  1731 fibrosing estropia  2278 fibrosis  1406 fibrovascular membranes  491, 492 file size  822, 822, 830 fine needle aspiration (FNA) canine orbital diseases  882, 888, 900 ocular pathology  482 Finoff transilluminator  837–838, 837–838, 842, 848, 857 FIP see feline infectious peritonitis fish exotic animal ophthalmology  2201–2206 general ocular examination  566 ocular disorders and lesions  2203–2206, 2204 ophthalmic anatomy  2201–2203, 2202 ophthalmic examination  2203 optics and physiology of vision  187–188, 187–189 fistulae  895 FIV see feline immunodeficiency virus fixations  234 fixatives  614–615 FLAIR see fluid attenuation inversion recovery flash electroretinography (fERG)  1183–1185, 1193, 1211 canine ocular fundus diseases  1480–1481, 1549–1550 canine optic nerve diseases  1636–1637 flash photography  820–825, 827–829, 827, 828, 832, 835, 836 flesh eye  2192, 2192 flicker detection  232–233, 233 floaters canine vitreous diseases  1466, 1469, 1470 diagnostic ultrasound  742 Florida spots canine corneal diseases  1140–1141, 1141 feline ocular surface disease  1723–1724, 1723 fluconazole canine anterior uvea diseases  1280 canine systemic disease with ocular manifestations  2363 clinical pharmacology and therapeutics  399–400 feline anterior uvea diseases  1749 fluid attenuation inversion recovery (FLAIR)  676, 677 fluorescein angiography (FA)  705–716 anterior segment and retinal imaging  704 basic principles and physics  705–707 canine ocular fundus diseases  1479, 1480

clinical applications  707–716, 709–717 equine ophthalmology  1889, 1889, 1911 hypo‐ and hyperfluorescence  707 laboratory animal ophthalmology  2155 ovine and caprine ophthalmology  2030–2031 photography  858 fluorescein dye examination  616–619, 616–619 bovine ophthalmology  1998 canine nasolacrimal diseases  991, 991 exotic animal ophthalmology  2200 fluorescence  169 fluorescent antibody (FA) testing fungal and algal diseases  322 viral infections  294, 298, 304 fluorometholone  419–420 fluorophotometry  145–146 fluoroquinolones (FQN) clinical pharmacology and therapeutics  394–396 feline neuro‐ophthalmic diseases  2293–2294 feline ocular surface disease  1695 feline posterior segment diseases  1780–1782, 1780–1781 feline systemic disease with ocular manifestations  2466–2468, 2467 5‐fluorouracil (5‐FU) canine corneal diseases  1149–1150 canine glaucomas  1229–1230 equine ophthalmology  1877, 1879 flurbiprofen  422–424, 1084 FNA see fine needle aspiration focal blepharitis  971 focal granulomas  1028 focal light  1460 focus  817–818, 824, 830, 832 folate metabolism  393–394 fold‐grasping method  940, 941 follicle‐associated epithelium (FAE)  271 follicular conjunctivitis canine conjunctival diseases  1050, 1050 canine nictitating membrane diseases  1069 slit‐lamp biomicroscopy  581 food and fiber animals bovine ophthalmology  1983–2021 neuro‐ophthalmology  2304–2310, 2305 ovine and caprine ophthalmology  2021–2033 porcine ophthalmology  2033–2037 systemic disease with ocular manifestations  2535–2569 acquired disorders  2540–2559 congenital disorders  2535–2538, 2536–2537 developmental disorders  2538–2540 hematologic diseases  2540–2541

i25

i26

Index

food and fiber animals (cont’d) idiopathic diseases  2541 immune‐mediated diseases  2541 infectious diseases  2541–2552, 2543, 2545, 2547–2549, 2551–2552 metabolic diseases  2553 miscellaneous diseases  2559 neoplasia  2553 nutritional disorders  2553–2556, 2554–2556 toxicities  2556–2559, 2558 FOPTS see feline ocular post‐traumatic sarcoma forage poisoning  2504–2505 forceps  810–812, 811–812 foreign bodies avian ophthalmology  2073 canine anterior uvea diseases  1290 canine conjunctival diseases  1055, 1056 canine corneal diseases  1116–1117, 1118 canine lacrimal secretory system diseases  1033–1034 canine lens diseases and cataract formation  1346–1347 canine nasolacrimal diseases  1001–1002, 1002 canine nictitating membrane diseases  1070 canine optic nerve diseases  1649 canine orbital diseases  883, 886–887, 897 computed tomography  670 equine ophthalmology  1894, 1894 feline orbital diseases  1792 four‐point block  570 fovea centralis  189–190, 200 foveae  96–97, 97 FPV see feline panleukopenia virus FQN see fluoroquinolones fractures canine orbital diseases  902–903 equine ophthalmology  1869–1870, 1870 free transplants  948, 949 FROMS see feline restrictive orbital myofibroblastic sarcoma FSE see feline spongiform encephalopathy Fuch’s dystrophy  1138 Fuchs procedure  953–954, 955 fucosidosis  2335–2337 full field electroretinography (fERG)  757–771 amplification and signal filtering  758–759 analysis of recordings  766–768, 767 a‐wave  766, 768–770 b‐wave  766, 768–770 canine glaucomas  1203 combined rod–cone response  765–766, 769

cone response  766 c‐wave  771 electrodes  759–760, 760 equipment and technical considerations  757–771, 758 flicker ERG  766, 770–771 grounding/common electrode  761 interpretation of results  768–770, 769–771 i‐wave  771, 772 light/dark adaptation  764–765, 764 mydriasis  763 oscillatory potentials  766–768, 769 patient preparation  763–765, 764 photopic negative response  771 placement of electrodes  760–762, 762 recording electrode  761 recording protocols  763, 765–768, 765, 767, 768 reference electrode  761 restraint  763–764 rod response  765 scotopic threshold response  771 signal averaging and electrical noise reduction  762, 769–770, 770–771 single flash  766 stimulator/stimulation  758, 759 full‐thickness corneal lacerations  1115– 1116, 1116–1117 fumonisin toxicity  2519 fundamentals of animal vision  225–257 color vision  239–241, 239, 240, 241 dark adaptation  230–231, 231 flicker detection  232–233, 233 globe size and sensitivity  229–230, 230 light adaptation  231–232 motion perception  233–234 photopic vision  225–227, 231–232, 249–250 processing of data from photoreceptors  225, 226 pupil  232, 232, 246–247, 246–247 rods and rod pathways  227–228, 228 scotopic vision  225–231, 228–231, 249–250 stereopsis  234–239, 236–238 tapetum  228–229, 229 threshold‐sensitivity inverse relationship  225–227, 227 visual acuity  242–252, 242–243, 244, 245–252 visual fields  234–237, 235 fundus see ocular fundus fundus autofluorescence (FAF)  1478, 1479 fundus photography see ophthalmoscopy and fundus photography fungal and algal diseases anti‐inflammatory agents  420 avian ophthalmology  2060–2061, 2067–2068

bovine ophthalmology  1988, 1993 canine anterior uvea diseases  1279– 1281, 1280, 1285, 1285 canine conjunctival diseases  1048, 1056 canine corneal diseases  1120–1121, 1120 canine eyelid disorders  969, 969 canine lens diseases and cataract formation  1345 canine ocular fundus diseases  1532– 1536, 1532, 1534, 1536 canine systemic disease with ocular manifestations  2353–2354, 2354, 2359–2364, 2363–2364 classification and mechanism of injury  319–320 clinical microbiology and parasitology  319–324 commensal ocular surface flora  311, 312 diagnostic methods  320–322, 321 equine ophthalmology  1859–1860, 1887–1897, 1895, 1897, 1898–1899 equine systemic disease with ocular manifestations  2507–2508, 2519 exotic mammals  2220–2221 feline anterior uvea diseases  1747–1749, 1748 feline eyelid diseases  1671–1673, 1673 feline ocular surface disease  1722–1724, 1723 feline orbital diseases  1792 feline posterior segment diseases  1782, 1782 feline systemic disease with ocular manifestations  2441–2446, 2441, 2443–2444 fish  2204 food animal systemic disease with ocular manifestations  2546 in vivo confocal microscopy  693, 696 laboratory sampling  612 New World camelid ophthalmology  2092, 2101 ocular pathology  490–491, 490 ovine and caprine ophthalmology  2024 pathogenic fungi  322–324 porcine ophthalmology  2035 reptiles  2214–2215 surgical procedures on the canine lens  1419–1421 see also antifungal agents; individual species/diseases Fusarium spp. antifungal agents  396–397, 399–402 bovine ophthalmology  1993 clinical microbiology and parasitology  322–323 equine systemic disease with ocular manifestations  2519

Index

GABA see γ‐amino butyric acid GAG see glycosaminoglycans galactocerebrosidosis canine systemic disease with ocular manifestations  2337–2338 food animal systemic disease with ocular manifestations  2538 galactosemia  1344 galactosylceramide lipidosis  2538 γ‐amino butyric acid (GABA)  200–201, 208 ganciclovir  1709 ganglion cells see retinal ganglion cells gangliosidosis  1526–1527 gastrulation  3–5, 6 gaze behaviors  234 GDP see gel diffusion precipitin; guanosine diphosphate GDRG see goniogenesis‐related glaucoma gel diffusion precipitin (GDP) test  321 gels  365 gender canine glaucomas  1198 tear tests  607 tonometry  628 generalized glycogenesis  2538–2539 generalized osteosclerosis  2433 generalized seborrhea  1019 gene therapy canine glaucomas  1239 canine ocular fundus diseases  1482, 1507–1508, 1511, 1519–1520, 1522, 1526 fluorescein angiography  708 genetics and DNA testing  778–786 alternative splicing of genes  780 autosomal dominant inheritance  781–782 autosomal recessive inheritance  781 breeding from carriers of recessive disease  785 canine genome  778 canine glaucomas  1183, 1185, 1187–1190, 1198–1201 canine lens diseases and cataract formation  1336, 1337–1339, 1355–1356 canine ocular fundus diseases  1503– 1527, 1504–1506 changes in coding regions of DNA  780 changes in noncoding regions of DNA  780, 781 complex traits  782 DNA changes in hereditary disease  780–782, 781 DNA sequencing  783–784 equine ophthalmology  1931–1932 feline ocular surface disease  1701 genetic traits  780 genome‐wide association study  783 identification of disease‐causing mutations  782–783

linked‐marker test  784–785 mitochondrial inheritance  782 multiplex testing  785 mutation detection tests  784 nonsense‐mediated mRNA decay  780–781 other genomes  779, 779 pharmacogenetics  782 quantitative trait loci  782 random X chromosome inactivation/ lyonization  782 sample collection  784 structure of genes  779–780 tests for genetic disease  784–785 X‐linked dominant and recessive inheritance  782 genome‐wide association study (GWAS)  783 gentamicin  390–391, 1720–1721 geographic corneal ulceration  297 geographic retinal dysplasia  1492–1493, 1493–1494 geriatric eye conditions see age and aging giant cells  489–490, 490 giant retinal tears  1588–1589, 1589–1590, 1596 glaucoma acquired/inherited disorders  516–517, 525–530, 527, 528, 529 amphibians  2208 anti‐inflammatory agents  420 avian ophthalmology  2066–2067 bovine ophthalmology  1999, 2010–2011, 2011–2012 calcium channel blockers  466–467 canine anterior uvea diseases  1273–1274, 1286–1287, 1286, 1292–1293, 1292–1293 canine glaucomas  1173–1255 canine lens diseases and cataract formation  1341–1342, 1356–1357 canine ocular fundus diseases  1549–1550 canine optic nerve diseases  1624–1625, 1629, 1632, 1633, 1653–1655, 1654–1655 carbonic anhydrase inhibitors  457–461 cholinergic agonists (miotics)  451–454 clinical microbiology and parasitology  300 clinical pharmacology and therapeutics  451–478 congenital disorders  497–498, 497, 500–501 corneal esthesiometry  601 diagnostic ultrasound  734, 744, 746, 748, 750, 751 drugs acting on adrenoceptors  454–457 epidemiology and signalment  1372, 1373, 1428

equine ophthalmology  1855, 1856, 1936–1937, 1937–1942 feline glaucomas  1764–1770, 1764, 1765–1768 gonioscopy  630, 634–636 laboratory animal ophthalmology  2122–2123, 2137–2138, 2143, 2155–2156, 2156 mydriatics/cyclopegics  435 new directions  469–470 New World camelid ophthalmology  2103–2104 ocular embryology and congenital malformations  30–31 ocular pathology  482, 485, 491 ocular physiology  143, 145 ophthalmic anatomy  107 optical coherence tomography  702 optic nerve degeneration  529–530 optics and physiology of vision  170–171 osmotic agents  467–469 ovine and caprine ophthalmology  2029 pathogenesis of secondary glaucoma  527–529, 528, 529 prostaglandin analogues  461–466 rabbit  2189, 2189 species characteristics of acquired glaucoma  526–527, 527 surgical procedures on the canine lens  1372, 1373, 1377–1378, 1428–1429, 1431, 1438 glial cells  104 glioma  1651–1652, 1652 globe avian ophthalmology  2055–2056, 2066 bovine ophthalmology  1983–1986, 1984–1986 canine glaucomas  1186 congenital disorders  888–892 diagnostic ultrasound  738–741, 739–741 displacement of  879, 881 equine ophthalmology  1841, 1842, 1870, 1870 general ocular examination  574–577, 576 indentation/deformation of  880 microsurgery  796–798, 797–798 ocular pathology  479–482, 481 ophthalmic anatomy  51–53, 51–53, 51–52 ovine and caprine ophthalmology  2022–2023, 2022 porcine ophthalmology  2033–2034, 2033 reptiles  2209–2210 scotopic vision  229–230, 230 size, shape, and topography  51–53, 51–52, 52–53

i27

i28

Index

globe (cont’d) surgery of the globe and the orbit  905– 914, 906, 908–915 tunics  51, 51 visual acuity  247, 248 globoid cell leukodystrophy canine systemic disease with ocular manifestations  2337–2338 feline systemic disease with ocular manifestations  2424 food animal systemic disease with ocular manifestations  2538 glucose/glycolysis  131, 150 glutamate  208, 1194–1195 glutathione  149–150, 1348 glycans  56–59, 57 see also glycosaminoglycans glycerin  468 glycocalyx  128 glycosaminoglycans (GAG) canine corneal diseases  1083–1084, 1096, 1100 canine glaucomas  1187 ocular physiology  129, 151 ophthalmic anatomy  58–59, 68, 77, 92, 94 GM1‐/GM2‐gangliosidosis canine systemic disease with ocular manifestations  2338 feline systemic disease with ocular manifestations  2424–2425 food animal systemic disease with ocular manifestations  2539 GME see granulomatous meningoencephalitis goats see ovine and caprine ophthalmology goblet cell atrophy  507–508 goblet cell density (GCD)  1717, 1717 goblet cells canine conjunctival diseases  1045– 1046, 1051 canine lacrimal secretory system diseases  1012, 1020–1021, 1028 laboratory sampling  615–616 goniodysgenesis see pectinate ligament dysplasia goniogenesis‐related glaucoma (GDRG)  1197 goniophotography  843–847, 849 gonioscopy  630–636 canine glaucomas  1177–1178, 1181–1182, 1181, 1203, 1209–1210 canine posterior segment surgery  1589 development and principle of the technique  630–631, 631 direct versus indirect goniolenses  631–633, 632–633 feline glaucomas  1765, 1766 practical application  633–636, 634–635 surgical procedures on the canine lens  1374

gradient recall echo (GRE) imaging  675, 675 gramicidin  388, 390 granulae iridica  1841 granulomas  1028, 1054–1055 granulomatous blepharitis  1028 granulomatous chorioretinitis  2360 granulomatous conjunctivitis  2370, 2370 granulomatous episcleritis  1053, 1053 granulomatous inflammation  489–490, 490 granulomatous meningoencephalitis (GME) canine neuro‐ophthalmic diseases  2283–2284, 2284 canine ocular fundus diseases  1552–1553 canine optic nerve diseases  1646–1647 canine systemic disease with ocular manifestations  2349–2350 magnetic resonance imaging  680–681 granulomatous uveitis  514–516, 530, 2362 grass tetany  2306, 2553 GRE see gradient recall echo grid keratotomy  2187 griseofulvin equine systemic disease with ocular manifestations  2497–2498 feline neuro‐ophthalmic diseases  2294, 2294–2295 feline orbital diseases  1791 feline posterior segment diseases  1782 feline systemic disease with ocular manifestations  2468 ocular pathology  494 Grussendorf procedure  955–956, 959 GTP see guanosine triphosphate guanosine diphosphate (GDP)  193–194 guanosine triphosphate (GTP)  193–194 guinea pig ancillary diagnostic values  2146, 2148 functional morphology  2127–2128 laboratory animal ophthalmology  2127–2132 ophthalmic examination  2110 small mammal ophthalmology  2190–2193, 2190–2194 spontaneous lesions and diseases  2128–2132, 2131 guttural pouch disease  2300–2301 GWAS see genome‐wide association study H5N1/2 see avian influenza virus HA see hyaloid artery; hyaluronic acid Habronema spp. clinical microbiology and parasitology  329 equine ophthalmology  1872–1873, 1874 equine systemic disease with ocular manifestations  2509–2510, 2510

Hackett–McDonald scoring system  2112 Haematopinus spp.  2509 Haemophilus spp.  315–316 Halicephalobus spp.  329–330, 2510 halothane  630 hamartomas  23, 25 haplopia  236–237 harderian glands avian ophthalmology  2065 guinea pig  2128 mouse and rat  2117 ophthalmic anatomy  49–50 reptiles  2209 HC see hereditary cataracts HCV see hog cholera virus head loupes  788–790, 790–791 heat shock proteins (Hsp)  264, 1085 hedgehog  2196–2197, 2196 Heidelberg retina tomography (HRT)  691–693, 692–693 height cues  1842 Helichrysum argyrosphaerum poisoning  2306, 2558 Helmbold procedure  951, 952 hemangioma canine anterior uvea diseases  1296–1297 canine conjunctival diseases  1052 canine corneal diseases  1150 canine nictitating membrane diseases  1068, 1069 equine ophthalmology  1880, 1881 feline nictitating membrane diseases  1688 ocular pathology  540 hemangiosarcoma canine anterior uvea diseases  1296–1297 canine conjunctival diseases  1052, 1052 canine corneal diseases  1150 canine nictitating membrane diseases  1068 canine systemic disease with ocular manifestations  2386, 2386 feline nictitating membrane diseases  1688 ocular pathology  540, 541 hematologic diseases canine systemic disease with ocular manifestations  2342–2345, 2344 equine systemic disease with ocular manifestations  2500 feline systemic disease with ocular manifestations  2429–2432 food animal systemic disease with ocular manifestations  2540–2541 hematoma  902–903 hemidesmosomes  56 hemidilated pupil  2271–2272, 2273 hemifacial spasm  2269–2271

Index

hemorrhage bovine ophthalmology  1991, 1991, 2020 canine anterior uvea diseases  1272, 1273 canine conjunctival diseases  1055, 1055, 1057 canine eyelid disorders  927–928 canine ocular fundus diseases  1487–1488 canine systemic disease with ocular manifestations  2341, 2344, 2374 canine vitreous diseases  1462, 1466, 1470–1471, 1470 diagnostic ultrasound  742–743, 743–745 direct ophthalmoscopy  593 equine ophthalmology  1858, 1862 feline systemic disease with ocular manifestations  2430 ocular pathology  503, 504 surgical procedures on the canine lens  1406, 1416, 1437 hemorrhagic stroke  2280, 2341 hemostasis canine eyelid disorders  927–928 microsurgery  798, 812–813, 813 heparan  58–59, 148 Hepatozoon spp.  2368–2369 HERDA see hereditary equine regional dermal asthenia hereditary cataracts (HC)  1333–1339, 1334–1336, 1339 hereditary equine regional dermal asthenia (HERDA)  1919 equine systemic disease with ocular manifestations  2498–2499 pachymetry  686 herpes simplex virus (HSV)  1674, 1675, 2212, 2213 HES see hypertonic hydroxyethyl starch heterochromia iridis bovine ophthalmology  2011–2012, 2012 canine anterior uvea diseases  1260, 1260 equine ophthalmology  1851, 1852 feline anterior uvea diseases  1733, 1733 miniature pig  2140 New World camelid ophthalmology  2089–2090, 2090 porcine ophthalmology  2035, 2035 heterochromic iridocyclitis  515 heterochromic iridocyclitis with secondary keratitis (HIK)  1935–1937, 1936 heterotopic bone formation  2131–2132, 2131, 2193, 2193 HEXB mutations  1526–1527 H‐figure plasty  976, 976–977 hibernomas  902

high‐frequency ultrasonography  1211 high‐resolution ultrasound (HRUS)  739, 741, 745–750, 748–751 canine corneal diseases  1152 canine glaucomas  1177–1178, 1182–1183, 1211, 1215 surgical procedures on the canine lens  1375 HIK see heterochromic iridocyclitis with secondary keratitis histiocytoma  537, 538, 1987 histiocytosis  972, 2393 histology/histopathology bovine ophthalmology  2006, 2006, 2012, 2017–2018 canine anterior uvea diseases  1279, 1280, 1294–1295 canine corneal diseases  1126, 1130 canine glaucomas  1211 canine lens diseases and cataract formation  1331–1332, 1331–1332 canine nictitating membrane diseases  1063 canine ocular fundus diseases  1488– 1489, 1493, 1496–1497, 1496, 1513 canine optic nerve diseases  1626, 1638–1639 canine posterior segment surgery  1588, 1589 canine systemic disease with ocular manifestations  2354, 2354, 2367–2370, 2370 conjunctival histology  615–616 equine ophthalmology  1931 feline neuro‐ophthalmic diseases  2292 feline ocular surface disease  1692, 1724 feline posterior segment diseases  1776–1778, 1780 feline systemic disease with ocular manifestations  2448, 2448 mouse and rat  2124–2125, 2124, 2126 ocular embryology and congenital malformations  24, 29, 31–32 ocular pathology  482, 483–484, 486 ophthalmic anatomy  46, 48–49, 54 ovine and caprine ophthalmology  2032 protozoal diseases  324 histomorphometry  1205 Histophilus spp.  2543–2544, 2543 Histoplasma spp. antifungal agents  400–401 canine anterior uvea diseases  1281 canine ocular fundus diseases  1533 canine systemic disease with ocular manifestations  2363–2364, 2364 clinical microbiology and parasitology  323 equine systemic disease with ocular manifestations  2508 feline anterior uvea diseases  1749

feline systemic disease with ocular manifestations  2444–2445 ocular pathology  532 hog cholera virus (HCV)  308, 2550 holangiotic retina  2195–2196 homatropine  437 hood conjunctival flap  1105, 1107 hood graft see advancement graft hordeolum/stye  971 horizontal cells ophthalmic anatomy  101, 102 optics and physiology of vision  196–201, 199–201 Horner’s syndrome equine ophthalmology  1881–1882 feline nictitating membrane diseases  1686–1687, 1686, 1687 neuro‐ophthalmology  2265, 2268– 2269, 2270, 2271–2272, 2288, 2294 horses see equine house‐inverted‐triangle blepharoplasty  975–976, 975 HRT see Heidelberg retina tomography HRUS see high‐resolution ultrasound HSF4 mutations  1338 Hsp see heat shock proteins Hunter syndrome  2339 Hurler syndrome  2339, 2426, 2427 HVS see hyperviscosity syndrome hyalocentesis  639–640, 639, 1461–1463, 1463 hyaloid artery (HA) canine lens diseases and cataract formation  1322 canine vitreous diseases  1459 equine ophthalmology  1853 ocular embryology and congenital malformations  13, 13, 15, 18 hyaluronic acid (HA) ocular drug delivery  363, 365 ocular physiology  151–153 ophthalmic anatomy  58–59, 92 surgical procedures on the canine lens  1426 hyaluronidase  1415 hydatid cysts  1869 hydrocephalus canine neuro‐ophthalmic diseases  2277–2278 canine systemic disease with ocular manifestations  2333, 2333 feline neuro‐ophthalmic diseases  2289–2290, 2289–2290 feline systemic disease with ocular manifestations  2422–2423 food animal neuro‐ophthalmic diseases  2304 food animal systemic disease with ocular manifestations  2536–2537 hydrocortisone  419, 421 hydrodissection  1398–1399, 1949

i29

i30

Index

hydrogels  1598–1599 hydroxyamphetamine  2264–2265 hydroxypyridinethione  1544 hygromycin B  2556 hyperadrenocorticism  2384 hypercalcemia  1342 hypercholesterolemia amphibians  2208 canine systemic disease with ocular manifestations  2342–2343 feline ocular surface disease  1730 hypercupremia  1342 hyperelastosis cutis  2536 hyperemia  1046, 1269 hyperkalemic periodic paralysis (HyPP)  2519–2520 hyperlipidemia canine anterior uvea diseases  1285–1286 canine ocular fundus diseases  1547 canine systemic disease with ocular manifestations  2342–2343 feline systemic disease with ocular manifestations  2430 hypermature cataracts canine anterior uvea diseases  1277 canine glaucomas  1218, 1219 canine lens diseases and cataract formation  1328, 1329, 1332, 1332 surgical procedures on the canine lens  1372, 1375 hyperopia avian ophthalmology  2059 fundamentals of animal vision  243 mouse and rat  2117 optics and physiology of vision  178– 181, 178, 187–189 retinoscopy  599 hyperosmotic solution  1138–1139, 1229 hyperpigmentation canine systemic disease with ocular manifestations  2331 ocular pathology  493 photography  845, 847 surgical procedures on the canine lens  1372 hyperplasia  484, 486, 493 see also individual locations hypersensitivity antibacterial agents  388, 394 canine anterior uvea diseases  1287 feline eyelid diseases  1674–1675, 1677 local anesthetics  441 hypertensive retinopathy  1547, 1547, 1783–1786, 1784–1785 hyperthermia  1341 hyperthermic therapy  2009 hyperthyroidism  2463 hypertonic hydroxyethyl starch (HES)  468 hypertriglyceridemia  1730

hypertrophy  484, 486, 708 see also individual locations hypertropia  1850, 1850 hyperviscosity syndrome (HVS) canine anterior uvea diseases  1287 canine ocular fundus diseases  1547, 1548 canine systemic disease with ocular manifestations  2343, 2344 feline posterior segment diseases  1786–1787 feline systemic disease with ocular manifestations  2430–2431 hyphema canine anterior uvea diseases  1272, 1272, 1291–1292, 1298 equine ophthalmology  1870 feline anterior uvea diseases  1753–1754, 1763 surgical procedures on the canine lens  1416 hypocalcemia canine lens diseases and cataract formation  1342, 1342 canine systemic disease with ocular manifestations  2385 feline systemic disease with ocular manifestations  2463 food animal neuro‐ophthalmic diseases  2306 food animal systemic disease with ocular manifestations  2553 ocular pathology  524 hypolipidemic drugs  2391 hypomagnesemia  2306, 2553 hypopigmentation  2421–2422 hypoplasia canine anterior uvea diseases  1262, 1262 ocular pathology  482, 484, 496, 496, 498–502 hypopyon  1272, 1272, 2214 hypothermia  1341 hypothiaminosis  2020 hypothyroidism  2384, 2516–2517 hypoxia  2294, 2431 hypoxic ischemic encephalopathy  1862 HyPP see hyperkalemic periodic paralysis iatrogenic retinal detachment  1580 IBK see infectious bovine keratoconjunctivitis IBR see infectious bovine rhinotracheitis ICA see iridocorneal angle ICCE see intracapsular cataract extraction ICG see indocyanine green ICH see infectious canine hepatitis; intracorneal stromal hemorrhage ICK see infectious crystalline keratopathy ICLE see intracapsular lens extraction ICP see intracranial pressure

icterus canine systemic disease with ocular manifestations  2343, 2344 equine ophthalmology  1882 equine systemic disease with ocular manifestations  2500 feline systemic disease with ocular manifestations  2431 food animal systemic disease with ocular manifestations  2540 idiopathic facial dermatitis  1678, 1678 idiopathic facial nerve paralysis  2281–2282 idiopathic granulomatous disease  1069 idiopathic lymphocytic plasmacytic uveitis  489 idiopathic oculomotor neuropathy  2281, 2281 idiopathic orbital inflammatory syndrome  503–504 idiopathic primary edema  1920–1921, 1921 idiopathic sterile granulomatous disease  1053 idiopathic systemic diseases canine systemic disease with ocular manifestations  2345–2347 equine systemic disease with ocular manifestations  2500–2502, 2501–2502 feline systemic disease with ocular manifestations  2432–2433, 2433 food animal systemic disease with ocular manifestations  2541 idiopathic uveitis  1754–1755, 2541 idiopathic vestibular disease  2282 idoxuridine  403, 1707 IF see immunofluorescence IFA see immunofluorescent antibody IFN see interferons IHC see immunohistochemistry IL see interleukins image quality  822, 822, 830 image size  821–822, 822, 830 imidazoles  399 IMMK see immune‐mediated keratitis immune‐mediated diseases canine eyelid disorders  970–971, 970 canine ocular fundus diseases  1549 canine systemic disease with ocular manifestations  2347–2353, 2348–2349, 2352–2353 equine systemic disease with ocular manifestations  2502–2503, 2503 feline anterior uvea diseases  1754 feline eyelid diseases  1676, 1677 feline systemic disease with ocular manifestations  2433–2435 food animal systemic disease with ocular manifestations  2541

Index

immune‐mediated keratitis (IMMK) endothelial IMMK  1917 epithelial IMMK  1916 equine ophthalmology  1913–1917, 1914–1915 midstromal IMMK  1917 ocular immunology  280 superficial IMMK  1916 immune‐mediated retinitis (IMR)  2282, 2348–2349, 2348 immune response see ocular immunology immunodeficiency  2499 immunofluorescence (IF) fungal and algal diseases  322 protozoal diseases  325 viral infections  294, 302 immunofluorescent antibody (IFA) tests external ophthalmic dyes  620 feline ocular surface disease  1704–1705 laboratory sampling  615 immunogenetics  268 immunoglobulin M deficiency  2499 immunoglobulins  128 immunohistochemistry (IHC)  299, 482, 484 immunosuppression canine anterior uvea diseases  1274–1276, 1279 canine corneal diseases  1130–1131 canine lacrimal secretory system diseases  1022–1024, 1023–1024 clinical pharmacology and therapeutics  425–427 equine ophthalmology  1933 feline ocular surface disease  1715 viral infections  303 immunotherapy bovine ophthalmology  2009–2010 equine ophthalmology  1877, 1879 implanted devices episcleral implants  368–369, 426 equine ophthalmology  1933–1934, 1933, 1941–1942 extrascleral shell implants  1868 gonioimplants  1941–1942 ocular drug delivery  371–372 impression cytology  613, 614 IMR see immune‐mediated retinitis inborn errors of metabolism (IEM)  2334–2335 inclusion cysts  509, 510 indirect‐acting sympathomimetics  438 indocyanine green (ICG) angiography  706, 1479, 1480 indolent corneal ulcers  1892–1893, 1893 indomethacin  422–423 induced retinal dysplasia  1497 infantile corneal dystrophy  1095, 1095 infectious blepharitis  1019 infectious bovine keratoconjunctivitis (IBK)  1994–2002

clinical signs  1998, 1998–1999 etiology and transmission  1994–1996, 1995–1996 incidence and impact  1994 medical treatment  1998–2001 pathogenesis  1997–1998 predisposing factors  1996–1997 surgical treatment  2001 vaccination  2001–2002 infectious bovine rhinotracheitis (IBR)  1993, 1993, 2003 clinical microbiology and parasitology  306 food animal systemic disease with ocular manifestations  2550–2551 infectious canine hepatitis (ICH)  1284, 2378–2380, 2379 infectious crystalline keratopathy (ICK)  1129–1131, 1129–1130 infectious keratitis  420, 423 infectious keratoconjunctivitis bovine ophthalmology  1992–1994, 1993 exotic mammals  2220 food animal systemic disease with ocular manifestations  2544–2545 New World camelid ophthalmology  2093–2094 ovine and caprine ophthalmology  2025 porcine ophthalmology  2035 infectious rhinotonsillitis  1530 infectious upper respiratory disease (IURD)  1711 inferior‐temporal palpebral (ITP) route  569, 905–906, 906 inflammation avian ophthalmology  2059–2063, 2060–2061 bovine ophthalmology  1987, 2013, 2018 canine conjunctival diseases  1053, 1053–1054, 1057 canine corneal diseases  1096–1131, 1136–1137 canine eyelid disorders  968–971, 969–971 canine glaucomas  1196–1197, 1210–1211, 1221–1222, 1228–1230 canine lacrimal secretory system diseases  1019, 1028 canine nictitating membrane diseases  1068–1070, 1070 canine ocular fundus diseases  1527–1528, 1528–1529 canine optic nerve diseases  1642–1647 canine orbital diseases  880, 883, 892–896, 894–897 canine vitreous diseases  1470–1471, 1471 clinical pharmacology and therapeutics  417

computed tomography  670 diagnostic ultrasound  744 equine ophthalmology  1868–1869, 1868, 1886–1888 exotic animal ophthalmology  2220–2222 feline eyelid diseases  1671–1680 feline orbital diseases  1791–1792, 1791 feline posterior segment diseases  1782–1783, 1782 infectious inflammatory ocular disease  531, 531–532, 532 noninfectious inflammatory ocular disease  503–506, 503, 504–505 ocular immunology  263–265, 265, 267–270, 278–281 ocular pathology  488–493, 488–494, 503–506, 503, 504–505 ovine and caprine ophthalmology  2029, 2031 porcine ophthalmology  2035–2037 repair of ocular tissues  491 sequelae of ocular inflammation  491–493, 492–494 surgical procedures on the canine lens  1380–1381, 1431 see also anti‐inflammatory agents; immunosuppression; individual disorders; uveitis influenza viruses  1048, 2515 infrared macrophotography  840–842, 843–847 infrared photoretinoscopy  175 inherited/presumed inherited disorders avian ophthalmology  2059 bovine ophthalmology  1991, 2020 canine lens diseases and cataract formation  1333–1339, 1334–1336, 1339, 1353–1354, 1355–1356 canine ocular fundus diseases  1496– 1497, 1496, 1498–1519, 1500–1502, 1504–1506, 1507–1509, 1511, 1514–1518 choroidal disorders  521–522 conjunctival disorders  508 corneal disorders  511–513 equine ophthalmology  1931–1932, 1946 feline posterior segment diseases  1777–1780 ocular pathology  505–506, 508, 511–514, 516–522 orbital disorders  505–506 ovine and caprine ophthalmology  2033 retinal disorders  517–520 scleral/episcleral disorders  513–514 storage disorders, amino acid, and lipid peroxidation disorders  522 uveal disorders  516–517 vitreous disorders  518–522 see also individual disorders

i31

i32

Index

inherited retinal degenerations (IRD)  778 innate immune response ocular immunology  266, 266 ocular surface innate immune response  271–273, 274 inner limiting membrane  104 inner nuclear layer (INL) ophthalmic anatomy  100–102, 101 optics and physiology of vision  196–201, 199–202 inner plexiform layer  102–103, 102 insect bites/stings canine conjunctival diseases  1049, 1049 canine systemic disease with ocular manifestations  2391 food animal systemic disease with ocular manifestations  2556–2557 insecticides  2557 inserts  366 in situ gel‐forming systems  365 instrument trays  801, 801 interferons (IFN) canine lacrimal secretory system diseases  1028–1029 clinical pharmacology and therapeutics  402, 404–405, 444 feline ocular surface disease  1712 feline systemic disease with ocular manifestations  2452, 2457–2458 ocular immunology  277, 279–280 interleukins (IL) canine corneal diseases  1085–1086 equine ophthalmology  1929 ocular immunology  264, 270, 278–280 interphotoreceptor retinoid‐binding protein (IRBP)  196 interplexiform cells  102, 198–199 interposition  1842 intracameral injection  369–370, 440 intracanalicular optic nerve  1628 intracapsular cataract extraction (ICCE)  1393, 1411, 1436–1438 intracapsular lens extraction (ICLE)  1357–1358, 1431–1438 intracorneal stromal hemorrhage (ICH)  1141–1142, 1142 intracranial neoplasia  2285 intracranial optic nerve  1628 intracranial pressure (ICP)  1643–1644 intraocular drug delivery  369–372 intracameral injection  369–370 intraocular implants  371–372 intravitreal injection  370–371 specular microscopy  690 intraocular hemorrhage  1406, 1416, 1487–1488 intraocular lens (IOL) avian ophthalmology  2068 basic IOL implantation  1403–1404 canine lens diseases and cataract formation  1317

canine posterior segment surgery  1579, 1583 decentration/luxation  1378, 1427–1428, 1427, 1434–1438 design and materials  1402–1403, 1403 diagnostic ultrasound  734, 736 equine ophthalmology  1950–1951 intraoperative complications  1408–1409 microsurgery  799, 802, 805 optics and physiology of vision  170, 180–182, 181 photography  850 postoperative complications  1412–1414, 1421–1428, 1423–1424, 1427 specular microscopy  689 spontaneous lens capsule rupture  1377–1378 sulcus intraocular lens fixation  1435–1436, 1435–1437 intraocular muscles  2251–2254, 2253 intraocular neoplasia canine anterior uvea diseases  1296 canine glaucomas  1224, 1225 feline glaucomas  1766 ocular pathology  487, 542, 543–544 intraocular optic nerve  1623–1626, 1623–1626 intraocular pressure (IOP) anti‐inflammatory agents  417, 420–421, 424 avian ophthalmology  2058–2059 canine anterior uvea diseases  1273–1274 canine corneal diseases  1083 canine optic nerve diseases  1624–1627, 1625 equine ophthalmology  1938–1942, 1961 exotic mammals  2218–2219 feline glaucomas  1768 general ocular examination  565, 577 hedgehog  2196–2197 laboratory animal ophthalmology  2129–2130, 2145–2147 medical therapy for glaucoma  451–470 mydriatics/cycloplegics  435 New World camelid ophthalmology  2088 ocular embryology and congenital malformations  9, 21, 30 ocular pathology  525–526, 528–529 ocular physiology  136, 138–139, 143–148, 147–148 ophthalmic anatomy  77 ovine and caprine ophthalmology  2021–2022 pachymetry  685 reptiles  2210 surgical procedures on the canine lens  1371, 1380, 1410, 1415–1417 tear tests  602–607

tonography  629–630 tonometry  620–629, 622–625 see also glaucoma intraocular prosthesis  1867–1868 intraocular tissues  136 intraorbital optic nerve  1627–1628, 1628 intrascleral plexus (ISP) canine posterior segment surgery  1578, 1578 equine ophthalmology  1937–1938 ophthalmic anatomy  61–62 intrascleral prosthesis  909–911, 910 intrastromal injection  834 intravenous administration  441, 467–468 intravenous fluid overload  2343–2344 intravitreal injection  370–371, 418 intravitreal membranes  1469 intrinsically photosensitive retinal ganglion cells (ipRGC) general ocular examination  573 ocular physiology  136 optics and physiology of vision  205–206, 205–206 intumescent cataracts  1218 in vivo confocal microscopy (IVCM) anterior segment and retinal imaging  696–697 basic principles and physics  690–691, 691 canine corneal diseases  1082–1084, 1084, 1084, 1089–1090, 1117, 1118, 1124, 1149 clinical applications  692–695, 694–696 corneal imaging  690–695 microscope types and operation  691–692, 692–693 involuntary blinking  131–132 IOL see intraocular lens ionic disturbances canine lens diseases and cataract formation  1342 canine systemic disease with ocular manifestations  2385 feline systemic disease with ocular manifestations  2463 food animal systemic disease with ocular manifestations  2553 see also individual disorders ionizing radiation canine systemic disease with ocular manifestations  2391–2392 feline systemic disease with ocular manifestations  2468 food animal systemic disease with ocular manifestations  2557 radiation‐induced cataracts  1341 radiation‐induced keratopathy  1919 radiation‐induced retinopathy  1545 iontophoresis  373–374 IOP see intraocular pressure; ophthalmomyiasis interna posterior

Index

ipRGC see intrinsically photosensitive retinal ganglion cells IQCB1 mutations  1510 IRBP see interphotoreceptor retinoid‐ binding protein IRD see inherited retinal degenerations iridectomy  1300–1301, 1301 iridociliary adenoma  752 iridociliary cysts  493 iridociliary epithelial tumors canine anterior uvea diseases  1295–1296, 1295, 1299 feline anterior uvea diseases  1761–1762, 1761 iridocorneal angle (ICA) canine glaucomas  1177–1179, 1181–1183, 1188–1189, 1201–1202, 1206–1207, 1211–1214 diagnostic ultrasound  750, 751 equine ophthalmology  1937–1938 exotic mammals  2218 feline glaucomas  1765, 1766 general ocular examination  576 gonioscopy  630–636, 631–635 ocular embryology and congenital malformations  16–17, 30 ocular pathology  525–527 ocular physiology  143 ophthalmic anatomy  60, 70–79, 71–78 optical coherence tomography  702 photography  843–847, 849 reptiles  2210 slit‐lamp biomicroscopy  588–589 surgical procedures on the canine lens  1413–1414 iridocyclectomy  1301–1302, 1301 iridocyclitis  1862, 1862, 2062 iridotomy  1302–1303 iris amphibians  2206 avian ophthalmology  2056, 2070, 2070 bovine ophthalmology  2011–2013, 2012 canine anterior uvea diseases  1259–1265, 1260–1262, 1264–1265, 1270–1273, 1273, 1286–1287, 1286, 1292–1293, 1292–1293 canine glaucomas  1189 diagnostic ultrasound  749 equine ophthalmology  1851–1853, 1852–1853 feline anterior uvea diseases  1733–1738, 1733–1737 general ocular examination  576–577 gonioscopy  633–634 neuro‐ophthalmology  2251–2254, 2253 New World camelid ophthalmology  2089–2090, 2090, 2097 ocular drug delivery  357, 359

ocular embryology and congenital malformations  16–17 ocular physiology  134–136, 135 ophthalmic anatomy  63–67, 64–67 ovine and caprine ophthalmology  2029 photography  838, 841, 845–846, 855–857, 856–858 porcine ophthalmology  2035, 2035 reptiles  2210 slit‐lamp biomicroscopy  580, 583–584, 587–588 iris atrophy  1736, 1736 iris bombé  1270, 1271 iris colobomas canine anterior uvea diseases  1260, 1260, 1262 equine ophthalmology  1852–1853, 1853 feline anterior uvea diseases  1735–1736, 1736 iris cysts feline anterior uvea diseases  1735, 1737–1738, 1737 ocular embryology and congenital malformations  29 iris freckles  1292–1293 iris hypoplasia canine anterior uvea diseases  1262, 1262 equine ophthalmology  1852–1853, 1853 iris neoplasia  544–546, 547, 585 iris nevi  1292–1293, 1293 iris prolapse equine ophthalmology  1889, 1897– 1899, 1902–1904, 1903 surgical procedures on the canine lens  1406 irrigation/aspiration  1388, 1400–1401, 1401 ischemic encephalopathy  2294, 2433 ischemic optic neuropathy  1959–1960, 1959 ischemic stroke  2280, 2341 island graft  1060, 1108, 1109 isoimmune hemolytic anemia of foals  2500 ISO number  817, 824, 829 isopropyl unoprostone  461, 462 isosorbide  468 ISP see intrascleral plexus ITP see inferior‐temporal palpebral itraconazole canine anterior uvea diseases  1274, 1280 canine systemic disease with ocular manifestations  2361 clinical pharmacology and therapeutics  400 feline anterior uvea diseases  1749 IURD see infectious upper respiratory disease

IVCM see in vivo confocal microscopy ivermectin canine ocular fundus diseases  1544, 1544 canine systemic disease with ocular manifestations  2389–2390, 2390 feline systemic disease with ocular manifestations  2468 Jaeger eyelid plate  800 Jameson calipers  800 jaundice see icterus Jones test  618–619, 619 juvenile pyoderma  2348, 2348 KCS see keratoconjunctivitis sicca KCSID see keratoconjunctivitis sicca and ichthyosiform dermatosis keratan sulfates  58–59 keratectomy canine corneal diseases  1098, 1102, 1136 equine ophthalmology  1901 feline ocular surface disease  1726–1728 keratic precipitates (KP) canine anterior uvea diseases  1271–1272, 1272, 1277, 1277 slit‐lamp biomicroscopy  583 keratitis canine orbital diseases  903–904 corneal esthesiometry  601 equine ophthalmology  1886 ocular pathology  508–509, 509–510 see also ulcerative keratitis keratoacanthomas  1989, 1989 keratocentesis  637–639, 639 keratoconjunctival disease bovine ophthalmology  1992–2002, 1993, 1995–1996, 1998–1999 dry eye disease syndromes  1716–1717, 1717, 1717 eosinophilic keratitis/proliferative keratoconjunctivitis  1714–1716, 1714 exotic mammals  2220–2221 feline herpesvirus type 1  1701–1712, 1702–1704, 1704–1705, 1706, 1708, 1710, 1715 feline ocular surface disease  1701–1717 mycoplasma‐associated ulcerative keratitis  1712 New World camelid ophthalmology  2093–2094 ovine and caprine ophthalmology  2025–2029, 2026–2027 porcine ophthalmology  2035 symblepharon  1712–1714, 1713 keratoconjunctivitis sicca and ichthyosiform dermatosis (KCSID)  2333–2334, 2334

i33

i34

Index

keratoconjunctivitis sicca (KCS) antibacterial agents  394 canine conjunctival diseases  1046–1047, 1050–1051 canine corneal diseases  1089, 1128, 1142 canine lacrimal secretory system diseases  1013–1019, 1014, 1015–1016, 1017–1018, 1022, 1027–1033 canine neuro‐ophthalmic diseases  2285–2286 canine systemic disease with ocular manifestations  2349, 2349, 2384, 2391–2392 causes of aqueous tear deficiency  1014–1016, 1016 clinical findings  1016–1018, 1017–1018 clinical microbiology and parasitology  303, 305 clinical signs  1014 diagnosis of aqueous tear deficiency  1018–1019 epidemiology and signalment  1015–1016, 1015–1016 equine ophthalmology  1912–1913 feline ocular surface disease  1716–1717, 1717, 1717 guinea pig  2192, 2192 immunosuppressant drugs  425, 427 in vivo confocal microscopy  692 medical treatment  1022, 1027–1029 ocular immunology  271, 277–278 slit‐lamp biomicroscopy  584 surgical treatment  1029–1033 tear film imaging  681–682, 682–683 tear substitutes and stimulators  441–444 tear tests  603, 608 keratocytes  129–131, 1885–1886 keratoglobus  2066 keratolenticular separation  11, 26, 27 keratomalacia canine corneal diseases  1088, 1088, 1109, 1117, 1119, 1122 exotic mammals  2220–2221 keratomycosis  398, 1993 keratotomy canine corneal diseases  1101–1102 New World camelid ophthalmology  2097 small mammal ophthalmology  2187 ketamine  565, 1782 ketoconazole  399, 2388 Key–Gaskell syndrome  2290–2291, 2432–2433 Kimura spatula  613–614, 613 Kirby–Bauer test see agar‐disk‐diffusion test Knemidokoptes spp.  2062–2063, 2067 Koch’s stop and chop technique  1399–1400

KP see keratic precipitates Krabbe’s disease canine systemic disease with ocular manifestations  2337–2338 feline systemic disease with ocular manifestations  2424 food animal systemic disease with ocular manifestations  2538 Kuhnt–Szymanowski procedure  947, 949–951, 950–952, 954, 957 LA see latex agglutination laboratory animal ophthalmology  2109–2178 advanced imaging in preclinical studies  2148–2151, 2150 ancillary diagnostic test values  2129–2130, 2145–2148 animal models in research and preclinical drug development  2151–2157, 2152–2154, 2155–2156 context  2109–2110 general ocular features, lesions and diseases  2113–2144, 2115–2116 guinea pig  2127–2132, 2131 miniature pig  2139–2141, 2140 mouse and rat  2114–2127, 2118, 2121, 2124, 2126 nonhuman primate  2141–2144 rabbit  2132–2139, 2137–2139 ophthalmic examination  2110–2113, 2110–2111, 2113–2114 laboratory sampling  610–616 additional tests  615 conjunctival histology  615–616 corneoconjunctival culture  611–612, 612 corneoconjunctival cytology  612–615, 613–614 recommendations and sample transport  613 lacerations avian ophthalmology  2067 bovine ophthalmology  1988, 1988 canine conjunctival diseases  1059, 1059 canine corneal diseases  1087, 1115–1116, 1116–1117 canine eyelid disorders  966–968 canine lens diseases and cataract formation  1346 canine nasolacrimal diseases  1000– 1001, 1001 equine ophthalmology  1858, 1860, 1872, 1873, 1897–1899 New World camelid ophthalmology  2096–2097 lacrimal canaliculus  967 lacrimal drainage‐associated lymphoid tissue (LDALT)  271, 1012

lacrimal glands avian ophthalmology  2065 equine ophthalmology  1864, 1883 guinea pig  2128 New World camelid ophthalmology  2090–2091 ocular pathology  500, 505–506, 506 ophthalmic anatomy  48, 50–51, 50 lacrimal nerve  129 lacrimal system canine lacrimal secretory system diseases  1008–1044 ocular drug delivery  354–355, 357–358 ocular physiology  126–129, 127 tear substitutes and stimulators  441–444 lacrimomimetics  441–442, 1024–1026, 1025–1026 lacrimostimulants  1021–1024, 1022–1024 Lafora disease  2278–2279 lagophthalmos  968 lamellar keratoplasty canine corneal diseases  1144, 1144–1145 equine ophthalmology  1907–1910, 1907–1910 lamina cribrosa (LC) canine optic nerve diseases  1623–1627, 1632, 1655 ophthalmic anatomy  106–107, 107 Langerhans giant cells  489–490, 490 lanosterol  1349 laser ablation  1299, 1303 laser‐assisted in situ keratomileusis (LASIK)  684–685, 692 laser cycloablation  1941 laser Doppler flowmetry (LDF)  703–704 laser excision  945 laser flare cell meters  704–705 laser fluorophotometry  704–705 laser photocoagulation  1299, 1302, 1302 laser posterior capsulotomy  1423 laser surgery  1583–1585, 1585, 1591, 1594–1596, 1603–1604 laser therapy  1152–1153, 1235–1236, 1236 LASIK see laser‐assisted in situ keratomileusis latanoprost clinical pharmacology and therapeutics  424, 461–466, 462, 464, 469–470 feline glaucomas  1769 latanoprostene bunod (LBN)  469–470, 1238 lateral canthoplasty  1033 lateral eyelid wedge excision  949, 950 lateral geniculate nucleus (LGN) canine optic nerve diseases  1622 fundamentals of animal vision  236

Index

neuro‐ophthalmology  2256–2257, 2262–2263, 2276, 2288–2290 optics and physiology of vision  202, 209–211, 210 latex agglutination (LA) test  321–322 LBN see latanoprostene bunod LC see lamina cribrosa LDALT see lacrimal drainage‐associated lymphoid tissue LDF see laser Doppler flowmetry lead toxicity avian ophthalmology  2060, 2073 food animal neuro‐ophthalmic diseases  2306 food animal systemic disease with ocular manifestations  2557 LEC see lens epithelial cells leiomyoma  540 leiomyosarcoma  1296 Leishmania spp. canine anterior uvea diseases  1282–1283 canine conjunctival diseases  1057 canine corneal diseases  1128 canine eyelid disorders  969–970 canine ocular fundus diseases  1537 canine systemic disease with ocular manifestations  2369–2371, 2370 clinical microbiology and parasitology  326–327 feline anterior uvea diseases  1746–1747, 1746 feline eyelid diseases  1675–1676 feline ocular surface disease  1697 feline systemic disease with ocular manifestations  2448–2449 food animal systemic disease with ocular manifestations  2547 lens amphibians  2206 anterior epithelium  85–86, 86 avian ophthalmology  2056–2057, 2071 bovine ophthalmology  2013–2015, 2013–2015 canine glaucomas  1190, 1200–1201, 1215–1220 canine lens diseases and cataract formation  1317–1370 congenital lens abnormalities  1319–1328, 1320–1321, 1323, 1324, 1325 diagnostic ultrasound  742, 742, 750 dimensions in domestic animals  85, 85 equine ophthalmology  1843, 1854– 1855, 1942–1951, 1943, 1945, 1950 feline lens diseases and cataract formation  1770–1773, 1770–1772 fish  2201–2202 general ocular examination  577 lens capsule  85, 85 lens fibers  86–90, 86–89 mouse and rat  2117, 2118

New World camelid ophthalmology  2102–2103 ocular embryology and congenital malformations  9–12, 11–13 ocular immunology  280–281 ocular pathology  501–502, 502, 522–525, 524 ocular physiology  148–151, 150 ophthalmic anatomy  85–91, 85, 86–91, 1317 optics and physiology of vision  172–176, 172, 174, 175, 182–188, 184–186, 188 ovine and caprine ophthalmology  2030 photography  857–858, 859 porcine ophthalmology  2036 rabbit  2134–2135 special techniques for lens examination  1317–1318, 1318–1319 surgical procedures on the canine lens  1371–1458 transparency  1317 zonular attachment  90–91, 90–91 lens capsule rupture canine vitreous diseases  1472 feline anterior uvea diseases  1760 surgical procedures on the canine lens  1376–1378, 1377–1378 lens colobomas  1855 lensectomy  1773 lens epithelial cells (LEC) canine lens diseases and cataract formation  1328–1332, 1331 ocular physiology  148–150 surgical procedures on the canine lens  1377–1378, 1421–1427 lens fibers  12, 13 lens‐induced uveitis (LIU) canine anterior uvea diseases  1277–1278, 1277 canine glaucomas  1218, 1219 canine lens diseases and cataract formation  1349–1350 canine posterior segment surgery  1579, 1579 ocular pathology  515–516, 515–516 surgical procedures on the canine lens  1371–1372, 1375–1376, 1416 lens loupe cannulas  1433 lens luxation/subluxation avian ophthalmology  2063 canine glaucomas  1190, 1200–1201, 1206–1207, 1214–1218, 1216, 1217 canine lens diseases and cataract formation  1326, 1341–1342, 1351–1358, 1352–1354, 1355–1356 canine posterior segment surgery  1582 canine vitreous diseases  1462, 1472 capsular tension ring  1432–1435, 1434, 1434

diagnostic approach  1357 epidemiology and signalment  1353–1354, 1355–1356 equine ophthalmology  1854–1855, 1942–1944 feline glaucomas  1766 feline lens diseases and cataract formation  1772–1773 medical management of lens or cataract luxation  1431–1432 New World camelid ophthalmology  2103 ocular pathology  525, 525 perioperative medications  1432 photography  834 presentation and clinical signs  1352–1353, 1352–1354 primary lens luxation  1351–1354, 1352–1354, 1355–1356, 1357–1358 secondary lens luxation  1354–1358 sulcus intraocular lens fixation  1435–1436, 1435–1437 surgical procedures on the canine lens  1431–1438, 1434–1437, 1434 treatment approaches  1357–1358 lens opacities  2141 lens placode  8–11, 9–10 lenticonus/lentiglobus canine lens diseases and cataract formation  1321–1322, 1321 ocular pathology  501, 502 lenticular degeneration  2063, 2063, 2215–2216 lentigo simplex  1678, 1679 lentodonesis  588 Leptospira spp. antibacterial agents  392 canine anterior uvea diseases  1285 canine conjunctival diseases  1057 canine ocular fundus diseases  1531–1532 canine systemic disease with ocular manifestations  2358 clinical microbiology and parasitology  316 equine ophthalmology  1925, 1928–1931 equine systemic disease with ocular manifestations  2505 feline anterior uvea diseases  1750 ocular immunology  282–283 lethal white foal syndrome  2495–2496 leukocytes equine ophthalmology  1887 fluorescein angiography  706 ocular immunology  263–264 leukotrienes  1268 levator palpebrae superioris muscle  47 levofloxacin  1142, 1143 LGN see lateral geniculate nucleus

i35

i36

Index

lidocaine canine orbital diseases  906–907 clinical pharmacology and therapeutics  440–441 general ocular examination  569–570 light‐activated drugs  374 light adaptation  231–232, 764–765, 764 light‐induced retinopathy  524, 1544–1545 lighting canine eyelid disorders  926 canine posterior segment surgery  1590–1591, 1593–1594, 1603 clinical studio  835 equipment considerations  832 external light sources  836–838, 837–839 forms of illumination  838–840, 839–843 photography  819, 819, 832, 835–840 light micrography  1542, 1779 light microscopy bacterial infections  309, 309–310 canine ocular fundus diseases  1508, 1526 fungal and algal diseases  320, 321 ocular embryology and congenital malformations  10 ocular pathology  501, 505–506 protozoal diseases  324 lightning strikes canine systemic disease with ocular manifestations  2391 equine neuro‐ophthalmic diseases  2299–2300 equine systemic disease with ocular manifestations  2518–2519 food animal neuro‐ophthalmic diseases  2306 food animal systemic disease with ocular manifestations  2556 ligneous conjunctivitis canine conjunctival diseases  1051, 1051 ocular pathology  508, 508 limbal carcinomas  2004, 2005, 2008 limbal colobomas and staphylomas  1096 limbal keratopathy  1918 limbal melanocytoma feline ocular surface disease  1731– 1732, 1732 ocular pathology  541–542, 542 limbal melanoma  1150–1153, 1151–1152 limbal papillomas  1989, 1989, 2004, 2004 limbal plaques  2004, 2004 limbal stem cells  1086 lincosamides  392–393 LINE see long interspersed nuclear elements linear corneal epithelial erosions  2187 linear keratopathy  1921

linear perspective  1842 linear retinopathy  2125 linked‐marker test  784–785 lipemia retinalis canine systemic disease with ocular manifestations  2342–2343 feline posterior segment diseases  1786 feline systemic disease with ocular manifestations  2430 lipid degeneration  509, 511 lipid keratopathy  1135, 1135, 1729–1730 lipidosis exotic mammals  2223–2224 guinea pig  2131 rabbit  2136–2137 lipid peroxidation disorders  522, 523 lipogranulomatous conjunctivitis  506–507, 1679–1680, 1680 lipoid aqueous  1271, 1272 lipopolysaccharide (LPS)  273, 279–280 liposomes  363–364, 368 lissamine green  620 lissencephaly  2278 Listeria spp. bovine ophthalmology  1985, 1985, 1993, 1993 canine conjunctival diseases  1057 clinical microbiology and parasitology  314 food animal neuro‐ophthalmic diseases  2306–2307 food animal systemic disease with ocular manifestations  2544 LIU see lens‐induced uveitis liver dysfunction  1344–1345 L‐lysine  405, 2458 lobular orbital adenoma  902, 1053 local anesthesia canine orbital diseases  905–907, 906 clinical pharmacology and therapeutics  438–441 intracameral administration  440 intravenous administration  441 regional administration  440–441 topical administration  439–440 locoweed poisoning  2020, 2029, 2033, 2307 long interspersed nuclear elements (LINE)  780 lortalamine  1091 loteprednol  419–420 LOXL1 mutation  1188 LPS see lipopolysaccharide LSCM see scanning confocal microscopes LTBP2 mutations  1765 lubricating ointments  1024–1026 luminance  170, 170, 251 lutein  1546–1547 Lyme disease see Borrelia spp. lymphangiosarcoma  1986–1987 lymphatic drainage  275, 925

lymphocytes  488–489, 489 lymphocytic plasmacytic conjunctivitis  507, 507 lymphoma bovine ophthalmology  1986 canine anterior uvea diseases  1297–1298, 1298 canine glaucomas  1224, 1225 canine nictitating membrane diseases  1068 canine ocular fundus diseases  1555–1556, 1555 canine optic nerve diseases  1652–1654 clinical microbiology and parasitology  301 equine ophthalmology  1880, 1880, 1924 feline anterior uvea diseases  1763, 1764 feline eyelid diseases  1684, 1685 feline nictitating membrane diseases  1689 feline ocular surface disease  1699–1700, 1699 feline systemic disease with ocular manifestations  2460 lymphopenia  2292 lymphoplasmacytic uveitis  514–515, 514, 1763 lymphosarcoma bovine ophthalmology  1986 canine anterior uvea diseases  1297–1299 canine conjunctival diseases  1052–1053, 1052 canine corneal diseases  1150, 1151 canine systemic disease with ocular manifestations  2385–2386 equine ophthalmology  1880, 1880 equine systemic disease with ocular manifestations  2517, 2518 feline anterior uvea diseases  1762–1763, 1762 feline orbital diseases  1793, 1794 feline systemic disease with ocular manifestations  2459, 2464 food animal systemic disease with ocular manifestations  2553 ocular pathology  533, 538, 539 lyonization  782 lysine therapy  1711–1712 lysosomal storage diseases bovine ophthalmology  2020 canine corneal diseases  1096 canine lens diseases and cataract formation  1343 canine ocular fundus diseases  1525–1527, 1526 canine systemic disease with ocular manifestations  2335, 2336–2337 feline ophthalmology  1730, 1788, 1789 feline systemic disease with ocular manifestations  2423

Index

food animal systemic disease with ocular manifestations  2538–2540 ocular pathology  522, 523 ovine and caprine ophthalmology  2033 lysozyme  128, 2090–2091 MAC see major arterial circle McDonald–Shadduck scoring system  2112 mace  1121 McPherson tying forceps  808–809, 809 macroblepharon  942, 946–956, 948–959 macrocornea  500 macrolides  392–393 macrophage inhibitory factor (MIF)  280 macrophages  263–264, 489–490, 490 macrophotography equipment considerations  824, 826–829, 828–829 external macrophotography  836 infrared macrophotography  840–842, 843–847 macula  190 maedi‐visna virus (MVV)  2551 magnetic resonance imaging (MRI)  671–681 basic principles and physics  665, 671–673 canine optic nerve diseases  1633–1635, 1647, 1648 canine orbital diseases  883–888, 886–887, 890, 893–905 canine vitreous diseases  1461 contrast MRI  676, 677 equine ophthalmology  1867 fat suppression  675–676, 675–676 fluid attenuation inversion recovery  676, 677 gradient recall echo imaging  675, 675 interpretation of specific pulse sequences  673–675, 674 neuro‐ophthalmology  2240, 2241–2245, 2250–2253, 2284, 2290 normal and pathologic findings  676–681, 678–681 T1‐weighted imaging  673, 674 T2‐weighted imaging  674–675, 674 magnification equipment  926 major arterial circle (MAC)  65, 65 major histocompatibility complex (MHC) canine corneal diseases  1126 ocular immunology  266–268, 273, 275, 282 Malassezia spp.  1678 MALDI‐TOF MS see matrix‐assisted laser desorption/ionization time of flight mass spectrometry male fern poisoning  2307, 2558 malignant catarrhal fever (MCF) bovine ophthalmology  1994 clinical microbiology and parasitology  306

exotic mammals  2221 food animal systemic disease with ocular manifestations  2551–2552, 2551–2552 ocular pathology  515, 515 malignant glaucoma  1221, 1767–1768, 1768 mal seco  2299, 2500–2501 MALT see mucosa‐associated lymphoid tissue mannitol  467–468 mannosidosis  2423–2424, 2539–2540 MAP9 mutations  1512 MAR see minutes of arc Marek’s disease virus  308 Marfan syndrome  1200, 2537–2538, 2537 marginal blepharitis  1019 margins of the eyelids  924–925 Maroteaux–Lamy syndrome  2339, 2426, 2427 Martinez corneal dissector  800 mast cell neoplasia canine conjunctival diseases  1051, 1051 equine ophthalmology  1880 feline eyelid diseases  1683, 1684 feline nictitating membrane diseases  1688 ocular pathology  537–538 mast cells  489, 490 masticatory muscle atrophy  880, 882 masticatory muscle myositis (MMM)  897–900, 897–900 masticatory myositis canine neuro‐ophthalmic diseases  2282–2283 canine systemic disease with ocular manifestations  2351–2352, 2352 ocular pathology  505, 505 matrix‐assisted laser desorption/ionization time of flight mass spectrometry (MALDI‐TOF MS)  310 matrix metalloproteinases (MMP) canine corneal diseases  1088–1089, 1098–1100, 1126 canine glaucomas  1188–1189 canine lens diseases and cataract formation  1354–1356 clinical pharmacology and therapeutics  462–463, 466 equine ophthalmology  1885–1886, 1888, 1891 maze test canine ocular fundus diseases  1477, 1502 equine ophthalmology  1844 neuro‐ophthalmology  2263 surgical procedures on the canine lens  1371 MCF see malignant catarrhal fever MCOAS see multiple congenital ocular anomaly syndrome

medetomidine  566 medial aberrant dermis  1056–1057 medial canthal pocket syndrome  1056 medial canthoplasty  999–1000, 1000 medial canthus  967 medication‐induced cataracts  1340 medulloepithelioma canine anterior uvea diseases  1296 canine ocular fundus diseases  1554 New World camelid ophthalmology  2104 ocular pathology  549–550, 550 megalocornea  1092, 1851 megestrol acetate  1715–1716, 2468 meibometry  610 meibomian gland adenoma  534–535 meibomian glands canine eyelid disorders  924–925, 932–934, 949–950, 950 canine lacrimal secretory system diseases  1009, 1019–1021, 1021, 1027–1029 feline eyelid diseases  1678–1680, 1679–1680 ophthalmic anatomy  47–48 slit‐lamp biomicroscopy  583 meibomian gland secretions (MGS)  126–127 meibomianitis canine eyelid disorders  971, 971 canine lacrimal secretory system diseases  1019–1020, 1020, 1027 meibomitis  1679, 1679 melanin  360 melanocytes  64, 65 melanocyte‐stimulating hormone (MSH)  2346–2347 melanocytic glaucoma  1222–1223, 1223 melanocytic hyperplasia  493 melanocytic neoplasia canine anterior uvea diseases  1293–1295, 1294, 1299, 1302, 1302 canine eyelid disorders  973 melanocytoma canine anterior uvea diseases  1293–1295, 1299 canine corneal diseases  1150 feline ocular surface disease  1731–1732, 1732 ocular pathology  539–542, 539, 542–544, 542 melanocytosis  516–517, 517 melanogenesis  465 melanoma canine anterior uvea diseases  1293–1295, 1299, 1302, 1302 canine conjunctival diseases  1051 canine corneal diseases  1150–1153, 1151–1152 canine eyelid disorders  973, 973

i37

i38

Index

melanoma (cont’d) canine ocular fundus diseases  1554, 1554–1555 canine systemic disease with ocular manifestations  2343, 2344 diagnostic ultrasound  751–752 direct ophthalmoscopy  593 equine ophthalmology  1879–1880, 1880, 1923–1924, 1924 feline anterior uvea diseases  1756–1759, 1757, 1759 feline ocular surface disease  1698–1699, 1699 magnetic resonance imaging  678, 678 New World camelid ophthalmology  2105 ocular pathology  540, 540, 544–546, 545, 547 slit‐lamp biomicroscopy  585 melanopsin  136 melanopsin‐expressing retinal ganglion cells  205–206, 205–206 Melophagus spp.  2025 melting ulcers see keratomalacia memantine  1240 membrana vasulosa retinae  2207, 2207 menace response avian ophthalmology  2058 canine ocular fundus diseases  1478 equine ophthalmology  1844 general ocular examination  571–572 neuro‐ophthalmology  2256–2257 ocular physiology  124–125, 125 meningioma canine optic nerve diseases  1650–1651, 1651–1652 canine orbital diseases  888 magnetic resonance imaging  679, 680 ocular pathology  551, 551 meningoencephalitis of unknown etiology (MUE)  2283–2284, 2284, 2349–2350 meningoencephalomyelitis of unknown origin (MUO)  1645–1647, 1645, 1648, 1653–1654 mepivacaine  569–570 merle gene  1260, 1260 merle ocular dysgenesis (MOD) canine ocular fundus diseases  1490, 1490 ocular embryology and congenital malformations  22, 24, 25 MERTK mutations  1521 mesenchymal cells  5, 12–13, 14–15 mesenchymal differentiation  497–498, 499 mesenchymal hamartoma  972 mesenchymal tumors  888 mesoderm  3, 5 metabolic disorders canine corneal diseases  1096 canine lens diseases and cataract formation  1342–1345, 1344

canine systemic disease with ocular manifestations  2334–2335, 2380–2385, 2382–2383 equine systemic disease with ocular manifestations  2516–2517 feline anterior uvea diseases  1753–1754 feline lens diseases and cataract formation  1771–1772 feline systemic disease with ocular manifestations  2461–2463, 2462 fish  2205 food animal systemic disease with ocular manifestations  2553 ocular pathology  530, 530 metaplasia  484, 486 metastatic disease bovine ophthalmology  2004–2005 canine anterior uvea diseases  1294–1295 canine conjunctival diseases  1051 canine glaucomas  1224 canine ocular fundus diseases  1555 canine optic nerve diseases  1652 canine orbital diseases  901–902 canine systemic disease with ocular manifestations  2386, 2386 feline anterior uvea diseases  1761, 1762–1764, 1762–1763 feline eyelid diseases  1684 feline nictitating membrane diseases  1689 feline systemic disease with ocular manifestations  2464 fluorescein angiography  707 food animal systemic disease with ocular manifestations  2553 New World camelid ophthalmology  2104–2105, 2105 ocular pathology  531, 537, 551–552, 552 metering  819, 820 methazolamide  459 methicillin‐resistant Staphylococcus aureus (MRSA)  388, 1118, 1119 methylcellulose products  1024 methylnitrosourea  1782 mfERG see multifocal electroretinography MGS see meibomian gland secretions MHC see major histocompatibility complex MIC see minimum inhibitory concentration micafungin  402 miconazole  399 microarrays  778 microblepharon  942, 956, 959–960 microcornea canine corneal diseases  1091–1092 ocular embryology and congenital malformations  15 ocular pathology  500 microinvasive glaucoma surgeries (MIGS)  1239

microneedles  374 micropapilla  1637–1639, 1638–1639 microphakia canine lens diseases and cataract formation  1320, 1320 ocular embryology and congenital malformations  26, 28 ocular pathology  501–502, 502 microphthalmos bovine ophthalmology  1984, 1984 canine ocular fundus diseases  1488 canine orbital diseases  889–890 equine ophthalmology  1849–1850, 1849 exotic mammals  2219 ferret  2195 guinea pig  2128–2130 mouse and rat  2118–2119, 2118 ocular embryology and congenital malformations  20–22, 20, 21, 22, 26, 28 ocular pathology  493–494, 494 ovine and caprine ophthalmology  2022 reptiles  2212 micropunctum  995, 996–997 microsaccades/micronystagmus  154 microsatellites  778 Microsporum spp. canine systemic disease with ocular manifestations  2363 clinical microbiology and parasitology  322 equine systemic disease with ocular manifestations  2508 feline eyelid diseases  1671–1673 feline systemic disease with ocular manifestations  2444, 2444 porcine ophthalmology  2035 microsurgery  787–814 anesthesia  794–795 concepts and definitions  787–788 conclusion and recommendations  813–814 foot controls  791, 791, 793 forceps  810–812, 811–812 head loupes  788–790, 790–791 headpieces and illumination  791, 791–792 hemostasis  798, 812–813, 813 history of ophthalmic microsurgery  788 incision  803–806, 804–806 instrumentation  798–803, 799, 800–802 instrument handling  803, 803 magnification  788–794, 788–795 magnification calculation  793 microscopes  790–794, 791–794 patient preparation and globe positioning  794, 794, 796–798, 797–798 presurgical checklist  796 sterilization  794, 794–795, 798, 798

Index

surgical needles and needle holders  809–811, 809–810 suture material and technique  806–807, 807 suture pattern  807–809, 808–809 viscoelastics  813 working distance and ergonomics  788–789, 788–789, 793–796, 793, 795 microvilli  94 midbrain syndrome  2266–2267, 2267 MIF see macrophage inhibitory factor MIGS see microinvasive glaucoma surgeries milk fever  2306, 2553 milk replacer‐induced disease  2386–2387 mineralization  669, 1919–1920, 1920 miniature pig ancillary diagnostic values  2147, 2148 functional morphology  2139–2140, 2140 laboratory animal ophthalmology  2139–2141 ophthalmic examination  2110 spontaneous lesions and diseases  2140–2141 minimum inhibitory concentration (MIC)  310–311 minutes of arc (MAR)  242, 243 miosis canine anterior uvea diseases  1270, 1270 equine ophthalmology  1870 surgical procedures on the canine lens  1406, 1415, 1432 see also cholinergic agents (miotics) mitochondrial inheritance  782 mitomycin‐C  1229–1230 mitosis  3 Mittendorf’s dot ocular embryology and congenital malformations  15 ophthalmic anatomy  92 slit‐lamp biomicroscopy  588 MMM see masticatory muscle myositis MMP see matrix metalloproteinases MND see motor neuron disease MOD see merle ocular dysgenesis modified Hotz‐Celsus procedure  1871–1872 modified Roberts–Jensen pocket procedure  953–954, 955 MODS see multiple ocular defect syndrome Mokola virus  1530 moldy corn disease  2519 monoclonal antibodies  270 monocular field  234–238, 235 monocular vision  1841–1843 Moraxella spp. antibacterial agents  386, 391–392 bovine ophthalmology  1988, 1994–2002, 1995–1996, 1998–1999 clinical microbiology and parasitology  315 New World camelid ophthalmology  2092–2094

Morbillivirus spp. see canine distemper virus Morgagnian cataracts  1328, 1330, 1332, 1332 morphometric analysis  2209, 2219 motion‐in‐depth processing  238 motion parallax  1842–1843 motion perception  233–234 motor neuron disease (MND) equine motor neuron disease  1956– 1957, 1956, 2501–2502, 2501 photography  850 mouse and rat ancillary diagnostic values  2145–2146 functional morphology  2114–2118, 2118 laboratory animal ophthalmology  2114–2127 ophthalmic examination  2110–2111, 2113 spontaneous lesions and diseases  2118–2127, 2121, 2124, 2126 MPS see mucopolysaccharide storage diseases; mucopolysaccharidosis MRI see magnetic resonance imaging MRSA see methicillin‐resistant Staphylococcus aureus MSH see melanocyte‐stimulating hormone mucinolytic–anticollagenase agents  1027 mucins canine lacrimal secretory system diseases  1011, 1020–1021, 1028 ocular immunology  271 ocular physiology  128 mucoceles canine conjunctival diseases  1056 canine orbital diseases  896–897 ocular pathology  505, 505 mucolipidosis type II  2425–2426, 2425 mucopolysaccharide storage diseases (MPS)  1526 mucopolysaccharidosis (MPS)  2339, 2426, 2427 mucopurulent discharge  990, 990 mucosa‐associated lymphoid tissue (MALT) canine lacrimal secretory system diseases  1012–1013, 1013 canine nasolacrimal diseases  989–990 canine nictitating membrane diseases  1063 ocular immunology  271 mucosal tolerance, ignorance, and privilege  273 mucus  1011 MUE see meningoencephalitis of unknown etiology Müller cells canine glaucomas  1195 ophthalmic anatomy  98–102, 99, 104 optics and physiology of vision  199–200 multidose eye preparations  353

multidrug resistance  352 multifocal electroretinography (mfERG)  774, 774, 1183–1185, 1482 multifocal lens  186, 186, 1843 multifocal retinal dysplasia  1491–1492, 1491–1492 multifocal retinopathies fluorescein angiography  708, 712–713 ocular pathology  519–520, 520 optical coherence tomography  702 multiphoton microscopy  716–717 multiple chalazia  1020, 1021 multiple congenital ocular anomaly syndrome (MCOAS) equine neuro‐ophthalmic diseases  2298–2299 equine ophthalmology  1851, 1853 equine systemic disease with ocular manifestations  2496–2497, 2497–2499 ocular embryology and congenital malformations  29, 30 multiple melanoma  2343, 2344 multiple myeloma  1057 multiple ocular defect syndrome (MODS)  2538 multiplex testing  785 muscular system canine eyelid disorders  924, 924 ciliary body  70–78, 70–72 iris  66–67, 66 ocular embryology and congenital malformations  19–20 ocular physiology  135–137, 153–154 optics and physiology of vision  175–177 orbit  42–47, 44–45, 46 mutation detection tests  784 muzzles  565 MVV see maedi‐visna virus myasthenia gravis canine neuro‐ophthalmic diseases  2284–2285 canine systemic disease with ocular manifestations  2350–2351 feline systemic disease with ocular manifestations  2434 Mycobacterium spp. antibacterial agents  393 clinical microbiology and parasitology  314 feline eyelid diseases  1676 feline ocular surface disease  1722 feline posterior segment diseases  1783 feline systemic disease with ocular manifestations  2438–2439, 2439 food animal systemic disease with ocular manifestations  2544 mycocutaneous grafts  976, 977–980 mycoplasma‐associated ulcerative keratitis  1712

i39

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Index

Mycoplasma spp. antibacterial agents  391–392 avian ophthalmology  2060–2061, 2061 clinical microbiology and parasitology  318–319 feline ocular surface disease  1694–1695, 1694, 1712, 1719–1720, 1720 feline systemic disease with ocular manifestations  2439, 2440 food animal systemic disease with ocular manifestations  2544–2545 ovine and caprine ophthalmology  2026–2028, 2026–2027 mycotic diseases see fungal and algal diseases mydriasis canine lens diseases and cataract formation  1346 direct ophthalmoscopy  591 electroretinography  763 equine ophthalmology  1847, 1932–1933 feline glaucomas  1769 laboratory animal ophthalmology  2112 neuro‐ophthalmology  2251–2254, 2253 New World camelid ophthalmology  2087 optics and physiology of vision  188 retinoscopy  598 slit‐lamp biomicroscopy  588 surgical procedures on the canine lens  1380 mydriatics/cycloplegics atropine  437 canine glaucomas  1185 cholinergic antagonists  435–436 clinical pharmacology and therapeutics  435–438, 436 cyclopentolate  437 epinephrine  438 equine ophthalmology  1847 general ocular examination  577 homatropine  437 indirect‐acting sympathomimetics  438 phenylephrine  438 retinoscopy  598–599 scopolamine  437 sympathomimetics  437–438 tropicamide  436–437 myelination  1484, 1484 myeloma  1057 myoclonic epilepsy  2278–2279 MYOC mutations  1213 myoid  98, 98 myopia avian ophthalmology  2059 fundamentals of animal vision  243 optics and physiology of vision  174–175, 175, 178, 180, 183–184, 183, 188 retinoscopy  599

myositis canine orbital diseases  897–900, 897–900 canine systemic disease with ocular manifestations  2351–2352, 2352 myotonia  2423 myxoid leiomyoma  1296–1297 myxomatosis  2182, 2183 myxoma virus  308 myxosarcoma  902 Na+/K+ ATPase pumps  58, 58 nAChR see nicotinic acetylcholine receptors NAD/EDM see neuroaxonal dystrophy/ equine degenerative myeloencephalopathy NADPH see nicotinamide adenine dinucleotide phosphate nanophthalmia  889–890 nanosuspensions  363–364 nasal fold  957–961, 960–962 nasolacrimal duct atresia canine nasolacrimal diseases  995–997, 998 equine ophthalmology  1850–1851, 1852, 1882 New World camelid ophthalmology  2091–2092 nasolacrimal duct neoplasia  1003, 1003 nasolacrimal duct (NLD) New World camelid ophthalmology  2089, 2089, 2092, 2092 ocular drug delivery  357–358 rabbit  2133–2134, 2180, 2181–2182 reptiles  2209, 2214, 2214 nasolacrimal duct obstruction canine nasolacrimal diseases  998 equine ophthalmology  1882–1883 feline systemic disease with ocular manifestations  2469, 2469 nasolacrimal flushing  636–637, 636–638, 991–992, 992 nasolacrimal lavage system (NLLS)  2089, 2089 nasolacrimal sac atresia  995–997, 998 nasolacrimal system bovine ophthalmology  1989–1990, 1990 canine nasolacrimal diseases  988–1007 contrast radiography  664–665, 664, 673 feline nasolacrimal system diseases  1684–1686, 1685 general ocular examination  574–575 New World camelid ophthalmology  2090–2092, 2092 ocular drug delivery  354–355 ocular physiology  129 ophthalmic anatomy  50–51, 50 rabbit  2133–2134 nasosinal tumors  901–902

natamycin  397, 1891, 1986 natural killer (NK) cells  266, 276–278 NCIT see noncontact infrared thermometry NCL see neuronal ceroid lipofuscinosis NEB mutations  1199 nebular‐type oval corneal opacity  1133, 1133 NECAP1 mutations  1512 necrosis canine conjunctival diseases  1060 canine corneal diseases  1112 ocular pathology  484–485, 487 necrotic scleritis  513, 514 necrotizing encephalitis  1646–1647 necrotizing granulomatous scleritis  1155 necrotizing leukoencephalitis (NLE)  2283, 2349 necrotizing meningoencephalitis (NME)  2283, 2349 necrotizing panophthalmitis  2220 Neisseria spp.  316 Neochlamydia spp.  318, 2436–2438, 2437 neomycin  390 neonatal conjunctivitis  1697 neonatal isoerythrolysis  2500 neonatal maladjustment syndrome  1862 neonatal ophthalmia  1666 neonatal septicemias  2545, 2545 neoplasia amphibians  2208–2209 avian ophthalmology  2064, 2071 bovine ophthalmology  1986–1987, 1989, 1989, 2002–2010, 2004–2008, 2013 canine anterior uvea diseases  1293–1299, 1294–1295, 1298 canine conjunctival diseases  1051–1053, 1051–1052, 1058 canine corneal diseases  1149–1155, 1149–1155 canine eyelid disorders  972–974, 973, 974 canine glaucomas  1224, 1225 canine lacrimal secretory system diseases  1034–1035 canine nasolacrimal diseases  1003, 1003 canine neuro‐ophthalmic diseases  2285 canine nictitating membrane diseases  1051–1052, 1068, 1068–1069 canine ocular fundus diseases  1553–1556, 1554–1555 canine optic nerve diseases  1650–1654, 1651–1652 canine orbital diseases  883, 888, 888–890, 900–902, 901, 911–914 canine systemic disease with ocular manifestations  2343, 2344, 2385–2386, 2386

Index

canine vitreous diseases  1471–1472 clinical microbiology and parasitology  300 computed tomography  669, 670 corneal and limbal neoplasia  541–542, 542 diagnostic ultrasound  742–744, 747–752, 747, 749 equine conjunctival diseases  1881, 1882 equine corneal diseases  1922, 1922 equine eyelid diseases  1874–1880, 1875–1876, 1876, 1878, 1879, 1880–1881 equine neuro‐ophthalmic diseases  2301 equine nictitating membrane diseases  1882 equine orbital diseases  1870, 1871 equine systemic disease with ocular manifestations  2517, 2518 equine uveal diseases  1923–1924, 1924 exotic mammals  2223 eyelid and conjunctival neoplasia  534– 541, 535, 536–541 feline anterior uvea diseases  1756– 1764, 1757, 1759–1763 feline glaucomas  1766 feline neuro‐ophthalmic diseases  2295 feline nictitating membrane diseases  1688–1689 feline ocular surface disease  1698–1700, 1699–1700, 1731–1732, 1732 feline optic nerve and CNS diseases  1790 feline orbital diseases  1793–1794, 1793–1794 feline posterior segment diseases  1788 feline systemic disease with ocular manifestations  2459–2460, 2463–2464 fish  2205 food animal systemic disease with ocular manifestations  2553 intraocular neoplasia  542, 543–544 magnetic resonance imaging  678–679, 678–679 metastatic ocular neoplasia  551–552, 552 mouse and rat  2127 neural crest neoplasia  551, 551 neuroectodermal neoplasia  547–551, 549–550 New World camelid ophthalmology  2091, 2104–2105, 2105 ocular pathology  479, 485–487, 487, 531–552 orbital neoplasia  532–534, 533, 534 ovine and caprine ophthalmology  2030 porcine ophthalmology  2035

rabbit  2137, 2138 reptiles  2215 uveal neoplasia  542–547, 545–549 Neospora spp. canine anterior uvea diseases  1283 canine ocular fundus diseases  1537 canine orbital diseases  900 canine systemic disease with ocular manifestations  2371 clinical microbiology and parasitology  326 food animal systemic disease with ocular manifestations  2548 nephritis  2356 nerve blocks bovine ophthalmology  2007–2008, 2007–2008 canine orbital diseases  906–907, 906 clinical pharmacology and therapeutics  440–441 equine ophthalmology  1845–1846, 1845, 1867 general ocular examination  567–571, 567, 569 nerve fiber layer  104 nervous system canine conjunctival diseases  1046 iridocorneal angle  79 iris  67 ocular embryology and congenital malformations  17–18, 22, 25, 32–33, 33 ocular physiology  132–134, 133, 141–142, 144, 153–155 optics and physiology of vision  176–178 netarsudil  469, 1238 neural crest  3, 15, 19, 25–26 neural crest neoplasia  551, 551 neurectodermal tumors  1553–1554 neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM)  1956–1957, 2501–2502, 2502 neurocrest differentiation  497–498, 499 neuroectodermal neoplasia  547–551, 549–550 neuroectoderm differentiation  495–496, 496 neurogenic keratitis  1127 neurogenic keratoconjunctivitis sicca  2285–2286 neuroleptic drugs  1340 neuromuscular blocking agents (NMBA)  569, 2070–2071 neuronal ceroid lipofuscinosis (NCL) canine ocular fundus diseases  1525– 1526, 1526 canine systemic disease with ocular manifestations  2339–2340, 2340 ocular pathology  523

neuro‐ophthalmology  2237–2328 brain  2238–2240, 2239–2245 Braund’s syndromes  2265–2268, 2265, 2266–2269 canine neuro‐ophthalmic diseases  2274–2288, 2276–2277, 2280–2281, 2284 canine optic nerve diseases  1628–1629 cavernous sinus syndrome  2269, 2272 clinical microbiology and parasitology  300, 302 computed tomography  2250–2253 distant examination  2247–2254, 2248–2253, 2249 equine neuro‐ophthalmic diseases  2296–2304, 2298, 2302 feline neuro‐ophthalmic diseases  2288–2296, 2288–2290, 2294–2295, 2297 formulating a differential diagnosis list  2273 general organization of the nervous system  2237–2238, 2238 gross topographical neuroanatomy  2237–2240 hemifacial spasm  2269–2271 Horner’s syndrome  2265, 2268–2269, 2270, 2271–2272, 2288 lesion localization  2265–2272 location of important nuclei and ganglia  2246–2247 magnetic resonance imaging  679–681, 681, 2240, 2241–2245, 2250–2253, 2284, 2290 neuro‐ophthalmic examination  1628–1629, 2247–2265, 2287 pharmacologic testing  2264–2265 Pourfour du Petit syndrome  2271 reflex and response testing  2254–2262, 2255–2256, 2261 schemata for localizing blindness and anisocoria  2272, 2273–2275 Schirmer tear test  2263–2264 static anisocoria and hemidilated pupil  2271–2272, 2273 vision testing  2262–2263, 2262 neuropeptide Y  127, 129, 135 neuroprotection  1239–1240 neuroregeneration  1239–1240 neurotransmitters  1010–1011 neurotrophic keratitis  903–904 neurulation  3–5, 7 neutrophilia  2292 neutrophils  488, 488 New Forest disease see infectious bovine keratoconjunctivitis New World camelid ophthalmology  2085–2108 amaurosis  2104 anterior segment  2097–2098, 2097, 2098–2099

i41

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Index

New World camelid ophthalmology (cont’d) conjunctiva  2092–2094, 2093 context  2085–2086 cornea  2094–2097, 2095–2096 examination techniques  2086–2088, 2088 eyelids and nasolacrimal system  2090–2092, 2092 general features of eye and orbit  2089–2090, 2090 glaucoma  2103–2104 lens  2102–2103 neoplasia  2091, 2104–2105, 2105 ocular medications  2088–2089 ophthalmic anatomy  2089–2090, 2090, 2094, 2097, 2099, 2102 posterior segment  2099–2102, 2100–2101 vision  2086, 2087 next‐generation sequencing (NGS)  296, 783–784 NGE see nodular granulomatous episclerokeratitis NGS see next‐generation sequencing NHEJ1 mutations  1489, 1640 NHP see nonhuman primates nicotinamide adenine dinucleotide phosphate (NADPH)  131 nicotinic acetylcholine receptors (nAChR)  2434 nictitans gland canine lacrimal secretory system diseases  1010, 1010–1011, 1015, 1029, 1033–1035 canine nictitating membrane diseases  1064–1067, 1065–1067 feline nictitating membrane diseases  1688, 1688 nictitating membrane (NM) avian ophthalmology  2055, 2068 bovine ophthalmology  2004, 2006, 2008 canine lacrimal secretory system diseases  1009–1010, 1010–1012, 1034, 1034 canine nictitating membrane diseases  1062–1071 canine orbital diseases  880, 882–883 equine ophthalmology  1865, 1868, 1881–1882 examination after topical anesthetic application  610, 611 feline nictitating membrane diseases  1686–1689, 1686, 1687, 1688 general ocular examination  571, 574 laboratory sampling  611, 612, 616 ocular physiology  124, 126–127 ophthalmic anatomy  48, 49–50, 49 reptiles  2216 slit‐lamp biomicroscopy  583 tear tests  609 tonometry  622

nictitating membrane protrusion feline neuro‐ophthalmic diseases  2294–2295 feline nictitating membrane diseases  1687 feline systemic disease with ocular manifestations  2433, 2433 Niemann–Pick disease (NPD)  2426–2428 night blindness see congenital stationary night blindness nitric oxide (NO)  469–470 NK see natural killer NLE see necrotizing leukoencephalitis NLLS see nasolacrimal lavage system NM see nictitating membrane NMBA see neuromuscular blocking agents NME see necrotizing meningoencephalitis NO see nitric oxide nodular episclerokeratitis  513, 513 nodular fasciitis canine conjunctival diseases  1053, 1054 canine eyelid disorders  972 canine nictitating membrane diseases  1069–1070 nodular granulomatous episclerokeratitis (NGE)  1068–1069, 1153–1154, 1153–1154 nodules  1680–1681, 1731–1732 noncontact infrared thermometry (NCIT)  1085 nonhuman primates (NHP) ancillary diagnostic values  2147, 2148 functional morphology  2141–2142 laboratory animal ophthalmology  2141–2144 ophthalmic examination  2110–2111, 2113–2114 spontaneous lesions and diseases  2142–2144 non‐necrotizing granulomatous scleritis  1155 nonophthalmos  2212 nonpigmented epithelium (NPE)  139, 140 nonsense‐mediated mRNA decay  780–781 nonsteroidal anti‐inflammatory drugs (NSAID) canine anterior uvea diseases  1268, 1275, 1300 canine systemic disease with ocular manifestations  2392 clinical pharmacology and therapeutics  421–425, 454 equine ophthalmology  1860, 1862, 1905–1906 feline anterior uvea diseases  1752, 1755–1756 indications for ocular disease  422 mechanism of action  421–422 New World camelid ophthalmology  2102

ophthalmic NSAIDs and their side effects  422–424 surgical procedures on the canine lens  1380–1381, 1426 systemic administration  424–425 nontapetal fundus  1483–1484, 1500 nonteratoid medulloepithelioma  2104 nonulcerative keratitis canine corneal diseases  1123–1131, 1124–1125, 1128–1131 chronic superficial keratitis  1125–1127, 1125 corneal abscessation  1127–1128 infectious crystalline keratopathy  1129–1131, 1129–1130 neurogenic keratitis  1127 ocular immunology  280 ocular pathology  508, 509 parasitic keratitis  1128, 1128 photography  841 pigmentary keratitis/superficial pigmentary keratitis  1123–1125, 1124 rabbit  2136–2137 superficial punctate keratitis  1128–1129, 1129 notch deformation  950, 951 Notoedres spp.  1673–1674, 2447 NPD see Niemann–Pick disease NPE see nonpigmented epithelium NPHP4 mutations  1510, 1511 NPHP5 mutations  1510 Nrf2/Keap1/ARE  1347–1348 NSAID see nonsteroidal anti‐inflammatory drugs nuclear sclerosis canine lens diseases and cataract formation  1350–1351, 1351 equine ophthalmology  1942 general ocular examination  577 slit‐lamp biomicroscopy  581 small mammal ophthalmology  2193, 2194 nucleic acids  264 nutritional disorders see diet and nutrition nystagmus bovine ophthalmology  1987 food animal neuro‐ophthalmic diseases  2304 neuro‐ophthalmology  2247–2248, 2259–2262, 2261 ocular physiology  154 nystatin  397 (O‐acyl)‐omega‐hydroxy fatty acids (OAHFA)  126–127 obstacle course test see maze test OCT see optical coherence tomography OCTA see optical coherence tomography angiography

Index

ocular albinism bovine ophthalmology  2012, 2016, 2016 ovine and caprine ophthalmology  2031 ocular conformers  1868 ocular drug delivery anti‐inflammatory agents  418 barriers to ocular drug delivery  349–352 blood–ocular barriers  350–352, 351, 373 clinical pharmacology and therapeutics  349–384 conjunctival and scleral membrane barriers  350 conventional eye drops  352–353 corneal membrane barriers  349–350 drug disposition after eye drop application  353–361, 353 drug efflux transporters  352 improvement of topical ocular drug delivery  361–366, 362 intraocular drug delivery  369–372 iontophoresis  373–374 light‐activated drugs  374 microneedles  374 periocular drug delivery  367–369, 367 sonophoresis  374 suprachoroidal drug delivery  369 systemic administration  372–373 topical administration  352–366, 353, 355, 357–358, 362 ocular embryology and congenital malformations  3–40 anterior segment dysgenesis  11, 21, 23–26, 25–28 canine lens diseases and cataract formation  1322–1326, 1323, 1324, 1325 canine nasolacrimal diseases  988, 989 canine vitreous diseases  1459 cataracts  26, 29–30 colobomatous malformations  22, 22–25, 25, 33, 33 cornea and anterior chamber development  15, 16 cyclopia and synophthalmia  20, 20 dermoids  22–23, 25 developmental ocular anomalies  20–33 extraocular muscles  19–20 eyelid coloboma  33, 33 eyelid development  18–19, 19 gastrulation and neurulation  3–5, 6–7 glaucoma  30–31 iris, ciliary body, and iridocorneal angle development  16–17 lens formation  9–12, 11–13 microphthalmia and anophthalmia  20–22, 20, 21, 22 multiple congenital ocular anomalies in horses  29, 30 optic nerve development  18

optic nerve hypoplasia  32–33, 33 optic vesicle and optic cup formation  5–9, 7–12 persistent hyperplastic primary vitreous/ persistent hyperplastic tunica vasculosa lentis  31, 31 retina and optic nerve development  17–18 retinal dysplasia  31–32, 31–32 sclera, choroid and tapetum development  18 sequence of ocular development  3, 4–5 uveal cysts  27–29, 28–29 vascular development  13–15, 13–14 vitreous development  18 ocular filariasis  1282 ocular fundus bovine ophthalmology  2015–2020, 2015–2020 canine glaucomas  1209–1210 canine ocular fundus diseases  1477–1574 confocal scanning laser ophthalmoscopy  697 exotic mammals  2223 fluorescein angiography  706–707, 712–714, 716–717 general ocular examination  578 nonhuman primates  2144 optical coherence tomography  703 ovine and caprine ophthalmology  2030–2033, 2030–2032 porcine ophthalmology  2036–2037, 2036 slit‐lamp biomicroscopy  588–589 ocular imaging  662–732 anterior segment and retinal imaging  696–704, 697, 699–701, 703 computed tomography  665–671, 667–668, 670–673 contrast radiography  663–665, 664 corneal imaging  682–696, 684, 686–688, 690–696 fluorescein angiography  704, 705–716, 709–717 future directions  716–717 laser fluorophotometry and laser flare cell meters  704–705 magnetic resonance imaging  665, 671–681, 674–681 optimizing conventional radiographic studies  662–663 role of conventional radiography  662 tear film imaging  681–682, 682–683 ocular immunology  263–292 adaptive/antigen‐specific immune response  263–264, 266–272, 272 anterior chamber‐associated immune deviation  268, 273–277 architecture of an immune response  263–270

bacterial keratitis  279–280 canine and feline uveitis  283–284 clinical ocular disease  277–285 corneal transplantation  278–279 equine recurrent uveitis  282–283 experimental autoimmune uveitis  282 immune keratitis/nonulcerative keratopathies  280 initiation of inflammation  263–265, 265 innate immune response  266, 266, 271–273, 274 keratoconjunctivitis sicca  271, 277–278 lens  280–281 ocular immune responses  270–277 ocular surface adaptive immune response  271–272, 272 ocular surface innate immune response  271–273, 274 retina  284–285 uveitis  281–282 ocular larva migrans (OLM)  1282 ocular malformations exotic mammals  2219–2220 reptiles  2211–2212, 2212 ocular melanosis canine anterior uvea diseases  1292– 1293, 1292–1293 canine glaucomas  1222–1223, 1223 canine ocular fundus diseases  1553, 1553 ocular membranogenesis  491, 492 ocular nodular fasciitis  2220 ocular pathology  479–563 acquired disorders  502–552 choroidal disorders  521–522, 522 congenital disorders  493–502 conjunctival disorders  506–508, 507–508 corneal and limbal neoplasia  541–542, 542 corneal disorders  508–513, 509–513 defective organogenesis  493–495, 494–496 defective tissue differentiation  495–502, 496–497, 499–502 degenerative disorders  505, 509, 516, 522–525, 529–530 eyelid and conjunctival neoplasia  534–541, 535, 536–541 fixation and processing of ocular tissues  479–482, 480, 481, 483–484 fundamental pathology  482–487, 484–487 glaucoma  525–530, 527, 528, 529 infectious inflammatory ocular disease  531, 531–532, 532 inflammation  488–493, 488–494 inherited/presumed inherited disorders  505–506, 508, 511–514, 516–522 intraocular neoplasia  542, 543–544

i43

i44

Index

ocular pathology (cont’d) introduction and principles  479 lacrimal gland disorders  506, 506 lens luxation/subluxation  525, 525 lenticular disorders  522–525, 524 metabolic diseases that affect the eye  530, 530 metastatic ocular neoplasia  551–552, 552 neoplasia  479, 485–487, 487, 531–552 neural crest neoplasia  551, 551 neuroectodermal neoplasia  547–551, 549–550 noninfectious inflammatory ocular disease  503–506, 503, 504–505 orbital neoplasia  532–534, 533, 534 retinal disorders  517–520, 518–520 scleral and episcleral disorders  513–514, 513–514 storage disorders, amino acid, and lipid peroxidation disorders  522, 523 uveal disorders  514–517, 514–518 uveal neoplasia  542–547, 545–549 vitreous disorders  518–522, 521 ocular perfusion pressure (OPP)  1189, 1195–1196 ocular physiology  124–167 anterior eye structures  124–126, 125–126 aqueous humor  130–131, 138–148, 140, 142, 143, 145, 147–148 blood–ocular barriers  138, 140–141, 145, 152 canine conjunctival diseases  1045 canine lacrimal secretory system diseases  1008–1013, 1009–1013 canine nasolacrimal diseases  988–990 canine optic nerve diseases  1622–1628, 1623–1626, 1628 canine vitreous diseases  1460 choroid  137 circulation/blood flow  136–138 cornea  129–134, 130, 132–133, 133 equine ophthalmology  1841–1844, 1864–1865, 1865, 1884–1886, 1937–1939 exotic mammals  2217–2219 feline ocular surface disease  1718 intraocular pressure  136, 138–139, 143–148, 147–148 iris and pupil  134–136, 135 lens  148–151, 150 nutrition of intraocular tissues  136 ocular mobility  153–154 ocular rigidity  146 oculocardiac reflex  154–155 optic nerve head  138 rabbit  2179–2180 retina  137–138 tear production and drainage  126–129, 127

uvea  136–137 vitreous  151–153, 152 ocular rigidity  146 ocular squamous cell carcinoma (OSCC) bovine ophthalmology  2002–2010, 2004–2008 clinical signs  2004, 2004–2006 diagnosis  2004–2006, 2006 etiology  2003–2004 incidence and geographic distribution  2002 metastatic potential  2004–2005 ovine and caprine ophthalmology  2029 signalment and genetic predisposition  2002–2003 treatment  2006–2010, 2007–2008 oculocardiac reflex  154–155 oculocephalic reflex see vestibulo‐ocular reflex oculodermal melanocytosis  2331 oculomotor cranial nerve  925 oculoskeletal dysplasia  1494–1496, 1495–1496 Oestrus spp.  2028 oil droplets  240 oil‐in‐water emulsions  363 ointments  364–365, 1024–1026 OLM see ocular larva migrans OMAG see optical microangiography Onchocerca spp. canine anterior uvea diseases  1282 canine corneal diseases  1128 canine systemic disease with ocular manifestations  2366, 2366 clinical microbiology and parasitology  329 equine ophthalmology  1918 equine systemic disease with ocular manifestations  2510–2511 feline systemic disease with ocular manifestations  2447–2448, 2448 ONH see optic nerve head ONL see outer nuclear layer operculum  76, 76 ophthalmic anatomy  41–123 aging  78–79 amphibians  2206–2207, 2206–2207 avian ophthalmology  2055–2057, 2056–2057 canine conjunctival diseases  1045–1046 canine corneal diseases  1082–1085, 1083–1084 canine eyelid disorders  923–925, 924 canine lacrimal secretory system diseases  1008–1010, 1009–1010 canine lens diseases and cataract formation  1317 canine nasolacrimal diseases  988, 989 canine nictitating membrane diseases  1062–1063, 1063

canine optic nerve diseases  1622–1628, 1623–1626, 1628 canine orbital diseases  879, 880 canine posterior segment surgery  1575–1578, 1576–1578 canine vitreous diseases  1459–1460 choroid  79–85, 80–84, 83 ciliary body  67–70, 67–69 ciliary body musculature  70–78, 70–72 ciliary body vasculature  72, 73 conjunctiva  48–49, 48 cornea  53–61, 53–60, 53, 57 diagnostic ultrasound  741 equine ophthalmology  1841–1844, 1862–1864, 1864, 1883–1884, 1937–1939 exotic mammals  2217–2219 eyelids  46–48, 46–48 feline anterior uvea diseases  1732 feline eyelid diseases  1665 feline ocular surface disease  1717–1718 feline posterior segment diseases  1773–1774, 1773 fish  2201–2203, 2202 globe  51–53, 51–53, 51–52 guinea pig  2127–2128 iridocorneal angle  60, 70–79, 71–78 iris  63–67, 64–67 lacrimal and nasolacrimal system  48, 50–51, 50 lens  85–91, 85, 86–91 miniature pig  2139–2140, 2140 mouse and rat  2114–2118, 2118 New World camelid ophthalmology  2089–2090, 2090, 2094, 2097, 2099, 2102 nictitating membrane  48, 49–50, 49 nonhuman primate  2141–2142 optic nerve  106–108, 106–109, 108 orbit  41–46, 42–45, 42–44, 46, 109–111, 109–111 rabbit  2132–2135, 2179–2180 reptiles  2209–2211, 2210–2212 retina  93–106, 93–95, 95–96, 97–102, 100, 103, 105 sclera  61–63, 61–63, 62 uvea  63–85, 63–64 uveoscleral outflow  77–78, 77–78 vasculature of the eye and orbit  109–111, 109–111 vitreous  91–93, 91, 92 ophthalmic examination and diagnostics  564–661 akinesia  567–568, 567 amphibians  2207 anterior and posterior segment  577–578 avian ophthalmology  2057–2059, 2065 bovine ophthalmology  1983, 1984

Index

canine optic nerve diseases  1628–1633, 1629–1635 close examination of adnexa and globe  574–577, 576 corneal esthesiometry  599–601, 600 diagnostic sequence for basic eye examination  564–565, 565 diagnostic ultrasonography  576 diagnostic ultrasound  733–756 direct ophthalmoscopy  589–594, 591–592, 592, 594 distant examination  571 electrodiagnostic tests  757–777 equine ophthalmology  1844–1849, 1845, 1847, 1961–1963 examination after topical anesthetic application  610, 611 exotic animal ophthalmology  2200–2201 exotic mammals  2217–2219 external ophthalmic dyes  616–620, 616–620 fish  2203 general ocular examination  564–578 gonioscopy  630–636, 631–635 history and signalment  564 indirect ophthalmoscopy  593, 594–597, 594–596 initial assessment in ambient lighting  571, 571 intraocular pressure  565, 577 laboratory animal ophthalmology  2110–2113, 2110–2111, 2113–2114 laboratory sampling  610–616, 612–614, 613 nasolacrimal flush  636–637, 636–638 neuro‐ophthalmology  1628–1629, 2247–2265, 2287 New World camelid ophthalmology  2086–2088, 2088 ocular imaging  662–732 ovine and caprine ophthalmology  2021–2022, 2021 paracentesis  637–641, 639, 640 pupil dilation  577 regional anesthesia/analgesia  568–571, 569 restraint  565–566 retinoscopy  597–599, 598 sedation/general anesthesia  565–566 slit‐lamp biomicroscopy  576–589, 578–579, 580, 581–590 surgical procedures on the canine lens  1371–1372 tear tests  574, 601–610, 601, 602–608, 605 tonography  629–630 tonometry  620–629, 622–625 vision assessment and neuro‐ ophthalmic examination  571–574, 572, 574

ophthalmic viscosurgical devices (OVD) capsulorhexis/capsulectomy  1394–1397, 1395–1397 commercial systems  1391, 1392 corneal incision  1393–1394, 1393–1394 functions and characteristics  1389–1391, 1390 intraoperative complications  1406–1410 phacoemulsification techniques  1397–1402, 1398–1399, 1401–1402 postoperative complications  1412–1415 removal and wound closure  1404, 1405 surgical approach  1392–1402 surgical procedures on the canine lens  1389–1402 ophthalmomyiasis canine ocular fundus diseases  1538 canine systemic disease with ocular manifestations  2364–2365 feline anterior uvea diseases  1751, 1751 feline posterior segment diseases  1787, 1787 feline systemic disease with ocular manifestations  2446, 2446–2447 New World camelid ophthalmology  2102 ophthalmomyiasis interna posterior (IOP)  1282, 1787, 1787 ophthalmoscopy and fundus photography bovine ophthalmology  2011, 2015– 2016, 2015–2017, 2019–2021 canine glaucomas  1182 canine lens diseases and cataract formation  1351 canine ocular fundus diseases  1478–1479 developmental anomalies  1487–1494, 1496–1498 inflammation and infections affecting the ocular fundus  1527–1529, 1528–1529, 1532, 1534, 1536 inherited retinal degenerations  1499, 1500–1502, 1511, 1514–1518 lysosomal storage diseases  1526 normal ocular fundus  1482, 1483–1485 nutritional retinopathies  1546 other retinal dystrophies  1520, 1523–1524 proliferative and neoplastic conditions  1553–1555 renal toxicities  1543–1544 secondary retinal degeneration  1550–1551, 1550–1552 specific retinopathies  1539, 1541 vascular disease  1547–1548 canine optic nerve diseases  1629–1632, 1629–1633, 1637–1640, 1638–1642, 1649–1651, 1653–1655

canine posterior segment surgery  1579–1580, 1582, 1586–1587, 1614 canine systemic disease with ocular manifestations cardiovascular diseases  2341 congenital disorders  2333 developmental disorders  2340 hematologic diseases  2344 immune‐mediated diseases  2353 infectious diseases  2355, 2357, 2363–2364, 2374–2377, 2381 metabolic diseases  2383 neoplasia  2386 nutritional disorders  2387 toxicities  2389–2390 canine vitreous diseases  1461, 1469 direct ophthalmoscopy  589–594, 591–592, 592, 594 equine ophthalmology  1847, 1848, 1857, 1953–1959 equine systemic disease with ocular manifestations  2498, 2501–2502 feline neuro‐ophthalmic diseases  2290, 2297 feline posterior segment diseases  1773–1777, 1776–1778, 1779–1782, 1784–1785, 1787–1788 feline systemic disease with ocular manifestations  2428–2429, 2444, 2446, 2449, 2465, 2467 fish  2201 food animal systemic disease with ocular manifestations  2536, 2543, 2549, 2554–2556, 2558 fundamentals of animal vision  229 indirect ophthalmoscopy  593, 594–597, 594–596 laboratory animal ophthalmology  2110, 2112, 2114, 2149–2150, 2150, 2155–2156 magnification  597 New World camelid ophthalmology  2089, 2099–2101 ocular embryology and congenital malformations  23–24, 31–33 ocular pathology  496 ovine and caprine ophthalmology  2030–2031, 2030–2032 panoptic ophthalmoscopy  594 photographic equipment and technique  847–852, 850–851, 853 porcine ophthalmology  2036, 2036 reptiles  2209 small mammal ophthalmology  2179, 2180 opioid growth factor  1084–1085 OPP see ocular perfusion pressure opportunistic infections  300

i45

i46

Index

opsin fundamentals of animal vision  239–241, 239, 240, 241 optics and physiology of vision  169, 170, 190–191, 193 optical coherence tomography angiography (OCTA)  704, 707–708, 2149–2150 optical coherence tomography (OCT) anterior segment and retinal imaging  697–704, 699–701, 703 avian ophthalmology  2072 basic principles and physics  697–701 canine glaucomas  1177, 1179 canine neuro‐ophthalmic diseases  2287 canine ocular fundus diseases  1478, 1541 canine optic nerve diseases  1632, 1634–1635, 1641, 1642, 1646, 1649 canine systemic disease with ocular manifestations  2347 clinical applications  701–703 color Doppler optical coherence tomography  704 corneal imaging  695–696 exotic animal ophthalmology  2209 feline ocular surface disease  1724, 1728–1729 future directions  716–717 laboratory animal ophthalmology  2113, 2150–2151, 2150 New World camelid ophthalmology  2088, 2094 ophthalmic anatomy  95 tear film imaging  682 optical microangiography (OMAG)  704 optical pachymetry  684, 684 optic chiasm canine optic nerve diseases  1628 neuro‐ophthalmology  2262–2263, 2262 optics and physiology of vision  208–210, 209 optic cup  8–9, 10–12 optic disc  2141 optic disc aplasia  1788 optic disc colobomas  1788, 1790 optic disc cupping  1629, 1631–1632, 1654–1655 optic disc hypoplasia  1788 optic nerve axon count and density  107–108, 108 bovine ophthalmology  2020–2021, 2021 canine optic nerve diseases  1622–1661 direct ophthalmoscopy  592 equine ophthalmology  1862, 1958– 1960, 1959–1960 feline optic nerve and CNS diseases  1788–1790, 1790 indirect ophthalmoscopy  596 neuro‐ophthalmology  2262–2263, 2262

nonhuman primates  2144 ocular embryology and congenital malformations  17–18 ocular pathology  479, 481 ocular physiology  138 ophthalmic anatomy  52, 106–108, 106–109, 108 optics and physiology of vision  208 optic nerve aplasia  1639, 1639 optic nerve atrophy canine optic nerve diseases  1649–1650, 1651 equine ophthalmology  1958, 1959 feline optic nerve and CNS diseases  1790 ocular pathology  483–484, 485, 496, 529–530 optic nerve colobomas canine optic nerve diseases  1639–1640, 1640–1641 ocular embryology and congenital malformations  22, 25 optic nerve dysplasia  2119 optic nerve head (ONH) canine glaucomas  1173, 1179, 1182, 1186, 1189–1196, 1191, 1194, 1204–1211, 1223, 1225 canine ocular fundus diseases  1478–1479, 1482, 1484, 1484, 1492, 1496–1498 canine optic nerve diseases  1622–1627, 1629–1633, 1630–1635, 1637–1639, 1641–1655, 1646 clinical pharmacology and therapeutics  463, 469–470 equine ophthalmology  1938, 1952 optical coherence tomography  697–703, 699–701, 703 optic nerve hypoplasia canine optic nerve diseases  1637–1639, 1638–1639 equine ophthalmology  1857 ocular embryology and congenital malformations  32–33, 33 ocular pathology  496, 496 optic nerve neoplasia canine optic nerve diseases  1650–1654, 1651–1652 feline optic nerve and CNS diseases  1790 magnetic resonance imaging  679, 680 ocular pathology  550–551, 550 optic neuritis canine neuro‐ophthalmic diseases  2279–2280, 2280, 2284, 2284 canine ocular fundus diseases  1530 canine optic nerve diseases  1644–1647, 1644, 1645–1646, 1648 canine systemic disease with ocular manifestations  2374

feline neuro‐ophthalmic diseases  2291–2292 feline optic nerve and CNS diseases  1788–1790, 1790 magnetic resonance imaging  675, 677, 679–681, 681 optics and physiology of vision  168–224 abnormal refractive states and optical errors  178–188, 178, 179, 181–189 accommodation  175–178, 175, 177 aphakic eyes and intraocular lenses  180–182, 181 astigmatism  182–183, 182 chromatic aberrations  185–187, 186 classical visual pigments and phototransduction  193–196, 194–195, 197 emmetropia and accommodation under water  187–188, 187–189 emmetropia and ametropia  178–182, 178 factors affecting visual acuity  243–247 geometric optics  171–172, 171–172 light and the electromagnetic spectrum  168–169, 169 photometry  169–170, 170 photoreceptors  169, 171, 186–187, 189–196, 190, 191, 192, 194–195 physical optics  168–170, 169, 170 physiology of retinoid cells  196–206, 197, 199–206 primary visual cortex  211–213, 212–213 pupil  177–178, 185–188, 185–186, 188 refraction  171–172, 171–172 refractive structures of the eye  172–175, 173–174, 175 retina  175, 178–179, 178, 189–211, 190 retinal synapses and neurotransmitters  206–208 retina to visual cortex  208–211, 209–210 spherical aberrations  184–185, 184–185 static accommodation  183–184, 183 transmission and reflection  170–171, 170 vergence  172, 172 visual optics  172–178 visual processing  189–213 optic sulci  5–7, 7 optic tract  208–210, 209, 2263 optic vesicle  5–11, 7–12 optokinetic reflex  234 oral administration  421, 424–425, 426–427 orbicularis oculi muscle  988–989 orbit avian ophthalmology  2065 bovine ophthalmology  1986–1987, 1987

Index

canine conjunctival diseases  1056, 1056 canine lacrimal secretory system diseases  1009–1010, 1010 canine orbital diseases  879–922 computed tomography  667–670, 668, 670–672 congenital disorders  888–892 diagnostic ultrasound  743–744, 747 equine ophthalmology  1850, 1862– 1870, 1864–1866, 1868, 1870 extraocular muscles and orbital fat  42–46, 44–45, 46 feline orbital diseases  1791–1794, 1791–1794 foramina  42, 44 guinea pig  2127–2128 magnetic resonance imaging  676–681, 678–681 miniature pig  2139 mouse and rat  2117 New World camelid ophthalmology  2089–2090, 2090 ocular pathology  503–506, 505 ophthalmic anatomy  41–46, 42–45, 42–44, 46 orbital fascia  42–43, 44 ovine and caprine ophthalmology  2022–2023, 2022 porcine ophthalmology  2033–2034, 2033 rabbit  2133, 2184, 2185–2186 surgery of the globe and the orbit  905– 914, 906, 908–915 vasculature  109–111, 109–111 orbital cellulitis/abscess computed tomography  670–671 feline orbital diseases  1791–1792, 1791 magnetic resonance imaging  679 ocular pathology  504–505 orbital cysts/mucoceles canine orbital diseases  891–892 diagnostic ultrasound  744–745 ocular pathology  505, 505 orbital emphysema  903 orbital fat prolapse canine conjunctival diseases  1054, 1054 canine orbital diseases  904, 905 equine ophthalmology  1870, 1871 orbital gland prolapse  2138, 2138 orbital neoplasia canine orbital diseases  883, 888, 888–890, 900–902, 901, 911–914 equine ophthalmology  1870, 1871 feline orbital diseases  1793–1794, 1793–1794 ocular pathology  532–534, 533, 534 orbital/retrobulbar fat  880, 882, 888 orbital rim–anchoring technique  1065, 1066

orbitotomy/orbitectomy  911–914, 912–915, 1868 organophosphorus inhibitors  452–453 organophosphorus insecticides  2557 OSCC see ocular squamous cell carcinoma oscillatory potential  2057 osmolarity/osmolality  128, 149, 610 osmotic agents adverse effects and contraindications  469 available products  467–468 clinical pharmacology and therapeutics  467–469 clinical use  468 mechanism of action  467 osseous metaplasia guinea pig  2131–2132, 2131 ocular pathology  484, 486 osteolysis  888, 891, 895 osteoma cutis  931 osteopetrosis‐induced ocular fundus disease  2018 osteosarcoma canine anterior uvea diseases  1297 feline orbital diseases  1793 ocular pathology  533 otitis media/interna amphibians  2207 canine neuro‐ophthalmic diseases  2286 feline neuro‐ophthalmic diseases  2295 outer limiting membrane  99, 99 outer nuclear layer (ONL) ophthalmic anatomy  99–100, 100, 100 optics and physiology of vision  193 outer plexiform layer  100, 100 oval lipid corneal dystrophy  1131–1133, 1133 OVD see ophthalmic viscosurgical devices OvHV‐2 see ovine herpesvirus‐2 ovine and caprine ophthalmology  2021–2033 conjunctiva and cornea  2025–2029, 2026–2027 eyelids  2023–2025, 2023–2024 glaucoma  2029 lens  2030 neoplasia  2030 ocular examination and ophthalmic parameters  2021–2022, 2021 ocular fundus  2030–2033, 2030–2032 orbit and globe  2022–2023, 2022 uveal tract  2029–2030 ovine herpesvirus‐2 (OvHV‐2)  306 oxazolidinones  392 oxidative stress  149–151, 1347–1348 oxybuprocaine  439–440, 568 oxygen‐induced retinopathy  1544–1545 oxytetracycline  1999–2000

PABA see paraaminobenzoic acid PACG see primary narrow‐angle/angle‐ closure glaucoma pachymetry  682–686 clinical applications  684–686, 686 in vivo confocal microscopy  693 optical and ultrasound modes  684, 684, 686 optical coherence tomography  696 paired antibody titer  325 palliative therapy  1138–1139 palpebral fissure  942, 946–956, 948–959 palpebral nerve block equine ophthalmology  1845–1846, 1845 general ocular examination  567, 567 palpebral reflex see blink reflex PAMP see pathogen‐associated molecular patterns pannus see chronic superficial keratitis panophthalmitis amphibians  2207, 2208 exotic mammals  2220 pathology  491 reptiles  2214, 2214 small mammal ophthalmology  2189 papilledema bovine ophthalmology  2021, 2021 canine optic nerve diseases  1642–1644 food animal systemic disease with ocular manifestations  2554–2555 papillomas bovine ophthalmology  1989, 1989, 2004, 2004 canine corneal diseases  1150, 1150 canine eyelid disorders  973 feline eyelid diseases  1684 ocular pathology  535–537, 538 papillomatosis  1051–1052, 1052, 2024 papillomavirus bovine papillomavirus  307, 2004 canine papillomavirus  305, 2380 paraaminobenzoic acid (PABA)  393–394 paracentesis  637–641, 639, 640 canine glaucomas  1230–1231, 1231 hyalocentesis  639–640, 639 keratocentesis  637–639, 639 recommendations for aqueous and vitreous samples  640–641, 640 Parachlamydia spp.  318 parametric image editing (PIE) software  861, 863, 864–870, 865–869, 868 paramyxovirus  2552 paranasal sinuses  1868 parasitic diseases avian ophthalmology  2062–2063, 2067 bovine ophthalmology  1988, 1992 canine anterior uvea diseases  1282 canine conjunctival diseases  1049, 1054–1055 canine corneal diseases  1128, 1128 canine eyelid disorders  969, 970

i47

i48

Index

parasitic diseases (cont’d) canine ocular fundus diseases  1537–1538 canine systemic disease with ocular manifestations  2364–2372, 2366, 2370 canine vitreous diseases  1471 clinical microbiology and parasitology  327–330 diagnostic methods  327 Dipteric larvae  330 equine ophthalmology  1872–1874, 1874, 1918 equine systemic disease with ocular manifestations  2508–2513, 2509–2510 exotic mammals  2220–2222 feline anterior uvea diseases  1746–1747, 1746 feline eyelid diseases  1673–1675, 1673 feline ocular surface disease  1697–1698 feline posterior segment diseases  1783 feline systemic disease with ocular manifestations  2446–2451, 2446–2450 fish  2203–2204 food animal systemic disease with ocular manifestations  2546–2548, 2547–2548 in vivo confocal microscopy  692 mites  328 nematodes  328–330 New World camelid ophthalmology  2094, 2102 ovine and caprine ophthalmology  2024–2025, 2028–2029 reptiles  2215 small mammal ophthalmology  2182 tapeworm disease  330 see also individual parasites/diseases; protozoal diseases parasympathetic lesions  2264 parasympathomimetics see cholinergic agonists (miotics) Parelaphostrongylus spp.  2222, 2511 parotid duct transposition (PDT) canine lacrimal secretory system diseases  1029–1033, 1029, 1030–1031, 1033 closed procedure  1031–1032, 1031 complications, sequelae, and postoperative considerations  1032–1033 composition of human parotid and tear secretions  1029 open procedure  1032 preoperative considerations  1029– 1030, 1030 PARR see polymerase chain reaction assay for antigen receptor rearrangement

pars plana  70, 1577–1578 pars plana vitrectomy (PPV) canine posterior segment surgery  1582–1583, 1605–1608 canine vitreous diseases  1464 equine ophthalmology  1934–1935 pars planitis  300 partial albinism canine systemic disease with ocular manifestations  2330–2331 equine systemic disease with ocular manifestations  2495 feline systemic disease with ocular manifestations  2421–2422 food animal systemic disease with ocular manifestations  2535 partial incision superficial keratectomy  1093, 1095 partial tarsorrhaphy  1033 parvovirus B  26 Pasteurella spp. clinical microbiology and parasitology  316 feline eyelid diseases  1676 small mammal ophthalmology  2182, 2188–2189, 2189 patent hyaloid artery  498 pathogen‐associated molecular patterns (PAMP)  264, 265, 269 pathology see ocular pathology patient position canine eyelid disorders  926 microsurgery  794, 794, 796–798, 797–798 pattern electroretinography (PERG)  1183–1185, 1202–1203, 1211 canine ocular fundus diseases  1481, 1549–1550 canine optic nerve diseases  1636–1637 electrodiagnostic tests  773, 773 pattern recognition receptors (PRR)  264, 269–270 PBED see porcine blue eye disease PCCC see posterior continuous curvilinear capsulorhexis PCG see pigmentary and cystic glaucoma; primary congenital glaucoma PCO see posterior capsule opacification PCR see polymerase chain reaction PCT see posterior capsular tears PDE6A/B mutations  1503–1507, 1507–1508 PDE see phosphodiesterase PD‐L1 see programmed death ligand‐1 PDT see parotid duct transposition; photodynamic therapy PE see pigmented epithelium pecten oculi avian ophthalmology  2071–2072 ocular physiology  136 ophthalmic anatomy  105–106, 105

pectinate ligament  74–75, 849 pectinate ligament avulsion  1921 pectinate ligament dysplasia (PLD) canine glaucomas  1177–1178, 1181–1182, 1187, 1197–1198, 1209–1215 gonioscopy  634–636, 635 ocular embryology and congenital malformations  30–31 ocular pathology  526–527, 527 pedicle conjunctival graft  1106–1108, 1108–1109, 1111 pedicle grafts  948, 949 pediculosis  2509 PEM see polioencephalomalacia pemphigus canine systemic disease with ocular manifestations  2347–2348 equine systemic disease with ocular manifestations  2503, 2503 feline eyelid diseases  1676, 1677 pendular nystagmus  2304 penetrating keratoplasty (PK) canine corneal diseases  1144–1148, 1144–1147 equine ophthalmology  1902–1904, 1905, 1906–1907 penetrating trauma canine anterior uvea diseases  1288–1290, 1289 canine optic nerve diseases  1649 canine vitreous diseases  1466 feline anterior uvea diseases  1752–1753 ocular pathology  503, 504 surgical procedures on the canine lens  1405 penetration enhancers  361 penicillinase‐resistant agents  386 penicillins  386–387 Penicillium spp.  322–323 perfluorocarbon liquids (PFCL)  1593, 1601–1604, 1604, 1606–1609, 1609 perforating trauma canine corneal diseases  1087, 1109–1111, 1112 canine lens diseases and cataract formation  1346 equine corneal diseases  1886–1887, 1897–1899 feline anterior uvea diseases  1752–1753 feline lens diseases and cataract formation  1771, 1771 ocular pathology  503, 504 PERG see pattern electroretinography periarteritis nodosa  1754, 2429 peribulbar administration  369 peribulbar nerve block  570–571 perinuclear/lamellar cataracts  1945–1946 periocular cellulitis  2060, 2061

Index

periocular drug delivery  367–369 episcleral implants  368–369 retrobulbar and peribulbar administration  369 subconjunctival administration  367–368, 367 sub‐Tenon’s administration  368 periocular leukotrichia  1678 periodontal disease  2469, 2469 peripheral cystoid retinal degeneration  1552, 1552 peripheral nerve sheath tumors (PNST)  1683–1684, 1684 peripheral ocular neuropathies  1430–1431 peripheral ulceration  1918 perivascular sheathing  2113, 2114 perivascular sheen  2113, 2114 permanent tarsorrhaphy canine eyelid disorders  952–953, 953–954, 978, 982 canine lacrimal secretory system diseases  1033 persistent corneal erosions  1860–1862, 2187 persistent hyaloid artery (PHA)  1464–1465, 1464 persistent hyaloid remnants  2124, 2124 persistent hyaloid vasculature  743 persistent hyperplastic tunica vasculosa lentis/persistent hyperplastic primary vitreous (PHTVL/PHPV) canine lens diseases and cataract formation  1322–1326, 1324, 1325 canine ocular fundus diseases  1496–1497, 1496 canine posterior segment surgery  1581 canine vitreous diseases  1459, 1465–1466, 1465–1466, 1467 diagnostic ultrasound  742, 743 ocular embryology and congenital malformations  31, 31 ocular pathology  498, 499 persistent keratolenticular attachment  1377 persistent primary vitreous  1853 persistent pupillary membranes (PPM)  498, 499 canine anterior uvea diseases  1260–1262, 1261 canine corneal diseases  1095–1096, 1095 canine lens diseases and cataract formation  1322, 1323, 1324 equine ophthalmology  1853, 1853 feline anterior uvea diseases  1734–1735, 1735 miniature pig  2141 ocular embryology and congenital malformations  23–25 persistent tunica vasculosa lentis  1465

Peters’ anomaly canine anterior uvea diseases  1262 diagnostic ultrasound  748, 749 ocular embryology and congenital malformations  26, 26 Peterson nerve block  570 PEV see primitive embryonic vasculature PFCL see perfluorocarbon liquids PG see prostaglandins PHA see persistent hyaloid artery phaco chop technique  1399–1400 phacoclastic uveitis canine anterior uvea diseases  1277–1278 canine lens diseases and cataract formation  1349–1350 feline anterior uvea diseases  1754 ocular pathology  515–516, 516 surgical procedures on the canine lens  1377 phacoemulsification canine glaucomas  1219 canine lens diseases and cataract formation  1357 canine posterior segment surgery  1579, 1579 chip and flip/crack and flip  1400 commercial systems  1384–1385, 1385 divide‐and‐conquer technique  1399, 1399 equine ophthalmology  1855, 1948, 1949–1950, 1950 feline anterior uvea diseases  1752 fluidics  1383–1385 foot pedal  1388 handpieces and needles  1385–1388, 1386–1387 hydrodissection  1398–1399 intraoperative complications  1409 irrigation/aspiration  1388, 1400–1401, 1401 lens capsule: polishing, opacities  1401–1402, 1402 lens stability  1431–1438 machine parameters  1383 machine settings  1388–1389, 1389 microsurgery  794, 797–799, 797, 802 one‐handed technique  1397–1398, 1398 phaco chop/stop and chop  1399–1400 postoperative complications  1412– 1413, 1423–1424, 1423, 1428–1430 retinoscopy  599 specular microscopy  689 surgical procedures on the canine lens  1375, 1378, 1382–1389, 1397–1402, 1431–1438 techniques  1397–1402, 1398–1399, 1401–1402 two‐handed/bimanual technique  1398 phacolytic glaucoma  1218, 1219

phacolytic uveitis canine lens diseases and cataract formation  1349–1350 feline anterior uvea diseases  1754 ocular pathology  515, 515 phacomorphic glaucoma  1218 phagocytosis  266 pharmaceutical corneal opacities  1142–1143, 1143 pharmacogenetics  782 pharmacokinetics conventional eye drops  358–361, 358 drug elimination from the anterior chamber  360 drug melanin binding  360 drug ocular metabolism  360–361 intraocular drug distribution  359–360 tear drug kinetic profile  358–359, 358 pharmacologic testing  2264–2265 phenazopyridine toxicity  2392 phenol red thread test (PRTT)  601, 605–610, 605 avian ophthalmology  2059, 2067 avian species  606–607 domesticated animals  602–603 exotic animal ophthalmology  2200, 2219 fish, reptiles, and amphibians  608 laboratory animal ophthalmology  2147–2148 nondomesticated animals  604–605 phenothiazine toxicity bovine ophthalmology  1991–1992 food animal systemic disease with ocular manifestations  2557 ovine and caprine ophthalmology  2029 porcine ophthalmology  2035 phenylephrine  438 PhNR see photopic negative response phosphodiesterase (PDE)  194–195 photic blink reflex see dazzle reflex photic headshaking  1960 photodermatitis  2216–2217 photodynamic therapy (PDT) equine ophthalmology  1875–1877 feline eyelid diseases  1683 ocular drug delivery  374 photography  815–875 aperture/intensity  816–817, 816, 823–826, 830 camera settings  829–830, 829, 831–832, 831 catalogue and image library configurations  871–873 clinical studio and practical aspects of image acquisition  834–835, 835–836 color space  822 compact point and shoot cameras  830–832, 832 concepts and definitions  815–822

i49

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Index

photography (cont’d) depth of field  818–819, 818, 823–826, 852–859 digital asset management  860–864, 862 digital cameras for ophthalmology  823 digital darkroom  859–860 digital single lens reflex cameras  823–824, 824, 825, 847–848 equipment considerations  823–834 ethics of editing and use of images  873–874 exposure  815–816, 823–824 exposure modes  817, 829–830 file types and naming conventions  860 flash  820–825, 827–829, 827, 828, 832, 835, 836 focus  817–818, 824, 830, 832 goniophotography  843–847, 849 image capture, storage, archiving, and retrieval  859–871 image use and publication  874 infrared macrophotography  840–842, 843–847 ISO/sensitivity  817, 824, 829 lenses for dSLR cameras  826–827, 826 lighting  819, 819, 832, 835–840, 835–843 macrophotography  824, 826–829, 828–829, 836, 840–842, 843–847 metering  819, 820 parametric image editing software  861, 863, 864–870, 865–869, 868 resolution, image size, file size, and image quality  821–822, 822, 830 sensors and image generation  821, 823 shutter speed/exposure time  816, 823–824 slit lamp photography  837, 837–839, 842–843, 847–849 smartphones  832–834, 833–834, 850–851 specific lesions  852–859 surgical photography  847, 850 techniques  836–840 white balance  822 workflow and data backup  870–871, 872 see also ophthalmoscopy and fundus photography photokeratoconjunctivitis  2216–2217 photometry  169–170, 170 photomicrography canine optic nerve diseases  1624, 1650 canine systemic disease with ocular manifestations  2382 feline posterior segment diseases  1784 food animal systemic disease with ocular manifestations  2548 ophthalmic anatomy  47, 61 photopic negative response (PhNR)  771

photopic vision fundamentals of animal vision  225–227, 231–232, 249–250 light adaptation  231–232 pupil  232, 232 photoreceptors avian ophthalmology  2072 equine ophthalmology  1841–1842 fish  2203 general ocular examination  573 miniature pig  2139 mouse and rat  2114 ophthalmic anatomy  96–99, 96, 97–99 optics and physiology of vision  169, 171, 186–187, 189–196, 190, 191, 192, 194–195 processing of data from photoreceptors  225, 226 rabbit  2132–2133 reptiles  2211 threshold‐sensitivity inverse relationship  225–227, 227 photosensitization avian ophthalmology  2060 bovine ophthalmology  1988–1989, 1992 ovine and caprine ophthalmology  2025 phototoxic retinopathy  2125–2126, 2126, 2204–2205 phototransduction  169, 193–196, 194–195, 197 phthisis bulbi  493–494, 494 PHTVL/PHPV see persistent hyperplastic tunica vasculosa lentis/persistent hyperplastic primary vitreous physiologic nystagmus  2259–2262, 2261 physostigmine  2264 pial septa  108, 109 pia mater  108, 109 PIE see parametric image editing PIFM see pre‐iridial fibrovascular membranes pigmentary and cystic glaucoma (PCG)  516–517, 1286–1287, 1286, 1292–1293, 1292–1293, 1379–1380 pigmentary chorioretinopathy  1524–1525 pigmentary keratitis/superficial pigmentary keratitis canine corneal diseases  1123–1125, 1124 ocular pathology  509, 511 pigmentary uveitis (PU) canine glaucomas  1223–1224, 1224 surgical procedures on the canine lens  1379–1380, 1379 pigmentation avian ophthalmology  2057, 2070 canine anterior uvea diseases  1259–1260, 1260

canine corneal diseases  1089–1090, 1089–1090 canine ocular fundus diseases  1482, 1483 clinical pharmacology and therapeutics  465 feline anterior uvea diseases  1732–1734, 1733–1734 feline eyelid diseases  1678, 1679 feline ocular surface disease  1727–1728 gonioscopy  633–634 laboratory animal ophthalmology  2112–2113 New World camelid ophthalmology  2097, 2099 nonhuman primates  2144 ocular physiology  135, 139 ophthalmic anatomy  63–64, 68–70, 69, 94 photography  845, 847 pigmented epithelium (PE)  139, 140 see also retinal pigment epithelium pig paramyxovirus  308 pig paramyxovirus of blue eye disease (PPBED)  2552 pigs see porcine ophthalmology pilin  1997–1998 pilocarpine canine anterior uvea diseases  1291 canine glaucomas  1228 clinical pharmacology and therapeutics  443, 452–454 neuro‐ophthalmology  2264 pimecrolimus  425, 427, 442–443 pink eye see infectious bovine keratoconjunctivitis pinniped eye  188, 189 pinpoint illumination  840, 843 piroplasmosis  2511–2512 pituitary pars intermedia dysfunction (PPID)  2517 PK see penetrating keratoplasty placental growth factor (PlGF)  15 plaques  2004, 2004 plasma cell infiltration (plasmoma)  1069, 1070 plasmapheresis  2343 plasmoid aqueous  140 PLD see pectinate ligament dysplasia pleomorphism  688–689, 690 PlGF see placental growth factor PLK see posterior lamellar keratoplasty PLL see lens luxation/subluxation PLR see pupillary light reflex PM see pupillary membrane PMLE17 mutations  1853 PMN see polymorphonuclear neutrophils pneumatic retinopexy (PR)  1585–1586 PNST see peripheral nerve sheath tumors POAG see primary open‐angle glaucoma

Index

POH see postoperative ocular hypertension polarized light biomicroscopy  1020–1021 polioencephalomalacia (PEM) bovine ophthalmology  2020 food animal neuro‐ophthalmic diseases  2307 food animal systemic disease with ocular manifestations  2553–2554 ovine and caprine ophthalmology  2023 poliosis  1278, 1278 polycarbophils  365 polycoria  1263 polycythemia canine systemic disease with ocular manifestations  2344–2345 feline systemic disease with ocular manifestations  2431–2432 food animal systemic disease with ocular manifestations  2540–2541 polyenes  396–397 polymegathism  688–689, 690 polymerase chain reaction assay for antigen receptor rearrangement (PARR)  900 polymerase chain reaction (PCR) bacterial infections  311 canine systemic disease with ocular manifestations  2355–2358, 2371–2373, 2377–2380 external ophthalmic dyes  620 feline ocular surface disease  1692, 1695–1697, 1703–1705, 1704–1705 feline systemic disease with ocular manifestations  2435, 2456 fungal and algal diseases  321 genetics and DNA testing  783 laboratory sampling  611–612, 615 paracentesis  640–641 protozoal diseases  324 viral infections  295–296, 295–296, 298–299, 302, 304–305 polymorphism  689 polymorphonuclear neutrophils (PMN)  1267–1268 polymyxin B  388, 390 polyneuritis equi  2301 polyvinyl alcohol (PVA)  1024 Pompe’s disease  2538–2539 pontomedullary syndrome  2268, 2268 population surveys  2219 pop‐up flash units  828–829 porcine blue eye disease (PBED)  2308 porcine ophthalmology  2033–2037 eyelids  2034–2035, 2034 lens  2036 neoplasia  2035 ocular fundus  2036–2037, 2036 orbit and globe  2033–2034, 2033 uveal tract  2035, 2035 porphyria  1991

posterior capsular tears (PCT)  1407–1408 posterior capsule opacification (PCO)  1379, 1401–1403, 1421–1427, 1422–1424 posterior capsulotomy  1950 posterior continuous curvilinear capsulorhexis (PCCC)  1372, 1402, 1402, 1408 posterior lamellar keratoplasty (PLK)  845, 1907–1909, 1907–1909 posterior lenticonus  1321–1322, 1321 posterior polar colobomas  1487, 1488 posterior polymorphous dystrophy  1140, 1140 posterior segment avian ophthalmology  2058, 2071–2073, 2072–2073 canine posterior segment surgery  1575–1621 equine ophthalmology  1855–1857, 1857, 1862, 1951–1958, 1953–1957 feline posterior segment diseases  1773–1788, 1773–1777, 1779–1782, 1784–1785, 1787–1788 general ocular examination  577–578 laboratory animal ophthalmology  2112 microsurgery  799 miniature pig  2141 New World camelid ophthalmology  2099–2102, 2100–2101 nonhuman primates  2144 rabbit  2135 posterior vitreal detachment (PVD)  1372 postoperative care canine conjunctival diseases  1062 canine corneal diseases  1112, 1147–1148 canine eyelid disorders  929, 943–944, 956, 968, 979–980 canine glaucomas  1232–1234 canine lacrimal secretory system diseases  1032–1033 surgical procedures on the canine lens  1382 postoperative ocular hypertension (POH) canine glaucomas  1220–1221 clinical pharmacology and therapeutics  452 surgical procedures on the canine lens  1372, 1380, 1413–1416, 1414 postseptal orbital cellulitis  670–671 Pourfour du Petit syndrome  2271 povidone–iodine  1381, 1421 poxviruses avian ophthalmology  2061–2062, 2067 clinical microbiology and parasitology  302, 308 exotic mammals  2221 ovine and caprine ophthalmology  2024 reptiles  2212, 2213

PPBED see pig paramyxovirus of blue eye disease PPID see pituitary pars intermedia dysfunction PPM see persistent pupillary membranes PPT1 mutations  1513 PPV see pars plana vitrectomy PR see pneumatic retinopexy PRA see progressive retinal atrophy pradofloxacin  1693, 1781 PRCD see progressive rod‐cone degeneration PRCD mutations  1512–1513 precorneal tear film (PTF) canine lacrimal secretory system diseases  1008–1014, 1009 equine ophthalmology  1883, 1886, 1888–1890 external ophthalmic dyes  616, 618 general ocular examination  575–576 guinea pig  2128 ocular physiology  124, 126–129, 127 ophthalmic anatomy  50, 56 optics and physiology of vision  172–173 prednisolone canine anterior uvea diseases  1280 canine corneal diseases  1142 clinical pharmacology and therapeutics  419, 421 pre‐iridial fibrovascular membranes (PIFM) canine anterior uvea diseases  1273, 1273 ocular pathology  491, 518, 527 surgical procedures on the canine lens  1417 prepurchase ophthalmic examination  1961–1963 presbyopia  176 preseptal orbital cellulitis  670–671 preservatives  1026 primary congenital glaucoma (PCG)  1765–1766 primary lens luxation (PLL) see lens luxation/subluxation primary narrow‐angle/angle‐closure glaucoma (PACG)  1173, 1177– 1188, 1179, 1193, 1196–1199, 1207–1215, 1208, 1209–1210, 1227 primary open‐angle glaucoma (POAG) canine glaucomas  1173, 1177–1197, 1179, 1191, 1194, 1200–1207, 1202–1204, 1227 ocular physiology  143 primitive embryonic vasculature (PEV)  498 prion disease feline systemic disease with ocular manifestations  2451 food animal neuro‐ophthalmic diseases  2308 food animal systemic disease with ocular manifestations  2549, 2549

i51

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Index

prodrugs  361–362, 362 programmed death ligand‐1 (PD‐L1)  279 progressive retinal atrophy (PRA) canine lens diseases and cataract formation  1341 canine ocular fundus diseases  1498–1519 cilia‐related gene mutations  1509–1512, 1511 classification  1502–1503 clinical signs  1499–1501, 1500–1502 diagnosis  1501–1502 feline posterior segment diseases  1780 fluorescein angiography  708 forms without a molecular diagnosis  1518–1519 genetics and DNA testing  780–784, 781 miscellaneous function gene mutations  1512–1517, 1514–1517 ocular pathology  518–519, 519 optical coherence tomography  702 other forms for which DNA tests are available  1517–1518, 1518 rhopsodin‐dominant progressive retinal atrophy  1508–1509 rod cGMP‐gated channel genes  1507– 1508, 1509 rod phosphodiesterase genes  1503– 1507, 1507–1508 S‐antigen  1509 specific forms by genetic mutation  1503–1519, 1504–1506 treatment  1519 progressive rod‐cone degeneration (PRCD)  782, 1512–1513, 1514–1517 proliferative diseases  1552–1553, 1553, 1732 proliferative keratoconjunctivitis  1714–1716, 1714 proliferative optic neuropathy  1958, 1958, 1959 proliferative vitreoretinopathy (PVR)  1576–1577, 1577, 1580, 1589, 1596–1597 proparacaine  439 prophylactic retinopexy  1583–1585, 1584–1586 proptosis canine orbital diseases  903–904, 903–904 feline orbital diseases  1791, 1791 prostaglandins (PG) adverse effects  465–466 canine anterior uvea diseases  1268, 1275 canine glaucomas  1222, 1228–1229 clinical pharmacology  463–464 clinical pharmacology and therapeutics  417, 421, 425, 461–466, 469–470 clinical use  464–465

feline glaucomas  1769 history and chemistry  461, 462 mechanism of action  461–463, 464 new directions  469–470 ocular drug delivery  350 prosthesis extrascleral prosthesis  911, 911 homologous and prosthetic lateral canthal ligament construction  947–948 intraocular prosthesis  1867–1868 intrascleral prosthesis  909–911, 910 retinal prosthesis  1611–1612, 1613 proteinases/proteinase inhibitors  1087– 1089, 1088, 1122, 1123 proteoglycans  350 protoporphyria  1991 Prototheca spp. canine anterior uvea diseases  1285, 1285 canine ocular fundus diseases  1536, 1536 canine systemic disease with ocular manifestations  2353–2354, 2354 clinical microbiology and parasitology  324 protozoal diseases avian ophthalmology  2060–2061, 2068 bovine ophthalmology  1992 canine anterior uvea diseases  1282–1283 canine corneal diseases  1128 canine lens diseases and cataract formation  1345 canine ocular fundus diseases  1536–1537 canine systemic disease with ocular manifestations  2368–2372, 2370 clinical microbiology and parasitology  324–327 diagnostic methods  324–325 equine neuro‐ophthalmic diseases  2300 equine systemic disease with ocular manifestations  2511–2512 feline anterior uvea diseases  1745–1747, 1745 feline eyelid diseases  1675–1676, 1720 feline posterior segment diseases  1782–1783 feline systemic disease with ocular manifestations  2448–2451, 2449–2450 food animal systemic disease with ocular manifestations  2547–2548, 2547–2548 pathogenic protozoa  325–327 see also individual protozoa/diseases provocative tests  1185 proxymetacaine  568 PRR see pattern recognition receptors

PRTT see phenol red thread test pseudobuphthalmos  2214, 2214 pseudocolobomas  501–502, 501 Pseudomonas spp. antibacterial agents  387–388, 390–391, 393–395 avian ophthalmology  2060 canine corneal diseases  1118 clinical microbiology and parasitology  314–315 external ophthalmic dyes  617 ocular immunology  280 pseudopapilledema  1641–1642, 1642, 1643 pseudophakic glaucomas  1218–1220, 1219 pseudopolycoria  1263 pseudopterygium  2136 pseudorabies canine systemic disease with ocular manifestations  2378 clinical microbiology and parasitology  308 food animal neuro‐ophthalmic diseases  2308–2309 food animal systemic disease with ocular manifestations  2552 Pteris aquilinum‐induced retinal degeneration  2032–2033, 2032 PTF see precorneal tear film ptosis  968 pump‐leak mechanism  130–131 punctal atresia  994–995, 995–996, 2091 punctal misplacement  997, 999 punctal plugs  366 punctal pucker technique  995, 997 punctum  2088–2092, 2180, 2182 pupil bovine ophthalmology  1983, 1984 equine ophthalmology  1841, 1842 general ocular examination  577 neuro‐ophthalmology  2250–2254, 2253 ocular physiology  134–136, 135 optics and physiology of vision  177–178, 185–188, 185–186, 188 ovine and caprine ophthalmology  2021, 2021 photography  840 photopic vision  232, 232 surgical procedures on the canine lens  1431 visual acuity  246–247, 246–247 pupil iridotomy  1302–1303 pupillary block glaucoma  435 pupillary constriction see miosis pupillary dilation see mydriatics/ cycloplegics pupillary light reflex (PLR) avian ophthalmology  2058 canine ocular fundus diseases  1477–1478, 1500

Index

canine optic nerve diseases  1628–1629, 1643–1644 canine systemic disease with ocular manifestations  2347, 2349 fundamentals of animal vision  232, 232 general ocular examination  572–573, 572 laboratory animal ophthalmology  2111 neuro‐ophthalmology  2250–2251, 2254–2255, 2255, 2274–2275, 2287 New World camelid ophthalmology  2086–2087 ocular physiology  134–136, 135 optics and physiology of vision  206 pupillary membrane (PM)  1322 pupillometry  1628–1629 pupillotonia  2286 purine nucleoside analogues  403–404 PVA see polyvinyl alcohol PVD see posterior vitreal detachment pyogranulomatous inflammation  490, 490 pyrimethamine  393–394 pyrimidines  397, 403 QTL see quantitative trait loci quadriplegia and amblyopia canine neuro‐ophthalmic diseases  2278 canine systemic disease with ocular manifestations  2334 feline systemic disease with ocular manifestations  2423 qualitative tear abnormalities canine lacrimal secretory system diseases  1019–1021, 1020–1021 causes  1019–1020 clinical findings  1020, 1020 diagnosis  1020–1021, 1021 medical treatment  1027–1029 quantitative trait loci (QTL)  782 Quickert–Rathbun procedure  938, 938 quinine  1544 quinolones  1340 RAB22A mutations  1199 rabbit ancillary diagnostic values  2146, 2148 cataracts  2186–2188, 2188 conjunctival overgrowth  2184, 2184 conjunctivitis and blepharitis  2182, 2182–2183 dacryocystitis and epiphora  2180–2182, 2180–2181 enucleation  2189–2190 functional morphology  2132–2135 glaucoma  2189, 2189 laboratory animal ophthalmology  2132–2139 ocular anatomy and physiology  2179–2180, 2180

ophthalmic examination  2110–2111, 2113 orbital disease and exophthalmos  2184, 2185–2186 small mammal ophthalmology  2179–2190 spontaneous lesions and diseases  2135–2139, 2137–2139 ulcerative keratitis  2184–2186, 2187 uveitis  2188–2189 rabies equine neuro‐ophthalmic diseases  2301–2303 equine systemic disease with ocular manifestations  2515–2516 feline neuro‐ophthalmic diseases  2295–2296 feline systemic disease with ocular manifestations  2461 food animal neuro‐ophthalmic diseases  2309 food animal systemic disease with ocular manifestations  2552 racetrack‐type oval corneal opacity  1133, 1133 radial tears  1406–1407, 1407 radiation therapy/radiotherapy  1058, 1058, 2010 see also ionizing radiation radiography avian ophthalmology  2057 canine nasolacrimal diseases  992, 992–993 canine orbital diseases  884 contrast radiography  663–665, 664 dacrycystorhinography  664–665, 664, 670, 673 equine ophthalmology  1849, 1865, 1866 interpreting radiographs  663 obtaining diagnostic radiography  663 optimizing conventional radiographic studies  662–663 role of conventional radiography  662 selecting appropriate views  662–663 zygomatic sialography  664 rafoxanide  1542–1544 ramp retina theory  183–184 random X chromosome inactivation  782 rapamycin  425, 427, 443, 1934 rapid eye movement (REM)  153, 154 rat see mouse and rat RCS complex  741, 744, 746 RD3 mutations  1513–1514, 1517 rdAc mutations  1778–1780 RDT see rectal digital thermometry reconstructive blepharoplasty canine eyelid disorders  974–977, 975–981 house‐inverted‐triangle blepharoplasty  975–976, 975

sliding skin and mycocutaneous grafts  976, 977–980 sliding skin graft or H‐figure plasty  976, 976–977 sliding Z‐plasty  976–977, 981 tarsoconjunctival grafts and whole lid grafts  977, 981 reconstructive surgery  1901–1902 recrudescent disease  1703, 1703 rectal digital thermometry (RDT)  1085 redundant skin folds  964–965, 966–967 reflection  171 refraction abnormal refractive states and optical errors  178–188, 178, 179, 181–189 optics and physiology of vision  171–172, 171–172 refractive structures of the eye  172–175, 173–174, 175 under water  187–188, 187–189 refractive error  243–244, 246, 1437–1438 regional anesthesia  440–441, 905–907, 906 regulatory T cells (Treg)  268, 276–279 REM see rapid eye movement reptiles exotic animal ophthalmology  2209–2217 ocular disorders and lesions  2211–2217, 2212–2217 ophthalmic anatomy  2209–2211, 2210–2212 resolution  821, 822, 830 restraint avian ophthalmology  2065 electroretinography  763–764 equine ophthalmology  1845–1846, 1845 general ocular examination  565–566 photography  837 tonometry  627 restrictive nasoventral strabismus  899, 900 retained spectacles  2216, 2216 retina aging  106 amphibians  2207, 2207 avian ophthalmology  2057 canine glaucomas  1192–1197, 1194, 1204–1205 canine ocular fundus diseases  1479–1482, 1481, 1484–1485, 1498–1525, 1538–1552, 1539, 1541–1542 clinical microbiology and parasitology  300 color Doppler optical coherence tomography  704 confocal scanning laser ophthalmoscopy  696–697, 697 diagnostic ultrasound  741, 743, 746 direct ophthalmoscopy  593

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retina (cont’d) feline posterior segment diseases  1774–1788, 1774–1777, 1779–1782, 1784–1785, 1787–1788 fish  2202–2203 function and organization  93–94, 93–94 ganglion cell layer  103–104, 103 ganglion cells  201–208, 203–206 geometry and retinal disparity  235–236, 236 guinea pig  2193–2194, 2194 horizontal and bipolar cells  196–201, 199–201, 206–208 indirect ophthalmoscopy  596 inner limiting membrane  104 inner nuclear layer  100–102, 101 inner plexiform layer  102–103, 102 laser Doppler flowmetry  703–704 miniature pig  2140 motion perception  233–234 mouse and rat  2124–2125, 2124 nerve fiber layer  104 neurosensory retina  95–104, 95–96, 97–102, 100, 103 ocular embryology and congenital malformations  9–15, 17–18 ocular immunology  284–285 ocular pathology  479, 482, 517–520, 518–520 ocular physiology  137–138 ophthalmic anatomy  93–106, 93–94 optical coherence tomography  697– 703, 699–701, 703 optical coherence tomography angiography  704 optics and physiology of vision  175, 178–179, 178 outer limiting membrane  99, 99 outer nuclear layer  99–100, 100, 100 outer plexiform layer  100, 100 photography  858–859, 859 photoreceptor densities and ratios  96 photoreceptor (rod and cone) layer  96–99, 97–99 photoreceptors, photopigments, and phototransduction  189–211, 190, 192, 194–195 physiology of retinoid cells  196–206, 197, 199–206 processing of data from photoreceptors  225, 226 processing retinal disparity  236–238, 237–238 rabbit  2132–2133, 2135, 2138 reptiles  2210–2211 retinal pigment epithelium  83–84, 94–95, 95 scanning laser polarimetry  697, 697 synapses and neurotransmitters  206–208

thickness  95 threshold‐sensitivity inverse relationship  225–227, 227 to visual cortex  208–211, 209–210 vasculature  104–106, 105, 137–138 visual acuity  247–250, 249 visual processing  189–211 retinal atrophy bovine ophthalmology  2019–2020, 2019–2020 canine lens diseases and cataract formation  1341 fluorescein angiography  708–712 ocular pathology  491–493, 493 ovine and caprine ophthalmology  2031–2033, 2031–2032 retinal colobomas  1857, 1857 retinal degeneration avian ophthalmology  2064 equine ophthalmology  1958 exotic mammals  2224 feline neuro‐ophthalmic diseases  2293–2294 feline systemic disease with ocular manifestations  2464–2466, 2465 fish  2205 mouse and rat  2125–2127, 2126 reptiles  2216 retinal detachment (RD) anatomic considerations  1575–1578, 1576–1578 canine glaucomas  1224–1225 canine ocular fundus diseases  1487, 1488, 1496, 1550–1552, 1550–1552 canine posterior segment surgery  1575–1621 canine systemic disease with ocular manifestations  2374 canine vitreous diseases  1462, 1466, 1472, 1472 demarcation and barrier retinopexy  1586–1588, 1587 diagnostic ultrasound  743, 746 endoscopic pars plana vitrectomy  1608–1609, 1609 epidemiology and signalment  1372–1374, 1373, 1429–1430 equine ophthalmology  1857, 1857, 1957–1958, 1957 factors responsible for retinal detachment  1578–1583, 1579– 1580, 1582 feline neuro‐ophthalmic diseases  2292 feline posterior segment diseases  1787–1788, 1788 feline retinal reattachment surgery  1608 fluorescein angiography  707 New World camelid ophthalmology  2100 ocular pathology  491, 493, 517, 518

ophthalmic anatomy  1575–1578, 1576–1578 pneumatic retinopexy  1585–1586 prophylactic retinopexy  1583–1585, 1584–1585 success of retinal detachment repair  1610–1611, 1611 surgical equipment  1590–1591, 1591–1596 surgical procedures on the canine lens  1372–1374, 1373, 1429–1430, 1438 transconjunctival sutureless vitrectomy  1605–1608 types of retinal detachment  1578 vitrectomy for giant retinal tears  1588–1589, 1589–1590 vitreoretinal surgical (23‐gauge) technique  1599–1605, 1600–1605 vitreous substitutes  1591–1599, 1597–1598, 1601–1604, 1604–1605, 1606–1609, 1609 retinal dysplasia avian ophthalmology  2059 bovine ophthalmology  2018, 2018 canine ocular fundus diseases  1490–1497, 1491–1496 clinical microbiology and parasitology  301 equine ophthalmology  1856, 1857 feline posterior segment diseases  1774–1775, 1775 ocular embryology and congenital malformations  31–32, 31–32 ocular pathology  483, 485, 495–496, 496 ovine and caprine ophthalmology  2031 retinal dystrophy  702 retinal folds canine ocular fundus diseases  1488, 1489, 1491, 1493 feline posterior segment diseases  1787–1788, 1788 mouse and rat  2124–2125, 2124 ocular pathology  496 retinal ganglion cells (RGC) canine glaucomas  1173, 1183–1185, 1189–1195, 1203–1205, 1239–1240 canine optic nerve diseases  1622–1623, 1627–1628, 1638–1639, 1655 fundamentals of animal vision  233–236, 247–248 mouse and rat  2118 New World camelid ophthalmology  2086 ocular pathology  496, 496 ophthalmic anatomy  100–104, 102, 103 optics and physiology of vision  201–208, 203–206

Index

retinal hemorrhage canine systemic disease with ocular manifestations  2341, 2344, 2374 equine ophthalmology  1862, 1863 feline systemic disease with ocular manifestations  2430 retinal hypopigmentation  2288–2289 retinal metaplasia  2073 retinal necrosis  487 retinal nerve fiber layer (RNFL) anterior segment and retinal imaging  697, 697 canine glaucomas  1179, 1193–1194, 1203 canine optic nerve diseases  1622–1624, 1627, 1630, 1645 nonhuman primates  2144 optical coherence tomography  701–702 retinal pigment epithelial dystrophy (RPED) canine ocular fundus diseases  1522– 1523, 1523–1524, 1546 canine systemic disease with ocular manifestations  2387–2388, 2387 ocular pathology  519, 520 retinal pigment epithelium (RPE) avian ophthalmology  2072 canine glaucomas  1197 canine ocular fundus diseases  1482, 1489–1494, 1498–1499, 1524–1530 canine posterior segment surgery  1578, 1612–1614 canine systemic disease with ocular manifestations  2346–2347 equine ophthalmology  1955–1956 feline neuro‐ophthalmic diseases  2290 fluorescein angiography  705–708, 714 nonhuman primates  2144 ocular drug delivery  350–352, 360 ocular embryology and congenital malformations  17, 18, 22, 23–24, 31–32 ocular pathology  479, 482, 486, 491, 496, 517, 518, 519–522, 520–523 ophthalmic anatomy  83–84, 94–95, 95 optics and physiology of vision  191– 192, 196 retinal prosthesis  1611–1612, 1613 retinal tears  2072 retinal thickness  2118 retinal vein occlusion (RVO)  713 retinitis pigmentosa (RP)  1546, 1611–1612, 1613 retinoblastoma canine anterior uvea diseases  1296 canine ocular fundus diseases  1554 canine vitreous diseases  1471 New World camelid ophthalmology  2105 ocular pathology  550, 550

retinoic acid  1028 retinopathy  2501–2502, 2501–2502 retinopexy demarcation and barrier retinopexy  1586–1588, 1587 pneumatic retinopexy  1585–1586 prophylactic retinopexy  1583–1585, 1584–1586 transpupillary retinopexy  1585, 1586 retinoschisis  1552, 1580, 1580 retinoscopy  178–180, 597–599, 598 retractor lentis  176 retrobulbar administration  369 retrobulbar disease  2130, 2138, 2138–2139 retrobulbar nerve blocks bovine ophthalmology  2007–2008, 2007–2008 canine orbital diseases  906–907, 906 clinical pharmacology and therapeutics  440–441 equine ophthalmology  1867 general ocular examination  569–570, 569 retrobulbar neuropathy  2019–2020, 2020 retrobulbar space‐occupying lesions bovine ophthalmology  1985–1986, 1986 diagnostic ultrasound  744 rabbit  2184, 2185–2186 retroillumination  839, 840, 856–857, 857 retrolaminar tissue pressure (RTLP)  1625–1626, 1625 retroviruses  293 RGC see retinal ganglion cells rhabdomyosarcoma  902 rhegmatogenous retinal detachment (RRD) canine glaucomas  1224–1225 canine posterior segment surgery  1576–1578, 1576–1577, 1588, 1596–1597, 1610–1611, 1611 Rhinosporidium spp.  1723–1724 Rhizopus spp.  2546 rho‐associated protein kinase (ROCK)  469, 689–690 Rhodococcus spp.  313–314, 2505–2506 rhopsodin  193 rhopsodin‐dominant progressive retinal atrophy  1508–1509 Rickettsia spp. antibacterial agents  393 canine anterior uvea diseases  1284 canine conjunctival diseases  1048–1049 canine ocular fundus diseases  1531 canine systemic disease with ocular manifestations  2372–2375, 2374–2375, 2375 clinical microbiology and parasitology  318

equine systemic disease with ocular manifestations  2513 fluorescein angiography  712 rimexolone  419–420 ring flash units  828, 835 ringworm see dermatophytosis ringwulst  88–89, 89 RMSF see Rocky Mountain spotted fever RNFL see retinal nerve fiber layer ROCK see rho‐associated protein kinase Rocky Mountain spotted fever (RMSF) canine anterior uvea diseases  1284 canine ocular fundus diseases  1531 canine systemic disease with ocular manifestations  2375 rod‐cone dysplasia/degeneration  1777–1780, 1777, 1779 rod dysplasia  1518–1519 rodenticides  2392–2393, 2392, 2558–2559 ropivicaine  569–570 Rose Bengal  619–620, 620, 1889–1890, 1890, 1911 rosettes  495, 496 RP see retinitis pigmentosa RPE65 mutations  1519–1520, 1520 RPE see retinal pigment epithelium RPED see retinal pigment epithelial dystrophy RPGRIP1 mutations  1512 RPGR mutations  1510–1511 RRD see rhegmatogenous retinal detachment RTLP see retrolaminar tissue pressure rubella  26 rule‐of‐thumb method  940, 940–941 RVO see retinal vein occlusion saccades  234 salivary retention cysts  896–897 Salmonella spp.  1697, 2506 Sandhoff disease  2539 Sanfilippo syndrome  2339 San Joaquin Valley fever  2361–2362 S‐antigen  1509 Sarcocystis spp.  2511, 2548 sarcoids equine ophthalmology  1877–1879, 1878, 1879 ocular pathology  540, 540 sarcoma canine anterior uvea diseases  1297 feline anterior uvea diseases  1759–1761, 1760–1761 ocular pathology  546–547, 548 Sarcoptes spp. bovine ophthalmology  1988 canine systemic disease with ocular manifestations  2368 equine systemic disease with ocular manifestations  2509

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SARDS see sudden acquired retinal degeneration syndrome scalpels  800, 803–804, 804 scanning confocal microscopes (LSCM)  691–692, 692 scanning electron microscopy (SEM) canine corneal diseases  1099 canine glaucomas  1184 canine lacrimal secretory system diseases  1011 canine ocular fundus diseases  1524 canine optic nerve diseases  1625 ocular embryology and congenital malformations  8, 10, 12, 14, 16, 19, 27 ocular pathology  482 ophthalmic anatomy  55–56, 55–57, 60, 60, 63–68, 74, 87, 90–91, 95, 108 scanning laser ophthalmoscopy (SLO)  1478 scanning laser polarimetry  697, 697 scarring  2137 SCC see squamous cell carcinoma SCCED see spontaneous chronic corneal epithelial defects SCFD2 mutations  1338 Scheiner’s disc phenomenon  135 Schiotz tonometry  146, 2218 Schirmer tear test (STT)  601–610, 601 avian ophthalmology  2059, 2067 avian species  606–607 canine conjunctival diseases  1050 canine lacrimal secretory system diseases  1018–1019, 1027 canine nasolacrimal diseases  991 canine nictitating membrane diseases  1063 domesticated animals  602–603 equine ophthalmology  1913 exotic animal ophthalmology  2200, 2218–2219 feline ocular surface disease  1716–1717, 1717, 1719 feline systemic disease with ocular manifestations  2456 fish, reptiles, and amphibians  608 immunosuppressant drugs  425, 427 laboratory animal ophthalmology  2147–2148 local anesthetics  439, 442–444 neuro‐ophthalmology  2263–2264 New World camelid ophthalmology  2087–2088 nondomesticated animals  604–605 ocular physiology  127, 129 porcine ophthalmology  2033–2034 small mammal ophthalmology  2192, 2194 schwannoma  538–539 scintigraphy  994 scissors  803, 804–806, 805–806

sclera canine corneal diseases  1153–1155, 1153–1155 canine glaucomas  1186 diagnostic ultrasound  741, 743, 746 fish  2201 miniature pig  2139 ocular drug delivery  350, 356–357, 360, 368–369 ocular embryology and congenital malformations  18 ocular pathology  513–514, 513–514 ophthalmic anatomy  61–63, 61–63, 62, 107 reptiles  2209 scleral laminal cribrosa  1185–1186, 1190–1192, 1191 scleral ossicles (SO)  63, 63 scleritis canine corneal diseases  1154–1155, 1155 diagnostic ultrasound  746 ocular pathology  513, 514 SCN see suprachiasmatic nucleus scopolamine  437 scotopic threshold response (STR)  771 scotopic vision dark adaptation  230–231, 231 fundamentals of animal vision  225–231, 249–250 globe size and sensitivity  229–230, 230 rods and rod pathways  227–228, 228 tapetum  228–229, 229 SCP see superficial corneal pigment scrapie food animal neuro‐ophthalmic diseases  2308 food animal systemic disease with ocular manifestations  2549, 2549 ovine and caprine ophthalmology  2033 SDAV see sialodacryoadenitis virus SD‐OCT see spectral‐domain optical coherence tomography sebaceous glands  2090, 2128 secondary iris atrophy  1264 secondary trichiasis  964 sector iridectomy  1300–1301, 1301 sedation general ocular examination  565–566 tear tests  609 tonography  630 tonometry  627 Seidel test  616–617, 618 selective breeding  785, 1338–1339 selenium toxicity  2023 SEM see scanning electron microscopy Semiquantitative Preclinical Ocular Toxicology Scoring (SPOTS)  2113 senile cataracts see age‐related cataracts senile iris atrophy  1263–1264, 1264 sensory system  925

sepsis  2506 septic endophthalmitis  488, 1868–1869, 1868 septic implantation syndrome  1277–1278, 1752–1753 sequestrae canine corneal diseases  1123 conjunctival sequestrae  507–508 corneal sequestrae  510–511, 511 diagnostic ultrasound  747–748, 748 equine ophthalmology  1919 feline ocular surface disease  1724–1728, 1725, 1727 slit‐lamp biomicroscopy  590 serology bacterial infections  311 canine anterior uvea diseases  1281 fungal and algal diseases  321 viral infections  294–295, 295, 303–304 serotonin  208 serrefine clamp  801 Setaria spp. clinical microbiology and parasitology  329 equine systemic disease with ocular manifestations  2511 food animal systemic disease with ocular manifestations  2547 severe combined immunodeficiency  2499 severe congenital lenticular malformation  1461 sex chromosomes  778 sharp trauma  2071 sheep see ovine and caprine ophthalmology short interspersed nuclear elements (SINE)  780 short posterior ciliary arteries (SPCA)  1626, 1626, 1655 short stature  1496 short tau inversion recovery (STIR)  675–676, 676 shutter speed  816, 823–824 sialoceles  896–897 sialodacryoadenitis virus (SDAV)  2120, 2121–2122 silicone oil canine glaucomas  1224–1225 canine posterior segment surgery  1593–1598, 1597–1598, 1604, 1605, 1608–1609, 1609 SINE see short interspersed nuclear elements single antibody titer  325 single cones  240 single‐nucleotide polymorphisms (SNP)  778 sinusitis  1869 siromilus see rapamycin size cues  1842 Sjögren’s‐like syndrome  2434–2435

Index

skeletal dysplasia–osteochondrodysplasia see dwarfism skiascopy see retinoscopy SLC4A3 mutations  1515 SLE see systemic lupus erythematosus sliding skin graft  976, 976–980 sliding Z‐plasty  976–977, 981 slit‐lamp biomicroscopy canine lacrimal secretory system diseases  1021 canine nasolacrimal diseases  991 canine vitreous diseases  1460, 1465 development and equipment  578–579, 578–579, 580 direct illumination versus retroillumination  580–582, 587–589 exotic animal ophthalmology  2200 general ocular examination  576–578 laboratory animal ophthalmology  2111, 2112 practical application  579, 582–589, 583–584, 586, 590 theory and principles  579–582, 581–589 slit lamp photography  837, 837–839, 842–843, 847–849 slit scanning confocal microscopes (SSCM)  691 SLO see scanning laser ophthalmoscopy SLRP see small leucine rich proteoglycans Sly syndrome  2339, 2426, 2427 SM see strip meniscometry small leucine rich proteoglycans (SLRP)  1086 small mammal ophthalmology  2179–2199 chinchilla  2193–2194 degu  2196, 2197 ferret  2194–2196, 2195–2196 guinea pig  2190–2193, 2190–2194 hedgehog  2196–2197, 2196 rabbit  2179–2190, 2180–2189 sugar glider  2196 snake bite trauma  966 Snellen acuity chart  242, 242 Snell’s law  171–172, 171 SNP see single‐nucleotide polymorphisms; subbasal nerve plexus SO see scleral ossicles soft contact lenses  365–366 solid intraocular xanthogranuloma  1287 sonophoresis  374 spastic pupil syndrome  2271–2272, 2273 SPCA see short posterior ciliary arteries spectacle abnormalities  2216, 2216 spectral‐domain optical coherence tomography (SD‐OCT) canine corneal diseases  1082–1083 exotic animal ophthalmology  2209

feline ocular surface disease  1728–1729 New World camelid ophthalmology  2088, 2094 specular microscopy  686–690 clinical applications  689–690, 690 contact and noncontact microscopes  687, 687–688 general ocular examination  576 laboratory animal ophthalmology  2151 techniques and image quality  687–688 zones of specular reflection  687, 688 specular reflection general ocular examination  575–576 slit‐lamp biomicroscopy  580, 585–586 specular microscopy  687, 688 spherical aberrations  184–185, 184–185 spherophakia canine lens diseases and cataract formation  1320, 1320, 1324 ocular embryology and congenital malformations  26, 28 ocular pathology  501 sphincterectomy  1302–1303 sphingomyelin lipidosis  2426–2428 spindle cells  1294 spindle cell tumors canine anterior uvea diseases  1297 feline anterior uvea diseases  1761, 1761 ocular pathology  544–546, 549 SPLS see subpalpebral lavage system SPN see sympathetic preganglionic neurons spontaneous chronic corneal epithelial defects (SCCED) canine corneal diseases  1097–1102, 1098–1099, 1101–1102 clinical appearance and pathophysiology  1097–1098, 1098–1099 diagnosis  1099–1100, 1099 feline ocular surface disease  1718–1719 treatment  1100–1102, 1101–1102 Sporotrichosis spp.  2445–2446 SPOTS see Semiquantitative Preclinical Ocular Toxicology Scoring squamous cell carcinoma (SCC) bovine ophthalmology  1986, 2002– 2010, 2004–2008 canine conjunctival diseases  1052 canine corneal diseases  1149–1150, 1149 canine nictitating membrane diseases  1068 canine orbital diseases  889 equine ophthalmology  1870, 1870, 1874–1877, 1875–1876, 1876, 1881–1882, 1922, 1922 feline anterior uvea diseases  1764

feline eyelid diseases  1681–1683, 1682 feline nictitating membrane diseases  1688–1689 feline ocular surface disease  1700, 1731 feline orbital diseases  1793, 1793 New World camelid ophthalmology  2091 ocular pathology  534–537, 536–537, 542 ovine and caprine ophthalmology  2029 SRBD1 mutations  1213 SSCM see slit scanning confocal microscopes Stades procedure  955, 958 Standardization of Uveitis Nomenclature (SUN)  2112–2113 Staphylococcus spp. antibacterial agents  386–388, 390–391, 394–395 clinical microbiology and parasitology  313 feline ocular surface disease  1697, 1718–1719 New World camelid ophthalmology  2092–2093 small mammal ophthalmology  2189 staphylomas  1096 stars of Winslow  83 static accommodation  183–184, 183 static anisocoria  2271–2272, 2273 statins  1340 stationary night blindness see congenital stationary night blindness stem cell therapy  1239 stereoacuity  238–239 stereopsis fundamentals of animal vision  234–239 geometry and retinal disparity  235–236, 236 processing retinal disparity  236–238, 237–238 stereoacuity  238–239 stereoscopy  88 sterilization  794, 794–795, 798, 798 Stevens tenotomy scissors  803, 805 sticky drapes  798, 798 stimulus parameters  251–252, 251–252 STIR see short tau inversion recovery STK38L mutations  1516–1517 Storz intraocular scissors  806 STR see scotopic threshold response strabismus bovine ophthalmology  1985, 1985 equine ophthalmology  1850, 1850 feline systemic disease with ocular manifestations  2422–2423 fundamentals of animal vision  239 neuro‐ophthalmology  2248–2250, 2248–2253, 2249, 2304–2305, 2304 ocular physiology  154

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strangles  2506–2507 Streptococcus spp. antibacterial agents  386–388, 391, 393–395 clinical microbiology and parasitology  313 equine systemic disease with ocular manifestations  2506–2507 feline ocular surface disease  1697 strip meniscometry (SM)  610 stroma  56–59, 56–59, 1086 stromal corneal ulcers amniotic membranes  1108–1109, 1110 bridge/bipedical graft  1104–1105, 1106 canine corneal diseases  1102–1109, 1103–1110 clinical appearance  1102, 1103 complications  1108 cyanoacrylate tissue adhesive  1103, 1104 hood conjunctival flap  1105, 1107 island conjunctival graft  1108, 1109 pedicle conjunctival graft  1106–1108, 1108–1109 progressive and non‐progressive types  1102–1103 surgical procedures  1103–1109 total conjunctival flap  1104, 1105 stromal dystrophy  511–512, 512 stromal keratitis  1703, 1704 stromal neovascularization  2208 stromal wound healing  1885–1886 Strongylidiasis  2366–2367 STT see Schirmer tear test stye see hordeolum/stye Stypandra glauca toxicity  2031–2032 subalbinism  1259 subbasal nerve plexus (SNP)  134 subconjunctival administration anti‐inflammatory agents  418, 418 local anesthetics  441 ocular drug delivery  367–368, 367 subconjunctival emphysema  1987, 1987 subconjunctival fat prolapse  1054, 1054 subconjunctival hemorrhage bovine ophthalmology  1991, 1991 canine conjunctival diseases  1055 equine ophthalmology  1858 subepithelial dystrophy  512–513 suborbital fistulae  895 subpalpebral lavage system (SPLS)  833, 2089 subretinal injection  1612–1614, 1613–1614 substance P canine anterior uvea diseases  1268–1269 ocular immunology  277 ocular physiology  127, 134 sub‐Tenon’s administration clinical pharmacology and therapeutics  441

general ocular examination  571 ocular drug delivery  368 sudden acquired retinal degeneration syndrome (SARDS) canine neuro‐ophthalmic diseases  2282, 2286–2288 canine ocular fundus diseases  1540–1542, 1541–1542 canine optic nerve diseases  1629, 1647 canine systemic disease with ocular manifestations  2346–2347, 2348–2349 ocular immunology  284–285 ocular pathology  517–518 sugar cataractogenesis  1348 sugar glider  2196 Suid herpesvirus‐1  308 sulcus intraocular lens fixation  1435–1436, 1435–1437 sulfonamides canine anterior uvea diseases  1287 canine lacrimal secretory system diseases  1014 canine systemic disease with ocular manifestations  2388–2389, 2389 clinical pharmacology and therapeutics  393–394 tear tests  608–609 sulfonylureas  1340 SUN see Standardization of Uveitis Nomenclature superficial corneal pigment (SCP)  1089, 1089 superficial corneal squamous cell carcinoma  427 superficial corneal ulcers  1097, 1097 superficial keratectomy  1092–1095, 1094–1095, 1127 superficial pigmentary keratitis see pigmentary keratitis/superficial pigmentary keratitis superficial punctate keratitis canine corneal diseases  1128–1129, 1129 equine ophthalmology  1904, 1904 supernumerary nasolacrimal openings  1990, 1990 suprachiasmatic nucleus (SCN)  205–206 suprachoroidal drug delivery  369 suprachoroidea  79–80, 79–80 supraorbital nerve block equine ophthalmology  1845, 1846 general ocular examination  568–569, 569 surface ectoderm differentiation  498–502, 500–502 surgery‐induced corneal astigmatism  1410–1411, 1411 surgical excision  1058 surgical knot  927, 928

surgical needles and needle holders  802, 809–811, 809–810 surgical photography  847, 850 surgical preparation  905, 926 surgical procedures on the canine lens  1371–1458 additional diagnostics in patient selection  1374–1375, 1374–1375 capsular tension ring  1409, 1426–1428, 1432–1435, 1434, 1434 decision for surgery, timing, prognosis, and outcome  1375–1376 epidemiology and signalment  1372–1374, 1373 history, systemic evaluation, and ophthalmic examination  1371–1372 intraocular lens  1377–1378, 1378, 1402–1404, 1403, 1408–1409 intraocular pressure  1371, 1380 intraoperative complications  1404–1410, 1407, 1410, 1436–1438, 1437 lens instability  1431–1438 ophthalmic viscosurgical devices and agents  1389–1402, 1390, 1392, 1393–1399, 1401–1402, 1406–1410 patient selection  1371–1376 perioperative therapy  1380–1382 postoperative care  1382 postoperative complications  1410–1431, 1411–1412, 1414, 1417, 1422–1424, 1427, 1436–1438, 1437 preoperative complications  1376, 1377 removal of OVD and wound closure  1404, 1405 spontaneous lens capsule rupture  1376–1378, 1377–1378 sulcus intraocular lens fixation  1435–1436, 1435–1437 surgical equipment and devices  1382–1389, 1385, 1386–1387, 1389 uveitis  1371–1372, 1375–1377, 1379–1380, 1379, 1416–1417, 1417 see also canine posterior segment surgery; phacoemulsification suture canine corneal diseases  1111, 1116, 1116, 1147, 1147 canine eyelid disorders  926–927, 926–931, 937–938, 938, 967 canine lacrimal secretory system diseases  1030 material and technique  806–807, 807 microsurgery  798 ocular embryology and congenital malformations  12, 13 pattern  807–809, 808–809 surgical procedures on the canine lens  1404, 1405, 1433–1436, 1434–1437 suture line cataracts  1946

Index

swabs  611–613, 612 sweat glands  925 swinging flashlight test  573, 2255–2256 symblepharon  1059, 1712–1714, 1713 sympathetic lesions  2264–2265 sympathetic preganglionic neurons (SPN)  2238, 2253–2254, 2271 sympathomimetics  437–438 synaptic triad  193, 206–208 synchysis scintillans  1469 synechiae  1270, 1271 synechiotomy  1302–1303 syneresis  520, 521, 1468 synophthalmos ocular embryology and congenital malformations  20, 20 ocular pathology  494 ovine and caprine ophthalmology  2022, 2022 systemic absorption  357–358, 357 systemic administration anti‐inflammatory agents  418–419, 424–425 carbonic anhydrase inhibitors  458–459 immunosuppressant drugs  427 ocular drug delivery  372–373 systemic disease with ocular manifestations canine conjunctival diseases  1057–1058, 1057 canine lens diseases and cataract formation  1342–1345, 1342, 1344, 1357 canine systemic disease with ocular manifestations  2330–2420 equine ophthalmology  1961 equine systemic disease with ocular manifestations  2495–2534 feline systemic disease with ocular manifestations  2421–2494 systemic histiocytosis  2393 systemic hypertension anti‐inflammatory agents  420–421, 424 canine ocular fundus diseases  1547, 1547 canine optic nerve diseases  1644 canine systemic disease with ocular manifestations  2341–2342, 2341 feline anterior uvea diseases  1754 feline posterior segment diseases  1783–1786, 1784–1785 feline systemic disease with ocular manifestations  2428–2429, 2428–2429 ocular pathology  530, 530 see also glaucoma; intraocular pressure systemic lupus erythematosus (SLE) canine ocular fundus diseases  1549 canine systemic disease with ocular manifestations  2348 feline eyelid diseases  1676

tacking  937–938, 938 tacrolimus  425, 427, 442–443 Taenia spp.  330, 2546–2547 tandem scanning confocal microscopes (TSCM)  691, 691 tapetal degeneration  521 tapetal fundus  1482–1483, 1499–1500 tapetum canine anterior uvea diseases  1263 direct ophthalmoscopy  592 fish  2201 indirect ophthalmoscopy  596 ocular embryology and congenital malformations  18 ocular pathology  482, 498 scotopic vision  228–229, 229 visual acuity  248–249, 249 tapetum cellulosum  1189–1190 tapetum lucidum (TL)  81–84, 82–84, 83 tarsal glands canine lacrimal secretory system diseases  1019 ocular pathology  487, 498–500, 500, 534–535, 536 tarsoconjunctival graft canine conjunctival diseases  1060–1061 canine eyelid disorders  977, 981 TASS see toxic anterior segment syndrome taurine deficiency feline posterior segment diseases  1775–1777, 1776 feline systemic disease with ocular manifestations  2464–2466, 2465 Tay‐Sachs disease  2539 TBEV see tick‐borne encephalitis virus TBI see traumatic brain injury TBUT see tear film breakup time T‐cell receptors (TCR)  267–269 TCR see T‐cell receptors TE‐aHC see tissue‐engineered human anterior hemi‐corneas tear ferning  681–682, 682–683 tear ferning test (TFT)  610 tear film see precorneal tear film tear film breakup time (TBUT)  682 canine lacrimal secretory system diseases  1021, 1021 external ophthalmic dyes  616, 618 feline ocular surface disease  1717, 1719, 1725 feline systemic disease with ocular manifestations  2456 laboratory animal ophthalmology  2147–2148 tear film osmolarity  610 tear‐staining syndrome  990, 990, 999, 1000 tear stimulators  442–444 tear substitutes see lacromimetics tear tests see individual tests

tear washout  354 telomerase  150 TEM see transmission electron microscopy TEME see thromboembolic meningoencephalitis temporal fossa  741 temporary tarsorrhaphy  977–978, 982 temporohyoid osteoarthropathy  2303, 2520 Tenon’s capsule  62, 1059–1060, 1060 teratogens feline neuro‐ophthalmic diseases  2294, 2294–2295 feline orbital diseases  1791 fish  2206 ocular embryology and congenital malformations  20–21, 26, 27 ovine and caprine ophthalmology  2022–2023, 2022 teratoid medulloepithelioma  1296 tetanus canine systemic disease with ocular manifestations  2358–2359 clinical microbiology and parasitology  319 equine systemic disease with ocular manifestations  2507 feline systemic disease with ocular manifestations  2439–2440 food animal systemic disease with ocular manifestations  2545 tetracaine  439, 568 tetrachromatic vision  240 tetracyclines canine corneal diseases  1100 clinical pharmacology and therapeutics  391–392 feline ocular surface disease  1693, 1695 texture  251–252, 252 texture gradient  1842 TFT see tear ferning test TGF‐β see transforming growth factor beta Theileria spp.  2511–2512 Thelazia spp. bovine ophthalmology  1992 canine conjunctival diseases  1049 clinical microbiology and parasitology  329 equine ophthalmology  1874, 1874 exotic mammals  2221 feline ocular surface disease  1698 New World camelid ophthalmology  2094 ovine and caprine ophthalmology  2028 T‐helper (Th) cells  267–268, 272, 275–280 thermal injury  1405 thermokeratoplasty (TKP)  1139–1140, 1139

i59

i60

Index

thiamine deficiency equine neuro‐ophthalmic diseases  2303 equine systemic disease with ocular manifestations  2517–2518 feline neuro‐ophthalmic diseases  2296 feline systemic disease with ocular manifestations  2466 thiram  1544 third eyelid see nictitating membrane three‐dimensional ultrasound  753–754, 753 thrombocytopenia canine conjunctival diseases  1057 canine systemic disease with ocular manifestations  2345 feline systemic disease with ocular manifestations  2432 food animal systemic disease with ocular manifestations  2541 thromboembolic meningoencephalitis (TEME)  2543–2544, 2543 thrombopathies canine systemic disease with ocular manifestations  2345 feline systemic disease with ocular manifestations  2432 food animal systemic disease with ocular manifestations  2541 TIA see transient ischemic attacks tick‐borne encephalitis virus (TBEV)  305, 2380, 2381 timolol  455–457, 1228 TIMP see tissue inhibitors of metalloproteinases tissue biopsy see biopsy tissue‐engineered human anterior hemi‐corneas (TE‐aHC)  1111 tissue inhibitors of metalloproteinases (TIMP) canine corneal diseases  1088 clinical pharmacology and therapeutics  462–463, 466 equine ophthalmology  1891 tissue loss  968 tissue plasminogen activator (tPA) canine anterior uvea diseases  1292 equine ophthalmology  1862 feline anterior uvea diseases  1752, 1756 feline systemic disease with ocular manifestations  2468 surgical procedures on the canine lens  1416 TKP see thermokeratoplasty TL see tapetum lucidum TLPG see translaminar pressure gradient TLR see toll‐like receptors TM see trabecular meshwork TNF‐α see tumor necrosis factor‐alpha tobramycin  391

tocainide toxicity  1142–1143, 2390–2391 toll‐like receptors (TLR)  264–265, 265, 270–271, 273, 274, 279–282 tonography  1183, 1184, 1211 tonometry  620–629, 622–625 applanation tonometry  623–625, 623–624 avian ophthalmology  2058–2059, 2066–2067 canine glaucomas  1177–1178, 1180–1181 digital tonometry  621 exotic animal ophthalmology  2200, 2207, 2218 factors that influence tonometric readings  626–629 indentation tonometry  621–623, 622 instrumental tonometry  621 laboratory animal ophthalmology  2145–2147 New World camelid ophthalmology  2088 rebound tonometry  625–626, 625 small mammal ophthalmology  2189, 2190, 2194 topical administration anti‐inflammatory agents  418, 420–424 carbonic anhydrase inhibitors  459–460 cholinergic agonists (miotics)  453–454 conventional eye drops  352–353 drug disposition after eye drop application  353–361, 353 drugs acting on adrenoceptors  455–456 enhancement of corneal absorption  361–362, 362 enhancement of drug residence time at ocular surface  362–366 examination after topical anesthetic application  610, 611 factors affecting corneal absorption  355–356 immunosuppressant drugs  425–427 improvement of topical ocular drug delivery  361–366, 362 local anesthetics  439–440 nasolacrimal drainage and tear washout  354–355 ocular drug delivery  352–366 penetration across the cornea  355, 355 penetration via conjunctival/scleral route  356–357 pharmacokinetics of conventional eye drops  358–361, 358 specular microscopy  690 systemic absorption  357–358, 357 total conjunctival flap  1104, 1105 toxic anterior segment syndrome (TASS)  1375, 1381, 1396, 1416–1419

toxic substances/plants avian ophthalmology  2060, 2073 bovine ophthalmology  2020 canine lens diseases and cataract formation  1340–1341 canine ocular fundus diseases  1542–1545, 1543–1544 canine systemic disease with ocular manifestations  2388–2393, 2389–2390, 2392 equine neuro‐ophthalmic diseases  2301, 2302 equine systemic disease with ocular manifestations  2518–2519 feline lens diseases and cataract formation  1771 feline systemic disease with ocular manifestations  2466–2469, 2467, 2469 fish  2206 food animal neuro‐ophthalmic diseases  2305–2307 food animal systemic disease with ocular manifestations  2556–2559, 2558 ovine and caprine ophthalmology  2022–2023, 2029, 2031–2033 porcine ophthalmology  2037 Toxocara spp. canine anterior uvea diseases  1282 canine ocular fundus diseases  1538 canine systemic disease with ocular manifestations  2367 clinical microbiology and parasitology  330 Toxoplasma spp. antibacterial agents  393 avian ophthalmology  2062 canine anterior uvea diseases  1283 canine conjunctival diseases  1049 canine corneal diseases  1128 canine ocular fundus diseases  1536–1537 canine systemic disease with ocular manifestations  2371–2372 clinical microbiology and parasitology  325–326 equine systemic disease with ocular manifestations  2512 feline anterior uvea diseases  1745– 1746, 1745, 1749, 1782–1783 feline systemic disease with ocular manifestations  2449–2451, 2449–2450 New World camelid ophthalmology  2094, 2101–2102 tPA see tissue plasminogen activator trabecular cells  73–79, 108 trabecular meshwork (TM) canine glaucomas  1177–1178, 1188–1189, 1203–1204, 1204

Index

equine ophthalmology  1937–1938 mouse and rat  2117 ocular pathology  526 ocular physiology  142–144 trabodenosine  469 tractional detachment canine ocular fundus diseases  1550, 1551 canine posterior segment surgery  1580–1581 transconjunctival strip  935 transconjunctival sutureless vitrectomy  1605–1608 transducer positioning  739–741, 740–741 transducin  193–194 transforming growth factor beta (TGF‐β)  1188 transient ischemic attacks (TIA)  2280, 2341 translaminar pressure gradient (TLPG)  1625–1626, 1625 translation  176 transmissible spongiform encephalopathies (TSE) feline systemic disease with ocular manifestations  2451 food animal neuro‐ophthalmic diseases  2308 food animal systemic disease with ocular manifestations  2549 transmission electron microscopy (TEM) canine corneal diseases  1141 canine glaucomas  1203–1204, 1204, 1206 ocular pathology  482, 487 ophthalmic anatomy  60–61, 60, 87, 95 transmittance  170–171, 170 transpupillary diode laser retinopexy  712, 714 transpupillary retinopexy  1585, 1586 transscleral cyclophotocoagulation (TSCPC)  1941 transscleral laser photocoagulation  1235– 1236, 1236 traumatic brain injury (TBI)  675, 675 traumatic injury ancillary diagnostic procedures  1288 avian ophthalmology  2065, 2067, 2071, 2072 bovine ophthalmology  1988, 1988 canine anterior uvea diseases  1277–1278, 1287–1290, 1289 canine conjunctival diseases  1059, 1059 canine corneal diseases  1087, 1091, 1115–1116, 1116–1117, 1124 canine eyelid disorders  965–968 canine glaucomas  1221 canine lens diseases and cataract formation  1345–1347, 1356 canine nasolacrimal diseases  1000–1001, 1001

canine nictitating membrane diseases  1070 canine optic nerve diseases  1647–1649, 1650 canine orbital diseases  902–904, 903–904 canine posterior segment surgery  1577, 1580 canine vitreous diseases  1466–1468, 1470, 1470 computed tomography  670, 671 emergency management of acute ocular trauma  1288 equine corneal diseases  1886–1887, 1897–1899 equine eyelid diseases  1858, 1860, 1869–1870, 1870, 1872, 1873 equine neuro‐ophthalmic diseases  2303 equine optic neuropathy  1958–1959 exotic mammals  2224, 2224 feline anterior uvea diseases  1751–1753, 1752 feline glaucomas  1766 feline lens diseases and cataract formation  1771, 1771 feline neuro‐ophthalmic diseases  2296, 2297 feline orbital diseases  1791, 1791 fish  2205 New World camelid ophthalmology  2095–2097, 2095 ocular pathology  503, 503, 504 penetrating foreign bodies  1290 photography  842 rabbit  2137 reptiles  2216, 2217 small mammal ophthalmology  2195, 2196 specular microscopy  689 surgical procedures on the canine lens  1405–1408, 1407 treatment of blunt injuries  1288 treatment of penetrating injuries  1288–1289, 1289 uveitis with lens rupture  1289, 1289 travoprost  461, 462, 463–465 Treg see regulatory T cells triazoles  399–401 trichiasis canine conjunctival diseases  1056–1057 canine eyelid disorders  956–964, 960–965 canine nasolacrimal diseases  990, 990, 999, 1000 caruncle  962, 964 guinea pig  2191 nasal fold  957–961, 960–962 other locations  962–964, 964–965 secondary trichiasis  964 upper eyelid  961–962, 963

trichomegaly  964 Trichophyton spp. bovine ophthalmology  1988 canine systemic disease with ocular manifestations  2363 clinical microbiology and parasitology  322 equine systemic disease with ocular manifestations  2508 feline eyelid diseases  1671–1673 feline systemic disease with ocular manifestations  2444, 2444 ovine and caprine ophthalmology  2024 trichromatic vision  239–240 trifluridine  403, 1707 trigeminal nerve canine eyelid disorders  925 canine neuro‐ophthalmic diseases  2281, 2285, 2288 neuro‐ophthalmology  2253–2254, 2257–2258, 2263–2264 ocular physiology  154 trigeminal neuropathy/neuritis  879–880, 2288 trimethoprim  393–394 Trombiculidae spp.  2509 tropicamide canine anterior uvea diseases  1276, 1291 clinical pharmacology and therapeutics  436–437 general ocular examination  577 tear tests  607–608 Troutman‐Castroviejo corneal section scissors  805–806 Trypanosoma spp. canine anterior uvea diseases  1283 canine systemic disease with ocular manifestations  2372 feline systemic disease with ocular manifestations  2451 food animal systemic disease with ocular manifestations  2546 ovine and caprine ophthalmology  2028–2029 trypan blue  620 TSCM see tandem scanning confocal microscopes TSCPC see transscleral cyclophotocoagulation TSE see transmissible spongiform encephalopathies T‐sign  744 TTP1 mutations  1526 tube agglutination test  322 tuberculosis  2544 tubocurare derivatives  577 tumor necrosis factor‐alpha (TNF‐α) canine anterior uvea diseases  1269 ocular immunology  264, 270, 278–280

i61

i62

Index

tunica vasculosa lentis (TVL) canine lens diseases and cataract formation  1322 ocular embryology and congenital malformations  12–13, 13, 31 Tyndall effect canine anterior uvea diseases  1271 general ocular examination  576 photography  840, 843 slit‐lamp biomicroscopy  580, 586, 588 tyrosinemia canine corneal diseases  1096 canine lens diseases and cataract formation  1342 canine systemic disease with ocular manifestations  2335 feline systemic disease with ocular manifestations  2421 UBM see ultrasound biomicroscopy UDS see uveodermatologic syndrome ulcerative keratitis amphibians  2208 autogenous lamellar corneal grafts  1113–1115, 1114 avian ophthalmology  2069, 2069 bacterial keratitis  1088, 1088, 1117–1118, 1119 bovine ophthalmology  1993, 1998–1999 canine corneal diseases  1096–1123, 1097–1099, 1101–1110, 1112–1121, 1123 cause of corneal disease  1117–1122 chemical‐induced keratitis  1121–1122, 1121 collagen cross‐linking  1122–1123 control of proteolytic activity  1122, 1123 corneal sequestrae  1123 corneoscleral and corneoconjunctival transposition  1112, 1113 depth of corneal involvement  1097–1117 descemetoceles and corneal perforations  1109–1111, 1112 diagnosis  1099–1100, 1099 equine ophthalmology  1888–1904 bacterial keratitis  1897, 1900 chemical keratitis  1893–1894 clinical features and diagnosis  1888– 1890, 1889–1890 complicated corneal ulcers  1892 foals  1858–1862, 1861 foreign bodies  1894, 1894 fungal/mycotic keratitis  1894–1897, 1895, 1897, 1898–1899 indolent corneal ulcers  1892–1893, 1893 medical therapy  1890–1892, 1892 superficial, uncomplicated corneal ulcers  1892 surgical therapy  1899–1904, 1903

external ophthalmic dyes  617, 617 feline ocular surface disease  1718–1721, 1720, 1722 fish  2205 foreign bodies  1116–1117, 1118 fresh or cryopreserved corneal grafts  1115, 1115 full‐thickness corneal lacerations  1115–1116, 1116–1117 melting ulcers/keratomalacia  1088, 1088, 1109, 1110, 1117, 1119, 1122 mycotic keratitis  1120–1121, 1120 New World camelid ophthalmology  2095–2097, 2095–2096 ocular pathology  508–509, 509–510 photography  833 rabbit  2136–2137, 2184–2186, 2187 spontaneous chronic corneal epithelial defects  1097–1102, 1098–1099, 1101–1102 stromal corneal ulcers  1102–1109, 1103–1110 superficial corneal ulcers  1097, 1097 surgical procedures on the canine lens  1411, 1411 viral keratitis  1118–1120, 1120 ulcerative keratomycosis  844, 2220 ultrasound see diagnostic ultrasound ultrasound biomicroscopy (UBM)  733, 745–750, 748–751 canine glaucomas  1177, 1179, 1182–1183, 1188, 1215 surgical procedures on the canine lens  1375, 1413–1414 ultrasound pachymetry (USP)  684, 684, 686, 686, 1082 ultrastructural studies  1515, 1517, 1777 upper eyelid trichiasis  961–962, 963 upper respiratory tract aspergillosis (URTA)  1792 urticaria  2348, 2503, 2503 USP see ultrasound pachymetry UTM see uveal trabecular meshwork Utrata capsulorhexis forceps  812 uvea aging  78–79 avian ophthalmology  2069–2071, 2070–2071 bovine ophthalmology  2011–2013, 2012 canine anterior uvea diseases  1259–1316 choroid  79–85, 80–84, 83 ciliary body  67–70, 67–69 ciliary body musculature  70–78, 70–72 ciliary body vasculature  72, 73 diagnostic ultrasound  748–750, 748–750 equine ophthalmology  1922–1937, 1923–1924, 1926–1927, 1933, 1936–1937

innervation  67, 79 iridocorneal angle  60, 70–79, 71–78 iris  63–67, 64–67 mouse and rat  2122 ocular pathology  514–517, 514–518 ocular physiology  136–137 ophthalmic anatomy  63–85, 63–64 ovine and caprine ophthalmology  2029–2030 porcine ophthalmology  2035, 2035 rabbit  2137 uveoscleral outflow  77–78, 77–78 uveal atrophy  516 uveal cysts canine anterior uvea diseases  1263–1265, 1264–1265 equine ophthalmology  1922–1923, 1923 ocular embryology and congenital malformations  27–29, 28–29 ocular pathology  516–517, 542 photography  846 uveal drainage system  750, 751 uveal hypoplasia  482, 484, 498 uveal neoplasia equine ophthalmology  1923–1924, 1924 ocular pathology  542–547, 545–549 uveal trabecular meshwork (UTM)  1937–1938 uveitic glaucomas  1221–1222, 1222 uveitis canine anterior uvea diseases  1264–1285, 1300 canine lens diseases and cataract formation  1341–1342, 1349–1350, 1357 canine systemic disease with ocular manifestations  2370, 2370 chemical mediators of inflammation  1268–1269 clinical manifestations and diagnosis  1269–1274, 1269, 1270–1273 diagnostic tests  1274 equine ophthalmology  1862, 1862, 1891, 1903, 1924–1925, 1926, 1946–1947 etiopathogenesis  1265–1266, 1266–1267 exotic mammals  2221 feline anterior uvea diseases  1738– 1756, 1739, 1740–1741, 1742–1746, 1748, 1751–1752 feline lens diseases and cataract formation  1771, 1772 feline systemic disease with ocular manifestations  2450 ferret  2196 general uveal inflammatory responses  1266–1268

Index

manifestations of selected diseases  1277–1285 mouse and rat  2122 New World camelid ophthalmology  2098, 2099, 2101–2102 ocular immunology  281–282 rabbit  2137, 2137, 2188–2189 secondary to corneal, scleral, and periocular disease  1278 surgical procedures  1300 surgical procedures on the canine lens  1371–1372, 1375–1377, 1379–1380, 1379, 1416–1417, 1417 therapy for anterior uveitis  1274–1276 traumatic uveitis with lens rupture  1289, 1289 see also equine recurrent uveitis; individual conditions uveodermatologic syndrome (UDS) canine anterior uvea diseases  1278–1279, 1278 canine ocular fundus diseases  1539–1540 canine systemic disease with ocular manifestations  2352–2353, 2353 ocular immunology  284 ocular pathology  516–517, 518 uveoscleral outflow  77–78, 77–78, 146 vaccination bovine ophthalmology  2001–2002 canine anterior uvea diseases  1284 canine systemic disease with ocular manifestations  2356 feline ocular surface disease  1693 feline systemic disease with ocular manifestations  2452 vacuum pillows  794, 794, 796 valacyclovir  403–404, 1709 Valley fever  2361–2362 vancomycin  388 vascular endothelial growth factor (VEGF), ocular embryology and congenital malformations  14–15 vascularization bovine ophthalmology  1998, 1998 canine corneal diseases  1091, 1092, 1098, 1100, 1101, 1135–1136, 1136 choroidal neovascularization  2151, 2155, 2155–2156 rabbit  2136–2137 stromal neovascularization  2208 vascular system bovine ophthalmology  2017–2018 canine conjunctival diseases  1046 canine eyelid disorders  925 canine lens diseases and cataract formation  1322–1326, 1323, 1324, 1325 canine nictitating membrane diseases  1063

canine ocular fundus diseases  1484– 1485, 1547–1549, 1547–1548 canine orbital diseases  890–891, 892 choroid  80–85, 81–84, 83, 109–110, 137 ciliary body  72, 73 eye and orbit  109–111, 109–111 feline ocular surface disease  1700 iris  65–66, 65 mouse and rat  2117 ocular embryology and congenital malformations  13–15, 13–14 ocular physiology  136–138 porcine ophthalmology  2036 retina  104–106, 105, 137–138 vasculitis  515, 515 vasoactive intestinal peptide (VIP)  134 vasodilation  263–264, 1542 VEE see Venezuelan equine encephalitis VEGF see vascular endothelial growth factor Venezuelan equine encephalitis (VEE)  306 VEP see visual‐evoked potentials Veratrum californicum toxicity  20, 2022–2023, 2558 vergence  172, 172 vestibular syndrome canine neuro‐ophthalmic diseases  2276, 2282 neuro‐ophthalmology  2267, 2267 vestibulo‐ocular reflex (VOR) general ocular examination  574 neuro‐ophthalmology  2259–2262, 2261 ocular physiology  154 veterinary ophthalmic pathology see ocular pathology vidarabine  404, 1707 VIP see vasoactive intestinal peptide viral infections anti‐inflammatory agents  420 avian ophthalmology  2061–2062, 2067, 2072–2073 canine anterior uvea diseases  1284 canine conjunctival diseases  1047–1048, 1048 canine corneal diseases  1118–1120, 1120 canine ocular fundus diseases  1528–1530 canine systemic disease with ocular manifestations  2375–2380, 2376–2377, 2379, 2381 classification and mechanism of injury  293–294 clinical microbiology and parasitology  293–308 diagnostic methods  294–296, 294–296, 300–302 equine neuro‐ophthalmic diseases  2299, 2300, 2304 equine ophthalmology  1910–1912, 1911

equine systemic disease with ocular manifestations  2513–2516, 2515 exotic mammals  2221 external ophthalmic dyes  617–618, 620 feline anterior uvea diseases  1739–1745 feline eyelid diseases  1674, 1675 feline neuro‐ophthalmic diseases  2291–2293 feline ocular surface disease  1689–1696, 1701–1712 feline posterior segment diseases  1782 feline systemic disease with ocular manifestations  2451–2461, 2452, 2455, 2459–2460 fish  2204 food animal neuro‐ophthalmic diseases  2305, 2308 food animal systemic disease with ocular manifestations  2549–2552, 2551–2552 laboratory sampling  612, 615 live virus isolation  294, 294, 298 New World camelid ophthalmology  2101 ocular signs  300 optical coherence tomography  702 ovine and caprine ophthalmology  2024 pathogenic avian and exotic animal viruses  308 pathogenic canine viruses  302–305 pathogenic equine viruses  305–306 pathogenic feline viruses  296–300 pathogenic production animal viruses  306–308 reptiles  2212, 2213 see also antiviral agents; individual viruses/diseases viscoelastics  813, 1024 viscosity enhancers  363 vision see fundamentals of animal vision; optics and physiology of vision visual acuity accommodation  244–246 equine ophthalmology  1841, 1843 factors affecting visual acuity  243–252 fundamentals of animal vision  242– 252, 242–243, 244, 245–252 globe size  247, 248 measurement and values for selected species  242–243, 242–243, 244, 245 miniature pig  2139 New World camelid ophthalmology  2086 optics of the visual system  243–247 pupil  246–247, 246–247 rabbit  2179 refractive error  243–244, 246 retina  247–250, 249 stimulus parameters  251–252, 251–252 visual cortex  250–251, 250

i63

i64

Index

visual cortex functional architecture of the striate cortex  211–212, 212 location  211 neuronal organization  211 para‐ and extrastriate visual areas  212–213, 213 retina to visual cortex  209–211, 209–210 visual acuity  250–251, 250 visual‐evoked potentials (VEP) canine glaucomas  1183–1185 canine ocular fundus diseases  1481–1482 canine optic nerve diseases  1636–1637 electrodiagnostic tests  772–773, 773 visual fields  234–237, 235 visual photopigments fundamentals of animal vision  231, 239–241 optics and physiology of vision  171, 193–196, 194–195, 197 visual placing  2263 visual rivalry  237 visual streak New World camelid ophthalmology  2086, 2087 optics and physiology of vision  190 rabbit  2133 vitamin A deficiency avian ophthalmology  2064 bovine ophthalmology  2019 canine lacrimal secretory system diseases  1028 canine neuro‐ophthalmic diseases  2288 canine ocular fundus diseases  1545–1547 canine systemic disease with ocular manifestations  2387 equine neuro‐ophthalmic diseases  2303–2304 equine systemic disease with ocular manifestations  2518 food animal neuro‐ophthalmic diseases  2309–2310 food animal systemic disease with ocular manifestations  2554–2556, 2554–2556 ocular embryology and congenital malformations  21–22, 32–33 ocular pathology  493, 496 porcine ophthalmology  2034 reptiles  2217, 2217 vitamin C deficiency  1348 vitamin E deficiency canine lens diseases and cataract formation  1348 canine ocular fundus diseases  1523, 1545–1546

canine systemic disease with ocular manifestations  2387–2388, 2387 equine systemic disease with ocular manifestations  2501–2502, 2501–2502 fluorescein angiography  708–712 vitrectomy canine vitreous diseases  1463–1464 endoscopic pars plana vitrectomy  1608–1609, 1609 equine ophthalmology  1934–1935 feline retinal reattachment surgery  1608 giant retinal tears  1588–1589, 1589–1590 pars plana vitrectomy  1582–1583, 1605–1608 success of retinal detachment repair  1610–1611, 1611 surgical equipment  1590–1591, 1591–1596 transconjunctival sutureless vitrectomy  1605–1608 vitreoretinal surgical (23‐gauge) technique  1599–1605, 1600–1605 vitreous substitutes  1591–1599, 1597–1598, 1601–1604, 1604–1605, 1606–1609, 1609 vitreoretinal surgical (23‐gauge) technique  1599–1605, 1600–1605 vitreoretinopathy  1469–1470 vitreous canine glaucomas  1190 canine posterior segment surgery  1575–1577, 1576–1577, 1580 canine vitreous diseases  1459–1476 diagnostic ultrasound  742–743, 744–745 equine ophthalmology  1853, 1952– 1954, 1953 feline posterior segment diseases  1774 functions  151–153 general ocular examination  577–578 mouse and rat  2124, 2124 ocular drug delivery  351, 370–371 ocular embryology and congenital malformations  18, 31, 31 ocular pathology  518–522, 521 ocular physiology  151–153, 152 ophthalmic anatomy  91–93, 91, 92 optics and physiology of vision  174–175, 175 slit‐lamp biomicroscopy  588 structure and aging  151, 152 vitreous paracentesis  639–640, 639 vitreous presentation  1409 vitreous substitutes  1591–1599, 1597–1598, 1601–1604, 1604–1605, 1606–1609, 1609 vitritis  1470–1471

Vogt–Koyanagi–Harada (VKH)‐like syndrome see uveodermatologic syndrome Vogt–Koyanagi–Harada (VKH) syndrome canine eyelid disorders  970–971 canine ocular fundus diseases  1539–1540 ocular immunology  284 VOR see vestibulo‐ocular reflex voriconazole  400–401 water provocative test  1185 WEE see Western equine encephalitis Weibel‐Palade bodies  1195 Weill–Marchesani syndrome (WMS)  1190, 1200 Werneckiella spp.  2509 Westcott tenotomy scissors  803, 805 Western equine encephalitis (WEE)  306 West Nile virus (WNV) avian ophthalmology  2072–2073 clinical microbiology and parasitology  306 equine neuro‐ophthalmic diseases  2304 equine systemic disease with ocular manifestations  2516 Wharton–Jones method  942, 942, 947, 948 white arc‐type oval corneal opacity  1133, 1133 white balance  822 whole lid grafts  977, 981 wing cells  55, 55 WMS see Weill–Marchesani syndrome WNV see West Nile virus wound closure canine eyelid disorders  927, 927–931, 941, 967 canine orbital diseases  914, 915 equine ophthalmology  1951 surgical procedures on the canine lens  1404, 1405 wound dehiscence  1410 wound healing anti‐inflammatory agents  420 canine corneal diseases  1085–1089, 1088 endothelial healing  1086–1087 epithelial healing  1085–1086 equine ophthalmology  1884–1886 full‐thickness corneal laceration/ perforation  1087 role of proteases  1087–1089, 1088 stromal healing  1086 Wyman and Kaswan method  954, 956 X‐linked dominant inheritance  782 X‐linked progressive retinal atrophy  1510–1511, 1519

Index

X‐linked recessive inheritance  782, 785 xylazine  566 zeaxanthin  1546–1547 ZFC see zonular fiber collagenization ZFD see zonular fiber dysplasia zinc deficiency  1547, 2388, 2388

zonal cataracts  1945 zona occludens  350 zonular attachment  90–91, 90–91 zonular dehiscence  1409 zonular dysplasia  1217 zonular fiber collagenization (ZFC)  1352

zonular fiber dysplasia (ZFD)  1352 zonular fibers  12, 18, 1351–1352 zonular instability  1433–1434 Z‐plasty  948, 949, 976–977, 981 zygomatic arch  570 zygomatic mucoceles  1056 zygomatic sialography  664

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Veterinary Ophthalmology

Veterinary Ophthalmology Volume I and Volume II Editor

Kirk N. Gelatt Associate Editors Gil Ben-Shlomo Brian C. Gilger Diane V.H. Hendrix Thomas J. Kern Caryn E. Plummer Sixth Edition

This edition first published 2021 © 2021 by John Wiley & Sons, Inc. Fifth Edition © 2013 John Wiley & Sons, Inc. Fourth Edition © 2007 Blackwell Publishing. Third Edition © 1999 Lippincott Williams & Wilkins. Second Edition © 1991 Lea & Febiger. First Edition © 1981 Lea & Febiger. Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley‐Blackwell. The right of Kirk N. Gelatt 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. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging‐in‐Publication Data Names: Gelatt, Kirk N., editor. Title: Veterinary ophthalmology / editor, Kirk N. Gelatt ; associate editors, Gil Ben‐Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, Caryn E. Plummer. Other titles: Textbook of veterinary ophthalmology Description: Sixth edition. | Hoboken, NJ : Wiley‐Blackwell, 2020. | Includes bibliographical references and index. Identifiers: LCCN 2020010772 (print) | LCCN 2020010773 (ebook) | ISBN 9781119441830 (hardback) | ISBN 9781119441823 (adobe pdf) | ISBN 9781119441816 (epub) Subjects: MESH: Eye Diseases–veterinary | Diagnostic Techniques, Ophthalmological–veterinary | Ophthalmologic Surgical Procedures–veterinary Classification: LCC SF891 (print) | LCC SF891 (ebook) | NLM SF 891 | DDC 636.089/77–dc23 LC record available at https://lccn.loc.gov/2020010772 LC ebook record available at https://lccn.loc.gov/2020010773 Cover image: Eye of a black horse © happylights / Shutterstock, Closeup of cat face. Fauna background © darkbird77 / Getty Images, Inquisitive Beagle Hound © bpretorius / Getty Images, Inset images courtesy of Kirk N. Gelatt. Cover design by Wiley Set in 9.5/12pt STIX TwoText by SPi Global, Pondicherry, India 10  9  8  7  6  5  4  3  2  1

This book is dedicated to the memory of Dr. Gil Ben-Shlomo, an exceptional scholar, teacher, father and friend. The veterinary ophthalmology community has lost a gentle doctor and a gentleman.

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Contents Contributors  xi Preface  xvii About the Companion Website  xix Volume 1 Section I  Basic Vision Sciences  1 Edited by Diane V.H. Hendrix 1 Ocular Embryology and Congenital Malformations  3 Cynthia S. Cook 2 Ophthalmic Anatomy  41 Jessica M. Meekins, Amy J. Rankin, and Don A. Samuelson 3 Physiology of the Eye  124 Diane V.H. Hendrix, Sara M. Thomasy, and Glenwood G. Gum 4 Optics and Physiology of Vision  168 Ron Ofri and Björn Ekesten 5 Fundamentals of Animal Vision  225 Björn Ekesten and Ron Ofri Section II  Foundations of Clinical Ophthalmology  261 Edited by Diane V.H. Hendrix, Gil Ben-Shlomo, and Brian C. Gilger 6 Ocular Immunology  263 Robert English and Brian C. Gilger 7 Clinical Microbiology and Parasitology  293 David Gould, Emma Dewhurst, and Kostas Papasouliotis 8 Clinical Pharmacology and Therapeutics Part 1  Ocular Drug Delivery  349 Alain Regnier

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Part 2  Antibacterial Agents, Antifungal Agents, and Antiviral Agents  385 Alison Clode and Erin M. Scott Part 3  Anti-Inflammatory and Immunosuppressant Drugs  417 Amy J. Rankin Part 4  Mydriatics/Cycloplegics, Anesthetics, and Tear Substitutes and Stimulators  435 Ian P. Herring Part 5  Medical Therapy for Glaucoma  451 Caryn E. Plummer 9 Veterinary Ophthalmic Pathology  479 Bruce H. Grahn and Robert L. Peiffer 10 Ophthalmic Examination and Diagnostics Part 1  The Eye Examination and Diagnostic Procedures  564 Heidi J. Featherstone and Christine L. Heinrich Part 2  Ocular Imaging  662 David Donaldson and Claudia Hartley Part 3  Diagnostic Ophthalmic Ultrasound  733 Ellison Bentley, Stefano Pizzirani, and Kenneth R. Waller, III Part 4  Clinical Electrodiagnostic Evaluation of the Visual System  757 Gil Ben-Shlomo 11 Ophthalmic Genetics and DNA Testing  778 Simon M. Petersen-Jones 12 Fundamentals of Ophthalmic Microsurgery  787 David A. Wilkie 13 Digital Ophthalmic Photography  815 Richard J. McMullen, Jr., Nicholas J. Millichamp, and Christopher G. Pirie Section IIIA  Canine Ophthalmology  877 Edited by Gil Ben-Shlomo, Brian C. Gilger, Kirk N. Gelatt, and Caryn E. Plummer 14 Diseases and Surgery of the Canine Orbit  879 Simon A. Pot, Katrin Voelter, and Patrick R. Kircher 15 Diseases and Surgery of the Canine Eyelid  923 Frans C. Stades and Alexandra van der Woerdt 16 Diseases and Surgery of the Canine Nasolacrimal System  988 Lynne S. Sandmeyer and Bruce H. Grahn

Contents

17 Diseases and Surgery of the Canine Lacrimal Secretory System  1008 Elizabeth A. Giuliano 18 Diseases and Surgery of the Canine Conjunctiva and Nictitating Membrane  1045 Claudia Hartley and Diane V.H. Hendrix 19 Diseases and Surgery of the Canine Cornea and Sclera  1082 R. David Whitley and Ralph E. Hamor 20 The Canine Glaucomas  1173 Caryn E. Plummer, András M. Komáromy, and Kirk N. Gelatt Index  i1 Volume 2 Section IIIB  Canine Ophthalmology  1257 Edited by Gil Ben-Shlomo, Brian C. Gilger, Kirk N. Gelatt, Caryn E. Plummer, and Thomas J. Kern 21 Diseases and Surgery of the Canine Anterior Uvea  1259 Diane V.H. Hendrix 22 Diseases of the Lens and Cataract Formation  1317 Marta Leiva and Teresa Peña 23 Surgery of the Lens  1371 Tammy Miller Michau 24 Diseases and Surgery of the Canine Vitreous  1459 Michael H. Boevé and Frans C. Stades 25 Diseases of the Canine Ocular Fundus  1477 Simon M. Petersen-Jones and Freya Mowat 26 Surgery of the Canine Posterior Segment  1575 Allison R. Hoffman, Joseph C. Wolfer, Samuel J. Vainisi, and András M. Komáromy 27 Diseases of the Canine Optic Nerve  1622 Gillian J. McLellan Section IV  Special Ophthalmology  1663 Edited by Caryn E. Plummer and Thomas J. Kern 28 Feline Ophthalmology  1665 Mary Belle Glaze, David J. Maggs, and Caryn E. Plummer 29 Equine Ophthalmology  1841 Caryn E. Plummer 30 Food and Fiber Animal Ophthalmology  1983 Bianca C. Martins

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31 Avian Ophthalmology  2055 Lucien V. Vallone and Thomas J. Kern 32 Ophthalmology of New World Camelids  2085 Juliet R. Gionfriddo and Ralph E. Hamor 33 Laboratory Animal Ophthalmology  2109 Seth Eaton 34 Small Mammal Ophthalmology  2179 David L. Williams 35 Exotic Animal Ophthalmology  2200 Thomas J. Kern 36 Neuro-Ophthalmology 2237 Aubrey A. Webb and Cheryl L. Cullen 37 Ocular Manifestations of Systemic Disease Part 1  The Dog  2329 Aubrey A. Webb and Cheryl L. Cullen Part 2  The Cat  2421 Aubrey A. Webb and Cheryl L. Cullen Part 3  The Horse  2495 Aubrey A. Webb and Cheryl L. Cullen Part 4  Food Animals  2535 Aubrey A. Webb and Cheryl L. Cullen Index  i1

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Contributors Gil Ben-Shlomo, DVM, PhD Diplomate ACVO, Diplomate ECVO Associate Professor of Ophthalmology Departments of Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, NY, USA Ellison Bentley, DVM Diplomate ACVO Clinical Professor, Comparative Ophthalmology Department of Surgical Sciences School of Veterinary Medicine University of Wisconsin‐Madison Madison, WI, USA Michael H. Boevé, DVM, PhD Diplomate ECVO Staff Ophthalmologist Department of Clinical Sciences of Companion Animals Faculty of Veterinary Medicine Utrecht University, The Netherlands Alison Clode, DVM Diplomate ACVO Port City Veterinary Referral Hospital Portsmouth, NH, USA Cynthia S. Cook, DVM, PhD Diplomate ACVO Veterinary Vision San Carlos and San Francisco, CA, USA

Cheryl L. Cullen, DVM Diplomate ACVO CullenWebb Animal Eye Specialists Riverview, NB, Canada Emma Dewhurst, MA, VetMB, MRCVS Diplomate ECVCP, FRCPath IDEXX Laboratories Wetherby, West Yorkshire, UK David Donaldson, BVSc(Hons), MRCVS, MANZCVS Diplomate ECVO European Specialist in Veterinary Ophthalmology Senior Clinician in Ophthalmology Langford Vets University of Bristol Veterinary School Langford, Bristol, UK Seth Eaton, VMD Diplomate ACVO Clinical Assistant Professor, Comparative Ophthalmology Department of Surgical Sciences School of Veterinary Medicine University of Wisconsin – Madison Madison, WI, USA Björn Ekesten, DVM, PhD Diplomate ECVO Professor of Ophthalmology Department of Clinical Sciences Faculty of Veterinary Medicine Swedish University of Agricultural Science Uppsala, Sweden

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Robert English, DVM, PhD Diplomate ACVO Animal Eye Care of Cary Cary, NC, USA Heidi J. Featherstone, BVetMed, DVOphthal, MRCVS Diplomate ECVO, Diplomate RCVS Head of Ophthalmology The Ralph Veterinary Referral Centre; Honorary Associate Professor Nottingham Veterinary School Marlow, Buckinghamshire, UK Kirk N. Gelatt, VMD Diplomate ACVO Emeritus Distinguished Professor of Comparative Ophthalmology Department of Small and Large Animal Clinical Sciences College of Veterinary Medicine University of Florida Gainesville, FL, USA

David Gould, BSc (Hons), BVM&S, PhD, DVOphthal, FRCVS Diplomate ECVO RCVS and European Specialist in Veterinary Ophthalmology Head of Ophthalmology Davies Veterinary Specialists Manor Farm Business Park Higham Gobion, Hertfordshire, UK Bruce H. Grahn, DVM Diplomate ACVO Professor Emeritus of Veterinary Ophthalmology Western College of Veterinary Medicine and Prairie Ocular Pathology of Prairie Diagnostic Laboratories University of Saskatchewan Saskatoon, SK, Canada Glenwood G. Gum, MS, PhD Director of Ophthalmology Absorption Systems San Diego, CA, USA

Brian C. Gilger, DVM, MS Diplomate ACVO, Diplomate ACT Professor of Ophthalmology Department of Clinical Sciences College of Veterinary Medicine North Carolina State University Raleigh, NC, USA

Ralph E. Hamor, DVM, MS Diplomate ACVO Clinical Professor of Comparative Ophthalmology Departments of Small and Large Animal Clinical Sciences College of Veterinary Medicine University of Florida Gainesville, FL, USA

Juliet R. Gionfriddo, DVM Diplomate ACVO Professor Emeritus of Ophthalmology Department of Clinical Sciences College of Veterinary Medicine Colorado State University Fort Collins, CO, USA

Claudia Hartley, BVSc, CertVOphthal, MRCVS Diplomate ECVO European Specialist in Veterinary Ophthalmology Head of Ophthalmology Langford Vets University of Bristol Veterinary School Langford, Bristol, UK

Elizabeth A. Giuliano, DVM, MS Diplomate ACVO Associate Professor of Ophthalmology Department of Veterinary Medicine and Surgery College of Veterinary Medicine University of Missouri Columbia, MO, USA Mary Belle Glaze, DVM Diplomate ACVO Gulf Coast Animal Eye Clinic Houston, TX, USA

Christine L. Heinrich, DVOphthal, MRCVS Diplomate ECVO RCVS and European Specialist in Veterinary Ophthalmology Eye Veterinary Clinic Leominster, Herefordshire, UK Diane V.H. Hendrix, DVM Diplomate ACVO Professor of Ophthalmology Department of Small Animal Clinical Sciences College of Veterinary Medicine University of Tennessee Knoxville, TN, USA

Contributors

Ian P. Herring, DVM, MS Diplomate ACVO Associate Professor of Ophthalmology Department of Small Animal Clinical Sciences Virginia‐Maryland College of Veterinary Medicine Virginia Tech Blacksburg, VA, USA

Bianca C. Martins, DVM, MSc, PhD Diplomate ACVO Clinical Associate Professor of Ophthalmology Department of Surgical and Radiological Sciences School of Veterinary Medicine University of California - Davis Davis, CA, USA

Allison R. Hoffman, DVM Diplomate ACVO Eye Care for Animals Pasadena, CA, USA

Gillian J. McLellan, BVMS, PhD, DVOphthal, MRCVS Diplomate ECVO, Diplomate ACVO Associate Professor of Comparative Ophthalmology Department of Surgical Sciences School of Veterinary Medicine and Department of Ophthalmology and Visual Sciences School of Medicine and Public Health University of Wisconsin‐Madison Madison, WI, USA

Thomas J. Kern, DVM Diplomate ACVO Associate Professor of Ophthalmology Department of Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, NY, USA Patrick R. Kircher, Dr.Med.Vet., PhD Diplomate ECVDI, Exec. MBA, UZH Professor of Veterinary Diagnostic Imaging Clinic for Diagnostic Imaging Department of Clinical Diagnostics and Services Vetsuisse Faculty, University of Zurich Zurich, Switzerland András M. Komáromy, DrMedVet, PhD Diplomate ACVO, Diplomate ECVO Professor of Ophthalmology Department of Small Animal Clinical Science College of Veterinary Medicine Michigan State University East Lansing, MI, USA Marta Leiva, DVM, PhD Diplomate ECVO Professor Associate Hospital Clinic Veterinari Fundació Universitat Autònoma de Barcelona; Departament de Medicina i Cirurgia Animal Facultat de Veterinària Universitat Autònoma de Barcelona Bellaterra, Barcelona, Spain David J. Maggs, BVSc Diplomate ACVO Professor of Ophthalmology Department of Surgical and Radiological Sciences School of Veterinary Medicine University of California – Davis Davis, CA, USA

Richard J. McMullen, Jr., Dr.Med.Vet, CertEqOphth (Germany) Diplomate ACVO, Diplomate ECVO Associate Professor of Equine Ophthalmology Department of Clinical Sciences Auburn University JT Vaughan Large Animal Teaching Hospital Auburn, AL, USA Jessica M. Meekins, DVM, MS Diplomate ACVO Associate Professor of Ophthalmology Department of Clinical Sciences Veterinary Health Center College of Veterinary Medicine Kansas State University Manhattan, KS, USA Tammy Miller Michau, DVM, MS, MSpVM Diplomate ACVO Vice President, Medical Affairs Operations Mars Veterinary Health Vancouver, WA, USA Nicholas J. Millichamp, BVetMed, PhD, DVOphthal, MRCVS Diplomate ACVO, Diplomate ECVO Eye Care for Animals‐Houston Houston, TX, USA Freya Mowat, BVSc, PhD Diplomate ECVO, Diplomate ACVO Assistant Professor of Ophthalmology Department of Surgical Sciences School of Veterinary Medicine University of Wisconsin‐Madison Madison, WI, USA

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Contributors

Ron Ofri, DVM, PhD Diplomate ECVO Professor, Veterinary Ophthalmology Koret School of Veterinary Medicine Hebrew University of Jersualem Rehovot, Israel Kostas Papasouliotis, DVM, PhD, MRCVS Diplomate RCPath (Vet.Clin.Path.), Diplomate ECVCP EBVS® European Specialist in Veterinary Clinical Pathology Senior Clinical Pathologist IDEXX Laboratories Wetherby, West Yorkshire, UK Robert L. Peiffer, Jr., DVM, PhD Diplomate ACVO Professor Emeritus of Ophthalmology and Pathology School of Medicine University of North Carolina Chapel Hill, NC, USA Teresa Peña, DVM, PhD Diplomate ECVO Professor Hospital Clinic Veterinari Fundació Universitat Autònoma de Barcelona; Departament de Medicina i Cirurgia Animal Facultat de Veterinària Universitat Autònoma de Barcelona Bellaterra, Barcelona, Spain Simon M. Petersen-Jones, DVetMed, PhD, DVOphthal, MRCVS Diplomate ECVO Myers‐Dunlap Endowed Chair in Canine Health Professor of Comparative Ophthalmology Department of Small Animal Clinical Sciences College of Veterinary Medicine Michigan State University East Lansing, MI, USA Christopher G. Pirie, DVM Diplomate ACVO Associate Professor of Ophthalmology Department of Small Animal Clinical Sciences College of Veterinary Medicine Michigan State University East Lansing, MI, USA Stefano Pizzirani, DVM, PhD Diplomate ACVO, Diplomate ECVS‐inactive Associate Professor of Ophthalmology Department of Clinical Science Tufts Cummings School of Veterinary Medicine North Grafton, MA, USA

Caryn E. Plummer, DVM Diplomate ACVO Professor of Comparative Ophthalmology Departments of Small and Large Animal Clinical Sciences College of Veterinary Medicine University of Florida Gainesville, FL, USA Simon A. Pot, DVM Diplomate ACVO, Diplomate ECVO Ophthalmology Section Equine Department Vetsuisse Faculty, University of Zurich Zurich, Switzerland Amy J. Rankin, DVM, MS Diplomate ACVO Associate Professor of Ophthalmology Department of Clinical Sciences Veterinary Health Center College of Veterinary Medicine Kansas State University Manhattan, KS, USA Alain Regnier, Dr.Med.Vet, PhD Emeritus Professor of Ophthalmology Department of Clinical Sciences School of Veterinary Medicine Toulouse, France Don A. Samuelson, PhD, MS Professor of Comparative Ophthalmology (Retired) Department of Small Animal Clinical Sciences College of Veterinary Medicine University of Florida Gainesville, FL, USA Lynne S. Sandmeyer, DVM, DVSc Diplomate ACVO Associate Professor of Ophthalmology (Retired) Department of Small Animal Clinical Sciences Western College of Veterinary Medicine University of Saskatchewan Saskatoon, SK, Canada Erin M. Scott, VMD Diplomate ACVO Assistant Professor of Ophthalmology Department of Small Animal Clinical Sciences College of Veterinary Medicine and Biomedical Sciences Texas A&M University College Station, TX, USA

Contributors

Frans C. Stades, DVM, PhD Diplomate ECVO Emeritus Professor of Veterinary Ophthalmology Department of Clinical Sciences of Companion Animals Faculty of Veterinary Medicine Utrecht University Utrecht, The Netherlands

Kenneth R. Waller III, DVM, MS Diplomate ACVR Clinical Associate Professor of Diagnostic Imaging Department of Surgical Sciences School of Veterinary Medicine University of Wisconsin-Madison Madison, WI, USA

Sara M. Thomasy, DVM, PhD Diplomate ACVO Professor of Comparative Ophthalmology Department of Surgical and Radiological Sciences School of Veterinary Medicine; Department of Ophthalmology & Vision Science School of Medicine University of California Davis, CA, USA

Aubrey A. Webb, DVM, PhD CullenWebb Animal Eye Specialists Riverview, NB, Canada

Samuel J. Vainisi, DVM Diplomate ACVO Animal Eye Clinic Denmark, WI, USA Lucien V. Vallone, DVM Diplomate ACVO Assistant Clinical Professor of Comparative Ophthalmology Department of Small Animal Clinical Sciences College of Veterinary Medicine Texas A&M University College Station, TX, USA Alexandra van der Woerdt, DVM, MS Diplomate ACVO, Diplomate ECVO The Animal Medical Center New York, NY, USA Katrin Voelter, DVM, Dr.Med.Vet., PhD Diplomate ECVO Equine Department Vetsuisse Faculty, University of Zurich Zurich, Switzerland

R. David Whitley, DVM, MS Diplomate ACVO Gulf Coast Veterinary Specialists Houston, TX; Departments of Small and Large Animal Clinical Sciences College of Veterinary Medicine University of Florida Gainesville, FL, USA David A. Wilkie, DVM, MS Diplomate ACVO Professor of Comparative Ophthalmology Department of Veterinary Clinical Sciences College of Veterinary Medicine The Ohio State University Columbus, OH, USA David L. Williams, MA, VetMB, PhD, CertVOphthal, MRCVS Senior Lecturer, Veterinary Ophthalmology Department of Clinical Veterinary Medicine University of Cambridge Cambridge, UK Joseph C. Wolfer, DVM Diplomate ACVO Toronto Animal Eye Clinic Toronto, ON, Canada

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Preface In 1965 when I entered veterinary ophthalmology, it became very quickly apparent that there was a very limited information base or knowledge in veterinary ophthalmology. If this new clinical discipline was to grow and develop into a respected clinical specialty, we would need to develop our own scientific base, and compete with the other emerging clinical specialties in veterinary medicine. And we have! With our limited English‐language books of Veterinary Ophthalmology by R.H. Smythe (1956), W.G. Magrane’s first edition of Canine Ophthalmology (1965; Lea and Febiger), and Diseases of the Canine Eye by F.G. Startup (1969; Williams and Wilkins), and the chapter in Advances in Veterinary Science called ‘Examination of the Eye’ and ‘Eye Operations in Animals’ by Otto Überreiter (1959; Academic Press), we needed to “roll up our sleeves” and get to work big time! We have available now (2021) a large number of veterinary ophthalmology books concentrating on the dog, cat, exotic animals, horses, ophthalmic pathology, and ophthalmic surgery. Two veterinary ophthalmology journals have proven invaluable to our success as a discipline. The first journal, Veterinary and Comparative Ophthalmology, was published by Fidia Research Foundation and Veterinary Practice Publishing (1991–1998), and our second journal was Veterinary Ophthalmology (published by Blackwell and Wiley‐Blackwell, 1998 to present); they greatly assisted our development and proved critical for the distribution of new scientific information. In fact, the current journal provides more than 90% of animal ophthalmic literature annually worldwide. In the late 1950s and extending into the 1970s, professional groups of budding veterinary ophthalmologists organized scientific societies to gather and exchange their knowledge and clinical experiences, which rapidly evolved to Colleges of Veterinary Ophthalmologists whose primary missions were to train new veterinary ophthalmologists (termed residents), and foster (and fund) research to “grow” the clinical discipline long term and worldwide. Nowadays these significant changes have greatly enriched veterinary ophthalmology, and markedly improved the quality of our ophthalmic animal patients.

The advances in this text, Veterinary Ophthalmology, have paralleled and documented the changes in veterinary ophthalmology, and has become our symbol of where we are today. In 1981, the first edition was released, consisting of 21 chapters (788 pages) by 22 authors, and was well received. As a result, subsequent editions followed: second edition (1991; 765 pages and 19 authors), and then in 1999 our last single‐volume release (1544 pages, 37 chapters, and 44 authors). The third edition was markedly expanded and had color illustrations throughout the text. The last two editions were two‐volume sets: for 2007, volume one 535 pages, 9 chapters, and 45 authors, and for the second larger volume 1672 pages, 20 chapters, and 36 authors; and in 2012 for volume one 789 pages, 12 chapters, and 26 authors, and for the second volume 1479 pages, 22 chapters, and 39 authors. All editions were well referenced; in fact, a great value of this text is that it documents the advances in veterinary ophthalmology during the past half of the twentieth century, and the first two decades of the twenty‐first century! The sixth edition again consists of two volumes, 37 ­chapters, and 64 contributors. Like the last two editions, the first volume contains the basic science and foundations of clinical ophthalmology chapters and the first part of the third section on canine ophthalmology. Basic vision science courses in veterinary medical colleges are often an afterthought, and our veterinary ophthalmic basic sciences are frequently documented by veterinary ophthalmologists (rather than anatomists, physiologists, pharmacologists, etc.). The first volume of the basic sciences and foundations of veterinary ophthalmology is designed to provide the base of those subjects that underpin the clinical sciences. They include embryology, anatomy, ophthalmology physiology, optics and physiology of vision, and fundamentals of vision in animals. In the foundations of clinical ophthalmology section, the chapters include immunity, microbiology, clinical pharmacology and therapeutics, ophthalmic pathology, ophthalmic examination and diagnostics, ophthalmic genetics and DNA testing, fundamentals of microsurgery, and photography. The third section starts with the chapters for

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Preface

the first part of the canine ophthalmology including orbit, eyelids, nasolacrimal system, lacrimal secretory system, conjunctiva and nictitating membrane, cornea and sclera, and glaucoma. The second volume focuses on clinical ophthalmology in the different species, and starts with the second part of canine ophthalmology (chapters- anterior uvea, lens and cataract formation, surgery of the lens, vitreous, ocular fundus, surgery of the posterior segment, and optic nerve), and continues with feline, equine, food and fiber‐producing animals, avian, New World camelids, laboratory animals, pocket pet animals, and exotics, and concludes with comparative neuro‐ophthalmology, ophthalmic manifestations of systemic diseases, and the index. The sixth edition more or less has devoted space relative to the amount of time based on different animal species encountered in veterinary ophthalmology practice. Now, in 2021, the sixth edition of Veterinary Ophthalmology continues to document this discipline’s advances. The magnitude of this edition has now required five associate editors, who devoted their time and expertise to make it happen. Like for me, I’m certain it was a learning experience! They are Drs. Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, Caryn E. Plummer, and Gil Ben‐Shlomo. Each editor chose their authors and respective chapters, based on their

expertise and preferences. A book like this is a huge undertaking, and all of us have devoted hundreds of hours to make it a successful product for the profession. Our 64 authors contributed hundreds of hours to this edition, taking time away from family and practice, and we thank them. When all the chapters had been submitted and production had started, the COVID‐19 pandemic spread across the world like a massive hurricane. Terms like “face masks,” “social distancing,” “isolation,” and “quarantine or shelter at home” became common terms, and our daily personal and professional routines were markedly disrupted. But progress in the production of the sixth edition continued uninterrupted. We thank Erica Judisch, Executive Editor, Veterinary Medicine and Dentistry, and Purvi Patel, Project Editor, of Wiley‐Blackwell for their expertise and assistance in making the sixth edition of Veterinary Ophthalmology a reality. Our copyeditors, Jane Grisdale and Sally Osborn, and project manager Mirjana Misina were superb. And lastly, we thank and appreciate the continued support and encouragement of our spouses and family members who bear with us as we struggle to meet our time schedules and other life priorities. Distinguished Kirk N. Gelatt, VMD, Diplomate, Professor of Comparative American College of Veterinary Ophthalmology, Emeritus Ophthalmologists

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About the Companion Website This book is accompanied by a companion website: www.wiley.com/go/gelatt/veterinary The website includes: ●● ●●

PowerPoints of all figures from the book for downloading References linked to CrossRef

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21 Diseases and Surgery of the Canine Anterior Uvea Diane V.H. Hendrix Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA

The uvea includes the iris, ciliary body, and choroid. The anterior uvea refers to the iris and ciliary body. The iris, because of the pupil, is responsible for regulating light entering the globe, and it is also important for normal esthetics. The ciliary body is contiguous with the choroid at its posterior aspect and is responsible for aqueous production and lens accommodation. The anterior uvea is the site of the blood–aqueous barrier, which normally prevents large, high-molecular-weight proteins from entering the aqueous humor, and it serves as the site for unconventional aqueous humor outflow. The rich blood supply and immunosensitivity of the anterior uvea make it the source for most of the inflammatory responses in the eye. A complete ophthalmic examination, including use of magnification such as that provided by a slit-lamp biomicroscope, is important for diagnosing uveal disease. The size of the pupil can vary tremendously, and abnormalities in its size, shape, color, or responsiveness may indicate ocular or neurologic disease. Diseases such as anterior uveitis, glaucoma, retinal detachment and degeneration, and lesions along the afferent and efferent pupillary pathways can alter pupil size and function. Inflammation of the anterior uvea, termed anterior uveitis, is very common with both ocular and systemic diseases and often causes intense intraocular pain, alters pupillary function, and can lead to blindness. Intraocular neoplasia is not unusual in dogs and varies in its appearance. In addition to inflammatory and neoplastic disorders, developmental, degenerative, and traumatic disorders can all affect the anterior uvea. This chapter focuses on diseases that primarily involve the iris and ciliary body, but because the anterior uvea is contiguous with the choroid (or posterior uvea), several of the diseases often affect the posterior segment as well.

Developmental Conditions Developmental abnormalities of the canine anterior uvea include disorders of incomplete development (e.g.,

c­ oloboma), maldevelopment (e.g., anterior segment dysgenesis), and incomplete regression of embryonal tissues (e.g., persistent pupillary membranes, PPMs). Most anterior uveal anomalies in the dog occur sporadically, but some are heritable. Normal anterior uveal development during embryogenesis occurs by invagination of the optic cup, resulting in a bilayered medullary epithelium. Continued differentiation of the innermost (i.e., more vitreal) layer forms the inner pigmented epithelium of the iris, the nonpigmented ciliary body epithelium, and the neurosensory retina. Differentiation of the outermost (i.e., scleral) layer forms the outer pigmented epithelium (and dilator and sphincter muscles) of the iris, the pigmented epithelium of the ciliary body, and the retinal pigment epithelium. Because normal ocular embryogenesis depends on initial development of the pigmented layers of the eye, several congenital defects relate directly to ocular color dilution and specifically to the merling gene. However, there is considerable variation of anterior uveal pigmentation in normal dogs, which accounts for the marked differences in eye color both within and among breeds.

Color Variants Subalbinism

Subalbinism refers to dilution of ocular pigment. In contrast to complete albinism, in which the eye lacks all pigment, subalbinism is seen as a blue iris with a red fundus reflex. The neuroectodermal layer of the iris has normal pigmentation; however, the overlying stroma lacks pigment. These animals have a nonpigmented fundus that allows visualization of choroidal vessels. Tapetal presence is variable. Complete albinism results in a translucent iris with visible iris vessels, which gives a reddish hue to the iris stroma. Complete ocular albinism has not been reported in the dog.

Veterinary Ophthalmology: Volume II, Sixth Edition. Edited by Kirk N. Gelatt, Gil Ben-Shlomo, Brian C. Gilger, Diane V.H. Hendrix, Thomas J. Kern, and Caryn E. Plummer. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc. Companion website: www.wiley.com/go/gelatt/veterinary

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Figure 21.1  Heterochromia iridis in a mixed-breed dog.

Figure 21.2  This merle Great Dane has a typical iris coloboma. The ciliary processes are visible because of the absence of iris. An immature cataract is also present.

Heterochromia Iridis

Heterochromia iridis refers to different colors within one iris or between the two irides. In the heterochromic eye, the iris is characterized by at least two distinct, solidly colored areas or by differently colored patches or spots (Fig.  21.1). Alternatively, each iris may be a different color. Heterochromia iridis is often the sole manifestation of ocular color dilution in many breeds, including the Old English Sheepdog, Siberian Husky, American Fox Hound, American Cocker Spaniel, Malamute, and Shih Tzu. Apart from the variation in appearance, simple heterochromia iridis has no significance. Heterochromia iridis can be a component of ocular merling, which is often accompanied by multiple ocular anomalies such as dyscoria, corectopia, iris hypoplasia, PPMs, staphylomas, cataract, and retinal detachment (Gelatt & McGill, 1973; Gwin et al., 1981). Iridal Changes Associated with Merling

Multiple ocular anomalies including iris anomalies occur in breeds affected by the merle gene (e.g., Australian Shepherds, Great Danes, Collies, and Dachshunds). The most severe ocular anomalies occur in homozygous merles with excessive white hair coat involving the head region. Affected animals also have varying degrees of congenital deafness (Gwin et  al., 1981). Anterior uveal manifestations of the merling gene include heterochromia iridis, iris hypoplasia, a blackrimmed pupil from prominent iridal pigmented epithelium, and an eccentric pupil (i.e., corectopia). Both typical and atypical iris colobomas (Fig. 21.2 and Fig. 21.3) and mild to severe PPMs are also common in merle dogs (Gelatt & McGill, 1973). Anomalies caused by the merle gene have been studied most extensively in the Australian Shepherd (Bertram et  al., 1984; Gelatt & McGill, 1973; Gelatt et  al., 1981). Multiple ocular anomalies, including microphthalmia, irregular pupils, cataracts, equatorial staphylomas,

Figure 21.3  An iris coloboma is present in the nasal aspect of the iris in this Australian Shepherd.

r­ etinal dysplasia, and retinal degeneration, occur as an autosomal-recessive trait in this breed. Severity of ocular lesions correlates with the amount of white in the hair coat. While the ocular disease is recessively inherited, the inheritance of merling appears to be dominant.

Persistent Pupillary Membranes The pupillary membrane is a layer of primitive mesodermal tissue on the anterior face of the iris during fetal development. This membrane consists of fine blood vessels and connective tissue. Normally, the central vascular arcades regress first, beginning during the sixth week of canine development. The peripheral arcades that have their origins at the iris collarette regress last (Aguirre et al., 1972). This process continues through the final three weeks of fetal development and into the immediate postnatal period. In most puppies, the pupillary membranes completely atrophy by 6 weeks after birth. The rate of pupillary membrane ­dissolution

Figure 21.4  A single benign, persistent pupillary membrane can be seen crossing the pupil. A nasal iris colobomas is also present.

varies, however, and it might not be completed for several months (Roberts & Bistner, 1968). Incomplete resorption of embryonal vasculature and mesenchymal tissues results in retained iris strands in both juvenile and adult dogs. These uveal remnants, which are termed persistent pupillary membranes, attach at the collarette region of the iris and usually retain the color of the adjacent iris. Total persistence of the fetal pupillary membrane with absence of the pupil is rare; when present, it is associated with other ocular anomalies (Martin & Leipold, 1974). PPMs occur commonly in the dog and are usually an incidental finding. Iris-to-iris strands that bridge over the iris surface or cross the pupil and remnants with a single iris attachment that occur as small, free-floating tags are benign (Fig. 21.4). Iris-to-cornea strands and iris-to-lens strands frequently result in significant corneal or lenticular opacities that can compromise vision (Fig.  21.5). Because pupillary membrane contact with the lens and cornea is not normal, strands that contact the cornea or lens are classified as “dysplastic” rather than persistent (Grahn & Peiffer, 2007). PPMs occur either unilaterally or bilaterally, and different forms can exist in the same dog. Iridocorneal adhesions are associated with corneal edema, fibroplasia, and changes in Descemet’s membrane causing a clinical leukoma (Roberts & Bistner, 1968). The corneal opacities often remain as the only sign of dysplastic pupillary membranes if the iris strands completely regress. Additionally, iridolenticular strands can extend from the iris collarette to the anterior lens capsule, with the adhesions resulting in capsular opacities or anterior polar subcapsular cataracts. Persistent or dysplastic pupillary membranes are differentiated from anterior or posterior synechiae by observing the origin of a pupillary membrane at the iris collarette and the origin of a synechia at the pupillary margin. PPMs within the width of the iris are seen most easily when the pupil is constricted. Iris-to-iris PPMs that span the pupil are visualized more easily with mydriasis as the strands are pulled taut

Figure 21.5  Persistent (dysplastic) pupillary membranes are present in this Rottweiler puppy. The membranes extend from the iris collarette to the lens, creating a circular opacity on the anterior lens capsule. They previously extended to the cornea, and an endothelial and deep stromal opacity remains.

(Barnett & Knight, 1969). Magnification assists in visualizing small PPMs. Heritable, clinically significant PPMs occur in the Basenji (Barnett & Knight, 1969; Bistner et  al., 1971; Roberts & Bistner, 1968). The incidence of PPMs in this breed is high. Examination for PPMs should be performed before pharmacologic dilation of the pupils. The most common manifestation is small, iris-to-iris PPM remnants. Mild forms appear as small, linear, or Y-shaped strands originating from the iris collarette. These minor lesions may spontaneously disappear by 8 months of age. Such lesions have no clinical significance, but they do present a problem regarding genetic control of the disease (Rubin, 1989). More severe PPMs in the Basenji manifest as cobweblike strands of iridal tissue that cross the pupil, with or without attachments to the cornea or lens. In severe cases, corneal opacities are present axially or periaxially, secondary to disruption of the endothelium by the pupillary membrane attachment. Corneal opacities vary in size from discrete white dots to long, linear, or broad circular opacities. Slit-lamp biomicroscopy reveals an irregular and optically denser Descemet’s membrane. A tail-like appendage or a complete band of pupillary membrane can extend from the opacities into the anterior chamber or iris. Multiple membranes inserting on the central or paracentral lens capsule often result in multifocal or diffuse anterior polar cataracts (Barnett & Knight, 1969; Roberts & Bistner, 1968). Microscopically, PPMs are nests of connective tissue cells, some of which are pigmented. Areas of corneal opacification seen clinically correlate with defects in Descemet’s membrane and the endothelium. Fibrous membranes in the area of the anterior lens capsule and disrupted, liquefied lens ­fibers are present in areas corresponding to anterior polar

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cataracts. Puppies with extensive pupillary membranes can be blind and have searching nystagmus (Roberts & Bistner, 1968). The mode of inheritance has not been determined, but it does not appear to be a simple recessive or dominant trait (Bistner et al., 1971). Familial PPMs also occur in the Pembroke Welsh Corgi, Chow Chow, and Mastiff breeds; breeding dogs with any form of PPM other than iris to iris should be avoided (Genetics Committee of the American College of Veterinary Ophthalmologists, 2015; Rubin, 1989). PPMs and congenital cataracts of varying densities occur in the English Cocker Spaniel (Strande et  al., 1988). Test matings have not been conclusive but suggest a complex mode of inheritance. A closely inbred line of Chow Chows had PPMs, cataracts, entropion, wandering nystagmus, microphthalmia, and multifocal retinal folds (Collins et  al., 1992). Additionally, both minor and severe PPMs occur in many other breeds as well. The genetic implications have not been determined (Barnett & Knight, 1969; Collins & Moore, 1999; Genetics Committee of the American College of Veterinary Ophthalmologists, 2015; Rubin, 1989). Therapy is rarely necessary for PPMs. Therapy might be beneficial in severely affected eyes, but options are limited. In cases of diffuse corneal opacities with considerable corneal edema, topical instillation of a hyperosmotic agent (i.e., 5% sodium chloride ointment) can be used 3–4 times daily for a trial period of 3–4 weeks. If this treatment is helpful, it can be continued indefinitely. Mydriasis is not recommended for dysplastic pupillary membrane-associated opacities, because pharmacologic dilation induces tension on the membrane attachments, thereby possibly aggravating the corneal or lens lesions. Surgically, the membranes attached to the cornea can be excised after entering the anterior chamber, and phacoemulsification can be done for an extensive anterior capsular or subcapsular cataract. Rarely is surgery indicated for PPMs, even in humans, but excision of the membranes with scissors after elevating the iris from the lens with sodium hyaluronate is effective (Oner et al., 2007; Sari et al., 2008).

endothelium, leading to corneal opacities, fit the definition of Peters anomaly. In humans, Peters anomaly is categorized based on severity. This condition has been associated with several genetic mutations (Bhandari et  al., 2011; Zaidman et  al., 2007). Penetrating keratoplasty is often indicated in humans with Peters anomaly (Zaidman et al., 2007).

Aniridia and Iris Hypoplasia Aniridia, iris hypoplasia, and iris coloboma all refer to incomplete iris development. Aniridia is a total absence of iris tissue, and it is exceedingly rare (Startup, 1966). In instances of apparent aniridia, a rudimentary iris base is usually present and would therefore be properly termed iris hypoplasia. Iris hypoplasia occurs as a partial- or fullthickness defect. Partial-thickness hypoplasia (i.e., incomplete iris coloboma) is a defect of one or more, but not all, layers of the iris. In cases of full-thickness hypoplasia, complete iris coloboma, the ciliary body processes, zonules, and equator of the lens can be visualized (Fig.  21.6). A complete iris coloboma is a result of localized developmental failure of all layers of the iris. These colobomas are located at the pupillary margin (i.e., notch coloboma), at the base of the iris (e.g., iridodiastasis), or within the iris body (i.e., pseudopolycoria; Barnett & Knight, 1969; Startup, 1966). Colobomas in the ventral aspect of the iris occur secondary to failure of closure of the optic fissure and are referred to as typical colobomas. Colobomas in other locations are referred to as atypical colobomas and are caused by primary abnormalities in the outer layer of the optic cup (Cook, 1995). Iris coloboma is a common feature of ocular merling (see Fig. 21.2 and Fig. 21.3).

Peters Anomaly Peters anomaly refers to a condition in which a central corneal leukoma is associated with iridocorneal or corneolenticular adhesions that are often associated with other ocular and systemic malformations (Bhandari et al., 2011; Dubielzig et  al., 2010; Zaidman et  al., 2007). A Springer Spaniel puppy had a central corneal leukoma with cords of uveal tissue extending from the iris collarette to the posterior cornea. Microscopic evaluation corroborated the clinical findings and showed disruptions in Descemet’s membrane at the sites of uveal adhesions (Swanson et al., 2001). Displastic pupillary membranes that disrupt the

Figure 21.6  This mixed-breed dog has unilateral iris hypoplasia. A complete lack of iris is seen clinically at the 7–9 o’clock position, revealing the ciliary processes and lens equator. No pupillary light response could be elicited in this dog. Vision and the remainder of the ocular examination were normal.

Other Congenital Pupillary Abnormalities Several other congenital pupillary abnormalities occur as sporadic abnormalities or in conjunction with previously described anomalies. Polycoria, an iris with more than one pupil with associated musculature, is extremely rare. More often, pseudopolycoria is present. Pseudopolycoria refers to multiple colobomas in the iris body that do not have associated pupillary musculature. Dyscoria is an abnormally shaped pupil, and corectopia is a pupil in an anomalous position. Microcoria is a congenital miosis resulting from absence of the dilator muscle.

Miscellaneous Congenital Abnormalities Abnormal, lightly pigmented irides occur in beagles with hereditary tapetal degeneration (Burns et  al., 1988). The melanosomes in the iris stroma and choroid of affected dogs are fewer in number than those found in the irides of unaffected beagles. The iris and ciliary body pigmented epithelium contain melanosome organelles, but no normal melanosomes. In addition, the melanin deposition is patchy and irregular. The condition might result from a defect in synthesis of the matrix component of melanosomes, resulting in absent or abnormal deposition of melanin and autophagy of these organelles (Burns et al., 1988). A litter of Springer Spaniel pups had multiple ocular defects, including microphthalmia, PPMs, ciliary body dysplasia, lens luxation, and cataract. The puppies were blind and smaller than normal but were otherwise healthy. Microscopically, the pars plicata had irregular and thickened margins, and the zonules were organized but abnormal in length and shape (Dubielzig et  al., 1985b). Ciliary body hypoplasia has been seen in dogs with multiple ocular defects (Gwin et al., 1981; Martin & Leipold, 1974). Congenital uveal cysts occur alone or in conjunction with other ocular anomalies. Additionally, congenital cysts might not be observed until the dog is older, making the diagnosis of “congenital” questionable. One explanation for the development of an iris cyst is failure of fusion of the two layers of the primary optic vesicle. Failure of the two embryonal neuroectodermal layers to fuse allows fluid to accumulate between these otherwise contiguous epithelial layers. Cysts located at the pupillary margin are associated with a persistent or excessive development of the marginal sinus (DukeElder, 1963a). Another possible explanation for congenital cysts is entrapment of surface ectodermal epithelium, neuroectoderm, and mesodermal tissue during development (Deehr & Dubielzig, 1998; Grutzmacher et al., 1987). Cysts often enlarge, suggesting that a limited proliferative or secretory activity of the epithelial cells remains (DukeElder, 1963b). Microscopically, the cysts are simply composed of heavily pigmented epithelial cells (Carter & Mausolf, 1970). Cysts are located caudal to the iris in associa-

tion with the ciliary body or the posterior epithelium of the iris, at the pupillary margin, or free in the anterior chamber or vitreous. Uveal cysts are particularly common in retriever breeds, but they also occur in other breeds (Corcoran & Koch, 1993; Genetics Committee of the American College of Veterinary Ophthalmologists, 2015; Rubin, 1989; Startup, 1966). Anterior uveal cysts are discussed in more detail under “Degenerative Iridal Changes.” Anterior segment dysgenesis, which is an anterior chamber–cleavage anomaly syndrome, has been described in Doberman puppies (Arnbjerg & Jensen, 1982; Bergsjo et al., 1984; Lewis et  al., 1986; Peiffer & Fischer, 1983). Affected eyes are blind and have variable microphthalmia and opaque corneas. Malformation of mesodermal, ectodermal, and neuroectodermal tissues is involved. The suspected cause is a primary defect in formation of the neuroectodermal optic cup (Peiffer & Fischer, 1983). Microscopically, anterior segment dysgenesis is characterized by a thinned corneal epithelium and stroma, absent Descemet’s membrane and endothelium, undifferentiated anterior uveal tissue with lack of irido­ corneal angle differentiation, and unencapsulated globules of lens material. Occasionally, rudimentary iris leaflets or elongated ciliary processes are present. Posterior segment anomalies include hyperplastic primary vitreous, hyaloid artery remnants, retinal dysplasia, and retinal detachment (Arnbjerg & Jensen, 1982; Lewis et al., 1986; Peiffer & Fischer, 1983). The mode of inheritance in Doberman Pinschers is thought to be autosomal recessive (Lewis et  al., 1986). Unfortunately, there is no treatment. Similar multiple congenital ocular anomalies occur in St. Bernard puppies with some differences, such as acorea, aphakia, and optic nerve hypoplasia (Martin & Leipold, 1974).

Degenerative Iridal Changes Senile Iris Atrophy Spontaneous, progressive thinning of the stroma or pupillary margin of the iris is a common finding in older dogs and occurs in all breeds. Most commonly, the pupillary margin develops a scalloped, moth-eaten appearance (Fig. 21.7). In these dogs, atrophy of the pupillary muscles often results in dyscoria and may lead to a reduced or absent pupillary light response. Therefore, iris atrophy can be a cause of efferent pupillary abnormalities. Senile iris atrophy often initially manifests as a subtle color change: the natural iris color fades, and foci of hyperpigmentation develop as stroma is lost and posterior pigmented epithelium is exposed. As degeneration progresses, additional thinning results in loss of pigmented epithelial layers. With transillumination, affected areas appear as translucent patches or openings within the iris, and are most striking when light is reflected from the tapetal fundus.

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Figure 21.7  Iris atrophy at the pupillary margin of the iris is present in a geriatric dog.

These full-thickness defects should not be mistaken for congenital iris colobomas (Fig. 21.8). Vision is unaffected by iris atrophy; however, severe atrophy results in photophobia.

Secondary Iris Atrophy Glaucoma and chronic uveitis often predispose to degenerative changes in the iris resembling those of senile iris atrophy. Signs of preexisting disease such as buphthalmia, lens subluxation, synechiae, or pigment dispersion on the anterior lens capsule aid in the diagnosis. As with senile iris atrophy, there is no specific treatment, but any active, concurrent glaucoma or uveitis should be treated.

Uveal Cysts Uveal cysts are common in dogs. They arise either from the posterior pigmented epithelium of the iris or from the inner ciliary body epithelium and therefore are neuroectodermal

Figure 21.8  Severe iris atrophy involves the iris stroma in this geriatric dog.

in origin (Carter & Mausolf, 1970; Hildreth et al., 1991; Rush et  al., 1982). Cysts are either congenital or acquired. They occur most commonly in Golden Retrievers, Labrador Retrievers, and Boston Terriers (Corcoran & Koch, 1993). Cysts arise from the pupillary margin, the posterior iris face, or the pars plicata of the ciliary body. Examination through a dilated pupil facilitates visualization of cysts in the posterior chamber. Potential sequelae of larger cysts include vision impairment, corneal endothelial opacities, pigmentation of the anterior lens capsule, mechanical interference with iris function, and aqueous outflow obstruction with secondary ocular hypertension (Bedford, 1980; Deehr & Dubielzig, 1998; Spiess et  al., 1998). Most cysts are first noted clinically in adult dogs and occur spontaneously; however, trauma and inflammation have also been proposed as initiating etiologies. When cysts occur without preexisting eye disease, it is possible that a defect was present at birth, and the cysts were not recognized until several years of age (see “Miscellaneous Congenital Abnormalities”; DukeElder, 1963a). Uveal cysts are usually benign and incidental findings in dogs. Iridal or ciliary cysts can be unilateral, bilateral, single, or multiple. Size varies and the dark or translucent masses can be spherical, oval, or elongated (Fig. 21.9). Uveal cysts are usually brown or black, though light brown and amelanotic cysts occur (Fig.  21.10). They are often found free-floating within the anterior chamber or attached to the iris or ciliary body. Rarely, dislodged uveal cysts can move into the vitreous if the vitreous is degenerated or detached. Occasionally, the cysts are not visible unless the pupil is dilated, especially if they are located on the posterior iris surface or the ciliary body. A deflated uveal cyst appears as a round, thin layer of pigment on the corneal endothelium or the anterior lens capsule. In most cases, uveal cysts do not obstruct vision or cause lens or corneal opacities. The association with cysts and glaucoma in Golden Retrievers, Great

Figure 21.9  A single large pigmented translucent uveal cyst and several smaller cysts are present in the ventral anterior chamber. An immature cataract is also visible.

chamber at the limbus. The precise point of entry will vary with the cyst location and should facilitate comfortable hand positioning for the surgeon. The tip of the needle is directed toward the cyst. The thin cyst wall is readily penetrated by the beveled needle tip. After the cyst wall is punctured, slight negative pressure is exerted on the syringe plunger to collapse the cyst. The needle is then slowly withdrawn. Portions of the collapsed cyst often remain free in the anterior chamber or as a residual layer of pigment on the ventral corneal endothelial or anterior lens surface. Postoperatively, a single instillation of topical mydriatic agent and short-term use (e.g., 3 times daily for 7 days) of a topical antibiotic–corticosteroid solution is recommended. Figure 21.10  A single nonpigmented uveal cyst is present in the nasal aspect of the anterior chamber.

Danes, and Bulldogs is described later under “Pigmentary and Cystic Glaucoma.” Uveal cysts are diagnosed based on clinical appearance. The most definitive diagnostic test is performed by transilluminating the cysts with a bright light source. Cysts should transilluminate, whereas neoplastic masses will not transilluminate. This test is not always reliable for very small cysts or cysts that are not within the pupil, as this location makes it difficult to generate a tapetal reflection through the cyst. Ocular ultrasound can be used in questionable cases, as cysts will not be hyperechogenic throughout as a mass would be. Uveal Cyst Removal

Because most uveal cysts are benign and generally do not interfere with vision, they usually do not require treatment. However, attached or free-floating uveal cysts that occlude the pupil and compromise vision, or multiple cysts that might occlude the angle, can be aspirated with a small-gauge needle or deflated with a laser. Because these cysts generally arise from the posterior iris pigment layer, they are darkly pigmented and are easily visualized. Poorly pigmented cysts might not be amenable to diode laser therapy. Surgical removal or aspiration of the cysts might prevent progressive angle closure when identified and treated early (Spiess et al., 1998). The use of semiconductor diode lasers for deflation and coagulation of anterior uveal cysts is effective. Perioperatively, mydriatics and corticosteroids are used topically. The operating microscope attachment and the indirect ophthalmoscope facilitate treatment of these cysts, because these two delivery systems emit a converging laser beam appropriate for transcorneal treatment of intraocular cysts and tumors. Topical anesthetic, sedation, or general anesthesia can be used. Discomfort or aqueous flare is not seen postoperatively (Gemensky-Metzler et al., 2004). Occasionally, remnants of the cyst remain attached to the corneal endothelium. Alternatively, a straight, 25- or 27-gauge needle attached to a tuberculin syringe can be introduced into the anterior

Uveal Inflammation Uveitis refers to inflammation of any aspect of the uvea. Uveitis occurs in conjunction with many intraocular and systemic diseases and is common because of the highly vascular nature of the tissue, its immunosensitivity, and its close proximity to other structures. Similar to inflammation elsewhere, inflammation in the uvea consists of three basic events: increased blood supply, augmented vessel permeability, and white blood cell migration to the injury site (DalmaWeiszhausz & Dalma, 2002). Anterior uveitis refers to inflammation of the iris and ciliary body, posterior uveitis refers to inflammation of the choroid, and panuveitis refers to inflammation of all three portions of the uvea. More specifically, iritis and cyclitis may be used to describe inflammation of the iris and ciliary body, respectively. However, anterior uveitis is the term most commonly used, because differentiating between iritis and cyclitis clinically is very difficult and usually both tissues are inflamed simultaneously. Posterior uveitis, or choroiditis, can occur independently from anterior uveitis. A more advanced condition, termed endophthalmitis, is inflammation involving the ocular cavities and adjacent structures. Panophthalmitis is inflammation involving all tunics of the eye, and it may result in signs of orbital disease as well. Chapter 25 discusses posterior segment inflammation.

Etiopathogenesis of Uveitis Uveitis occurs either independently of disease in other ocular structures or secondary to lens, corneal, or scleral disease. Additionally, uveitis can be associated with primary ocular disease or be secondary to neoplastic, infectious, or immune-mediated diseases. Elucidating the etiology of uveitis in the dog can be difficult. However, because uveitis can lead to blindness or be a sign of a potentially fatal disease, attempting to define the etiology is always warranted. Uveitis should be approached in a systematic fashion, evaluating for the most common diseases based on signalment, historical

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information including travel, ocular and physical examination findings, and locale. Many etiologies for uveitis exist in all animal species. Most simply, causes can be divided into endogenous and exogenous. Endogenous causes originate from within the eye or spread to the eye from the bloodstream or from contiguous structures. Endogenous causes account for most cases of uveitis and include infectious, neoplastic, toxic, metabolic, and autoimmune diseases. Immune-mediated and autoimmune disease is the most rapidly growing group of diseases responsible for endogenous uveitis. Several endogenous antigens have been found to be associated with uveitis, including retinal-S antigen, melanin, and lens and corneal proteins (Bellhorn et  al., 1988; Kanemaki et  al., 2015; Morgan, 1989; Parma et al., 1985; Wilcock & Peiffer, 1987). Exogenous causes arise from outside the eye and most commonly involve various traumas but also include radiation exposure and chemical injuries (Jamieson et  al., 1991; Martins et  al., 2016; Tetas Pont et  al., 2016). Trauma also includes surgical procedures and both perforating and nonperforating injuries, with or without secondary infection. As stated previously, many diseases and conditions cause uveitis in the dog. Idiopathic uveitis is the most common diagnosis given to dogs with anterior uveitis (Gelatt & MacKay, 2004; Massa et al., 2002). One review found that an etiology for anterior uveitis could not be determined in 47% of the dogs. Infectious disease accounted for 18%, there was neoplasia in 25%, and uveodermatologic syndrome (UDS) or a vaccine reaction in 10% of the dogs (Massa et  al., 2002). This study excluded dogs with anterior uveitis secondary to cataracts or trauma. Known causes of uveitis in the dog are listed in Table 21.1. Several reviews have also addressed uveitis in small animals (Crispin, 1988; Gwin, 1988; Hakanson & Forrester, 1990; Massa et al., 2002; Townsend, 2008).

General Uveal Inflammatory Responses Most knowledge regarding canine uveitis has been derived from experimental and clinical observations in a variety of animal species, including humans. Clinicians must recognize that species variation exists and that some data is not applicable, and might even be contradictory to mechanisms occurring in the dog. Still, several unique aspects of uveal inflammation do cross species and play a role in the uveal response. These include (1) the blood–aqueous barrier, (2) the concentration of ascorbic acid and other antioxidants in the aqueous humor, and (3) anterior chamber-associated immune deviation (ACAID; Rosenbaum et al., 1999). Uveitis is always initiated by tissue injury, often incited by trauma, bacteria, fungi, parasites, viruses, or immunemediated disease. The ensuing clinical signs are attributed to disruption of the blood–ocular barrier and release of various chemical mediators after tissue damage. The blood–ocular barrier is composed of the blood–aqueous

Table 21.1  Diseases proved or suspected of causing uveitis in the dog. Algal Prototheca sp. Bacterial Brucella canis Borrelia burgdorferi Leptospira sp. Septicemia of any cause Fungal Aspergillus fumigatus Blastomyces dermatitidis Candida albicans Coccidioides immitis Cryptococcus neoformans and C. gattii Histoplasma capsulatum Immune-mediated Cataracts (lens-induced uveitis) Immune-mediated thrombocytopeniaa Immune-mediated vasculitis Lens trauma (phacoclastic uveitis) Uveodermatologic syndrome Metabolic Diabetes mellitus (particularly diabetic cataract-induced uveitis) Hyperlipidemiaa Systemic hypertensiona Miscellaneous Coagulopathiesa Deep necrotizing or nonnecrotizing scleritis Drug-induced (particularly miotic and prostaglandin agents) Idiopathic Idiopathic uveitis and exudative retinal detachment Pigmentary and cystic glaucoma in the Golden Retrievera Radiation therapya Snake bite (pit vipers) periocular and ocular Traumaa Toxemia of many causes (e.g., pyometra) Ulcerative keratitis (any cause) Miscellaneous Parasitic Ophthalmomyiasis interna posterior (Diptera sp.) Ocular filariasis (Dirofilaria immitis; Angiostrongylus vasorum) Ocular larval migrans (Toxocara and Balisascaris sp.) Neoplastic and Paraneoplastic Disorders Histiocytic proliferative disease Hyperviscosity syndromea

Table 21.1  (Continued) Granulomatous meningoencephalitis Primary and secondary neoplasms (lymphosarcoma most common)a Protozoan Leishmania infantum Toxoplasma gondii Neospora caninum Trypanosoma evansi Rickettsial Ehrlichia canis or E. platys Rickettsia rickettsii Viral Adenovirus infection (including postvaccinal “blue eye”) Herpes virus a

 These etiologies often lead to aqueous flare or hyphema, but do not necessarily have an inflammatory component.

barrier anteriorly and the blood–retinal barrier posteriorly. Morphologically, the blood–aqueous barrier consists of tight junctions (zonulae occludens) between nonpigmented ciliary body epithelial cells, tight junctions and gap junctions in the iris vascular endothelium, and nonfenestrated impermeable capillaries in the iris (Freddo & SacksWilner, 1989; Gabelt & Kaufman, 2011). Evolutionary divergence in ocular defense mechanisms has resulted in extreme differences of blood–aqueous barrier stability among different mammalian species. Primates have a very stable barrier, whereas the rabbit has an extremely labile barrier, which destabilizes in response to minute ocular irritants (Bito, 1984). Stability of the canine blood–aqueous barrier lies somewhere between these two extremes. Destabilization of the blood–aqueous barrier marks the onset of anterior uveitis. Three phases of the ocular inflammatory response have been described: active, subacute, and chronic responses (Peiffer, 1980; Yanoff & Sassani, 2014). As with inflammation in other tissues, the acute phase has the five cardinal signs, including redness and heat, which are both caused by increased rate and volume of blood flow; increased mass, caused by exudation of fluid and cells; and pain and loss of function, which are both caused by outpouring of fluid and irritating chemicals. Immediately after injury, the arterioles contract for approximately 5 minutes and then gradually dilate because of histamine release from mast cells and factors released from plasma (kinin, complement, and clotting systems). The chemical mediators, which include histamine, serotonin, kinins, plasmin, complement, prostaglandins (PGs), and peptide growth factors, increase vascular ­permeability by causing the intercellular tight junctions in

the vascular endothelial cells to open, allowing fluid to leak into the tissues. After several hours, the blood flow decreases to below normal because of increased viscosity of the blood resulting from fluid loss. Early after injury, various types of blood cells marginate (polymorphonuclear neutrophils, PMNs), then leave the vessels via emigration (PMNs), emperipolesis (PMNs, small lymphocytes, macrophages, and immature erythrocytes), and diapedesis (mature erythrocytes; Yanoff & Sassani, 2014). Additionally, plasma proteins, initially albumin and then larger globulins, leak through the vessel walls (Peiffer, 1980). Reported mean values for aqueous protein in the noninflamed canine eye using different assays range from 21 ± 1.2 mg/dL to 37.4 ± 7.9 mg/ dL (Blogg & Coles, 1971; Brightman et al., 1981; Krohne & Vestre, 1987; Olin, 1977). In sharp contrast, aqueous protein values at various intervals after the onset of uveitis range from approximately 1200 mg/dL to as high as 6600 mg/dL in experimental and clinical cases, respectively. Additionally, flaremetry readings in clinically normal canine eyes range from 1.4 to 7.0 photon count (PC)/msec, with actual protein measurements ranging from 5 to 28 mg/dL. One eye with uveitis that was considered subjectively to have a 3+ flare had flaremetry readings as high as 246 PC/msec and a protein concentration of 729 mg/dL (Krohne et al., 1995). The acute phase of the ocular inflammatory response is exudative. There are four types of exudates: serous exudate is composed primarily of protein; fibrinous exudate is composed primarily of fibrin; sanguineous exudate is composed primarily of erythrocytes; and purulent exudate is composed primarily of PMNs and necrotic products. These exudates are seen clinically as aqueous flare, fibrin clot, hyphema, or hypopyon, respectively (Yanoff & Sassani, 2014). In acute inflammation, the PMN is the predominant type of inflammatory cell present (Olin, 1977). The degranulation or death of PMNs causes additional tissue destruction and increases inflammation by inducing the chemotaxis of mononuclear phagocytes characteristic of the subacute stage (Yanoff & Sassani, 2014). The subacute stage has special significance because during this period the immunologic reactions are initiated, healing occurs, or there is necrosis, recurrence, or chronicity (Yanoff & Sassani, 2014). If the inflammatory response is localized, the PMNs and mononuclear phagocytes can resolve the injury, and healing is possible with minimal scarring. If the inflammation is profound and uncontrolled, however, granulation tissue formation can result in excessive scarring, with subsequent ocular dysfunction. Granulation tissue is composed of leukocytes, fibroblasts, and proliferating blood vessels, which tend to be leaky when new. If healing ensues, the blood vessels involute, the leukocytes disappear, and the fibroblasts return to a resting state. If healing does not occur because of the inability to control both acute and subacute inflammatory events, the inability to eliminate the causative agent, or both, the inflammation

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becomes chronic (Yanoff & Sassani, 2014). Permanent alterations in uveal vascular structure, permeability, or both have been implicated as the cause of recurrent or chronic episodes of uveitis (O’Connor, 1983). Distinguishing acute (< 4 weeks) from chronic (> 4 weeks) uveitis on the basis of aqueous protein and cellular determinations is possible. Dogs with acute uveitis have higher protein values (3.5 g/dL) than those suffering from chronic uveitis (1.8 g/dL). Polymorphonuclear cells are more typical of acute uveitis compared with a predominance of small and large mononuclear cells in chronic uveitis (Olin, 1977).

Chemical Mediators of Inflammation Much effort has been directed to identifying the chemical mediators of ocular inflammation because of the direct therapeutic implications. While progress is always being made toward understanding inflammation, the variations in species’ responses to inflammation and the varying diseases among species slow the progress. PGs are the most widely studied mediators of ocular inflammation and are considered to be primary mediators of ocular inflammation (O’Connor, 1983; Wilkie, 1990b). Cyclooxygenase has been identified in all cell types, except for mature red blood cells (Kulkarni & Srinivasan, 1986), and PGs are produced by the irides of all species studied to date (Yoshitomi & Ito, 1988). The most notable pathologic ocular effects of PGs include miosis, hyperemia, changes in vascular permeability, and alterations in intraocular pressure (IOP), depending on the particular PG and species in question. Most of these effects are caused by direct action on the specific tissue. PGs disrupt the tight junctions between nonpigmented ciliary body epithelial cells and, to a lesser extent, the iridal vasculature, thereby allowing protein exudation and aqueous flare (Adler, 1992; Laties et al., 1966). In the dog, PGF2 is a potent constrictor of the iris sphincter muscle, whereas PGE1 and PGE2 have little effect (Dziezyc et al., 1992; Yoshitomi & Ito, 1988). This action is independent of cholinergic or adrenergic innervations (Yoshitomi & Ito, 1988). PGs also have normal physiologic functions such as moderation of inflammation, hypotensive effects, and other beneficial therapeutic effects (Bito, 1986; Havener, 1983). The PGs involved in uveitis, however, are present in excessive quantities. The eye has limited amounts of PG 15-dehydrogenase, which is the enzyme responsible for inactivation of PGs; therefore, PGs must be removed by active transport through the ciliary body for inactivation elsewhere. When uveitis is present, these active transport mechanisms are diminished (Bito, 1986; Eakins et al., 1974). Arachidonic acid derivatives appear to play a key role in ocular inflammation. Arachidonic acid is released from damaged cellular membranes through phospholipases acting on cellular phospholipids (Boothe, 1984). It can then enter one of at least three metabolic pathways: the

cyclooxygenase, lipoxygenase, or oxidation pathway (Millichamp & Dziezyc, 1991; Wilkie, 1990a). Each of these pathways has been identified in the eyes of various species, but the relative contribution of each in the genesis of uveitis is poorly defined (Collins & Moore, 1999). The cyclooxygenase pathway produces PGs, thromboxane, and prostacyclin, and the lipoxygenase pathway produces leukotrienes, hydroperoxy, and hydroxyeicosa-tetraenoic acids (Millichamp & Dziezyc, 1991; Wilkie, 1990a). Leukotrienes are synthesized in the cornea, conjunctiva, anterior uvea, and lens. Species variations exist in the extent and duration of leukotriene production (Dziezyc et  al., 1989). Leukotrienes are potent vasoactive substances and chemoattractants. Their chemotactic, humoral, and cellular activities are greater than those of PGs (Boothe, 1984). Leukotriene B4 has almost no vasoconstrictive activity, but allows adherence of leukocytes to vascular endothelium; this may be an early mechanism for cell migration into the inflamed uvea (O’Connor, 1983). In a canine model of lensinduced uveitis (LIU), levels of leukotriene B4 were increased during early inflammation (Dziezyc et al., 1989). In addition, dogs that received systemic lipoxygenase inhibitors did not experience the transient rise in IOP during acute uveitis often attributed to PGs, whereas the control dogs did. Another study that used a mild paracentesis model of uveitis concluded on the basis of similar results in treated and control dogs that leukotrienes are not important mediators of blood–aqueous barrier disruption in dogs (Ward et  al., 1992a). Furthermore, it was suggested that leukotriene inhibitors might exacerbate uveitis through shunting of arachidonic metabolites to the cyclooxygenase and epoxygenase pathways. Substance P, an undecapeptide normally present in sensory nerves, appears to be important in uveitis, particularly when associated with corneal irritation (O’Connor, 1983). Ulcerative keratitis causes varying degrees of uveitis, but it does so through a poorly understood “axonal reflex.” With corneal irritation, antidromic impulses mediated by the trigeminal nerve (ophthalmic branch) reaching the iris and ciliary body are believed to stimulate release of substance P. This causes vascular dilation and altered permeability as well as PMN chemotaxis. These effects are transient and unlikely to result in permanent uveal changes. The role of substance P in canine uveitis is unclear (O’Connor, 1983; Unger & Tighe, 1984). One study indicated that PGs play a greater role than substance P in the canine ocular irritative response induced by rapid paracentesis, because inhibition of neuropeptide release by topical application of proparacaine did not affect the response of blood–ocular barrier breakdown and miosis (Ward et al., 1992a). However, when topically applied pilocarpine is used as a model for measuring aqueous flare and miosis, pretreatment with proparacaine or with nonsteroidal anti-inflammatory drugs (NSAIDs) inhibits the response equally (Krohne et al., 1998).

The variation in results of the two studies might be due to the method of inducing aqueous flare. While the pilocarpine model does increase protein in the aqueous humor, it does not appear to do so by interfering with the blood–aqueous barrier (Freddo et al., 2006). Tumor necrosis factor-alpha (TNF-α) is a cytokine that plays a role in inflammation and immune activation. Durieux et al. (2015) confirmed elevated levels of TNF-α in dogs with acute anterior uveitis and in chronic primary angle-closure glaucoma in comparison to normal controls. The levels were higher in dogs with uveitis than glaucoma (Durieux et  al., 2015). Inhibition of TNF-α is used therapeutically in humans; unfortunately, its use is species specific. Numerous other chemical mediators also have contributory, albeit largely undefined, roles in ocular inflammation. Histamine is important in the initiation of many inflammatory processes, and its release from mast cells leads to an increase in vascular permeability (Yanoff & Sassani, 2014), but histamine’s role in canine uveal disease is poorly understood. Reactive oxygen metabolites, angiotensin-converting enzyme, and basic fibroblast growth factor may also play roles in uveitis (Abrams, 1989; Grahn et  al., 1992; Mittag, 1984). For information on the direct functional impact of immune cells on the ocular microenvironment and mechanisms of ocular immune homeostasis, see Chapter 6.

Clinical Manifestations and Diagnosis Anterior uveitis manifests many clinical signs. Some signs are specific for uveitis, such as aqueous flare and hypopyon,

while others are general ocular responses, such as blepharospasm and ocular hyperemia. Anterior uveitis can also be a secondary component of other ocular diseases, such as corneal ulceration and glaucoma, demonstrating the need for a complete ophthalmic examination. The clinical signs of uveitis are listed in Table 21.2. Excessive lacrimation, blepharospasm, and photophobia are readily observed. These signs suggest varying degrees of ocular discomfort not specific to uveitis. Acute uveitis tends to be more painful than chronic uveitis. The pain is referred to the ocular and periorbital regions. Pain and photophobia are caused by ciliary spasm. Excessive lacrimation might occur secondary to photophobia (Hogan et al., 1959). Ciliary flush is hyperemia of the deep, perilimbal, or circumcorneal anterior ciliary vessels and is common with deep corneal and intraocular disease (i.e., uveitis and glaucoma). Congestion of the conjunctival vessels also commonly occurs with uveitis, and in severe cases uveitis can even lead to chemosis (Hogan et  al., 1959). Ciliary flush must be distinguished from superficial conjunctival hyperemia, which is commonly seen with extraocular disease such as allergic conjunctivitis. Distinguishing between these vascular patterns is facilitated by topical application of a sympathomimetic agent (e.g., 1% epinephrine solution). The topical sympathomimetic agent will have a greater immediate vasoconstrictive effect on the superficial conjunctival vessels than on the deeper anterior ciliary vessels (Rubin, 1968). In addition, conjunctival vessels move with the conjunctiva on the surface of the globe, whereas the anterior ciliary vessels remain stationary within the sclera during movement of the conjunctiva over the globe.

Table 21.2  Clinical signs of uveitis. Anterior Uveitis

Posterior Uveitis

Additional Adverse Sequelae

Aqueous flare

Vitreous opacity

Deep corneal vascularization

Fibrin in anterior chamber

Decreased vision

Ectropion uvea

Keratic precipitates

Chorioretinal granulomas

Iris atrophy

Hypopyon

Retinal detachment

Rubeosis iridis (or preiridal fibrovascular membrane)

Hyphema

Retinal hemorrhage

Secluded pupil and iris bombé

Miosis

Choroidal effusion

Secondary glaucoma

Decreased intraocular pressure

Optic neuritis

Cataract

Ciliary flush

Lens luxation

Corneal edema

Endophthalmitis/panophthalmitis

Iris color change (usually darker)

Phthisis bulbi

Iris swelling Pain Posterior synechiae Decreased vision Conjunctival hyperemia

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Figure 21.11  Severe corneal edema, corneal vascularization, and conjunctival hyperemia are present in this dog with anterior uveitis secondary to blastomycosis.

Corneal edema with an associated increase in corneal thickness develops with anterior uveitis secondary to both an increase in endothelial permeability and a decrease in Na/K ATPase pump site density (Fig.  21.11; MacDonald et  al., 1987). Severe edema may result in bulla formation. Morphologically, edematous endothelial cells with disrupted intercellular junctions and a normal cell density are seen. The exact mechanisms for the damage to the endothelium probably include PGs, oxygen free radicals, and hydrolytic enzymes liberated in part by leukocytes. Persistent corneal edema may be followed by peripheral corneal vascularization. The use of steroids prevents these morphologic and physiologic changes. IOP determination helps to distinguish the corneal edema of uveitis from that of glaucoma, but the two often occur together. Peripheral corneal edema can also occur from extension of inflammation from the limbal circulation (Hogan et al., 1959). Pupillary constriction, or miosis, is a very common sign with anterior uveitis. Miosis occurs in response to PGF2 acting directly on the iris sphincter muscle (Fig.  21.12; Dziezyc et al., 1992; Yoshitomi & Ito, 1988). Inflammatory mediators also cause painful spasm of the ciliary body musculature, causing what is described as “brow ache” in humans. Subtle miosis is often more apparent when examining both eyes simultaneously in a darkened room using retroillumination with a penlight or Finoff transilluminator. The comparison of light reflected from the tapetal fundi in this technique readily allows detection of disparities in pupil size, or anisocoria. Iris swelling from edema and cellular infiltrates, in conjunction with inflammatory mediators, impedes normal pupil mobility. Subclinical uveitis often manifests with a pupil that dilates more slowly after short-acting mydriatic therapy (i.e., 1% tropicamide) compared with the normal eye. This observation is diagnostic. Conversely, the pupil often responds sluggishly to light. In addition, the pupil may be nonresponsive

Figure 21.12  Congestion of iris vessels and miosis are evident in a Pharaoh Hound with anterior uveitis secondary to blastomycosis.

because of increased IOP seen with secondary glaucoma or synechiae. Synechiae formation is one of the more serious complications of anterior uveitis. It results from inflammatory cells, fibrin, and fibroblasts leading to adhesions of the iris to the lens or peripheral cornea. Both posterior synechiae and peripheral anterior synechiae occur (Fig. 21.13). Peripheral anterior synechiae form because of anterior chamber shallowing as a result of pupillary block, secondary to organization of inflammatory exudates in the angle with gradual movement of the iris toward the angle structures, and with intense swelling of the iris root (Hogan et al., 1959). Posterior synechiae are a consequence of the lens shape, with the central portion of the lens extending more anteriorly than the peripheral lens. With miosis, the iris is in more intimate contact with the lens, increasing the surface area for synechia formation. Fibrin and other inflammatory products facilitate iris adherence to the lens capsule. Posterior synechiae can cause occlusion of the pupil leading to loss of sight, or seclusion of the pupil resulting in iris bombé with subsequent acute glaucoma (Fig. 21.14). Synechiae often result in a fixed miotic or mid-range pupil. With chronic synechiae, pigment frequently migrates from the surface of the iris onto the anterior lens capsule, which is more likely to interfere with vision if the pupil is miotic. Pigment clumps on the anterior lens capsule usually indicate previous uveitis; however, the pigment clumps can result from congenital remnants of the pupillary membrane. Lens capsular pigment from uveitis is generally darker than the pigment associated with pupillary membranes, and in the latter instance pigment is normally confined to the axial lens surface. Prolonged inflammation in the iris epithelium and stroma often eventually results in iris atrophy that is patchy or diffuse. Aqueous flare, increased turbidity of aqueous humor, occurs as protein-rich aqueous humor and cellular components accumulate within the anterior chamber after the blood– aqueous barrier has been disrupted. Aqueous flare is

Figure 21.15  The visible haziness in this eye is caused by slight corneal edema and aqueous flare. Figure 21.13  Posterior synechiae is the only evidence of previous anterior uveitis in this eye that has a hypermature cataract.

Figure 21.14  Iris bombé developed secondary to 360 degrees of posterior synechiae, which led to anterior ballooning of the iris in this dog. Episcleral injection is also present.

visualized when particles suspended in the anterior chamber scatter the light, causing a continuous light reflection throughout the chamber. This continuous beam effect is called the Tyndall phenomenon, and it is analogous to shining a flashlight in fog or smoke. Observation of the Tyndall phenomenon is indicative of aqueous flare, and aqueous flare is pathognomonic for anterior uveitis (Berliner, 1966). Varying degrees of aqueous flare are possible, and though this scheme is highly subjective, some clinicians attempt to quantitate flare numerically as 1+ to 4+, with higher numerals indicating increased severity. One grading scheme describes the severity of flare as follows: 1+ indicates faint flare (barely detectable); 2+ indicates moderate flare (iris and lens details are clear); 3+ indicates marked flare (iris and lens details are hazy); and 4+ indicates intense flare (fixed, coagulated aqueous humor with fibrin; Fig.  21.15;

Hogan et  al., 1959). Flare is best detected with slit-lamp biomicroscopy, but other focal light sources (e.g., the small aperture of a direct ophthalmoscope) in a very dark room are also useful. Experimentally, laser flaremetry and fluorophotometry are used to assess the amount of protein in the aqueous humor. The flare meter quantitates the level of aqueous humor protein by measuring the photon count of scattered light, which is proportional to the amount of protein in the anterior chamber (Krohne et  al., 1995). In experimental studies of uveitis, fluorophotometry, in which fluorescein concentrations in the anterior chamber are measured after intravenous injection of fluorescein, has also been used (Ward et al., 1991). The term fibrinous (or plasmoid) aqueous refers to aqueous humor that has an increased level of protein, approximating that of normal plasma. This condition occurs most commonly in cases of acute, severe anterior uveitis. If fibrinous exudation is severe, fibrin clots form in the anterior chamber. Lipid-laden aqueous is also possible if the patient has concurrent hyperlipidemia, in which the aqueous assumes a milky-white appearance (Fig.  21.16; Olin et  al., 1976). A specific cause-and-effect relationship between hyperlipidemia and uveitis is not well established; however, in most instances lipids simply enter the chamber with blood–aqueous barrier breakdown, as do large proteins. Cells from the inflammatory process pass into the aqueous humor either from diffusion or from active migration from the uvea. They are either manufactured locally or egress through the capillary walls from the blood into the uveal tissue and into the aqueous humor (Hogan et al., 1959). Keratic precipitates (KPs) are accumulations of inflammatory cells, fibrin, and iris pigment that settle on the corneal endothelium (Fig.  21.17). KPs are usually located inferiorly on the cornea in a triangular shape, with the apex located superiorly. Convection currents in the anterior chamber that rise along the warm iris and fall along the cooler cornea create the characteristic formation (Tessler, 1989). KPs can be readily missed, however, if the examiner is not specifically looking for them. Detection of KPs is facilitated by magnification and

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Figure 21.16  Lipoid aqueous is visible in the anterior chamber of this Miniature Schnauzer.

Figure 21.18  Hyphema, filling over half the depth of the anterior chamber, occurred secondary to systemic hypertension and retinal detachment in this Beagle.

Figure 21.17  Small keratic precipitates are visible on the ventral half of the corneal endothelium.

gently tilting the animal’s head downward, thereby facilitating upward rotation of the eye and ready examination of the ventral cornea. In painful eyes with protrusion of the nictitating membrane, KPs are especially difficult to observe. It is important to note KPs because their presence is always indicative of active or previous uveitis. In some granulomatous conditions, KPs tend to form as large, waxy-yellow deposits. Berliner (1966) notes that these deposits are made of plasma cells and macrophages typical of granulomatous inflammation, and that they have a greater tendency to agglutinate and adhere to the cornea than do lymphocytes and polymorphonuclear cells, which are typical of nonspecific uveitides. However, lymphocytes and polymorphonuclear cells can also form “nongranulomatous” KPs, which tend to be smaller (Whitcup, 2010). Varying amounts of pigment are present in KPs, with larger amounts seen with chronicity. The deposits of red and white blood cells within the anterior chamber are the most marked examples of blood– uveal barrier breakdown and are termed hyphema and hypopyon, respectively (Fig.  21.18 and Fig.  21.19). In both

Figure 21.19  Hypopyon is present in the ventral anterior chamber in this dog with lymphosarcoma.

instances, cellular components typically gravitate toward the ventral anterior chamber and settle in a homogenous layer. If bleeding was initially extensive or is continuous, complete (i.e., total) hyphema with filling of the entire anterior chamber occurs. Layering in the hyphema often indicates rebleeding. Occasionally, iridal hemorrhage occurs (Fig.  21.20). Clotted blood can also be observed. The term eight-ball hyphema has been used to describe complete hyphema of 5–7 days’ duration, when the blood turns from bright red to bluish black. Blood staining of the cornea can occur, especially with large hyphemas, corneal epithelial damage, and elevated IOP (Brandt & Haug, 2001). Hypopyon can be a result of sterile inflammation, infection, or neoplasia. Hypopyon rarely occupies more than a third of the anterior chamber and is easily missed, because the ventral anterior chamber is often obscured by the third eyelid. Generally, hypopyon leaves the eye rapidly through the trabecular meshwork when treatment of the inflammatory processes is initiated.

Figure 21.20  Iridal hemorrhages are present on the iris of this dog with immune-mediated thrombocytopenia.

Preiridal fibrovascular membranes (PIFMs) arise from the anterior border layer of the iris and develop secondary to chronic ocular diseases such as uveitis, glaucoma, intraocular neoplasia, and retinal detachment (Peiffer et  al., 1990). The clinical term for this condition is rubeosis iridis. Clinically, a haphazard array of very small vessels is seen on the iridal surface (Fig.  21.21). PIFMs can extend over the lens or pectinate ligaments and are differentiated from normally present but dilated iridal vessels by the haphazard organization, as compared to the radial orientation of normal iridal vessels. PIFMs are always preceded by ocular disease, and their development can lead to hyphema because of the vessel wall fragility, and to glaucoma because of membrane extension over the iridocorneal angle. Microscopically, cellular, vascular, and fibrous membranes are observed on the anterior face of the iris. Cellular membranes appear as a monolayer of plump to spindloid cells; fibrous membranes consist of fibrous tissue at varying stages of maturation; and fibrovascular membranes contain blood vessels that arise from the iridal vessels. Well-developed PIFMs consist of blood vessels with plump endothelial cells, spindle cells, inflammatory cells (primarily lymphoplasmocytic), and an extracellular matrix. Immunohistochemically, the extracellular matrix stains positive for collagen, mucins, and usually laminin. The vessels, which are CD31 positive, and spindle cells are both positive for laminin, vimentin, smooth muscle actin, vascular endothelial growth factor (VEGF), and COX-2 (Zarfoss et al., 2010). Another study found that both the cellular and fibrovascular membranes are negative for cytokeratin AE1/AE3 and positive for vimentin. The endothelial cells lining the vessels in the fibrovascular membrane are positive for factor VIII-related antigen, but the cellular membranes are not (Bauer et  al., 2012). The pathogenesis of membrane formation is not known, but may be related to hypoxia and angiogenic and fibroblastic stimulatory factors from chronic inflammation and neoplasia (Peiffer et  al.,

Figure 21.21  A preiridal fibrovascular membrane is present on the surface of this iris. Because this iris was very lightly pigmented, the membrane can be seen as a fine meshwork of small vessels on the iris. The clinical term is rubeosis iridis. Areas of posterior synechiae are also present.

1990; Yanoff & Sassani, 2014). These three types of membranes most likely represent a continuum of maturation, or the cellular membrane might arise from a separate mechanism (Bauer et al., 2012; Peiffer et al., 1990). Because of the positivity for VEGF, VEGFR1, VEGFR2, and COX-2 and similarities between all PIFMs regardless of the inciting ocular disease, in the future there may be a way to pharmacologically interfere with PIFM formation (Binder et al., 2012; Zarfoss et al., 2010). In addition to rubeosis iridis, diffuse iris hyperpigmentation can occur with chronic anterior uveitis. This condition is more obvious in eyes with lightly pigmented irides and in cats. Decreased IOP is one of the earliest and subtlest indications of uveitis. Proposed mechanisms for decreased IOP include both decreased aqueous humor production with breakdown of the blood–aqueous barrier and increased uveoscleral flow, mediated in part by PGs (Gabelt & Kaufman, 2011; Millichamp & Dziezyc, 1991; Toris & Pederson, 1987). IOP varies depending on the duration and severity of uveitis. In acute or subacute uveitis, IOP is usually decreased for the previously mentioned reasons; in chronic uveitis, fibrosis or atrophy (or both) of the ciliary body may contribute to decreased secretory function, with subsequent ocular hypotony. Marked ciliary body dysfunction and hypotony often result in phthisis bulbi. Secondary glaucoma is a common manifestation of severe or protracted uveitis. The causes of secondary glaucoma include obstruction of the angle by inflammatory debris, iris bombé that occurs with formation of annular posterior synechiae, extensive anterior peripheral synechiae, and formation of PIFMs. An IOP of less than 10 mmHg is consistent with uveitis. A difference of more than 5 mmHg in IOP between the two eyes, even if the values obtained are in the

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normal range, is often significant and suggests that the eye with the lower IOP has uveitis or the higher has impending glaucoma. In one study, nonsurgical anterior uveitis was found to be the most common cause of secondary glaucoma (Johnsen et al., 2006). In another study, cataract formation, specifically, was found to be the most common cause of secondary glaucoma (Gelatt & MacKay, 2004). Some infectious diseases, such as blastomycosis, frequently lead to secondary glaucoma. Glaucoma can result from intraocular neoplasia; however, it is usually a late manifestation. Cataracts, especially anterior subcapsular cataracts, commonly develop secondary to chronic anterior uveitis. They most likely arise from inflammatory mediators in the aqueous humor interfering with normal lens metabolism. Lenticular changes are not specific and include epithelial metaplasia or posterior migration and liquefaction, degeneration, or necrosis of lens fibers (Eagle & Spencer, 1996). Posterior synechiae can also result in cataract formation.

Diagnostic Tests for Uveitis When uveitis is diagnosed, an attempt should be made to identify the etiology. Some causes are readily apparent, such as when anterior uveitis occurs in conjunction with a hypermature cataract. Conversely, extensive diagnostic testing and evaluation frequently do not lead to a specific etiology. Complete ophthalmic and physical examinations are always indicated. Regarding the ophthalmic examination, special attention should be paid to the cornea and lens of the affected eye and the fundi of both eyes (e.g., presence of chorioretinitis). Physical examination should include evaluation of the skin, looking for depigmented areas or draining lesions; lymph node palpation, auscultation, and abdominal and possibly rectal (especially in intact male dogs) palpation. A complete blood count and serum panel are usually indicated. Selected titers or antigen testing are run based on the endemic diseases in the dog’s location and in areas where the dog may have traveled. Thoracic radiographs are also considered part of the minimal screening protocol when systemic disease is suspected. Radiographs are evaluated for evidence of metastatic or fungal diseases. Additional serologic tests and diagnostics are indicated according to the clinician’s index of suspicion. Refer to “Uveal Manifestations of Selected Diseases” in this chapter as well as to Chapter 36, Part 1 for further discussion. Cytologic evaluation of aqueous humor, bacterial or fungal culture of the aqueous, vitreous aspirates, or a combination thereof may be beneficial in determining the cause of uveitis. Aqueous aspirates yield useful and positive results most often in eyes with visible exudate or in animals with lymphosarcoma (Linn-Pearl et al., 2015; Olin, 1977; Wiggans et al., 2014b). Most commonly, aqueous aspirates yield nonspecific inflammatory cells. Because of the rarity of specific results and the exacerbation of existing uveitis, the procedure is not

recommended in most cases. In patients with concurrent posterior uveal involvement, vitreous aspirates are more likely to yield positive results than aqueocentesis (see Chapters 24 and 25). This procedure should be considered for eyes with marked vitreous opacity, exudative retinal detachments, or panophthalmitis. Care must be taken not to puncture the lens. Intraocular hemorrhage following either aqueous or vitreous aspiration is possible.

Therapy for Anterior Uveitis Topical anti-inflammatory therapy should be instituted immediately after the diagnosis of anterior uveitis is made, even in those patients with suspected systemic disease. Failure to initiate therapy early in the disease process could result in many adverse sequelae, including synechiae formation, cataract, secondary glaucoma, endophthalmitis, and phthisis bulbi. Topical therapy alone may suffice for mild anterior uveitis, but for severe anterior uveitis, posterior uveitis, and systemic disease, systemic therapy as dictated by the primary disease is also indicated. Corticosteroids are the primary therapy for the treatment of anterior uveitis. Corticosteroids inhibit phospholipase and the release of arachidonic acid. They decrease cellular and fibrinous exudation and tissue infiltration, inhibit fibroblastic and collagen-forming activity, diminish postinflammatory neovascularization, and decrease vascular permeability (Duke-Elder & Ashton, 1951). Treatment with topical corticosteroids can be initiated in all cases of uveitis pending diagnostics, except in those cases with corneal ulceration. Prednisolone acetate, 1% suspension, is the most commonly prescribed ophthalmic corticosteroid because of its potency and availability. Dexamethasone is also a potent steroid; however, topically applied 1% prednisolone acetate is more effective than dexamethasone sodium phosphate in stabilizing the blood–aqueous barrier (Ward et  al., 1992b). Both prednisolone acetate and dexamethasone are more potent than hydrocortisone, and are available as ophthalmic preparations either alone or in combination with antibiotics. An initial application frequency of 4–6 times daily is often required with solutions, compared with 3–4 times daily as recommended for ointments. Subconjunctival corticosteroids are administered in select cases as an adjunct to topical therapy, but they do not serve as a substitute. Triamcinolone acetonide and betamethasone are long-acting steroids that can be administered subconjunctivally. Risks include scleral perforation at the time of injection, granuloma formation, and extraocular muscle atrophy and paralysis (Pappa, 1994). Long-acting steroids should be used judiciously because the effects cannot be reversed in the case of corneal ulceration or infection. Treatment with systemic corticosteroids or other systemic immunosuppressive drugs is not indicated until diagnostics have been completed. Systemic infectious disease often requires treatment with antibiotics or antifungal drugs.

Systemic neoplasia frequently requires treatment with chemotherapeutic agents. Systemic corticosteroids are contraindicated in most cases of infectious systemic disease. When systemic prednisone is indicated, a recommended initial dosage is 1–2 mg/kg per day in divided doses per os, followed by gradual reduction. Contraindications for the use of topical and systemic corticosteroids differ. In general, topical steroids are not used on eyes with corneal ulceration because of the inhibition of corneal healing and possible potentiation of infection and collagenolysis (Hendrix et al., 2002; Tolar et al., 2006). Systemic steroids can be used in dogs with simple, superficial, noninfected corneal ulcers; however, caution should be used, and the cornea should be monitored frequently for deterioration and collagenolysis. Systemic corticosteroids should be avoided in diabetic dogs if possible, and though topical therapy may alter an animal’s glucose levels and subsequently its insulin requirements, the clinician must weigh the benefits against the risks. Topical steroids are frequently used to control uveitis after cataract surgery in diabetic animals with very few complications. Additionally, it is well known that systemic steroids suppress the hypophyseal–adrenal axis; topical steroids applied frequently cause a similar suppression (Glaze et al., 1988; Roberts et al., 1984). Therapy with either topical or systemic therapy is gradually reduced as the clinical signs of uveitis resolve and is then maintained at the lowest necessary dose. Many topical NSAIDs are available for ophthalmic use. NSAIDs prevent intraoperative miosis, control postoperative pain and inflammation after intraocular surgery, control symptoms of allergic conjunctivitis, and alleviate signs of uveitis (Giuliano, 2004; Krohne et  al., 1998; Ward, 1996; Ward et  al., 1992b; Wilkie, 1990b). Most NSAIDs inhibit PG-mediated inflammation by interrupting the cyclooxygenase pathway (Opremcak, 1994). PGs generated via the cyclooxygenase pathway appear to have a greater effect on the blood–ocular barrier in the dog than do leukotrienes or sensory neuropeptides after anterior chamber paracentesis (Ward et  al., 1992a). Additional anti-inflammatory actions may include suppression of polymorphonuclear leukocyte locomotion and chemotaxis, decrease in the expression of cytokines and mast cell degranulation, and action as a freeradical scavenger (Giuliano, 2004). The anterior chamber paracentesis model showed that flurbiprofen and prednisolone acetate were equally effective in preventing blood– aqueous barrier disruption (Ward et  al., 1992b). In a laser capsulotomy model, flurbiprofen was more effective at preventing blood–aqueous barrier disruption than was prednisolone acetate (Dziezyc et al. 1995). Topical NSAIDs may be used either alone or in combination with corticosteroid therapy; the therapeutic effects of using both NSAIDs and corticosteroids are additive. Many ophthalmic NSAIDs are available and include indomethacin, flurbiprofen, suprofen, bromfenac, ketorolac, and diclofenac. Bromfenac is effective

in human patients when dosed once daily, which is in difference to the other ophthalmic NSAIDs that are usually dosed four times daily; however, it is expensive (Henderson et al., 2011; Silverstein et al., 2011). One study showed that injectable flunixin meglumine (50 mg/mL) administered topically gave similar results to topical dexamethasone in dogs with naturally occurring anterior uveitis (Andrade et al., 2003). An experimental study evaluating the relative blood–aqueous barrier–stabilizing effects of topical NSAIDs in dogs found that diclofenac and flurbiprofen appear to be more efficacious than suprofen (Ward, 1996). Although topical NSAIDs most likely delay corneal wound healing, they are commonly used to treat eyes with concurrent uveitis and corneal ulceration in dogs (Hendrix et al., 2002). However, dogs with corneal ulceration should be monitored judiciously, because a tenuous link with topical NSAID use and collagenolysis has been made in humans. Most cases appear to be associated with increased administration, diabetes mellitus, and the presence of concurrent ocular disease (Gaynes & Fiscella, 2002). The adverse corneal effects might be related to increased matrix metalloproteinase production and alterations in epithelial cell membranes and surface microvilli. Despite the possible adverse effects, the clinical risk–benefit of topical ophthalmic NSAIDs should be assessed. If a favorable response is not noted with treatment, reevaluating the therapeutic approach rather than switching NSAID classes is recommended. In addition, increasing the frequency of administration will not enhance the antiinflammatory action of NSAIDs, and tapering NSAIDs might help avoid inflammatory rebound (Gaynes & Fiscella, 2002). Topical NSAIDs are applied as often as four times daily. Relatively little research has been done evaluating the effect of systemic NSAIDs on anterior uveitis. In a repeated anterior chamber paracenteses model, dogs treated with carprofen had lower levels of PGE2 than placebo-treated dogs, although the levels in both groups were low (Pinard et al., 2011). Results of an aqueocentesis model of induced anterior uveitis showed that flunixin meglumine and tepoxalin, which is no longer commercially available, decreased aqueous PGE2 concentrations significantly more than carprofen and meloxicam, which did not have significantly lower concentrations than the control (Gilmour & Lehenbauer, 2009; Gilmour & Payton, 2012). Many other systemic NSAIDs are available, but their ocular effects have not been evaluated. Etodolac has been associated with the development of keratoconjunctivitis sicca and should be avoided (Klauss et al., 2007). For years, aspirin and flunixin meglumine were the mainstays of systemic NSAID therapy; however, use of these drugs has been replaced with newer and safer systemic NSAIDs. Systemic NSAIDs are not used in conjunction with systemic corticosteroids because of the greater potential for gastrointestinal complications, and their use is contraindicated when hyphema or generalized bleeding tendencies are present.

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Immunosuppressive drugs, such as azathioprine, are commonly employed in cases of uveitis that are deemed immune mediated and are unresponsive to conventional therapy. Azathioprine has been used most commonly in therapy for UDS in the dog (Morgan, 1989). Frequent blood and platelet counts as well as liver enzyme testing are recommended with this therapy because of potential hepatotoxic and myelosuppressive effects (Moore, 2001). Cyclosporine is another immunosuppressive agent that can be used systemically in the treatment of immune-mediated diseases. Cyclosporine primarily affects T-lymphocyte functions. Topical cyclosporine, as used in the treatment of keratoconjunctivitis sicca, has relatively poor intraocular penetration (Kaswan, 1987). Oral cyclosporine is used in the treatment of UDS; however, many complications have been reported in conjunction with the systemic use of cyclosporine, therefore close monitoring of the patient is imperative when this medication is used (Blackwood et al., 2011; Radowicz & Power, 2005; Steffan et  al., 2005). Mycophenolate is also used for immunosuppression in dogs. Dosage adjustments may be necessary in dogs with renal disease. Vomiting, diarrhea, and lethargy are a few of the possible adverse effects (Plumb, 2015). There are few indications for the use of topical antibiotics in the treatment of anterior uveitis, both because the intraocular inflammation is rarely bacterial in origin and because the intraocular penetration of topically administered antibiotics would not be adequate for treatment of an intraocular infection. Topical antimicrobial therapy is primarily used to prevent bacterial infection of corneal ulcers that may be present concurrently with anterior uveitis. If ulceration occurs during topical steroid therapy, treatment with an ophthalmic antibiotic preparation should be initiated. The topical steroid should be discontinued and initiation of treatment with an ophthalmic NSAID might be indicated. While ophthalmic antibiotics are often combined with corticosteroids, there is little indication for the use of this combination of drugs in the treatment of anterior uveitis. Frequently the greatest indication for the use of antibiotic–steroid combinations is when an ointment is needed because there are no commercially available ointments that contain only a steroid. Systemic antimicrobial therapy for uveitis is indicated for treatment of specific systemic diseases, or for prophylaxis against infection in the case of corneal perforation or intraocular surgery. The blood–aqueous barrier is normally impermeable to many antibiotics, but during active uveitis the blood–aqueous barrier is compromised and drug permeability enhanced. Therefore, it is assumed that systemically administered antibiotics will reach the aqueous humor when trauma, infection, or ocular surgery dictates their use. Chloramphenicol penetrates the normal blood–aqueous barrier more effectively than do other antibiotics (Mauger, 1994). Recovery of infectious organisms by microbial culture

of aqueous humor is unlikely in most instances, so antibiotic choice should be based on the odds of a certain bacteria causing the disease process (Olin, 1977). Fortunately, bacterial uveitis is extremely rare in the dog. A particular antimicrobial may be indicated in specific instances, such as doxycycline for the therapy of uveitis secondary to rickettsial diseases and itraconazole for the treatment of blastomycosis. Parasympatholytic agents are important in uveitis therapy. Atropine is the most efficacious ophthalmic parasympatholytic drug. The two major benefits of parasympatholytic drugs are mydriasis and cycloplegia. Dilating the pupil decreases contact between the iris and lens, thereby minimizing the likelihood of posterior synechiae formation. Dilating the pupil also decreases the possibility of occlusion of the pupil resulting in vision loss. Parasympatholytic agents paralyze the iris (i.e., iridoplegia) and ciliary body (i.e., cycloplegia) musculature (Kachmer-McGregor, 1994). Intraocular pain is primarily derived from ciliary body muscle spasm. Atropine also stabilizes the blood–aqueous barrier by blocking the effect of acetylcholine, which dilates blood vessels (Van Alphen & Macri, 1966). Atropine is contraindicated when IOPs are elevated, with the rare exception of early iris bombé, for which atropine may be beneficial in breaking posterior synechiae. Atropine ointment or solution is the most commonly used parasympatholytic agent and is given to effect with mild uveitis requiring therapy once or twice daily, and more severe cases requiring more frequent application (e.g., four times daily) initially. The actively inflamed eye reacts much more slowly to atropine than does the normal eye, and the effects are shorter lived. The duration of mydriasis in the normal dog eye is 96–120 hours after administration of topical 1% atropine (Rubin & Wolfes, 1962). If synechiae are present at examination, repeated drops of atropine might help break them free. If the synechiae have been present longer than a few days, the continued application of atropine might break them down over several days. The addition of 10% phenylephrine could aid in breaking the synechiae. Side effects of frequent treatment with topical atropine might include decreased tear production, tachycardia, decreased gut motility, and the potential to precipitate acute glaucoma (Moore, 2001). While the decrease in tear production is statistically significant, the levels do not typically drop below normal (Hollingsworth et al., 1992). However, caution should be used in dogs with borderline tear production and in dogs with ulcerative keratitis. Tropicamide is a very weak parasympatholytic in comparison to atropine. It can be useful in treating cases of anterior uveitis in which the IOP is borderline high. Tropicamide can dilate the pupil just enough to prevent synechiation and tends to alter the IOP less than atropine. Tropicamide also has a greater mydriatic effect than cycloplegic effect; therefore, mydriasis does not necessarily indicate cycloplegia (Kachmer-McGregor, 1994).

Uveal Manifestations of Selected Diseases The following discussion summarizes selected diseases that are documented causes of uveitis in the dog. Complete ophthalmic and physical examinations are necessary in all cases of uveitis. Many ophthalmic and systemic diseases can lead to uveitis, and results from ocular and physical examinations in conjunction with ancillary diagnostic tests are necessary to confirm or rule out etiologies. Referral to textbooks on internal medicine and infectious diseases is recommended for detailed discussions of specific disorders, diagnostics, and systemic treatment. Refer also to Chapter 36, Part 1.

Lens-Induced Uveitis LIU is a common complication of cataract in the dog (Dziezyc et  al., 1997; Paulsen et  al., 1986; van der Woerdt et  al., 1992). LIU is typically associated with hypermature cataracts, but fluorophotometry, laser flaremetry, and IOP studies show that dogs with all stages of cataracts have evidence of at least subclinical uveitis (Dziezyc et  al., 1997; Krohne et al., 1995; Leasure et al., 2001). Additionally, PGE2 concentrations are similarly elevated in dogs with mature and hypermature cataracts in comparison to dogs without cataracts (Renzo et  al., 2014). Lastly, the presence of D-dimers in the aqueous humor of diabetic dogs and nondiabetic dogs with cataracts and systemically ill dogs supports the presence of intraocular fibrinolytic activity in these dogs. The fibrinolytic activity is greater in dogs with diabetic cataracts than in those without cataracts and those with nondiabetic cataracts (Escanilla et al., 2013). Most likely, small amounts of lens protein escape the normal lens and induce T-cell tolerance (Denis et  al., 2003). Increased immune system exposure to lens crystallins by lens trauma, spontaneous lens resorption, or cataract extraction often overwhelms this tolerance and induces an intraocular or systemic cell-mediated and/or humoral immune response. A negative association between the presence and maturity of cataract and the presence of anti-lens crystallin serum antibodies has been shown. This negative association might occur because of the alteration of lens proteins with maturity of the cataract, affinity maturation of anti-crystallin antibodies, or ACAID (Denis et al., 2003). Two distinct types of LIU occur in the dog (Fischer, 1983; Wilcock & Peiffer, 1987). Phacolytic uveitis occurs in dogs with rapidly developing or hypermature cataracts, in which soluble lens protein leaks through an intact lens capsule. This type of LIU is nongranulomatous and is characterized by mild lymphocytic-plasmacytic uveitis, not unlike that occurring with most idiopathic uveitides (Fischer, 1983; Wilcock & Peiffer, 1987). The diagnosis of this type of LIU is presumptive and is made on the observation of cataracts

and the absence of other ocular or systemic disease. Phacolytic LIU may develop more rapidly in young dogs after the onset of cataract. While phacolytic LIU usually responds to conventional therapy, young dogs may respond more poorly to uveitis therapy, possibly because of higher concentrations of lenticular α-crystallin protein and faster cataract resorption in young dogs (van der Woerdt et  al., 1992). LIU must be recognized and treated prior to cataract surgery. Long-term success rates of cataract surgery in dogs with LIU might be lower than in dogs without LIU (van der Woerdt et al., 1992). LIU also needs to be treated in dogs that are not surgical candidates because the uveitis is painful, and treatment may delay the onset of secondary glaucoma. Granulomatous LIU also occurs in dogs with an intact lens capsule but usually occurs in older dogs with rapidly progressing cataracts, especially Miniature Schnauzers, or longstanding cataracts (Fischer, 1983). These eyes have severe uveitis, often with large KPs, and are less responsive to therapy (Fig. 21.22). Even when dogs undergo cataract surgery, anterior uveitis often persists for months, reducing postoperative success rates. There are many proposed mechanisms, including persistent blood–aqueous barrier breakdown, exposure of the uvea to sufficient amounts of intact lens protein to overwhelm the normal low-dose T-cell tolerance, acquired ability of vasculature endothelial cells to express major histocompatibility complex to antigens, and cross-reaction of anti-lens antibodies with uveal antigens (Strubbe, 2002). After surgery, uveitis can lead to cyclitic membranes, posterior synechia, or pigment migration across the lens capsule. Phacoclastic uveitis occurs with sudden exposure of intact lens protein in amounts sufficient to overwhelm the normal low-dose T-cell tolerance to lens proteins (Davidson et  al., 1991; Wilcock & Peiffer, 1987). Usually this occurs secondary to trauma. Septic implantation syndrome is a relatively new term that probably applies to many of the previously described phacoclastic uveitis cases. In these cases, there is

Figure 21.22  Large keratic precipitates, cataract, and posterior synechia are present in this diabetic Miniature Schnauzer.

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often recent or months-long history of ocular trauma (usually a cat scratch). The early clinical sign is uveitis with a slowly progressive course. Often, the eye is not examined until late in the course of disease, when the cause is not immediately apparent and puncture wounds have healed. Clinically, there is inflammatory exudate centered on the lens with a varying frequency of uveitis, cataract, glaucoma, and corneal disease. Microscopically, there is lens capsule rupture, cataract, and a lenticular abscess with neutrophils in the lens cortex. The inflammation is suppurative with fibrin; lymphoplasmacytic infiltrates are in the iris stroma; and bacteria or fungi are often present within the lens distant from the inflammatory infiltrates. The more common organisms are Gram-positive cocci and Gram-positive rods. Bell et al. (2013) suggest that the term phacoclastic uveitis might be better reserved for cases of sterile lens capsule rupture. Both medical and surgical therapies are used for phacoclastic uveitis (see “Traumatic Uveitis with Lens Rupture” and “Foreign Body Trauma,” and Chapters 22 and 23).

Anterior Uveitis Secondary to Corneal, Scleral, and Periocular Disease Anterior uveitis occurs commonly secondary to corneal ulceration. This response is much greater in horses and rabbits than in dogs. Miosis is the most common clinical sign of anterior uveitis seen in dogs with corneal ulceration, but decreased IOP and aqueous flare also occur. The purpose of topical atropine in the treatment of corneal ulceration is to decrease ciliary spasm, thereby decreasing pain. The mechanism for uveitis secondary to corneal disease was described in “Chemical Mediators of Inflammation.” Non-necrotizing scleritis in dogs is relatively common and does not typically involve the anterior and posterior segments of the eye. Necrotizing scleritis, however, can cause anterior uveitis, vitritis, subretinal masses, tapetal degeneration, hemorrhage, and edema. Scleral biopsies reveal an infiltration of lymphocytes, plasma cells, and macrophages with few neutrophils. Therapy with immunosuppressive dosages of prednisone and azathioprine is indicated, but may not be effective (Grahn et al., 1999). Periocular snakebites from pit vipers typically cause pain, facial edema, chemosis, and conjunctival hyperemia. Uveitis is present in many dogs with periocular bites, as well in dogs with direct ocular bites. Pit viper venom contains many enzymes such as phospholipase A2 that most likely contribute to the influx of inflammatory cells to the eye and periocular area after a bite (Martins et al., 2016).

was initially termed VKH-like syndrome because of similarities to a disease in humans known as VKH syndrome. The term uveodermatologic syndrome was adopted to further separate the disease in dogs from that in humans because of the absence of neurologic signs in dogs. The disease was first reported in two Akitas in Japan (Asakura et al., 1977). Many case reports and case series reporting UDS in other breeds have followed. The pathogenesis of UDS is not completely understood. VKH in humans is an autoimmune disease directed against melanocytes and is mainly mediated by cellular immune responses (Yamaki et al., 2005). Experimentally, Akita dogs have been immunized with tyrosinase-related protein, an enzyme involved in melanin formation that is expressed specifically in melanocytes. The Akitas developed clinical and histologic signs consistent with UDS, supporting the similarities between the canine and human diseases (Yamaki et  al., 2005). Additionally, the canine leukocyte antigen DLA-DQA1*00201 has been associated with a significantly higher relative risk for UDS syndrome in American Akitas than other DLA Class II alleles (Angles et al., 2005). UDS appears to affect primarily young adult dogs; the mean age from two reports was 3 years (Kern et  al., 1985; Morgan, 1989). UDS also appears to occur more frequently in the Akita, Samoyed, Siberian Husky, and Shetland Sheepdog, but many other breeds are affected. Ocular findings include bilateral anterior uveitis or panuveitis, iris or choroidal depigmentation, bullous retinal detachment, and blindness. Cataract, extensive posterior synechiae, iris bombé, and secondary glaucoma occur with chronicity. Dermatologic changes usually follow the development of ocular signs, and include vitiligo of the facial mucocutaneous junctions, nasal planum, scrotum, and footpads; however, generalized vitiligo may occur. Poliosis is confined to the facial region or is generalized. Alopecia occurs inconsistently (Kern et  al., 1985; Morgan, 1989) (Fig. 21.23).

Uveodermatologic Syndrome UDS, previously referred to as Vogt–Koyanagi–Harada (VKH)-like syndrome, is a canine disease that leads to anterior uveitis, chorioretinitis, poliosis, and vitiligo. The syndrome

Figure 21.23  This black Labrador Retriever has poliosis secondary to uveodermatologic syndrome.

General physical examination on affected dogs is normal. Clinically evident neurologic disease manifested as dysacusis and meningitis is common in humans with VKH; however, neurologic signs have not been confirmed in the dog, and this is thought to be due to the lack of pigment in the canine meninges. Analysis of cerebrospinal fluid (CSF) and postmortem examination of central nervous system (CNS) tissue has been normal in the few cases examined (Morgan, 1989). Routine laboratory parameters are normal. Immunefunction tests and titers for multiple infectious diseases have been negative (Kern et  al., 1985; Morgan, 1989). Microscopically, the primary ocular change is a granulomatous panuveitis with prominent perivascular lymphoid aggregates and melanophages. The anterior chamber often contains many lymphocytes and plasma cells. Retinal detachment, destruction of the retinal pigmented epithelium, subretinal neovascularization, choroidal scarring, and signs consistent with secondary glaucoma are also seen frequently. Pigment-containing macrophages and melanophages are a prominent feature (Bussanich et al., 1982; Carter et al., 2005; Kern et al., 1985; Morgan, 1989). Histopathologic examination of the skin reveals interface dermatitis with a primarily lichenoid pattern. Large histiocytic cells, plasma cells, melanophages, and small mononuclear cells are characteristic (Kern et al., 1985). Results of an immunohistochemical study of two cases suggested that the skin lesions were mediated by T-cells and macrophages (Th1 immunity), whereas the ocular lesions were more consistent with a B-cell and macrophage response (Th2 immunity; Carter et al., 2005). Immunosuppressive drugs are the mainstay of therapy. Standard therapy for anterior uveitis with topical steroids, topical NSAIDS, and atropine (if the IOP is not elevated) is initiated. Oral prednisone at immunosuppressive doses is also used. Generally, there is a relatively rapid response to therapy. Unfortunately, many dogs have recurrence of clinical signs if the dose of oral prednisone is decreased and have the undesirable side effects of weight gain, polyuria, and polydipsia if it is continued. Therefore, other immunosuppressive drugs, such as azathioprine and cyclosporine, are often combined with corticosteroids or used alone in the treatment of UDS (Blackwood et al., 2011; Pye, 2009; Sigle et  al., 2006). However, even with appropriate therapy, secondary glaucoma is a common sequela.

Mycoses-Associated Uveitis Disseminated mycotic infections with ocular involvement are relatively common among dogs living in endemic areas. Even though mycotic infections typically involve multiple body systems, ocular disease is often the reason for presentation. The more common systemic mycoses include blastomycosis, coccidioidomycosis, histoplasmosis, cryptococcosis,

and aspergillosis. Candidiasis occurs less frequently but can cause uveitis (Enders et al., 2017; Linek, 2004). Inhalation is believed to be the primary route of infection for all the major systemic mycoses, with later hematogenous spread to the eye. Both unilateral and bilateral ocular disease occurs, and infections of the paranasal sinus, orbit, and optic nerve occasionally affect the eye secondarily. The diagnosis is made on the basis of concurrent clinical signs, which vary between mycotic organisms; identification of organisms in ocular or other tissue aspirates; or the results of fungal culture, histopathologic examination, or various serologic tests. The typical histologic pattern for all mycoses is granulomatous or pyogranulomatous inflammation characterized by variable numbers of neutrophils, lymphocytes, plasma cells, histiocytes, and occasionally epithelioid cells. Histopathologic identification of organisms is facilitated by special stains, such as Gomori’s methenamine-silver, periodic acid–Schiff, and mucicarmine. The preferred systemic therapy for each type of mycosis varies. Eyes that are potentially visual should be treated topically with corticosteroids and atropine if hypotensive or normotensive, but a painful, blind eye is best enucleated. Histologic evaluation of enucleated globes often facilitates diagnosis. Blastomycosis

Blastomyces dermatitidis is the causative agent of blastomycosis. The endemic distribution is primarily the Mississippi, Missouri, and Ohio River valleys, the mid-Atlantic states, Quebec, Manitoba, and Ontario in North America, but it has been identified in other countries as well. Blastomycosis has a propensity for young, male, large-breed dogs (Albert et al., 1981; Bloom et al., 1997; Buyukmihci, 1982; Buyukmihci & Moore, 1987; Hendrix et al., 2004; Legendre, 2012). Ocular disease occurs in 30%–43% of dogs with systemic blastomycosis (Arceneaux et al., 1998; Brooks et al., 1991; Legendre et al., 1981). Anterior uveitis has been reported as the most common ocular sign, though anterior segment lesions often appear secondary to posterior segment lesions (Buyukmihci & Moore, 1987; Peiffer & Wilcock, 1991). Clinically, anterior uveitis, posterior segment disease, or endophthalmitis, with all of their sequelae, is commonly seen (Fig. 21.24; also see Fig. 21.11 and Fig. 21.12). Microscopically, all tunics of the eye are usually involved. Infection appears to center in the choriocapillaris of the nontapetal choroid, with a relative sparing of the tapetal choroid. The most common findings are pyogranulomatous inflammation in the anterior and posterior segments, secondary glaucoma, and retinal detachment. Additionally, lens rupture, cataract, optic nerve inflammation, PIFMs, and periorbital cellulitis with extrascleral extension are seen (Buyukmihci & Moore, 1987; Hendrix et  al., 2004). The yeast form is often seen on cytology or histology. The yeasts are 5–20 mm in diameter and have a

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Figure 21.24  This mixed-breed dog has blastomycosis. This eye has endophthalmitis with corneal edema, corneal vascularization, conjunctival hyperemia, and chemosis. Aqueous flare was visible on examination.

Figure 21.25  Pyogranulomatous inflammation and a budding Blastomyces dermatitidis organism are present in the posterior chamber of this dog with systemic blastomycosis.

thick, refractile, double-contoured cell wall (Fig.  21.25). The ease of diagnosing blastomycosis is variable. Infection commonly involves the lungs, skin, bones, lymph nodes, brain, and testes, in addition to the eyes (Legendre, 2012). Aspirates of enlarged lymph nodes, or vitreous when posterior segment disease is present, frequently yield organisms. Cytologic examination of impression smears from draining skin lesions can also be diagnostic. Antigen detection in urine is the preferred method of diagnosis if the organism itself is not seen cytologically or cultured. The sensitivity for the detection of antigen in urine is 93.5%, and the sensitivity of antibody detection is only 17.4% by agar gel immunodiffusion (AGID) and 76.1% by enzyme-linked immunosorbent assay (ELISA; Spector et al., 2008).

Itraconazole is considered to be the treatment of choice and is clinically very effective in most dogs with blastomycosis (Legendre et al., 1996; Mazepa et al., 2011). The typical dose is 5 mg/kg orally once daily for approximately 90 days (Legendre, 2012). Urine antigen levels decrease with itraconazole treatment and should be used to monitor ­disease resolution (Spector et al., 2008). Even with systemic itraconazole and topical therapy for anterior uveitis, the prognosis for vision in affected eyes is guarded. Brooks et  al. (1991) showed that there is a positive response to treatment in 76% of dogs with posterior segment disease alone, 18% with anterior uveitis, and 13% with endophthalmitis. Many eyes that do not respond to treatment, continue to have uveitis, and develop glaucoma have Blastomyces dermatitidis organisms that appear to be thriving in the eye and/or may have lens rupture secondary to the severe inflammatory response (Hendrix et al., 2004). These findings may explain why the inflammation is intractable in many dogs. Fluconazole is less effective and requires a longer treatment time than itraconazole, but it is less expensive (Mazepa et  al., 2011). Dogs should be monitored for hepatotoxicity with both drugs. Parenteral amphotericin B is also effective, but renal toxicity is problematic with this drug (Aguirre, 1974). A combination treatment with itraconazole and amphotericin B–lipid complex has been used successfully in dogs at risk of losing vision from retinal detachment (Collins & Moore, 1999). Studies have evaluated the use of corticosteroids via different routes to augment therapy with systemic antifungals. Oral prednisone has been administered with itraconazole or fluconazole in an attempt to preserve vision. In one study, the prednisone dosage ranged from 0.2 mg/kg/day to 1.4 mg/ kg/day, and the mean duration was 3 months. The prednisone did not appear to adversely affect the survival rate. All eyes with mild or moderate lesions and half of the dogs with severely affected eyes were visual at their last recorded recheck examination (Finn et al., 2007). However, many clinicians do not advocate systemic corticosteroid treatment in dogs with mycotic infection (Collins & Moore, 1999), although topical prednisolone acetate should be used in the treatment of anterior uveitis secondary to blastomycosis. Topical atropine should be used in eyes without evidence of secondary glaucoma to increase comfort and decrease synechia formation. If IOP is elevated, dorzolamide and timolol should be used in conjunction with steroids. Coccidioidomycosis

Coccidioidomycosis, caused by Coccidioides immitis, is endemic to the Lower Sonoran life zone, which includes the southwestern United States, Mexico, and areas of Central and South America (R.T. Greene, 2012). Ocular changes include keratitis, granulomatous panuveitis, endophthalmitis, chorioretinitis with retinal detachment, and orbital cel-

lulitis (Angell et  al., 1987). In one study 80% of dogs had uniocular lesions, and 43% of dogs demonstrated ocular disease alone (Angell et  al., 1987). Similar to blastomycosis, anterior segment lesions are thought to be an extension of posterior segment disease. Several tests are available for use in making a serologic diagnosis (R.T. Greene, 2012). The tube precipitin test measures immunoglobulin (Ig) M antibody levels; IgM both appears and disappears early in the course of disease. The complement fixation test measures IgG antibody, which persists longer. The complement fixation titer is indicative of the severity of infection: a titer of 1 : 64 or greater is indicative of disseminated disease. It is possible to have one test be positive and the other negative depending on the stage of infection; thus, the two tests should be performed in parallel. Latex agglutination, AGID, and ELISA are now also employed by some laboratories (R.T. Greene, 2012). Cytology and biopsy are often diagnostic as well. Oral ketoconazole, fluconazole, and itraconazole are all commonly used in the treatment of coccidioidomycosis (Angell et al., 1987; R.T. Greene, 2012). Cryptococcosis

Cryptococcosis is typically caused by Cryptococcus neoformans or Cryptococcus gattii. C. neoformans commonly causes CNS, ocular, respiratory, and cutaneous signs. Fever, lymphadenomegaly, and lameness secondary to lytic bone lesions occur less frequently. CNS signs usually relate to meningoencephalitis and often include head tilt, nystagmus, facial paralysis, ataxia, mild paresis to complete paralysis, depressed reflexes, circling, and seizures (Berthelin et  al., 1994a; Sykes & Malik, 2012). Ocular signs include optic neuritis, granulomatous chorioretinitis, exudative retinal detachment, anterior uveitis, and occasionally orbital abscess, cellulitis, or exophthalmos (Carlton, 1983; Carlton et al., 1976; Sykes & Malik, 2012; Trivedi et al., 2011; Wolfer et al., 1996). Anterior uveitis, though reported, is rare with cryptococcosis. As with other mycoses, even when anterior uveitis is present, organisms are rarely demonstrated in the anterior uvea. Posterior segment disease is the most common ocular manifestation, and funduscopic examination often reveals chorioretinitis characterized by single or multiple raised, gray, yellow, or white exudative lesions and retinal detachment. Rarely, anterior uveitis and retinal detachment occur without the presence of granulomas. The eye is involved secondary to hematogenous spread or extension from the brain along the optic nerve (Sykes & Malik, 2012). One report describes uveitis caused by C. gattii in a systemically affected dog (Gerontiti et al., 2017). Cryptococcosis is diagnosed on the basis of clinical signs, identification or culture of the organism in ocular or other tissue aspirates including CSF, results of histopathologic examination, and results of serologic testing (Berthelin et al., 1994b; Sykes & Malik, 2012). The organisms are round to

oval with a variably sized capsule and reproduce by budding. Because the daughter cells separate from the parent at varying sizes, the organisms vary in size. The latex cryptococcal agglutination test is considered to be the most reliable serologic test, because it can detect the presence of cryptococcal antigen in body fluids, including serum, urine, CSF, aqueous humor, and vitreous. The magnitude of antigen titers tends to correlate with severity of disease and response to therapy (Berthelin et  al., 1994b; Fujita et  al., 1983; Sykes & Malik, 2012). Molecular genotyping is used to differentiate C. neoformans and C. gattii. The prognosis for dogs with cryptococcosis is generally poor because of the severity of meningoencephalitis, the difficulty of reaching organisms within large lesions, possible decreased immunity, and poor penetration of most antifungal drugs into the CNS. Variable responses have been obtained with systemic therapy with itraconazole, amphotericin B, flucytosine, ketoconazole, and fluconazole, either singly or in various combinations (Berthelin et  al., 1994b; Sykes & Malik, 2012). One dog recovered without medical treatment after enucleation, suggesting localized disease (Berthelin et al., 1994b). Histoplasmosis

Histoplasma capsulatum is widely distributed in soil in temperate and subtropical regions. In the United States, major endemic areas are associated with the Ohio, Missouri, and Mississippi rivers, but histoplasmosis has been identified in most states (Brömel & Greene, 2012). In the dog, clinical signs of disseminated histoplasmosis are most often referable to the gastrointestinal tract or liver. Reports of ocular involvement are relatively rare, but usually include chorioretinitis, conjunctivitis, blepharitis, retinal detachment, and optic neuritis (Brömel & Greene, 2012; Gwin, 1980). In experimentally infected dogs, peripheral granulomatous choroiditis was the most common finding (5 of 17 dogs; Salfelder et al., 1965). Diagnosis is via cytology, histopathology, or urine antigen enzyme immunoassay (Cunningham et al., 2015). The organisms in tissue are relatively small at 2–4 μm in diameter and are often located within cells of the mononuclear phagocyte system. Aspergillosis

Systemic aspergillosis occurs less frequently than the preceding systemic mycoses. Dogs often have concurrent systemic signs, such as renal or neurologic disease, or they might present with only ocular signs. Ocular signs include panuveitis, retinal detachment, and secondary glaucoma. Microscopically, clinical signs are those of uveitis and its manifestations. However, Aspergillus sp. might have a propensity to invade the lens, as several reports describe lens capsule rupture with numerous hyphae within the lens (Gelatt et al., 1991; Wooff et  al., 2018). Unlike other fungal infections described here, Aspergillus exists in hyphal form in tissue.

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Parasitic Diseases

SECTION IIIB

Ocular Nematodiasis

Intraocular nematodiasis is reported infrequently in domestic animals. Ocular nematodiasis includes two distinct conditions: ocular filariasis and ocular larva migrans (OLM). Ocular filariasis due to aberrant migration of immature Dirofilaria immitis occurs in dogs and humans. The condition occurs in dogs with and without concurrent microfilaremia. Uveitis and mild to severe corneal opacity are the predominant signs. Uveitis is commonly attributed to direct mechanical trauma or reaction to metabolic waste products of the parasite. In one case, it was speculated that antigen– antibody complex formation was an additional factor in uveitis when severe corneal scarring and pigmentation occurred after removal of the parasite (Bellhorn, 1973). Typically, one 5–10 cm filaria is seen undulating in the anterior chamber; migration between the anterior and posterior chambers and vitreous occurs. Light stimulation tends to increase the motility of the filaria and, subsequently, the discomfort to the patient. The prognosis is favorable with anti-inflammatory therapy and manual removal of the filaria (Carastro et al., 1992). Delay in surgical removal increases the likelihood of posterior segment migration, and with continued inflammation enucleation might be required (Miller & Cooper, 1987). Presurgical adulticide therapy is not advised, as the severe inflammatory reaction to the dead filaria leads to intractable uveitis. Microfilaricide administration caused increased activity of the filaria and transient exacerbation of clinical signs in one case (Lovers, 1968). Angiostrongylus vasorum is a metastrongylid nematode that infects the pulmonary artery and right ventricle. Adult nematodes reach the eye via aberrant migration. Clinical signs range from iris hyperemia to uveitis and hyphema. Diagnosis is suspected when an adult motile nematode approximately 10 mm in length is seen in the anterior chamber. The parasite can be removed via anterior chamber paracentesis or surgery, followed by appropriate systemic anthelmintic therapy. This parasite is primarily diagnosed in Europe (Colella et  al., 2016; King et al., 1994; Rosenlund et al., 1991). OLM generally refers to aberrant ocular migration of Toxocara spp.; Toxocara canis is suspected to be the most commonly involved (Hughes et al., 1987; Rubin & Saunders, 1965). T. canis is of public health significance because the nematode causes OLM and visceral larval migrans (VLM) in children. In dogs and humans, OLM resulting from Toxocara spp. is characterized by inflammation, primarily of the retina and vitreous. Ophthalmoscopy reveals areas of hyperreflectivity, hyperpigmentation, and vascular attenuation. Uveal involvement is rare and was seen microscopically in only one study (Hughes et al., 1987). Infection with Onchocerca lupi most commonly causes subconjunctival pea- to bean-sized masses beneath the bulbar conjunctiva (McLean et  al., 2017; Orihel et  al., 1991;

Sreter et  al., 2002; Szell et  al., 2001). Other signs include exophthalmos, conjunctival congestion, protrusion of nictitating membrane, uveitis, retinal detachment secondary to globe compression, and localized corneal edema and vascularization (Komnenou et  al., 2003; McLean et  al., 2017; Zarfoss et al., 2005). While intraocular infection is rare, an adult worm was seen and surgically removed from an eye that had concurrent uveitis (Komnenou et  al., 2016). Microscopically, a pyogranulomatous or granulomatous reaction with eosinophils is associated with the adult worms. Lymphoplasmacytic uveitis, PIFMs, and evidence of secondary glaucoma are also seen (Zarfoss et al., 2005). Microfilariae are present in the uteri of females and in the surrounding tissues and can be isolated from skin biopsy specimens (Eberhard et al., 2000; Szell et al., 2001). The granulomas can be excised when they are easily accessible, followed by medical therapy including a filaricide. Some cases resolve with medical therapy alone, and medical therapy is indicated when lesions are not easily accessible or an identifiable ­granuloma is not visible. Treatment regimens include combinations of a filaricide agent (melarsomine), ivermectin, prednisone, and doxycycline (Komnenou et  al., 2003, McLean et al., 2017). Ophthalmomyiasis

Ophthalmomyiasis refers to aberrant ocular migration of fly larvae of the order Diptera. Some reported include Cuterebra sp., the sheep nasal botfly (Oestrus ovis), and the cattle warble (Hypoderma bovis; Edelmann et  al., 2014; Gwin et  al., 1984). Both intraocular and extraocular disease occur in domestic animals, but the intraocular disease ophthalmomyiasis interna posterior (OIP) has been reported most often in dogs, cats, and humans. As the name implies, OIP is primarily a disease of the posterior segment. The characteristic lesion has active or inactive roadmap-like subretinal tracts. Active disease is associated with uveitis, retinal detachment, and hemorrhage. Larvae have been identified in the anterior segment with concurrent uveitis. Increased numbers of migratory tracts in the retina appear daily in active infections (Gwin et al., 1984). Visible larva can be removed surgically via a keratotomy and larval extraction (Edelmann et al., 2014). Inactive infections require no therapy, whereas antiinflammatory therapy is indicated in active disease. Organophosphates can be administered in an attempt to kill the larva, but a dead larva might exacerbate inflammation. The larvae also spontaneously depart from the globe.

Protozoal Diseases Leishmaniosis

The flagellate organism Leishmania infantum is the most common cause of visceral leishmaniosis. The disease is endemic along the Mediterranean shore and in parts of East Africa, India, and Central and South America, and it is

endemic in the United States in hunting dogs (Boggiatto et al., 2011; Pena et al., 2000; Vida et al., 2016). Domestic and wild members of Canidae serve as reservoir hosts, and the intermediate host is the sandfly (Phlebotomus spp.). In the United States and Canada, vertical transmission is the predominant means of transmission between dogs (Vida et al., 2016). Ocular findings are present in the majority of dogs and include blepharitis, keratoconjunctivitis, uveitis, retinitis, and endophthalmitis (Ciaramella et al., 1997; Koutinas et al., 1999; Pena et  al., 2000). Ocular disease is the only clinical sign in some dogs. The anterior segment is usually more severely involved than the posterior segment. Anterior uveitis developing during or after antiprotozoal therapy is attributed to treatment itself, an allergic response to death of the organisms, or to recurrence of disease (Di Pietro et al., 2016). Additional signs include lymphadenopathy, splenomegaly, hepatomegaly, renal failure, anemia, thrombocytopenia, and varying dermatologic conditions (Ciaramella et  al., 1997; Koutinas et al., 1999). Microscopically, vasculitis and intense granulomatous inflammatory zones are seen in the conjunctiva, fibrous tunic, uvea, optic nerve sheath, lacrimal duct, and both smooth and striated ocular muscles (Garcia-Alonso et  al., 1996; Naranjo et al., 2010; Pena et al., 2008). The parasite has been found using immunohistochemical stains in 27% of affected eyes (Pena et al., 2008). Treatment usually consists of pentavalent antimonials and/or allopurinol. However, complete elimination of the organisms is rare, the clinical response to therapy is variable, and relapses are common (Baneth & Solano-Gallego, 2012; Pena et al., 2000). Encephalitozoon cuniculi

Encephalitozoon cuniculi is an obligate intracellular, sporeforming, microsporidial parasite that has been associated with cataracts in rabbits, cats, dogs, and other mammals (Benz et al., 2011; Nell et al., 2015; Wolfer et al., 1993). Three young dogs had anterior uveitis, chorioretinitis, and focal posterior synechia with associated focal anterior cortical cataracts. All dogs had positive serum antibody titers for E. cuniculi. Two dogs maintained vision after undergoing phacoemulsification. Polymerase chain reaction on the lens material was positive for E. cuniculi strains II and IV. Evidence of microsporidia was seen via immunohistochemistry of the anterior lens capsule in one dog. All dogs were treated long term with topical and systemic steroids or other topical anti-inflammatory drugs and fenbendazole (Nell et al., 2015). Toxoplasmosis

Toxoplasma gondii is a protozoan-obligate intracellular parasite that affects most warm-blooded animals. The cat is considered the only definitive host and is therefore integral to transmission of the disease. Dogs are infected by ingesting

sporulated oocysts from cat excreta, ingesting tissue cysts in infected meats, or ingesting a transport host. Infection is usually subclinical (Bussanich & Rootman, 1985; Dubey, 1987), but neuromuscular, respiratory, gastrointestinal, or ocular signs do occur. Ocular toxoplasmosis has been reported infrequently in dogs; when it is present, anterior uveitis, retinochoroiditis, and vitritis are seen (Bussanich & Rootman, 1985; Dubey, 1987; Piper et al., 1970; Wolfer & Grahn, 1996). Additional findings include optic neuritis and extraocular myositis. Even if signs of anterior uveitis are not seen clinically, microscopically inflammation of the iris can be seen (de Abreu et al., 2002). Diagnosis of ocular toxoplasmosis is based on clinical signs, serologic testing, and histopathologic examination. Serologic evaluation is beneficial, but does not always correlate with clinical disease, as some subclinically affected dogs may have high antibody titers. A test that distinguishes IgM and IgG antibodies is necessary, and convalescent titers should be run (Dubey, 1987). Granulomatous or nongranulomatous inflammation is possible. Clindamycin is the drug of choice for treating toxoplasmosis (Dubey & Lappin, 2012). Other Protozoal Diseases

Neospora caninum was diagnosed in four litters of puppies from one owner. The most common clinical sign was hindlimb paralysis. Some had generalized encephalomyelitis. Histopathology showed tachyzoites and tissue cysts in the brain and spinal cord. Lesions in the eyes included retinitis, choroiditis, nonspecific iridocyclitis, and myositis of the extraocular muscles (Dubey et al., 1990). Trypanosoma evansi causes corneal opacities, conjunctivitis, and anterior uveitis in dogs. Therapy with subconjunctival steroids and intramuscular diminazene aceturate leads to corneal clearing and restoration of vision (Varshney et al., 2003). Parasitemia in peripheral blood smears and aqueous fluid confirms the infection.

Rickettsial Diseases Ehrlichiosis

Ehrlichia canis is an obligate intracellular parasite transmitted by the brown dog tick, Rhipicephalus sanguineus. Pronounced clinical and laboratory abnormalities often occur with E. canis infections (canine monocytic ehrlichiosis) and include fever, lymphadenopathy, anemia, leukopenia, thrombocytopenia, monoclonal or polyclonal gammopathy, neurologic signs, and generalized bleeding tendencies (Stiles, 2000). Ocular signs are common, and dogs can have ocular signs with no other apparent clinical signs. Ocular signs are most commonly bilateral and occur in both the acute and chronic forms of E. canis infections. Anterior uveitis and exudative retinal detachment are reported to be the most common

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ophthalmic signs. Other signs include conjunctivitis, conjunctival or iridal petechiations, corneal opacity, corneal ulceration, necrotic scleritis, low tear production, orbital cellulitis, panuveitis often with hyphema, diffuse retinitis or vasculitis, retinal hemorrhage, papilledema, and optic neuritis (Bayon et al., 1999; Harrus et al., 1998; Komnenou et al., 2007; Leiva et al., 2005; Oria et al., 2004; Stiles, 2000). The ocular hemorrhage associated with ehrlichiosis is thought to be related to thrombocytopenia, platelet dysfunction, and/or hyperviscosity (Harrus et al., 1998). Experimentally, ocular signs consist of papilledema, perivascular retinal infiltrates, retinitis, and anterior uveitis. The ocular signs are evident 3 weeks after the onset of fever. The most consistent microscopic finding is a predominantly monocytic cellular infiltrate of the ciliary body and, to a lesser extent, the iris, choroid, retina, and optic nerve (Panciera et al., 2001; Swanson & Dubielzig, 1986). Diagnosis is made on the basis of clinical signs, hematologic abnormalities, and serologic testing. Multiple intracytoplasmic subunits of E. canis (i.e., morulae) occur within monocytes. Serologic diagnosis is by immunofluorescent antibody (IFA) testing. Doxycycline and several other antibiotics are commonly used for systemic therapy (Harrus et al., 2012; Stiles, 2000).

Rocky Mountain Spotted Fever Rocky Mountain spotted fever (RMSF) is an acute infectious disease caused by Rickettsia rickettsii and transmitted by ticks of the Dermacentor spp. Vasculitis is the primary lesion, caused initially by direct infection of the vascular endothelium and perithelial smooth muscle, and later by immunologic phenomena. It is postulated that an Arthus-type reaction may be involved (Davidson et  al., 1989; Keenan et  al., 1977). Common clinical signs include fever, neurologic dysfunction, polyarthritis, thrombocytopenia, nonregenerative anemia, and ocular disease. Ocular lesions are common in dogs with serologically confirmed RMSF. Anterior segment findings include subconjunctival hemorrhage, iris stromal petechiations, anterior uveitis, and hyphema. Posterior segment findings include retinitis characterized by perivasculitis, focal areas of edema, and petechiation. Because ocular disease is often confined to the retina, ophthalmoscopy should always be done when RMSF is suspected. Generally, ophthalmic lesions are mild with RMSF (Davidson et al., 1989). The histologic appearance of RMSF is different from ehrlichiosis in that the most prominent lesion is necrotizing vasculitis, with perivascular accumulations of polymorphonuclear and lymphoreticular cells (Davidson et  al., 1989; Keenan et al., 1977). Confirmation of the diagnosis of RMSF is made by a demonstration of rising serum IFA titers; therefore, a single titer is nondiagnostic (Greene et  al., 1985). Doxycycline, tetracycline, chloramphenicol, enrofloxacin, and trovafloxa-

cin are all effective systemic therapies (Breitschwerdt et  al., 1991, 1999; Stiles, 2000). Anaplasma platys infection rarely causes anterior uveitis (Glaze & Gaunt, 1986; Harvey et  al., 1978).

Viral Diseases Infectious Canine Hepatitis

Infectious canine hepatitis (ICH) is caused by the canine adenovirus-1 (CAV-1). Natural infection is most common in unvaccinated dogs less than 1 year of age, in which the disease can be fatal. The virus replicates in reticuloendothelial, hepatic parenchymal, and vascular endothelial cells (Aguirre et al., 1975). Clinical findings include fever, vomiting, diarrhea, abdominal tenderness, hepatitis or hepatic necrosis, hemorrhagic diathesis, tonsillar enlargement, pneumonia, glomerulonephritis, and CNS and ocular disease (C.E. Greene, 2012). Nongranulomatous anterior uveitis and secondary corneal edema (so-called blue eye) are reported in approximately 20% of dogs recovering from natural ICH. This keratouveitis may be the only abnormality in otherwise subclinically affected dogs. Persistent corneal edema, secondary glaucoma, and phthisis bulbi are possible sequelae of severe keratouveitis. The pathogenesis of ICH keratouveitis is related primarily to immune-complex deposition or to an Arthustype reaction (Aguirre et  al., 1975; Carmichael, 1965; Carmichael et al., 1975; Curtis & Barnett, 1981). Keratouveitis occurs as a postvaccinal reaction in approximately 0.4% of dogs that receive the CAV-1 vaccine. An increased susceptibility of the Afghan hound to postvaccinal keratouveitis has been suggested (Curtis & Barnett, 1981). The CAV-2 vaccine is thought to cause ocular disease only when experimentally injected into the anterior chamber (C.E. Greene, 2012). However, anecdotal accounts exist of rare keratouveitis following subcutaneous administration of CAV-2 vaccines. Therapy for dogs suffering from systemic disease with ICH is primarily supportive. Anti-inflammatory therapy of keratouveitis in dogs recovering from natural ICH infection or suffering postvaccinal reaction is debatable, since some consider the keratouveitis self-limiting. Corticosteroid therapy may be contraindicated and has been implicated in the ­prolongation of corneal lesions and even blindness in dogs suffering postvaccinal reactions (Carmichael, 1965). However, the potential for severe sequelae without therapy may be sufficient justification to treat affected eyes.

Bacterial Disease Brucella canis is an aerobic, gram-negative coccobacillus that survives in mononuclear cells. Infection is by penetration of the organisms through mucous membranes of the oropharynx, genital tract, and conjunctiva. The ­concentration

of the organism is highest in semen and vaginal discharge in infected dogs (Dziezyc, 2000). Abortion and infertility are common clinical signs that occur in breeding dogs, but neutered dogs are also affected (Greene & Carmichael, 2012; Ledbetter et  al., 2009). Ocular signs occur in -14% of dogs with brucellosis. The more common ocular findings include endophthalmitis, chronic uveitis, hyphema, and chorioretinitis (Ledbetter et al., 2009; Vinayak et al., 2004). Other signs include diskospondylitis, glomerulopathy, and meningoencephalitis, but overt systemic disease does not always occur. Diagnosis is made using the slide agglutination test in combination with AGID or by positive culture. Antimicrobial therapy is complicated and must be continued long term because of the intracellular nature of the organism (Ledbetter et al., 2009). Due to the zoonotic potential of brucellosis and the difficulty in eradicating the organism, euthanasia may be elected. Bartonella vinsonii subsp. berkhoffii is one subspecies of a group of intraerythrocytic bacteria most likely transmitted by the brown dog tick, Rhipicephalus sanguineus. Clinical signs in dogs infected with this organism include lethargy, weight loss, muscle and joint pain, hindlimb paresis, endocarditis, myocarditis, lymphadenitis, and fever (Breitschwerdt & Chomel, 2012; Breitschwerdt et  al., 2004). Various other neurologic and dermatologic signs also occur. Ophthalmic signs include anterior uveitis, chorioretinitis, hyphema, and retinal detachment (Breitschwerdt et al., 2004; Michau et al., 2003). Diagnosis is based on serologic testing. Multiple antibiotics have been used for treatment. Leptospirosis is caused by a spirochete, a filamentous bacterium, belonging to the genus Leptospira, which includes many species and serovars. Leptospira organisms are most commonly transmitted through urine. Vasculitis and endotheliitis involving the kidneys, liver, spleen, muscles, CNS, and eyes occur. Anterior uveitis is infrequently seen (Dziezyc, 2000; Gallagher, 2011; Lajeunesse & DiFruscia, 1999; Thirunavukkarasu et al., 1995). Leptospira organisms have been cultured from the aqueous humor (Greenlee et al., 2004).

Algal Disease Prototheca zopfii and Prototheca wickerhamii are achlorophyllic algae that are pathogenic in dogs and other animals. The primary clinical sign is usually hemorrhagic diarrhea; however, dogs often present with blindness or uveitis and chorioretinitis as the initial signs (Schultze et  al., 1998; Stenner et al., 2007). Ocular signs are common and include anterior uveitis, hyphema, secondary glaucoma, chorioretinitis, and retinal detachment (Fig.  21.26). Neurologic signs rarely occur (Hosaka & Hosaka, 2004). Cytology or culture of vitreal or subretinal aspirates or CSF with appropriate clinical signs is often diagnostic (Fig. 21.27). Prototheca sp. are extracellular, round to oval single-celled 2–20 μm encapsulated

Figure 21.26  This dog has protothecosis. Iridal thickening and dyscoria suggestive of posterior synechia along with aqueous flare and hyphema were the primary findings of panophthalmitis. Other signs were corneal vascularization, conjunctival hyperemia, chemosis, and ocular discharge.

Figure 21.27  Multiple Prototheca sp. organisms are present in this vitreal aspirate.

organisms that contain sporangia with variable numbers of sporangiospores. Microscopically the most common findings are granulomatous chorioretinitis with retinal detachment and variable numbers of organisms within the inflammatory infiltrate. Signs associated with uveitis are also seen (Shank et  al., 2015). Therapy with antifungal drugs has been attempted, but long-term survival is exceedingly rare.

Miscellaneous Hyperlipidemia Dogs with hyperlipidemia resulting from elevations in either cholesterol or triglycerides can have associated ocular abnormalities. Lipid-laden aqueous humor was discussed briefly under “Uveal Inflammation,” as it occasionally occurs with anterior uveitis (see Fig.  21.16). Dogs’ lipoproteins range

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from 50 to 350 Å in diameter (Olin et al., 1976). However, the iridal vascular endothelium and nonpigmented ciliary body epithelium normally prevent particles greater than 40 Å from entering the aqueous humor. Breakdown of the blood– aqueous barrier (i.e., anterior uveitis) concurrent with hyperlipidemia results in lipid-laden aqueous. Lipoid aqueous can occur in dogs with known uveitis, especially diabetic dogs following cataract surgery. However, it is seen in dogs without a history of ocular disease, suggesting that the lipids may also incite leakage of the blood–aqueous barrier. Additional ocular manifestations of hyperlipidemia include lipid engorgement of retinal vessels and infiltration of the perilimbal cornea, conditions referred to as lipemia retinalis and corneal lipidosis (or arcus lipoides corneae), respectively (Crispin, 2016). Lipid-laden aqueous and lipemia retinalis are likely to resolve with resolution of the primary disorder. However, if anterior uveitis is the inciting cause, treating with topical anti-inflammatory drugs is indicated to help restore the blood–aqueous barrier.

Pigmentary and Cystic Glaucoma Uveal cysts are generally considered benign; however, cysts associated with glaucoma occur in Golden Retrievers, Great Danes, and American Bulldogs. The syndrome that occurs in Golden Retrievers in the United States is referred to as both pigmentary uveitis, and pigmentary and cystic glaucoma (PCG; Esson et al., 2009; Sapienza et al., 2000; Townsend & Gornik, 2013). Pigment dispersion on the anterior lens capsule in a radial orientation is the most frequently observed early clinical sign (Fig.  21.28). Other clinical signs include thin-walled iridociliary cysts, spiderweb-like fibrinous debris in the anterior chamber, cataracts, and posterior synechia (Fig. 21.29). Secondary glaucoma occurs in the majority of eyes, and this disease is usually bilateral.

Figure 21.28  Multifocal areas of pigment in the classic radial pattern are present on the anterior capsule of this Golden Retriever with breed-related pigmentary and cystic glaucoma. An area of posterior synechia is also present.

The disease progresses from thin-walled iridociliary uveal cysts as the only finding to radial pigment on the anterior lens capsule and finally glaucoma. In one study 62% of dogs made this transition within one year (Holly et al., 2016). The cysts might not be visible on every exam in the same dog, but this could result from variations in degree of mydriasis or in morphologic changes in the cysts. In eyes evaluated that had only a single cyst, the cyst was located nasally and rarely extended past the pupil margin. When multiple cysts are present, they are always located nasally, with extension dorsally or ventrally (Townsend & Gornik, 2013). Generally, the thin-walled cysts are seen in dogs 4–6 years of age, with the PCG developing several years later (Holly et  al., 2016; Townsend et al., 2013). Pedigree analysis is most consistent with an autosomal-dominant mode of inheritance with reduced penetrance (Holly et  al., 2016). When seen alone, the thicker-walled uveal cysts that are usually free within the anterior chamber are not necessarily associated with the development of PCG. One histologic study evaluating eyes enucleated because of glaucoma reported that all eyes had thin-walled iridociliary cysts (Esson et al., 2009). The cysts are lined with attenuated cuboidal epithelium and fill most of the posterior chamber, stretch across the anterior face of the vitreous, or attach to the lens capsule. Many cysts contain an Alcian blue–positive material, indicating that these cysts contain hyaluronic acid. Iris bombé, PIFMs, trichromepositive collagen deposition on the lens capsule, mild uveitis, peripheral anterior synechiae, posterior synechiae, and free pigment within the trabecular meshwork are also seen in some cases (Deehr & Dubielzig, 1998; Esson et al., 2009). Clinically, many dogs have mild visible turbidity (aqueous flare); however, microscopically, only about half of the eyes have evidence of very mild uveitis (Esson et al., 2009). The clinical appearance of aqueous turbidity in many cases is likely the result of protein and cellular material in the aqueous due to escape of cyst contents. Iridociliary epithelial

Figure 21.29  This Golden Retriever had multiple iris cysts caudal to the iris and one anterior to the iris, which is part of the breed-related pigmentary and cystic glaucoma syndrome.

21: Diseases and Surgery of the Canine Anterior Uvea

Solid Intraocular Xanthogranuloma in Miniature Schnauzer Dogs Solid intraocular xanthogranulomas were identified in four globes from three older Miniature Schnauzers that all had a history of diabetes mellitus, hyperlipidemia, and bilaterally severe uveitis, with glaucoma that was believed to be lens induced. Grossly, all globes are filled with a heterogenous

tan mass. Microscopically, intraocular contents are effaced by solid sheets of foamy macrophages admixed with hemorrhage, necrosis, and Alcian blue–positive refractile crystalline material in stellate patterns. Additionally, episcleral atherosclerosis is present, as evidenced by foamy macrophages within vessel walls (Zarfoss & Dubielzig, 2007).

Hyperviscosity Syndrome Monoclonal gammopathy associated with lymphoproliferative disorders can result in hyperviscosity syndrome (HVS). HVS causes clinical signs referable to multiple organ systems, including the cardiac, renal, hemostatic, ocular, and central nervous systems (Kirschner et al., 1988; Lane et al., 1993). In the dog, HVS is associated with increased serum concentrations of IgG, IgM, and IgA (Center & Smith, 1982; Hendrix et al., 1998; Kirschner et al., 1988; MacEwen et al., 1977). HVS secondary to polycythemia vera has also been reported (Gray et  al., 2003). Ocular anterior segment findings include conjunctival hyperemia, corneal edema, hyphema, and secondary glaucoma, all of which are likely related to concurrent anterior uveitis. However, ocular findings are most often referable to the posterior segment and include retinal vascular dilation, tortuosity, microaneurysms, retinal hemorrhage, retinal detachment, chorioretinitis, and papilledema.

Sulfonamide Hypersensitivity Dogs with sulfonamide hypersensitivity often have multiple clinical abnormalities (Giger et  al., 1985; Trepanier, 2004; Trepanier et  al., 2003). Signs might include fever, arthropathy, blood dyscrasias, glomerulonephropathy, hepatopathy, skin eruption, uveitis, retinitis, and keratoconjunctivitis sicca.

Uveal Trauma Ocular trauma often results in clinical signs that vary from mild miosis to disruption of the cornea or sclera. Often, blunt trauma manifests with flare, fibrin or hyphema, corneal edema, or iridodialysis, but rarely hypopyon. With sharp trauma or extremely severe blunt trauma, fibrin, hemorrhage, uveal prolapse, and perforation of the cornea or sclera can occur. Uveal prolapse occurs with globe rupture because the sudden decompression of the anterior chamber with aqueous outflow forces the iris into the wound, plugging it (Dalma-Weiszhausz & Dalma, 2002). Intraocular hemorrhage exhibits as hyphema, iridal stromal hemorrhage, or hemorrhage around the equator of the lens or in the vitreous. In all cases of trauma, careful examination with necessary additional diagnostics should be done to determine the extent of ocular and periocular damage.

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cysts might not be clinically evident in dogs with microscopic evidence of cyst formation (Sapienza et al., 2000). The mechanism of glaucoma secondary to iridociliary cysts appears to be multifactorial and could include mechanical angle closure by the cysts, plateau iris syndrome, heavy deposition of pigment in the filtration angle, secondary pigment dispersion syndrome, pupillary block, release of cyst contents, and inflammatory cellular infiltration blocking aqueous outflow (Deehr & Dubielzig, 1998; Lois et al., 1998). Progressive posterior synechia is common, leading to iris bombé. In humans, mucogenic glaucoma has been described in which mucus from cysts or an inflammatory reaction to mucus has obstructed the trabecular meshwork (Werblin et al., 1983). Ophthalmic NSAIDS, corticosteroids, and glaucoma medications are often used in affected dogs, but therapy does not prevent disease progression. A syndrome similar to PCG of Golden Retrievers occurs in Great Danes. Consistent findings in Great Danes include ciliary body cysts, multiple cysts in the anterior and posterior chambers, and glaucoma. The cysts are variable in size, very poorly pigmented, and usually translucent. Often the entire posterior chamber is filled with cysts that push the iris forward. Microscopically, stacked cysts are seen in the area of the pars plicata and between the iris and ciliary body. The cysts originate from the ciliary body epithelium and are composed of a layer of epithelial cells that contain few melanin granules and are irregularly periodic acid–Schiffpositive. Commonly, a PIFM covers the drainage angle and the anterior surface of the iris. The mechanism of glaucoma is thought to be anterior displacement of the iris with narrowing of the angle and a possible contribution by PIFMs. Evidence suggests that both glaucoma and ciliary body cysts are inherited in the Great Dane (Spiess et al., 1998). One report describes a series of American Bulldogs that had multiple cysts in the anterior chamber and iridociliary sulcus as well as glaucoma. Clinically and microscopically the dogs had cysts, PIFMs, narrow or closed iridocorneal angles with possible pectinate ligament dysplasia, and a perivascular mononuclear infiltrate in the iris and sclera. Any association between the cysts and the iridocorneal angle abnormalities was not clear. The Bulldogs do not have the radial pigment dispersion on the anterior lens capsule, cataracts, or fibrinous debris in the anterior chamber that is often present in Golden Retrievers, as already described (Pumphrey et al., 2013).

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If the cornea is intact and the media sufficiently clear to permit examination of intraocular structures, the integrity of the iris, lens, vitreous, and retina can be determined by direct visualization of these structures. However, miosis, fibrin, or hyphema often precludes a thorough examination. In the case of globe rupture, uveal prolapse might be evident on examination if the rupture occurred in the cornea or anterior sclera, but a posteriorly located rupture is usually not evident. When ocular changes preclude a detailed direct examination, ultrasonographic imaging is an invaluable tool for assessing the extent of intraocular damage.

Emergency Management of Acute Ocular Trauma Cases of acute ocular trauma must be handled on an emergency basis. When a dog is presented with ocular trauma, the dog should be restrained or sedated as needed to facilitate an ocular examination. Care must be used to prevent further trauma. If debris, exudates, or hemorrhage are present, they should be gently irrigated from the ocular surface with warm, physiologic saline solution (without preservative). If possible, the clinician should determine whether a laceration or rupture of the globe is present. Assessment of the extent of globe laceration or rupture is not always easy, but it is important as a prognostic indicator. Note that corneal lacerations frequently extend across the limbus under an intact but often hemorrhagic conjunctiva. If the globe is ruptured, further examination to assess the degree of rupture and foreign body examination should be delayed until the animal has been anesthetized. However, the appearance of intraocular contents (e.g., lens material or vitreous) within the wound or on the ocular surface is usually seen with minimal effort. It must be determined whether surgical repair is feasible or if enucleation or implantation of an intraocular prosthesis should be advised. This determination is made on the basis of the extent of intraocular damage, the likelihood of preserving vision, and cosmetic concerns. Systemic antibiotics should also be administered if the globe is ruptured. If the globe appears to be intact, topical anesthetic solution should be applied, and the ocular surfaces, including the conjunctival fornices and both sides of the nictitating membrane, should be inspected for foreign bodies.

Ancillary Diagnostic Procedures Additional diagnostics are often required after the ocular exam to acquire more information. Radiography of the skull, including oblique views of the orbit or orbits, will confirm or rule out the presence of fractures and establish whether gunshot injury is involved. Brightness scan (B-scan) ultrasonography is specifically indicated when the normally transparent ocular media are opaque. Integrity of the lens and posterior sclera as well as the position of the lens and

retina can generally be determined with B-scan ultrasonography. In traumatized eyes, echo-dense areas in the vitreous cavity usually indicate vitreal hemorrhage. Computed tomography (CT) and magnetic resonance imaging (MRI) are beneficial in assessing trauma, especially when intraocular foreign bodies (IOFBs) are suspected. Care should be taken with MRI, because metallic foreign bodies can incite additional damage.

Treatment of Blunt Injuries Intense pressure exerted on the globe during blunt trauma results in vector forces reflecting off the posterior sclera and transferring anteriorly, causing a blowout rupture of the perilimbal cornea or anterior sclera. Some causes of blunt injuries are impacts by golf balls and baseball bats; commonly, the owner is not aware that the dog is in such close proximity when the accident occurs. Acute traumatic uveitis or hyphema from blunt injury is treated similarly to other causes of anterior uveitis and hyphema (see “Uveal Inflammation” and “Hyphema”). A ruptured globe resulting from blunt trauma is handled similarly to cases of penetrating corneal trauma with uveal prolapse (see Chapter  19). When globe rupture has occurred secondary to forceful trauma, retinal detachment with vitreal hemorrhage is a common complicating factor. Iris bombé, traumatic cataract, endophthalmitis, and phthisis bulbi can follow. Therefore, the prognosis following severe blunt trauma to an eye is guarded to grave.

Treatment of Penetrating Injuries Focal punctures of the globe usually cause minimal damage to the cornea and often seal spontaneously. If the eye is examined within a few hours of the injury, it can be difficult to determine whether the cornea is completely penetrated or the extent of intraocular damage. Penetrating corneal injuries that seal spontaneously are treated with topical and systemic antibiotics and topical NSAIDs. Topical corticosteroids are usually not applied until the corneal epithelium has healed, unless the uveitis is severe. Systemic antibiotics are administered for a minimum of 10 days. In the absence of an IOFB, the primary concerns after such injuries are focal anterior or posterior synechiae, lens puncture with phacoclastic uveitis or septic implantation syndrome, traumatic cataract, secondary glaucoma, and infectious endophthalmitis. Most penetrating injuries of the globe result in uveal prolapse, which appears as a protrusion of darkly pigmented tissue through the cornea or sclera. A grayish, fibrinous membrane typically covers the prolapsed uvea (Fig. 21.30). Sometimes the uvea abuts the penetrating wound and exudes fibrin, creating a mass of fibrin on the surface of the cornea. A shallow or absent anterior chamber, pupil loss, and hyphema are often present (Fig. 21.31). Traumatic uveal

21: Diseases and Surgery of the Canine Anterior Uvea

Figure 21.30  Uveal prolapse secondary to a corneal laceration is present. Fibrin is exuding from the surface and is prominent on the corneal surface adjacent to the prolapse.

Figure 21.31  A long fibrin strand is exuding from a laceration in the dorsal sclera. Hyphema is also present, obscuring the pupil and lens. The injury was caused by a cat’s claw. The scleral rent was closed primarily.

several days or weeks after the trauma. Even eyes that are repaired surgically might undergo phthisis if the uveal trauma is marked. Severely traumatized globes often become a source of chronic pain, because panophthalmitis and secondary glaucoma are possible sequelae.

Traumatic Uveitis with Lens Rupture Lens capsule rupture is most commonly caused by a penetrating foreign body or a cat claw injury. Lens capsule rupture allows the release of lens cortex into the anterior chamber, which often precipitates fulminating endophthalmitis (Davidson et al., 1991; Paulsen & Kass, 2012; Wilcock & Peiffer, 1987). Frequently there is a history of recent ocular trauma; however, lens penetration is rarely suspected. Often the corneal wound has sealed, and the anterior chamber has reformed by the time of examination. Capsular rents are generally difficult to detect, but overlying fibrinous or inflammatory cellular material is suggestive of capsular disruption (Davidson et  al., 1991). Medical therapy of uveitis secondary to lens capsule rupture needs to be aggressive, with the use of topical and immunosuppressive doses of prednisone and topical atropine. Phacoemulsification might be necessary to treat lens rupture in some cases and, when indicated, it must be done early in the disease process (Davidson et al., 1991). However, medical treatment alone as above in conjunction with fluoroquinolones is often successful if the cornea has self-sealed. Many dogs also respond to medical therapy and surgical corneal repair without lensectomy (Paulsen & Kass, 2012). Small capsular rents often seal spontaneously and result in only a focal cataract (Fig. 21.32). Lens changes might even regress as the capsule is sealed with fibrosis (Paulsen & Kass, 2012). For additional information, see “Lens-Induced Uveitis” and Chapters 22 and 23.

Figure 21.32  Posterior synechiae and a focal cataract with overlying fibrin are present in this dog that had a penetrating trauma to sclera, iris, and lens. The anterior uveitis has resolved. This is the same dog as in Figure 21.31.

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prolapse requires surgical repair that involves replacement or amputation of the prolapsed uvea. Specific steps in the repair of uveal prolapse are covered in Chapter 19. The prognosis after uveal prolapse repair varies depending on the time between injury and treatment, the extent of injury, concurrent infection, presence of a pupil opening, patency of the iridocorneal angle, and integrity of other intraocular structures (e.g., lens and retina). Large lacerations or tears of the cornea or sclera with prolapsed uvea, total hyphema, and the presence of vitreous, lens capsule, or lens cortical material within the wound or on the surface of the eye indicate a very poor prognosis. In such cases, enucleation or globe evisceration with a prosthetic silicone implant are recommended alternatives to primary surgical repair. Severely injured eyes that are not repaired or enucleated will usually become phthisical within

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Foreign Body Trauma Corneal foreign bodies are common in dogs, but anterior segment foreign body trauma and retained foreign bodies are less common. Dogs less than 5 years old and hunting and working breeds are predisposed (Tetas Pont et  al., 2016). Plant material is the most common type of ocular foreign body in dogs (Tetas Pont et al., 2016). Organic foreign bodies, such as splinters, thorns, and porcupine quills, are more likely to cause endophthalmitis than inorganic foreign bodies. Inorganic foreign bodies such as glass, plastic, and lead are nonreactive, while iron and copper foreign bodies are reactive and are more likely to cause direct toxicity to intraocular structures (Lit & Young, 2002; Mester & Kuhn, 2002; Schmidt et al., 1975). Diagnosing IOFBs can be difficult. A thorough history and a complete ocular examination including biomicroscopy, with special attention to evaluation of the lens and inspection of the conjunctival fornices, both sides of the nictitating membrane, and all remaining conjunctival surfaces, are essential. The location, depth, size, and composition of the foreign body often correspond to the extent of associated tissue damage and the amount of uveal inflammation. Additionally, these factors dictate the method of removal (Tetas Pont et al., 2016). Small, inert foreign bodies can be left alone. In contrast, organic foreign bodies that remain inside the eye often stimulate severe, usually nonresponsive endophthalmitis; therefore, every effort should be made to remove all organic foreign material from the globe. Regardless of the type of foreign body, both septic and nonseptic endophthalmitis are sequelae that often necessitate enucleation. A penetrating foreign body that is tapered, smooth, and relatively small in diameter can be removed directly after administration of general anesthesia. A hypodermic needle can be used to remove the foreign body. A single suture is placed at the site of penetration to seal the cornea and prevent aqueous leakage. Rough, jagged, or barbed penetrating foreign bodies often require a full-thickness incision adjacent to or over the top of the foreign body to facilitate removal. For retained linear foreign bodies that have penetrated the globe tangentially, an oblique, full-thickness corneal or scleral incision directly over the foreign body is often necessary for removal. After incising the cornea or sclera with a pointed surgical blade (e.g., a No. 65 Beaver blade), the foreign body is removed, and the wound is irrigated liberally with balanced salt solution. The defect is sutured with 8-0 polyglactin 910. The associated uveitis is treated topically with fluoroquinolones, 1% atropine, and NSAIDs. Some cases require the judicious use of topical corticosteroids. Systemic treatment should include antibiotics (fluoroquinolones) and anti-inflammatory agents. Unless there is a gaping corneal wound or an exceptionally large foreign body, a foreign body located completely within

the anterior chamber should be removed from a site distant from the entrance wound to minimize scarring and damage to endothelial cells (Lit & Young, 2002). This positioning allows for visualization of an instrument as it approaches the IOFB, and minimizes obscuration from corneal edema if more manipulation is required than expected. The entrance wound should be closed, with reestablishment of IOP prior to creating a new surgical wound through which to remove the foreign body. Saline or viscoelastics can be used to dislodge foreign bodies that are located near the angle. Maintaining the anterior chamber with viscoelastics aids with visualization. Possible complications of full-thickness corneal foreign body penetration include keratomalacia at the site of penetration, iridal abscess formation, septic endophthalmitis with secondary glaucoma, or retinal detachment. Minor lens involvement can result in an incipient cataract alone. If the anterior lens capsule is torn, uveitis is more severe, and cataract formation will be more advanced. However, with focal lens punctures the lens capsule often seals spontaneously. Rarely the foreign body is retained in the lens. Intralenticular hemorrhage or abcessation can also occur. Most cases of lens capsule rupture are successfully treated medically with mydriatics and topical and systemic antibiotics and antiinflammatories. In the majority of those cases lenticular changes remain stable, but a very few dogs have long-term follow-up. Lensectomy using phacoemulsification is necessary for some cases of traumatic lens rupture. One study showed that the average number of days to referral in cases amenable to surgery was 3, versus 10 days in dogs that were not considered surgical candidates. Those cases seen later in the time course of disease had profound uveitis and extensive posterior synechiae (Davidson et al., 1991). Many of the cases that require phacoemulsification retain vision, but some develop secondary glaucoma, retinal detachment, or have chronic uveitis (Tetas Pont et al., 2016). Risk factors for enucleation after foreign body trauma include full-thickness foreign body penetration, severe lens trauma, and severe uveitis (Tetas Pont et  al., 2016). Ocular ultrasound is valuable to rule out retinal detachments when contemplating treatment options. Immediate referral to a veterinary ophthalmologist is advised in difficult cases to confirm the diagnosis, offer a prognosis, perform any necessary surgery, or treat any complications, which frequently arise. While most foreign bodies need to penetrate deep into the cornea or enter the anterior chamber to cause significant uveitis, the setae from the pine processionary caterpillar, Thaumatopoea pityocampa (southern European and Mediterranean pine forests), causes anterior uveitis in 80% of affected dogs. In these eyes only a small superficial, crescent-shaped nonulcerative corneal lesion is present with the uveitis. The lesions might be caused by mechanical irritation, hypersensitivity, or a toxin. Generally, hydropulsion to remove the setae and medical therapy with topical antibiotics and NSAIDS are effective (Costa et al., 2016).

Hyphema Hyphema, or blood in the anterior chamber, occurs when uveal or retinal vessels are damaged or abnormally formed (see Fig.  21.18). Causes of hyphema in the dog include trauma, neoplasia, retinal detachment, blood dyscrasias, PIFMs, hypertension, infectious disease, severe uveitis, congenital anomalies, and canine ocular gliovascular syndrome (Bayon et  al., 2001; Cullen et  al., 2000; Grahn et  al., 1997; Gray et  al., 2003; Habin & Else, 1995; Heath et  al., 2003; Kilrain et al., 1994; LeBlanc et al., 2011; Littman et al., 1988; Nelms et  al., 1993; Oria et  al., 2004; Peiffer et  al., 1990; Stades, 1980; Treadwell et al., 2015; Trepanier, 2004; van de Sandt et al., 2004; Vinayak et al., 2004). Retinal detachment is the disease process most commonly associated with hyphema seen at referral institutions (Nelms et  al., 1993). Chronic uveitis, chronic glaucoma, neoplasia, and retinal detachments often lead to the development of PIFMs, which can result in hyphema (Peiffer et al., 1990). The prognosis for hyphema is dependent on the etiology and presence of posterior segment damage. Hemorrhage from damaged choroidal or retinal vessels can move anteriorly through the pupil to the anterior chamber. Vitreal, retinal, or choroidal hemorrhages with retinal detachment indicate severe intraocular disease and a poor visual prognosis. Also, the cause of hyphema influences whether blood clots in the anterior chamber. If the hyphema is secondary to a clotting abnormality, the hyphema is unlikely to clot. However, hyphema occurring secondary to trauma or iridocyclitis will usually clot. Hemorrhage resulting from neoplastic, retinal detachment, or congenital ocular diseases is often recurrent, and the hyphema in these cases frequently forms multiple layers within the anterior chamber. A detailed history and complete physical and ocular examinations are essential. In young dogs with no history of trauma, congenital anomalies must be considered. Examining the eyes of littermates and being familiar with breed predilections to hereditary congenital ocular disease, such as Collie eye anomaly or persistent hyaloid artery, are helpful in making a diagnosis. Other differential considerations in young adult dogs with spontaneous hyphema include infections (e.g., ehrlichiosis) and toxic bleeding disorders. Neoplasia and systemic hypertension are causes that must be considered in older animals. Regardless of the animal’s age, both genetic and acquired hemostatic diseases should be ruled out. A complete ophthalmic examination including fluorescein stain and IOPs is indicated for all cases of hyphema. A full physical examination in association with a diagnostic evaluation, including appropriate laboratory tests, is indicated to rule out systemic disease in animals with atraumatic hyphema (see Chapter 37, Part 1). In many cases of hyphema, the most informative ancillary diagnostic procedure is

ocular ultrasonography. Extensive hyphema prevents intraocular evaluation; therefore, intraocular masses, vitreal hemorrhage, retinal detachments, or scleral rupture are only detectable with B-scan ultrasonography. CT or plain-film radiographs of the skull and orbit are used to diagnose concurrent orbital fractures or foreign bodies. While MRI can be used, additional damage to the globe and contents from intraocular ferromagnetic foreign bodies is a risk with this imaging modality. Thoughts on the best medical treatment of hyphema vary. Veterinary studies addressing medical management are lacking, in part because of the many common causes of hyphema. This contrasts with human medicine, where trauma is by far the most common etiology of hyphema. Gharaibeh et al. (2013) conducted a meta-analysis evaluating medical intervention for traumatic hyphema in humans. They found no evidence that the use of corticosteroids, cycloplegics, miotics, or nondrug interventions, such as bed rest, showed benefit. They also demonstrated that topical and systemic antifibrinolytics, such as aminocaproic acid and tranexamic acid, reduced the rate of secondary hemorrhage, but slowed the clearance rate. The authors concluded that treatment should be individualized (Gharaibeh et  al., 2013). Following are the medications most commonly used in the treatment of hyphema and the reasoning behind their use. Topical dexamethasone or prednisolone acetate with or without systemic prednisone is typically used, assuming no contraindications, to reduce and control intraocular inflammation and to possibly reduce the incidence of rebleeding (Brandt & Haug, 2001; Walton et al., 2002). The use of pupilloactive drugs is somewhat controversial. Topical 1% atropine might be indicated initially to reduce the possibility of posterior synechiae formation, to decrease ciliary spasm, and to stabilize the blood–aqueous barrier. However, IOPs often increase with hyphema due to occlusion of the trabecular meshwork by clots, inflammatory cells, or erythrocytic debris, and the use of atropine can exacerbate ocular hypertension (Walton et al., 2002). Therefore, tonometry should be done regularly to monitor for changes in IOP. If an increased IOP is noted after the initiation of mydriatic treatment, atropine should be discontinued immediately and topical timolol and dorzolamide initiated to reduce the IOP (see Chapter  20). Tropicamide (1%) prevents synechia formation without having the risk of elevating IOP if used judiciously. Conversely, pilocarpine can be efficacious because it enhances the outflow of aqueous humor, facilitates the removal of blood through the trabecular meshwork, and increases the surface area of the iris (via miosis), thereby enhancing fibrinolysin activity (Havener, 1983). The potential disadvantages of pilocarpine or other miotics are that miosis predisposes patients to posterior synechiae and, subsequently, to iris bombé, and cholinergic agents might potentiate uveitis (Havener, 1983; Krohne et al., 1998).

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Tissue plasminogen activator (tPA) is effective in the treatment of hyphema when large blood clots and fibrin are present in the anterior chamber or the IOP is elevated secondary to fibrin blocking the iridocorneal angle (Gerding et al. 1992; Martin et  al., 1993). An injection of tPA into the anterior chamber leads to rapid clot dissolution, and tPA is most effective when injected within 72 hours of clot formation. The recommended dosage for intracameral injection is 0.1 mL of a 25 mg/100 μL solution (Gerding et  al. 1992; Martin et al., 1993). However, tPA should not be injected if recurrent bleeding is likely, although the risk of rebleeding is low due to clot specificity (Crabbe & Cloninger, 1987). Lastly, confining the dog’s activity to a cage or small room in a quiet area might minimize the possibility of recurrent hemorrhage. Establishing a prognosis or elucidating the cause of hyphema is not always possible. Evaluating the response to medical or surgical therapy (e.g., corneal laceration repair) helps to determine the extent of disease. Uncomplicated hyphema usually clears within 1 week (Walton et al., 2002). In cases of unexplained, nonresponsive, or recurring hyphema, the etiology must be reassessed. When intraocular neoplasia is present or strongly suspected to be the cause of hyphema, the affected eye should be enucleated and submitted for microscopic evaluation. The prognosis for vision is best with cases of small hyphema volumes not associated with retinal detachment, hypertension, or trauma. Initial exam findings of unilateral hyphema, complete hyphema, the absence of a dazzle or consensual pupillary light reflex, an elevated IOP, and retinal detachment, regardless of cause, are associated with permanent blindness (Jinks et al., 2018). Chronic hyphema can lead to all of the sequelae observed with chronic uveitis. Ghost cell glaucoma is a common complication of hyphema in humans that also occurs in dogs (Campbell, 1981). The prognosis for vision in dogs with hyphema secondary to retinal disease is grave, and most dogs develop secondary glaucoma (Nelms et al., 1993).

Non-neoplastic Iridal Proliferations Ocular Melanosis (Pigmentary Glaucoma) Abnormal ocular pigment deposition and glaucoma (ocular melanosis or pigmentary glaucoma) are described primarily in Cairn Terriers, but also in the Boxer and Labrador Retriever (Covitz, 1981; Petersen-Jones, 1991; van de Sandt et al., 2003). The disease appears to be familial and tends to occur in older dogs. This syndrome has been compared with the pigmentary dispersion syndrome in humans. Clinically, hyperpigmentation involves the iris, ciliary body, choroid, and filtration angle. Often the iris appears thickened, and pigment is dispersed in the aqueous humor. Additionally, patchy pigment deposition around the perilimbal zone of

Figure 21.33  This Cairn Terrier has pigmentary glaucoma. Pigment is dispersed in the aqueous humor and is present on the anterior lens capsule. Additionally, there is pigment deposition in the perilimbal zone of the sclera. Secondary glaucoma has caused buphthalmia and lens subluxation.

the sclera, progressive pigmentation of the tapetal fundus, and secondary glaucoma occur (Fig. 21.33; Petersen-Jones, 1991; van de Sandt et  al., 2003). Affected dogs are poorly responsive to long-term therapy. Microscopically, many large, round, pigment-laden cells are seen infiltrating the anterior uvea, sclera, and episclera and obscuring the drainage angle. Fewer cells are present in the posterior segment of the globe, the optic nerve meninges, and the periphery of the optic nerve. Many globes have changes secondary to chronic glaucoma, and some have evidence of uveitis. While there has been debate as to whether the melanin-containing cells are melanophages or melanocytes, immunohistochemical ultrastructural characterization of the cells reveals that most of them are melanocytes, with fewer being melanophages. The melanocytes contain both immature and mature melanosomes (Petersen-Jones et al., 2008). The melanocytic infiltration can be so extensive as to simulate diffuse melanoma; however, this process is not neoplastic. Pedigree analysis suggests a possible autosomaldominant mode of inheritance (Petersen-Jones et al., 2007). While this disease is not considered to be neoplastic, three dogs in one large study were subsequently diagnosed with uveal melanocytic neoplasms (Petersen-Jones et al., 2007).

Iris Freckles and Nevi Non-neoplastic areas of hyperpigmentation are common on the canine iris. These are referred to as iris freckles or iris nevi (Trucksa et al., 1985). Iris freckles, benign melanosis, or pigment cell clusters are used to describe benign hyperplasia or increased pigmentation of normal melanocytes (Peiffer, 1981; Trucksa, 1983). These clusters of cells are located in the superficial iridal stroma and do not tend to distort the normal iris architecture, but are occasionally raised (Gelatt et  al.,

Figure 21.34  An iris nevus is present in the iris of this German Shepherd mix.

1979; Peiffer, 1981). Iris freckles infrequently coalesce to cause diffuse pigmentation, which can be bilateral. Observation of freckles in the opposite eye assists diagnosis (Peiffer, 1981). An iris nevus is a proliferation of melanocytes that forms a well-circumscribed, slightly elevated mass on the iris face (Fig. 21.34; Gelatt et al., 1979; Peiffer, 1981). Nevi tend to occur in young dogs. Microscopically, cells replace the iris stroma, and cystic areas may be present. Mitotic figures are not observed, and the cell population is relatively homogenous (Gelatt et al., 1979). Nevi have the potential to undergo malignant transformation; however, diffuse malignant melanoma of the iris rarely occurs in dogs, in comparison to cats, and usually the iris is thickened concurrently (Peiffer, 1981).

Anterior Uveal Tumors Intraocular tumors are primary or secondary to metastatic disease or local invasion. The great majority of primary intraocular tumors have their origin in the anterior uvea. While distant metastasis from primary intraocular tumors is rare, local tissue destruction and secondary glaucoma occur commonly. Tumors must be differentiated from other intraocular masses, including iris cysts, granulomatous lesions, and staphylomas. Tumors must also be considered in any eye with secondary glaucoma or opaque media. Diagnosis is based on findings from complete ophthalmic and physical examinations and whether the masses are unilateral or bilateral, singular or multiple, raised or flat, and static or changing in appearance.

Primary Neoplasms Melanocytic Neoplasms

Melanocytic neoplasia (i.e., melanoma) is the most common primary intraocular neoplasm in the dog (Saunders &

Barron, 1958; Trucksa, 1983). Melanomas in veterinary medicine are often referred to as benign or malignant. Alternatively, melanocytoma can be used for benign melanomas. This is in contrast to human medicine, where melanoma implies malignancy. Larger studies of canine ocular melanomas classify canine uveal melanomas as melanocytomas and (malignant) melanomas (Giuliano et  al., 1999; Nasisse et al., 1993; Wilcock & Peiffer, 1986). The term melanocytoma refers to benign anterior uveal melanomas, limbal melanomas, and choroidal melanomas. Melanocytomas are differentiated from (malignant) melanoma by nuclear pleomorphism, nuclear-to-cytoplasmic ratio, and mitotic index. Tumors are considered malignant if cellular morphology includes prominent nucleoli, a nuclear-to-cytoplasmic ratio greater than one, and more than four mitotic figures per 10 high-power fields (HPFs; Bussanich et  al., 1987; Dubielzig, 1990; Giuliano et  al., 1999; Labelle & Labelle, 2013; Wilcock & Peiffer, 1986). Most canine ocular melanomas arise in the anterior uvea, and both the iris and the ciliary body are common sites of origin. With large masses, the tissue of origin is often difficult to determine even microscopically. Several large studies have provided the majority of the clinical and histologic information on canine uveal melanomas (Bussanich et  al., 1987; Giuliano et  al., 1999; Ryan & Diters, 1984; Wilcock & Peiffer, 1986). Intraocular melanocytic tumors are most common in older dogs, with a mean age of around 9 years and an age range of 2 months to 17 years. While German Shepherds and retrievers are the more commonly affected breeds reported in studies, population statistics have not been done to determine if breed is a risk factor. Inherited iris melanoma has been reported in a family of Labrador Retrievers, but the diagnosis was made on the basis of clinical examination with no microscopic confirmation (Cook & Lannon, 1997). A color change or mass effect in the eye is often the first abnormality observed; however, if these initial changes go unnoticed, secondary uveitis or glaucoma develops. Melanomas in dogs tend to produce nodular growth rather than diffuse infiltration, as seen in cats and humans (Acland et  al., 1980). At clinical presentation, melanomas are frequently focal and confined to the iris, or they can be extensive. Large masses often bulge through the pupil, displace the iris anteriorly, or cause dyscoria. Iris thickening, an irregular pupil, blindness, and ocular pain are the most common clinical signs (Fig.  21.35). Degree of pigmentation is variable, but amelanotic melanomas are rare (Dubielzig, 1990). Additionally, keratitis, anterior uveitis, hyphema, secondary glaucoma, buphthalmos, and retinal detachment frequently occur with chronicity. Anterior uveal melanomas are often locally invasive, extending to involve the choroid, sclera, filtration angle, cornea, and orbit. Lens subluxation occurs if the mass displaces the lens. Neoplastic melanocytes or melanophages (or both) are frequently free-floating in the

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21: Diseases and Surgery of the Canine Anterior Uvea

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Section IIIB: Canine Ophthalmology

Figure 21.35  Melanocytic neoplasia is present in the nasal aspect of the iris. The tumor is protruding through the limbus.

anterior chamber, and their obstruction of the filtration angle contributes to secondary glaucoma. Uveal melanomas that penetrate the perilimbal sclera can simulate a limbal (i.e., epibulbar) melanoma. Diagnosis is usually made on clinical examination. Possible differentials include uveal cysts, staphylomas, and limbal melanocytoma. Iris cysts transilluminate, and limbal melanocytomas are located on the external surface of the globe. Ultrasound can be used to differentiate between cysts and tumors and to help determine the extent of tumor growth when the cornea or ocular media is opaque. Gonioscopy facilitates differentiation between uveal and limbal melanocytomas. Uveal melanomas with extraocular extension often invade the filtration angle, whereas limbal melanocytoma, though extending deep into the sclera, will compress but less commonly invade the angle; still, invasion of limbal melanomas into the filtration angle and anterior uvea has been reported. Primary choroidal melanoma has been reported infrequently in the dog, and anterior uveal melanomas can infiltrate posteriorly into the choroid (Dubielzig et al., 1985a). It is important to rule out metastasis from a distant site by doing a thorough physical examination that includes examining the oral cavity, footpads, and nail beds. The histopathologic descriptions of intraocular melanocytic tumors vary (Bussanich et al., 1987; Diters et al., 1983; Dubielzig, 2002; Ryan & Diters, 1984; Trucksa et  al., 1985; Wilcock & Peiffer, 1986). Some authors use quantification of relative proportions of cell types (e.g., spindle, ovoid, epithelioid) to define benign or malignant qualities; however, even the criteria for certain cell types vary significantly. Spindle A and epithelioid cells are described by some but not by others. Most authors agree that plump or round pigment cells are a feature of canine uveal and limbal melanomas. These cells are typically polyhedral and heavily pigmented. Results of ultrastructural studies have revealed that plump cells are neoplastic melanocytes rather than melanophages. Plump

cells occur with much greater frequency in microscopically benign melanomas; accordingly, these melanomas tend to be more heavily pigmented and lack mitotic figures. The plump cell is postulated to be a hypermature spindle cell that is amitotic and prone to lysis, whereas the cell types typical of microscopically malignant melanomas are thought to represent anaplasia rather than spindle cell maturation. In cases of a poorly pigmented or poorly differentiated melanoma, it might be difficult to make the histopathologic diagnosis, but immunohistochemical staining with Melan A can be beneficial. Additionally, monoclonal antibodies designed to detect melanoma-associated antigens in human tissues have been used with some success to diagnose canine melanomas, and such antibody markers might be useful in these rare instances (Berrington et al., 1994). While the Callender classification is used for correlating histopathologic features of uveal malignant melanomas with their metastatic potential in humans, its use is not deemed appropriate for use in dogs because many canine tumors are benign, are of the mixed or epithelioid-cell type, or have plump cells not seen in human uveal melanomas (Bussanich et  al., 1987; Callender, 1931; Ryan & Diters, 1984; Trucksa et al., 1985; Wilcock & Peiffer, 1986). Severity of intraocular destruction has also been used as a sole indicator of malignancy; however, most canine anterior uveal melanomas, though frequently invasive, do not conform to the strictest definition of malignancy, which includes metastasis having the potential to cause death (Ryan & Diters, 1984; Wilcock & Peiffer, 1986). Most primary ocular melanocytic neoplasms arise from the anterior uvea, with 79% of the benign lesions and 95% of the malignant melanomas arising from that site. Regardless of histologic characteristics, approximately the same number of tumors remained inside the sclera (-7%), invaded the sclera (-56%), or had extra-scleral extension (-28%; Giuliano et al., 1999). Most tumors arising from the anterior uvea grow expansively rather than invasively and occupy the filtration angle and deep stroma of the peripheral cornea and sclera (Wilcock & Peiffer, 1986). Malignant melanomas tend to be less pigmented and comprise 20% of intraocular melanocytic tumors (Dubielzig, 2002). Metastasis occurs hematogenously and typically involves the thoracic and abdominal viscera, although other sites are sporadically reported (Bussanich et al., 1987; Giuliano et al., 1999; Ryan & Diters, 1984; Wilcock & Peiffer, 1986). Microscopically, neoplastic cells are identified in the scleral emissaria or the optic nerve, confirming the egress of neoplastic cells from the globe. Extraocular extension or glaucoma (or both) might predispose to metastasis (Trucksa et  al., 1985). Metastasis to the contralateral eye has been reported once (Render et  al., 1997). Metastasis to the eye from cutaneous or oral sites rarely occurs, so the primary tumor site may be difficult to determine (Ryan & Diters, 1984; Trucksa et  al., 1985). Cytologic indices (i.e., mitotic

21: Diseases and Surgery of the Canine Anterior Uvea

Iridociliary Epithelial Tumors Iridociliary epithelial tumors are the second most common primary intraocular tumor in the dog (Dubielzig et al., 1998; Peiffer, 1983a). These tumors arise from either the epithelial cells of the iris or the ciliary body (Dubielzig, 2002). Primary iridociliary epithelial tumors have one of the following criteria: noninvasive epithelial growth extending into the aqueous adjacent to the iris or ciliary body, pigmented epithelial cells, or thick basement membrane structures on the cell surface (Dubielzig et al., 1998). Iridociliary epithelial tumors are more common in middle-aged to older dogs (mean age 9.0 years; Beckwith-Cohen et al., 2015; Dubielzig et al., 1998; Peiffer, 1983a; Peiffer et al., 1978). Labrador and Golden Retrievers appear to be overrepresented in a new study compared to older studies, suggesting that genetic traits may be related to this tumor occurrence in retrievers (Beckwith-Cohen et  al., 2015). These tumors appear clinically as segmental or nonsegmental, solid or papillary, and invasive or noninvasive (Fig. 21.36). Generally they are pink with little to no apparent pigmentation. The incidences of adenoma (i.e., benign) and adenocarcinoma (i.e., potentially malignant) are approximately equal, and these tumors combined are suggested to have an incidence approximately half that of uveal melanoma. Distant metastasis of ciliary body adenocarcinomas has been reported sporadically (Bellhorn, 1971; Dubielzig et  al., 1998; Peiffer, 1983a). Adenomas are more often limited to the ciliary body, but can usually be visualized through a dilated pupil. Adenocarcinomas, on the other hand, are typically more invasive, extend through the iris base or pupil, but rarely metastasize. A cystic adenoma has also been reported (Peiffer et al., 1978). Rarely, iridociliary epithelial tumors are difficult to differentiate from melanomas (Peiffer et  al., 1978).

Figure 21.36  A ciliary body adenoma can be visualized extending into the pupil in this Labrador Retriever.

SECTION IIIB

index, nuclear pleomorphism, nuclear–cytoplasmic ratio) are sensitive and accepted indicators of malignant potential in many tumors. For all cases of canine anterior uveal melanomas in which metastasis has been confirmed, the neoplasms have shown morphologic characteristics easily recognizable as being indicative of malignancy. Specifically, the mitotic index has been suggested as bei