Introduction by

Daniel M. Albert  James A. Render 

MD, MS

DVM, PHD, DACVP

It has been 30 years since Gustavo Aguirre asked me if I would be interested in reviewing ocular pathology cases for the benefit of the ophthalmology residents and faculty at the University of Pennsylvania, and 25 years since the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) began receiving specimens. With more than 25 000 cases in the COPLOW archive and all these years of ocular pathology experience, I became motivated to put into a textbook what I have learned about veterinary eye pathology. I hope this will benefit those who are active in the field and those who will continue the work in the future.

I have found Ocular Pathology by Myron Yanoff and Ben Fine (Mosby) to be helpful in my own work and borrowed from their text the idea of combining clinical and pathology photographs. My goal is to present a more unified clinical and pathological context to understand veterinary ocular pathology. Like Yanoff and Fine, this book is in an outline format, because I have found that model helpful to access descriptive information.

One of the unique aspects of our text is that it uses the COPLOW database to provide information about the relative frequency of various diagnoses. Emphasis is given to conditions seen in the pathology laboratory. There is a bias toward removal of the globe and submission of the specimen, when ocular disease is seen as a risk to the health of the animal, such as cancer. For that reason, neoplastic conditions are over-represented in a pathology archive and, therefore, also in this ocular pathology text. When there is not a perceived risk to the health of the animal, there is little reason to remove an eye, unless it is both blind and painful or ugly. For this reason, we see severe intractable glaucoma, trauma, or inflammation overrepresented in the pathology laboratory. We seldom see conditions that may cause visual impairment but leave the eye comfortable and unblemished. Retinal conditions, anomalies and treatable conditions are usually not submitted to the pathology laboratory and have received less emphasis in this book.

Readers should be aware that we present conditions that appear as diagnoses from the COPLOW laboratory but have not yet appeared in other veterinary literature. We hope that pathologists will use this text as a guide to diagnosis and that insight from the experience of someone who has managed a large caseload of ocular pathology will be valued. We expect that, in time, either the COPLOW laboratory or others will take the effort to properly document those topics that appear in the text but not in the peer-reviewed literature.

In ocular pathology, as in skin pathology, the clinician is able to make direct observation of the pathology both outside and inside the globe. That is why it is exciting to put together a text that is so rich in clinical photography. Kerry Ketring has been a careful recorder of the

morphologic variants of ocular disease throughout his long and productive career. His photography skills are widely admired and he has assembled numerous photographic essays and atlases illustrating veterinary ophthalmology. It was a delight to work with Kerry on this project and his contributions add a rich dimension that bridges the gap between clinical ophthalmology and ocular pathology.

Although ocular pathology has been my main focus for three decades and, during that time, I have attended meetings of ophthalmologists, published in ophthalmology journals, and have daily dialogues about case material with ophthalmologists, my perspective is always as a pathologist. Co-author Gillian McLellan has made this text accessible to veterinary ophthalmologists. A veterinary ophthalmologist familiar with ocular pathology, she has an exceptional and comprehensive knowledge of the literature. Gillian is an academic veterinary ophthalmologist, with extensive experience in the practice of ophthalmology, who has used ocular pathology throughout her research career. Most importantly, she was able to rephrase my words and make them more appropriate and understandable to practitioners. Clinicians and pathologists use medical terminology in different ways and we see different case material. There are also different priorities and different goals in our approach to vision science. Gill’s editing and reworking of the text has had a huge and positive impact on the final product. Dan Albert deserves to be acknowledged in many ways. He has been a friend, an inspiration, and a mentor for most of my career. Dan’s sage advice was helpful in managing my career path. We are delighted that he agreed to read this material and write the ‘Comparative Comments’ interspersed throughout the text articulating the similarities and differences between veterinary ocular pathology and human ocular pathology.

The authors are also indebted to the support and skills of several individuals who made significant contributions to this project. Marsha Ketring was an invaluable resource, who put together the clinical photography for the text. Her skills with Photoshop and her ability to convert Kerry Ketring’s images, which are archived as two-by-two slides, into high quality digital images, made this book possible. Doris Dubielzig’s talents as an editor and wordsmith were also a valuable part of the project. She devoted a huge effort into taking the figure legends, written by two authors with different styles, and blending them so that the styles and word use are consistent. To compensate for a lack of familiarity with the technical language, she constantly sought the most accepted terminology. We are also indebted to Dan Williams, as well as Doris, who both entertained the McLellanWilliams twins while Gillian edited the book.

The soil from which this book has taken root has been the work of the Comparative Ocular Pathology Laboratory of Wisconsin

(COPLOW). The lab has received, photographed, processed, diagnosed and archived more than 3000 mail-in cases in each of the last 3 years. The results are maintained in a digital format that allows easy searching for case retrieval and quick comparative studies. This is the work of many individuals and they all deserve our appreciation. Kate Lieber, in particular, manages the nuts and bolts of the lab. She handles the billing, manages the money, supervises the student help and accommodates the needs of our frequent visitors. She has an amazing facility with the smallest details and makes order when all else slips towards chaos. Kate has great empathy for the clients and the animals, keeping us focused on the customer and not just the pathology. Dr Chuck Schobert is the coordinator of COPLOW’s research projects. In addition to conducting his own research, he coordinates the projects of scientists at other institutions who use the

collection for their studies. Chuck pioneers new immunohistochemistry techniques, interfaces with the electron microscopy laboratory, and interacts with veterinary students on both research and educational projects. To date, we have had 14 ocular pathology fellows study at and contribute to COPLOW. These young veterinarians, interested in careers in ophthalmology or pathology, have chosen to spend a year at COPLOW as a step toward reaching their career goals. These bright, motivated, energetic, and hardworking young people have forced me, daily, to explain, justify and clarify my thoughts about ocular pathology.

Richard R. Dubielzig, Madison, Wisconsin

2010

The organ of vision, as it appears in the infinitely varied forms of animal life, has amazed and inspired man since prehistoric times. Observations regarding diseases of the eye across the animal kingdom can be found in the ancient writings of India, China, Assyria, Egypt, Greece, and Rome. From the time of Hippocrates, the study of the eye has brought together physicians and veterinary specialists in an attempt to understand ocular disease. Although not formally recorded in studies on medical history, the beginning of ophthalmology was also the beginning of comparative ophthalmology. As medicine and veterinary medicine evolved, the significant findings of the postmortem examination, including an examination of the eye, became important for understanding diseases. A notable example is Leonardo da Vinci’s many dissections of both human and animal cadavers. Numerous early works in veterinary ophthalmology focused on the study of the equine eye. As early as the 13th century, Giordano Ruffo wrote a chapter on equine eye diseases in his text, Ippiatrics, and Theodorico Borgognoni mentioned equine eye diseases in the text, Ippiatraia Mulomedicinae. The continuing interest in the equine eye is evidenced in the 1600s, by the chapter on the eye in the book by Andrew Snape, The Anatomy of the Horse.

The founder of ophthalmic pathology is generally regarded to be James Wardrup (1782–1869), a Scottish general surgeon with a lifelong interest in the diseases of the eye of both man and horse. Subsequently, human and veterinary ophthalmic pathology specialties have for the most part evolved separately, except for the notable study of laboratory animals and experimental models. We hope this book will help to bring these separated disciplines together again as comparative ophthalmic pathology.

The early history of comparative ophthalmic pathology has been primarily the domain of veterinary ophthalmology, and its achievements have been well documented in review articles by Milton Wyman, a veterinary ophthalmologist, and Leon Saunders, a veterinary pathologist. The 19th century saw veterinary ophthalmology advance and the importance of veterinary ocular pathology gain recognition. J. Carver, a veterinary surgeon, published a significant study related to the pathology of the horse’s eye and, with other publications on the eye of animals starting to appear, veterinary ophthalmology developed as a viable discipline in European veterinary schools. Urbain Leblanc, a Parisian veterinarian, wrote a book on veterinary ophthalmology that was later translated into German. With Helmholtz’s discovery of the ophthalmoscope in 1850, the ability to diagnose ocular disease in humans and animals became a reality.

The late 19th through the early 20th century was a critical period for veterinary ophthalmology, with increased activity in veterinary schools in Europe. In Berlin, Heinrich Möller, a veterinarian, made

major contributions to veterinary ophthalmology, which were included in his book, Lehrbuch der Augenheilkunde für Tierärzte. Physicians teaching ophthalmology at the veterinary colleges developed a broad interest in ocular diseases in animals, and some, like Rudolf Berlin at the Veterinary College of Stuttgart, became interested in pathology. Josef Bayer, an Austrian physician and veterinarian, was devoted to the study of equine recurrent uveitis; while at the Vienna Veterinary College, he examined hundreds of enucleated eyes of horses. His findings were published in books and papers, and many of the specimens ended up in a notable museum collection in Vienna.

By the late 19th and early 20th century, the study of veterinary ophthalmology and veterinary ocular pathology was well underway throughout Europe. In Vienna, Otto Überreiter made important observations on canine glaucoma and equine cataract. In Hungary, veterinary ophthalmology was a topic of research and teaching at the Royal Veterinary College. Béla Plósz worked on the ocular histology of farm animals and studied lenticular opacities of horses. László Szutter was active in the area of ocular pathology and wrote a book, Tierärztliche Augenheilkunde. In England, Edward Nettleship, an ophthalmic pathologist at Moorfields Eye Hospital in London, published information on ocular diseases in dogs as well as humans, and George Coats, also an ophthalmic pathologist at that institution, studied congenital anomalies of animals’ eyes. Edward Hilding Magnusson, a veterinary pathologist, described observations of hereditary retinal atrophy in the Gordon setter, and Theodor Kitt, a pathologist, produced the first textbook of veterinary pathology to seriously treat the subject of ophthalmic diseases (Lehrbuch der pathologischen Anatomie der Haustiere). Henry Gray, an English veterinarian, contributed to the literature on veterinary ophthalmology, while in France, Eugéne Nicolas, a veterinary ophthalmologist, published a text on veterinary and comparative ophthalmology (Ophtalmologie, Vétérinaire et Comparée). Nicolas’ book was translated into English by Henry Gray and served as a major source of information for veterinarians in the British Empire and in the United States into the 1950s.

The 5th and final edition of Kitt’s textbook appeared in 1927, and three decades elapsed before a comparable section on the diseases of the eye was published. This occurred in the American textbook on veterinary pathology published by Thomas C. Jones. Jones had previously published a series of articles on ocular pathology, particularly on uveitis in horses. Then, in the early 1950s, another veterinary pathologist in the United States, Leon Saunders, published a paper in the Cornell Veterinarian on blindness in dogs and a paper in the Journal of Comparative Pathology on intraocular lesions of canine distemper. In 1957, Hilton A. Smith and Thomas C. Jones included a chapter on ocular pathology in their textbook, Veterinary Pathology. This book

chapter marked the beginning of renewed interest in veterinary ophthalmic pathology, especially in North America, and included information on intraocular tumors in dogs by veterinary pathologists Leon Saunders and Charles Barron.

During the 1960s, veterinary ophthalmology and veterinary ocular pathology continued to evolve in the United States. In 1964, William G. Magrane started a clinical practice focused exclusively on veterinary ophthalmology, and Stuart Young, a veterinary pathologist at Colorado State University and honorary diplomate of the American College of Veterinary Ophthalmologists (ACVO), began to be actively involved in veterinary ocular pathology. In 1968, the main topic of the annual meeting of the American College of Veterinary Pathologists (ACVP) was ophthalmic pathology, with Lorenz E Zimmerman, head of the Ophthalmic Pathology Branch of the Armed Forces Institute of Pathology (AFIP), as the featured guest.

The development of veterinary ophthalmology and veterinary ocular pathology continued in the United States during the 1970s. In 1974, Lionel Rubin, a veterinary ophthalmologist, published an atlas of veterinary ophthalmoscopy that included information on both domestic animals and laboratory animals. Included in the textbook were pictures, provided by Leon Saunders, of histopathologic findings in the retina that correlated to the funduscopic pictures. This was the beginning of many subsequent interactions between clinical veterinary ophthalmologists and veterinary ocular pathologists. William Carlton, a veterinary pathologist at Purdue University, routinely examined enucleated eyes as part of a diagnostic service and incorporated his findings into material for a graduate course on ophthalmic pathology. At this time, Leon Saunders was rewarded for his contribution to veterinary ophthalmology by becoming an honorary diplomate of the ACVO, and another veterinary pathologist, Richard Dubielzig, began to give lectures on comparative ophthalmic pathology.

During the 1980s, the findings in diagnostic veterinary ophthalmic pathology from previous years of study were being shared and organized. The C L Davis Foundation offered symposia on ophthalmic pathology. Brian Wilcock from the University of Guelph, Richard Dubielzig, and William Carlton were invited speakers. In December 1980, a symposium on comparative ophthalmic pathology was held in Chapel Hill, bringing together veterinary ophthalmologists and pathologists with an interest in comparative ocular pathology. This symposium was organized by two veterinary ophthalmologists actively involved in comparative ocular pathology: Robert Peiffer Jr, at the University of North Carolina, and Robert Trucksa, at the AFIP. Among the presenters was Richard Dubielzig. The symposium was followed by the publication of the textbook, Comparative Ophthalmic Pathology, in 1983. This textbook contained contributions from veterinary pathologists William Carlton, Brian Wilcock, and Jantine van der Linde-Sipman from the University of Utrecht; and veterinary ophthalmologists Stephen Bistner from the University of Minnesota, Craig Fischer from the Animal Eye and Medical Clinic of Tampa Bay, Charles Martin of the University of Georgia, Ron Riis of Cornell University, and Frans Stades of the University of Utrecht.

This symposium gave rise to the ophthalmic pathology short course, ‘The Histologic Basis of Ocular Disease’, which included Robert Peiffer, Brian Wilcock, Richard Dubielzig, William Carlton, Leon

Saunders, Herb Whiteley, and Stuart Young as faculty members. The faculty gradually changed over the years to include additional veterinary pathologists and ophthalmologists with an interest in veterinary ophthalmic pathology. The course continues to meet every other year and has been integrated into a larger course on veterinary ophthalmology sponsored by the ACVO (William Magrane Basic Science Course in Veterinary and Comparative Ophthalmology).

In the 1990s, the International Life Sciences Institute (ILSI) sponsored a course, organized by Thomas C. Jones of the Harvard Medical School, Ulrich Mohr of the Hannover Medical School in Germany and Yoichi Konishi of the Nara Medical University on the pathology of the eye that was offered in the three countries. During this period, ILSI sponsored a book by Thomas C. Jones, Ulrich Mohr, and Ronald D. Hunt, entitled Eye and Ear, which discussed the pathology of the eye and ear in laboratory animals. Although the book was not a comprehensive review, it mentioned comparisons with other species and with similar lesions in man. Also at this time, the topic of veterinary ocular pathology was presented at the annual meeting of the ACVP. This meeting was held jointly with the annual meeting of the ACVO to foster the interactions between veterinary pathologists and veterinary ophthalmologists.

In the present millennium, Brian Wilcock and Richard Dubielzig were honored for their advancements in the area of veterinary ophthalmic pathology by becoming honorary diplomats of the ACVO. In addition, Kenneth Simons, an ophthalmologist with expertise in ocular pathology from the Medical College of Wisconsin, and Robert Peiffer, edited a publication entitled, Ocular Tumors in Animals and Humans. This publication took the novel approach of combining information on veterinary and human ocular oncology for comparative purposes. The editors solicited contributions from experts in human ocular pathology (Daniel Albert from the University of Wisconsin); veterinary ocular pathology (Jeffrey Everitt, CIIT Centers for Health Research, and William Carlton); and veterinary ophthalmology (Nedim Buyukmihci from the University of California in Davis, Bernard Clerc from d’Afort Veterinary School, Craig Fischer from Animal Eye Clinics of Florida, Gia Klauss from the University of Wisconsin, Denise Lindley from Animal Eye Consultants, John Mould from the Glasgow University Medical School, and Claudio Peruccio from the University of Turin).

The present book, Veterinary Ocular Pathology: a Comparative Review, is an accumulation of years of painstaking observations regarding the gross and microscopic appearance of eyes from a wide variety of species with naturally occurring and experimentally induced disease. The book draws heavily from the extensive collection of ocular pathology specimens housed at the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW). With the same spirit of enthusiasm and interest in discovery as their predecessors in the field, Richard Dubielzig and his associates have written a textbook on comparative ophthalmic pathology that is current and comprehensive, to aid ophthalmologists and pathologists in both the veterinary and human medical fields.

Daniel M. Albert

James A. Render

2010

OBJECTIVES

•To characterize the case material seen in an ocular pathology service

•To present the basics of tissue handling

•To present the nuts and bolts of an ocular pathology service.

GENERAL POINTS

Throughout this book, when relevant, the collection of the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) will be

referenced to provide data regarding the relative numbers for categories of disease. The COPLOW collection as it exists at January 2008 will be used. Throughout the book, at the conclusion of each chapter, readers seeking further detail will find lists of suggested published texts, papers and other source material. It should be noted that these lists are intended to be illustrative, rather than exhaustive.

Comparative Comments

Most human ocular pathology laboratories handle all of the tissue removed by ophthalmologists. In addition to globes, there are exenteration specimens, including the lids and orbital contents, or the contents of the globe after evisceration surgery. The majority of specimens, however, are skin lesions, conjunctival lesions, and orbital lesions following incisional or excisional biopsy.

Characteristics of eyes submitted to the COPLOW pathology service

Reasons for submissions: Most submissions are from animals where the globes have been enucleated in the interest of the patient with the following justifications:

•Blind, non-cosmetic and painful eyes

•To facilitate the diagnosis of a systemic disease, e.g. blastomycosis

•To remove a mass lesion perceived to represent a threat to the general health of the animal, should local invasion or metastatic disease subsequently occur.

Species represented include:

•68% canine (15 016 cases)

•24% feline (5203 cases)

•4% equine (758 cases)

•4% other (1.2% avian).

Tissue:

•Enucleated globes: 67%

•Evisceration specimens: 10%

•Other specimens: 23%

Disease type (these categories are not mutually exclusive):

•Neoplasia: 39%

•Glaucoma: 34%

•Inflammation: 29%

•Trauma: 15%

•Congenital disease: 2%.

Characteristics of conditions infrequently encountered in the pathology laboratory

Conditions that have largely cosmetic implications:

•Breed-related pigmentary variations

•Congenital abnormalities where vision and comfort are not impacted and which remain static

•Non-progressive focal lesions, e.g. corneal scars.

Conditions that may be successfully treated by means other than enucleation or excision including:

•Inflammatory conditions amenable to medical therapy, e.g. chronic superficial keratitis (Fig. 1.1)

•Cataract: cataracts are generally removed surgically by phacoemulsification and specimens are seldom submitted for histopathology

Conditions that may affect vision but rarely necessitate eye removal, such as:

•Retinal degenerations, including progressive retinal atrophy (Fig. 1.2)

•Chronic but inactive keratitis

•Optic neuritis or compression without progressive disease.

Comparative Comments

A large percentage of the globes removed and submitted to a human ocular pathology laboratory is composed of blind eyes following surgical or non-surgical trauma. Others represent end-stage diabetes, glaucoma, vascular occlusion, retinopathy of prematurity, phakomatoses, and malignant tumors. Criteria for enucleation are similar in that, except in the case of neoplasia, only blind eyes that are painful and/or disfiguring are generally removed.

Figure 1.1  Canine chronic superficial keratitis (degenerative pannus). This potentially blinding disease is seen frequently, but treated successfully with anti-inflammatory topical medications and seldom results in a pathology submission. German Shepherd dog, 5 years old: the right cornea illustrates temporal pigment with a cellular infiltrate and neovascularization extending nasally.

COPLOW RECOMMENDED TISSUE HANDLING

PROCEDURES (Figs 1.3, 1.4)

Enucleated globes

•Immediately dissect all extraneous tissues from the globe, unless directly involved in the pathologic process or considered important for orientation, e.g. conjunctival squamous cell carcinoma or an orbital meningioma

•Identify the location of the lesion of interest with a suture or a mark or provide a simple drawing.

Adnexa and other soft tissues

•Label each tissue submitted using sutures or ink to provide the pathologist with anatomic orientation. A simple drawing is also often an important aid in orientation

•Tiny fragments of tissue that cannot be properly oriented should be identified as to their anatomic origin or source. If they are all from one source, they can be processed and sectioned together but, if they are each from different areas, they might have to be labeled separately

•Tissues prone to wrinkling or folding, like keratectomy specimens, should be supported on plastic, not paper or wood (Fig 1.4)

■Avoid placing delicate tissues onto porous material, like wood or paper because they will adhere to these materials and may be destroyed during attempts to remove them from these substrates (Fig. 1.5).

Bone

•The pathologist should be alerted to the presence of bone in a sample in order to ensure that the tissue is decalcified prior to further processing and histo-sectioning

•A simple drawing on the submission form will help with the orientation of a specimen with a bony component.

Tissue fixation and mailing

General considerations in the selection of fixatives for the eye (Table 1.1)

Regardless of the fixative used, the volume of tissue to be fixed should be kept to a minimum, without sacrificing the integrity of the tissue’s anatomic orientation.

Figure 1.3  A drawing by the submitting clinician can be very useful in understanding the orientation and anatomic distribution of a lesion.

Formalin (10% neutral buffered formalin, or 4% formaldehyde)

•100% formalin is a concentrated solution (40% w/w) of formaldehyde in water.

•This most common of fixatives is cheap and effective as a general all-purpose fixative.

Figure 1.4  Keratectomy specimens mounted flat on plastic. These specimens from the left and right eyes are mounted on a non-absorbent surface, which will allow them to fix flat and rigid and make orientation easier.

Figure 1.5  Evisceration sample on paper. This specimen was wrapped in absorbent paper, which is difficult to remove without damaging the tissues.