key: cord-0044586-ee0e0b52
authors: Labelle, Philippe
title: The Eye
date: 2017-02-17
journal: Pathologic Basis of Veterinary Disease
DOI: 10.1016/b978-0-323-35775-3.00021-7
sha: f4d2b863dd597ca0ceb3f79d21236e79b8f62023
doc_id: 44586
cord_uid: ee0e0b52

nan

The eye is unique among organs in that its superficial anatomic location and the transparency of cornea allows for direct and detailed evaluation in the clinical setting. In fact, complete clinical examination of the eye in the living patient will generally provide as much or more information than evaluation at necropsy or gross assessment of an enucleated globe. Even in eyes in which corneal transparency is lost, the superficial location lends itself well to imaging modalities such as ultrasound. The complex terminology of ophthalmic pathology has roots in the terminology of clinical ophthalmology. Historical terms that are anatomically incorrect are widely used in both clinical and pathological settings. For example, "retinal detachment" is an acceptable diagnosis denoting the separation of the sensory neuroretina from the retinal pigment epithelium despite the fact that the two structures are part of the retina and are truly apposed rather than attached. The term "uveitis" in particular causes confusion between clinicians and pathologists. The histologic diagnosis of uveitis heavily relies on the infiltration of leukocytes in the uveal tract, whereas many of the clinical entities and processes diagnosed as uveitis represent vascular-mediated inflammation. Such clinical lesions can be difficult to evaluate histologically and may go unrecognized. For example, mild fibrin in the aqueous humor of the anterior chamber, easily diagnosed as aqueous flare clinically, may be difficult to appreciate grossly and may not be recognized histologically because the aqueous humor is not typically preserved during sectioning and processing. Furthermore, fibrovascular proliferation secondary to release of vascular mediators within the globe is often considered histologically as a separate event from inflammation with leukocytic infiltration. As such, both clinicians and pathologists must remember that the absence of leukocytes in the globe histologically is not incompatible with a clinical diagnosis of uveitis.

The embryologic development, general reactions to injury, and specific diseases vary significantly between the different components of the globe. There are some diseases affecting the eye as a whole, but most tend to affect one structure of/within the globe predominantly or exclusively. As such, the anatomic, physiologic, and pathologic features of the globe are usually presented separately for each portion: cornea and sclera, uvea, lens, vitreous, retina and optic nerve, and orbit. The features of eyelid, conjunctival, and orbital diseases are similar to those of skin, mucosa, and connective tissue elsewhere in the body, but there are particularities of periocular structures that warrant inclusion as part of a discussion on the eye.

All adult mammalian globes have similar general anatomy, depicted in Fig. 21-1 . The globe is a spherical biologic camera with a transparent surface, an elaborate autofocus lens derived from surface ectoderm, and a light-absorbing retina created by an outgrowth of specialized neurons from the brain. The other structures within the globe and those adjacent to it mainly provide support to ensure the optimal function of the cornea, lens, and retina in order to maintain vision.

The eye develops as a outpouching of brain tissue that extends to the skin surface of the developing embryo. The eye's purpose is to gather sensory information in the form of photons of light, which is absorbed by neurons specifically adapted to convert light into electrical energy. To facilitate access by those photons to the lightsensitive neurons of the retina, the surface ectoderm, which elsewhere would normally form ordinary opaque skin, undergoes specialized differentiation into the cornea and lens as the tentacle of the brain comes into proximity with it. Details of embryogenesis are discussed in later sections of this chapter.

Ocular anatomy includes specific features that are particularly relevant to ocular pathology. The globe is a sealed, media-containing organ, which is protected from injury by a bony orbit and mobile eyelids. It has a thick fibrous outer shell of cornea and sclera, and a series of barriers and mechanisms intended to reduce bystander injury.

Proper visual function requires that very precise anatomic relationships be maintained among the constituent parts of the globe. Minor alterations that would be insignificant in most other tissues can have devastating results within the globe. For example, even mild accumulation of fluid behind the retina (serous retinal detachment) can result in blindness; repair with granulation tissue that can restore some function elsewhere can lead to opacity and loss of light perception.

Vision requires that the cornea, lens, and fluid media within the globe remain optically clear. This means that accumulation of • Chemical mediators of wound healing in chronic uveitis that stimulate corneal stromal vascularization and fibrovascular proliferation • Fibrovascular proliferation in turn can cause tractional retinal detachment or glaucoma secondary to pupillary block or peripheral anterior synechia

The globe has a complex embryogenesis involving carefully orchestrated interactions of neuroectoderm, surface ectoderm, and periocular mesenchyme throughout embryogenesis and in early life . In carnivores the ocular development continues into the fifth or sixth week after birth. As such, not all developmental errors are congenital, especially in carnivores. Because the globe is not essential for in utero survival, both mild and severe ocular congenital anomalies are encountered in otherwise normal patients. Selective breeding practices have increased the frequency of ocular anomalies. Those that are important or prevalent are discussed in sections dealing with diseases of the specific ocular segment affected. The eye begins very early in gestation as an outgrowth from the primitive neural tube ectoderm, essentially the primitive forebrain. This primary optic vesicle grows outwardly from the brain toward the overlying surface ectoderm, remaining connected to the brain by the optic stalk. As the primary optic vesicle approaches, the overlying ectoderm will focally thicken to form the lens placode. The lens placode thickens, invaginates, and separates from the surface ectoderm migrating inwardly as the lens vesicle to indent the spherical optic vesicle. As the lens vesicle pushes into that optic vesicle, the optic vesicle collapses and invaginates to form a bilayered optic cup. When the lens vesicle separates from the surface ectoderm, that ectoderm re-forms to eventually become corneal exudates or changes in refractive properties related to conditions such as edema and fibrosis are extremely detrimental to visual acuity. Responses intended to save the globe itself can cause loss of function, essentially defeating the purpose of protecting the globe.

Most of the visually critical tissues within the globe have limited to no regenerative capacity. Some, like the adult retina, are essentially postmitotic and cannot regenerate at all. Others, such as the lens and cornea, are capable of limited regeneration, but the regeneration almost never re-creates a perfect structural or functional replica of the original tissue. Many of the most significant intraocular lesions are related to events of healing, at times from very minor injuries. There are essentially no functionally insignificant lesions within the globe because every injurious event has a visual consequence even if the degree of impairment is not easily measured or depends on a cumulative effect.

The same unique features of ocular anatomy and physiology that serve to protect the globe from injuries affecting other parts of the body also render the globe vulnerable to the propagation of injury once those defenses have been overcome. The same defenses that prevent entry of various types of chemical or biologic agents also prevent or limit drainage of dangerous by-products of tissue injury and inflammation. The fluid media within the globe allows diffusion of infectious toxic agents and chemical mediators of inflammation throughout the globe.

Ocular bystander injury occurs when injury to one component of the globe "spills over" and affects other parts of the globe. Many diseases that predominantly affect one portion of the globe can also cause significant functional impairment by extension in adjacent components. Examples include the following: • Inflammatory effusion from choroiditis, which can cause retinal detachment • Alteration in aqueous humor composition and flow, which can lead to cataracts The primary optic vesicle migrates from the brain toward the overlying surface ectoderm while remaining connected to the brain by the optic stalk. The overlying ectoderm will thicken to form the lens placode. B, The lens placode thickens and invaginates to form the lens vesicle, eventually pushing into the optic vesicle. The optic vesicle also invaginates to form the bilayered optic cup. C, The lens vesicle separates from the surface ectoderm, which re-forms to become the corneal epithelium. The inner layer of the optic cup will progress to form the inner and outer neuroblastic layers and eventually differentiate into the neuroretina. 

pathologic features than those of the globe itself. However, the diseases of these structures, the eyelid and conjunctiva in particular, represent a significant proportion of ocular conditions in clinical ophthalmology.

The epithelium of the eyelids develops from the surface ectoderm adjacent to the cornea. After separation of the lens vesicle, the surface ectoderm regains continuity to form the cornea. Ectoderm at the periphery of the cornea then migrates over the surface of the embryonic cornea, accompanied by underlying periocular mesenchyme to form the eyelids. The ectoderm forms the surface epithelium and glands; the accompanying periocular mesenchyme forms the dermis and the eyelid muscles. These ingrowing eyelids fuse over the central cornea. This fusion provides a physical protection to the globe and provides the immature cornea with a sterile environment in which to complete its embryologic development. Physiologic ankyloblepharon or fusion of the eyelids in the postnatal period is normal in dogs and cats, and it persists 10 to 15 days allowing tear production to reach adequate levels.

The mature eyelids are movable folds of skin that slide across the surface of the cornea on a film of mucus and fluid known as the tear film. This blinking movement serves to help distribute the protective tear film across the corneal surface and to remove unwanted particulate debris from the corneal surface. Each eyelid has an anterior surface of haired skin, with all of the adnexal glands as seen in skin at other sites. The dermis is modified by the addition of striated muscle (orbicularis oculi and levator muscles). The inner surface of the eyelid, which apposes the cornea and bulbar conjunctiva, is covered by a mucous membrane known as the palpebral conjunctiva (see Conjunctiva below). The transition between the eyelid skin and palpebral conjunctiva is termed the eyelid margin. The eyelid margin is characterized by several rows of large modified hairs (eyelid cilia/eyelashes), which serve a direct protective purpose. The cilia are largest and most numerous along the margin of the upper eyelid; they may be infrequent or absent along the lower eyelid. The eyelid margin also includes a row of large modified sebaceous glands known as meibomian glands (or tarsal glands). The meibomian glands produce meibum, which forms the superficial lipid layer of the tear film that prevents evaporation and aids in the dispersal of the aqueous component of the tear film.

The conjunctiva is a mucous membrane extending from the palpebral margin of the eyelid to the periphery of the cornea. The conjunctiva is continuous from the inner surface of the eyelid to the surface of the globe. The portion of conjunctiva that covers the posterior surface of the eyelid is the palpebral conjunctiva, and the portion attached to the surface of the globe and continuous with the peripheral cornea at the limbus is the bulbar conjunctiva.

The conjunctival epithelium includes goblet cells, melanocytes, dendritic cells, and other leukocytes. The palpebral conjunctiva is composed of stratified squamous nonkeratinizing epithelium near its origin at the eyelid margin. Most of the palpebral conjunctival consists of stratified columnar epithelium with variable numbers of goblet cells. The bulbar conjunctiva extends over the globe and merges with the corneal epithelium at the limbus. The epithelium of the bulbar conjunctiva lacks goblet cells. At the junction between bulbar conjunctiva and corneal epithelium, there is a population of germinal cells that are the permanent replicative cells of the corneal epithelium (stem cells). They are the source of replacement corneal epithelial cells in both physiologic processes and pathologic responses.

epithelium. The presence of the corneal epithelium seems to stimulate one or more waves of periocular mesenchyme that forms the primitive corneal stroma and endothelium. This periocular mesenchyme is derived from the neural crest and eventually also forms the sclera, the uveal stroma, and a well-developed but transient intraocular network of blood vessels (hyaloid artery and tunica vasculosa lentis) that nourish the developing retina and lens ( Fig. 21-3) . Following lens placode induction, the inner layer of the optic cup will progress to form the inner and outer neuroblastic layers. These neuroblastic layers will eventually differentiate to form the neuroretina. The retinal pigment epithelium (RPE) originates from the pigmented outer layer of the optic cup. Differentiation of the neuroretina beyond the neuroblastic layers requires a functional RPE. The eyelids, extraocular muscles, lacrimal gland, and orbit mostly develop independent of the globe and are generally not affected by those diseases that impair development of the eye itself.

In the adult globe of domestic animals, only the corneal epithelium and lens epithelium are derived from the surface ectoderm. The neuroretina, retinal pigment epithelium, posterior iris epithelium, iris dilator and sphincter muscles, and ciliary epithelium are derived from the neural ectoderm. The neural crest is the origin of the corneal stroma, corneal endothelium, uveal stroma, ciliary muscle, and trabecular cells. The mesoderm provides the vascular endothelium.

The first line of defense for the globe includes the eyelids, conjunctiva, and the soft tissues and bones of the orbit. These create a protective physical barrier against outside forces as well as extension of diseases from surrounding structures (e.g., nasal cavity, oral cavity). This protective wall allows light penetration, but it excludes the many elements of the external environment that might injure the structures responsible for vision (cornea, lens, and retina) .

The diseases of the eyelids, conjunctiva, and orbit tend to mimic those of similar tissues at other sites and have fewer unique The periocular mesenchyme is organizing to form the choroid and sclera. The anterior chamber has been formed, but the anterior lip of the optic cup has not yet folded inwardly to induce the formation of the iris and ciliary body. The relatively large lens is surrounded by a rich vascular tunic derived from the hyaloid artery and pupillary membrane. RPE, Retinal Corneal transparency is essential for vision and is the result of a number of anatomic and physiologic features listed in Box 21-1. The corneal epithelium differs from that of the conjunctiva or skin in that there is no keratinization or pigmentation. The corneal stroma resembles conjunctival substantia propria or dermis, but it lacks blood vessels, hair follicles, glands, and leukocytes. The narrow collagen fibrils are arranged in compact lamellae separated by a space that corresponds to the wavelength of visible light. Thus the cornea allows the passage of light without any scattering. To further facilitate the unimpaired passage of light, the corneal stroma is maintained in a dehydrated state compared with that of most other tissue. That dehydrated state is maintained passively by intercellular junctions within the corneal epithelium and endothelium, which exclude water from the tear film and anterior chamber, respectively. It is further maintained by the active removal of solutes (and thus fluid) by energy-dependent sodium potassium membrane pumps within the corneal endothelium. The corneal stroma lacks blood

The space between the palpebral and bulbar conjunctiva is the conjunctival sac. The space between the upper and lower eyelid is known as the palpebral fissure. The medial (nasal) limit of the palpebral fissure (where the upper and lower eyelids are continuous) is the medial canthus. The lateral (temporal) margin of the palpebral fissure is the lateral canthus.

The substantia propria of both the palpebral and bulbar conjunctiva resembles the lamina propria of any other mucous membranes. It consists of well-vascularized loose connective tissue. There are both diffuse lymphoid tissue and lymph nodules (mucosaassociated lymphoid tissue [MALT] and conjunctiva-associated lymphoid tissue [CALT] ) in the substantia propria. The CALT responds immunologically to the microbial flora within the conjunctival sac.

The ventral conjunctiva, as it transforms from palpebral to bulbar conjunctiva, undergoes an additional specialization to form the third eyelid (nictitating membrane). This large fold of conjunctiva protrudes from the ventral-medial canthus over the anterior surface of the cornea and contains a central supporting plate of cartilage and a stroma of dense fibrous tissue, containing an accessory lacrimal gland (gland of the third eyelid). Both its anterior and posterior surfaces are covered by stratified squamous nonkeratinizing epithelium. In most domestic species, its movement is passive, serving to cover the globe and provide an extra level of protection when the globe is retracted into the orbit by the retractor bulbi muscle.

The cornea and sclera form the fibrous tunic of the globe. The cornea is the anterior third of the fibrous tunic. At the limbus the cornea merges with the conjunctiva and sclera. The cornea and sclera provide structural support for the globe. In addition, the cornea allows light penetration and therefore vision by its transparency. The cornea has four histologic layers ( The tear film is a clinically important functional layer that covers the corneal epithelium, but it cannot be evaluated histologically. The cornea is 0.5 to 0.8 mm thick, depending on species, regions of the cornea, and age. The corneal epithelium, the anterior most layer, is derived from fetal surface ectoderm and consists of stratified nonkeratinizing epithelium that includes surface (nonkeratinized squamous) cells, intermediate (wing) cells, basal cells, and a basement membrane. The corneal epithelium is 5 to 7 layers thick in dogs and cats and approximately 8 to 15 layers thick in larger animals. The corneal epithelium is completely renewed every 5 to 7 days. The corneal stroma represents roughly 90% of the corneal thickness. The corneal stroma is composed of rare keratocytes, which are modified fibroblasts. The keratocytes are interspersed between the collagen fibrils that form parallel lamellae. The stroma also contains abundant water and the extracellular matrix composed of glycoaminoglycans and other components. The corneal stroma lacks blood vessels. The posterior (inner) surface is covered by a single layer of cuboidal epithelial cells, known as the corneal endothelium, which like the stroma is derived from periocular mesenchyme. The basement membrane of the corneal endothelium, termed Descemet's membrane, lies between the stroma and endothelium and is easily recognizable histologically. The corneal endothelium in adults of most domestic mammals is postmitotic and has no or limited ability to replicate. Descemet's membrane carnivores and those of herbivores. The iridocorneal angle also includes a network of trabeculae termed ciliary cleft and corneoscleral trabecular meshwork that allow drainage of aqueous humor. The ciliary cleft lies posterior to the pectinate ligament and consists of widely separated collagen beams lined by trabecular cells. The corneoscleral trabecular meshwork is embedded in the inner sclera. It is similar in composition to the ciliary cleft but has smaller trabeculae and smaller intertrabecular spaces.

The choroid is the posterior portion of the uvea and lies between the retina and sclera. The innermost layer is the choriocapillaris, a thin layer of capillaries delimited on the inner aspect by a basement membrane (Bruch's membrane). The choriocapillaris provides nutrition to the outer retina. The choroidal stroma is the middle layer and includes numerous blood vessels supported by connective vessels, and the cornea is dependent on the tear films, conjunctival and scleral vessels, and the aqueous humor for nutrition and oxygen.

The sclera represents most of the fibrous tunic of the globe. It consists of three layers. The outermost layer is the episclera, which is a densely vascularized fibrous layer that connects Tenon's capsule to the sclera proper. The sclera proper (scleral stroma) consists of densely packed collagen with elastic fibers, fibroblast, as well as proteoglycans and glycoproteins. The innermost layer is the lamina fusca, which contacts the choroid. Blood vessels and peripheral nerves use channels within the sclera to vascularize and innervate to the uveal tract. The scleral venous plexus that provides some of the outflow for the aqueous humor is located in the anterior aspect of the sclera, within the sclera proper. On the posterior aspect of the sclera, there is a specialized fenestrated area termed lamina cribosa, which allows the axons of the retinal ganglion cells to exit the globe and form the optic nerve.

The uvea, or uveal tract, is the vascular tunic of the globe. It is divided into three portions: the iris, ciliary body, and choroid. The iris and ciliary body form the anterior uvea, and the choroid may be termed posterior uvea. The uveal tract contains virtually no resident lymphoid tissue and lacks true lymphatic vessels.

The anterior aspect of the iris consists of a layer of modified stromal cells. Most of the iris consists of connective stroma with blood vessels and nerves. Variable numbers of melanocytes are dispersed in the stroma, mostly in the posterior stroma. Irides of blue eyes have noticeably fewer melanocytes than brown irises. There are two smooth muscle groups within the iris, the constrictor and dilator muscles, which control the size of the pupil and therefore light penetration. The posterior aspect of the iris consists of a layer of neuroepithelium termed posterior iris epithelium, which is continuous with its counterpart in the ciliary body. In horses and ruminants, the posterior iris epithelium forms a nodular and cystic structure termed corpora nigra in horses and granula iridica in ruminants. This protrusion of neuroepithelium further contributes to the control of light penetration.

The ciliary body extends from the base of the iris to the junction with the choroid and retina. The ciliary body consists of connective stroma with blood vessels and nerves and a prominent smooth muscle, the ciliary muscle, which is aligned along a meridional plane. This muscle allows accommodation through changes in the position or shape of the lens, and contraction of the muscle increases the drainage of aqueous humor through the trabecular meshwork. The anterior portion of the ciliary body includes numerous (70 to 100) processes or folds (pars plicata) that are absent in the posterior portion (pars plana). The ciliary body is lined by two layers of neuroepithelium . The inner layer is nonpigmented, whereas the outer layer is pigmented. The ciliary epithelium, specifically the nonpigmented epithelium, contributes to aqueous humor production through both filtration and active transport mediated processes such as the carbonic anhydrase pathway. The ciliary epithelium provides the extracellular matrix that forms the zonular ligaments that suspend the lens and also produces the hyaluronic acid incorporated in the vitreous.

The iridocorneal angle is delimited anteriorly by the pectinate ligament, which extends from the anterior base of the iris to the inner peripheral cornea at the termination of the Descemet's membrane . In the dog and cat, the normal pectinate ligament is difficult to evaluate histologically because the fibers are more slender and more widely dispersed than in other domestic species. Horses and ruminants have robust pectinate ligaments. The pectinate ligaments of pigs are intermediate between those of Figure) , Cat. The aqueous humor is produced by the ciliary epithelium (black arrowhead), enters the posterior chamber (PC), flows around the pupillary margin of the iris (I), and enters the anterior chamber (AC). The aqueous humor then percolates through the ciliary cleft (asterisk) and corneoscleral trabecular meshwork (arrows) to access the scleral veins. Most of the aqueous humor exits the globe via the scleral veins ("conventional" pathway). A small proportion of aqueous humor exits via the uveoscleral outflow pathway ("unconventional" pathway). White arrowhead, Termination of Descemet's membrane; C, cornea; S, sclera; CB, ciliary body. H&E stain. (Courtesy Dr. P. Labelle, Antech Diagnostics.) PC AC CB I * C S the mature lens epithelium expresses vimentin, a filament typically found in mesenchymal cells.

The lens epithelium produces new lens fibers throughout life. As new fibers are produced, there is a progressive increase in the density at the center of the lens (lens nucleus), which is formed by the oldest lens fibers. The lens is avascular and dependent on the aqueous humor for transport of nutrients and removal of cellular waste products. Lens metabolism is primarily via anaerobic glycolysis and the hexokinase pathway. There is limited aerobic glycolysis via the citric acid pathway. Glucose is delivered by the aqueous humor and is absorbed across the lens capsule.

The purpose of the lens is to further refract light that has passed through the cornea and to focus that light onto the retina. As such, the lens must remain transparent and in its proper location within the pupillary aperture. Lens transparency depends on the precise orientation of the lens fibers, the scarcity of cytoplasmic organelles, unique intracellular crystalline proteins, and on the maintenance of a state of dehydration. This dehydration is maintained primarily by excretion of electrolytes through an active sodium-potassiumdependent adenosine triphosphatase pump, located mostly in the membranes of anterior lens epithelium and in the lens fibers. The location of the lens within the pupillary aperture is maintained by the circumferential zonular ligaments that extend from the ciliary body to the lens equator. Contraction and relaxation of the ciliary muscle alters the tension on the zonular ligaments, resulting in changes in the shape or position of the lens, thus facilitating accommodation/focus.

The vitreous is an optically clear elastic hydrogel. It is a modified extracellular space, not a cavity, and represents approximately 80% of the volume of the globe. It is composed almost entirely of water (99%). The remaining 1% consists mostly of collagen, hyaluronic acid, and widely dispersed cells called hyalocytes. Little is known about the production and turnover of the vitreous humor. The ciliary epithelium produces the hyaluronic acid and other components. Nonneuronal cells of the retina may also contribute. The collagen fibers form a complex network and provide attachment to the adjacent structures including the posterior lens capsule, ciliary epithelium, internal limiting membrane of the retina, and optic stroma that is typically heavily pigmented. In domestic species except the pig, the inner aspect of the choroidal stroma includes the tapetum lucidum. The tapetum lucidum is a specialized layer located only dorsal to the optic nerve in domestic animal species and serves to reflect light that has already passed through the retina further stimulating the photoreceptor cells and improving vision in low light. Domestic carnivores have a cellular tapetum lucidum composed of regularly arranged cells containing reflective rods suggestive of modified melanocytes. Domestic herbivores have a fibrous tapetum lucidum composed of regularly arranged collagen fibers and only rare fibrocytes. The pig does not have a tapetum lucidum. The outer aspect of the choroidal stroma includes larger vessels. The suprachoroid is the outermost layer of the choroid and provides the transition between the choroid and sclera.

The purpose of the lens is to refract light on the retina and provide focus. The lens is a biconvex, avascular, transparent accumulation of elongated epithelial cells. It is located posterior to the iris and anterior to the vitreous. It is suspended by the zonular ligaments (zonules, zonular fibers) formed by the ciliary epithelium and held in position in part by the presence/pressure of the vitreous. The relative size, shape, and elasticity vary significantly between species and to a lesser extent with age. The lens capsule is the basement membrane of the lens epithelium. It is composed of predominantly type IV collagen and is produced throughout life by the lens epithelium. The lens capsule is impermeable to large proteins but allows diffusion of water and electrolytes that nourish the lens epithelium. The lens contains only one cell type, the lens epithelium, which forms a single layer of cuboidal epithelial cells just internal to the anterior lens capsule. Epithelium is absent from the posterior surface of the lens. At the lens equator, the epithelial cells are mitotically active and more columnar. The cells migrate inwardly, rotate, and elongate to become lens fibers ( Fig. 21-8) . The lens fibers elongate to reach opposite poles of the lens. As the cells differentiate, they lose most of their cytoplasmic organelles and lose their nuclei. The lens fibers are arranged in layers with interdigitations of their plasma membranes and gap junctions that allow each lens fiber to adhere tightly to adjacent fibers. The lens epithelium arises from the surface ectoderm and expresses cytokeratin early during embryogenesis, but The retina includes three layers of neurons (ganglion cell layer, inner nuclear layer, and outer nuclear layer) separated by cell-free layers created by the intermingling of the axons and dendrites of those neurons. The cell types found in the retina include five types of neurons: ganglion cells, bipolar cells, horizontal cells, amacrine cells, and photoreceptors (rods and cones). The retina also includes nonneuronal Müller glial cells. The rods and cones transmit the neuronal signal through the bipolar cells to the ganglion cells. Horizontal and amacrine cells modulate the signal. Müller cells are nonneuronal glial cells that provide support for the retina.

Histologically, the retina is separated in 10 layers ( Fig. 21-9 ). The 9 internal layers comprise the neuroretina (neurosensory retina). The inner limiting membrane is a basement membrane that includes the inner processes of Müller cells. The nerve fiber layer consists of the axons of the ganglion cells. The axons are arranged parallel to the retinal surface and continue to form the optic nerve. The axons exit the globe through a series of perforations, known as the lamina cribrosa, present within the sclera at the posterior pole of the globe. The axons within the nerve fiber layer are unmyelinated in order to maintain transparency. In most species, axons become myelinated at about the level of the lamina cribrosa as they exit the globe. The ganglion cell layer consists of the cell bodies of the ganglion cells and occasionally includes displaced amacrine cells, and it is only one cell layer thick throughout the retina except the central retina (area centralis). The density of ganglion cells varies between species but is lowest in the peripheral retina. The inner plexiform layer is composed of synapses including those between retinal ganglion cells and both bipolar and amacrine cells. There are also synapses between bipolar and amacrine cells. The inner nuclear layer includes the nuclei of the bipolar, horizontal, and amacrine cells. The nuclei of the nonneuronal Müller cells are also within the inner nuclear layer. The outer plexiform layer is composed of synapses between the photoreceptors (rods and cones) and the bipolar and horizontal cells as well as synapses between the adjacent photoreceptors. The outer nuclear layer includes the nuclei nerve head. The hyalocytes are thought to have secretory and phagocytic functions and are the source of fibroblasts in healing responses. Along the anterior surface of the vitreous is a shallow depression known as the hyaloid fossa, in which lies the posterior surface of the lens. The anterior surface of the vitreous undergoes condensation to form the anterior hyaloid membrane, which separates the vitreous from the aqueous humor. The vitreous seems to function mainly to maintain the shape of the globe, help support the lens and retina in normal positions, and provide some cushioning against blunt trauma.

The retina transduces visible light into electrical neuronal impulses, which are transmitted to the visual cortex of the brain. Light passes through the transparent cornea, ocular media, and lens to reach the photoreceptors of the retina. The photoreceptors, the rods and cones, contain photopigment that helps convert light energy in neuronal signals. The electrical signal generated by activation of the photopigment is transmitted in a stepwise manner from the outer nuclear layer to the neurons of the inner nuclear layer, then to the ganglion cells, and finally via the nerve fiber layer to the optic nerve and brain. The number of photoreceptors linked to a single ganglion cell varies greatly among species and is one of the variables determining visual acuity and the efficiency of low-light vision. In all domestic animals except the pig, light not absorbed by the photoreceptors is reflected by the tapetum lucidum to stimulate the photoreceptors a second time. The tapetum lucidum is therefore assumed to be a choroidal adaptation to increase the efficiency of vision in low light. The retina lines the posterior aspect of the globe with the exception of the optic nerve head. It lies between the vitreous and choroid. The neuroretina is not attached to the retinal pigment epithelium (RPE) and/or choroid except at the optic disc and at its very periphery, where it becomes continuous with the epithelium of the pars plana of the ciliary body (the site of transition is known as the ora ciliaris retinae). numerous foramina through which blood vessels and nerves reach or leave the globe. The orbit is formed by the fusion of five to seven bones, depending on the species. It is a complete bony shell, except in dogs, cats, and pigs, in which the dorsal roof of the orbit is formed only by the supraorbital ligament that extends from the frontal bone to the zygomatic bone, leaving the dorsal orbit incomplete. The orbit contains the globe itself but also the extraocular muscles, abundant fat, lacrimal gland, zygomatic salivary gland, and all the muscles and nerves that support these structures.

The lacrimal gland is a specialized serous salivary gland located in the orbit, dorsolateral to the globe. Along with the histologically similar gland of the third eyelid, it is responsible for the production of the serous component of tears. It empties through 15 to 20 small excretory ducts at the lateral part of the fornix of the superior conjunctival sac.

The eyelids respond to insult in a manner similar to that of haired skin elsewhere on the body (see Chapter 17). Infections, immunemediated diseases, and neoplasms with a predilection for the head and neck may affect the eyelids directly or by extension. The eyelids are most often involved as part of multicentric skin diseases or affected by diseases that could affect other areas of skin. The few inflammatory diseases and neoplasms that have a predilection for the eyelids are described later under specific diseases.

Although the responses of the eyelids mimic those of haired skin elsewhere, there may be vision-threatening consequences to altered eyelid structure and function. Changes to the shape of the eyelids as a result of inflammation, fibrosis/scarring, or neoplasia may interfere with proper eyelid closure and function. This may cause inappropriate exposure of the conjunctiva and cornea, changes to tear film distribution and contents, or inability to properly protect the globe from injury. The abnormal eyelid may cause mechanical injury with direct contact to the cornea. There may also be extension of eyelid inflammation or neoplasia to the adjacent conjunctiva or cornea.

of the photoreceptors. The outer limiting membrane is not an actual structure and is not a basement membrane. It is a band formed by tight junctions between cell membranes of photoreceptors and Müller cells. The outer limiting membrane is a barrier between the potential subretinal space and the outer nuclear layer. The photoreceptor layer is composed of the inner and outer segments of the rods and cones. The inner segments include the cells organelles. The outer segments contain the photopigments where light is converted into a neuronal signal. The retinal pigment epithelium (RPE) is the outermost layer of the retina. It is a single layer of cells continuous with the pigmented ciliary epithelium and located between the neuroretina and choroid. The RPE has a different embryology than the neuroretina and is not directly involved in vision. The photoreceptors are embedded into crevices within the surface of the adjacent RPE, but there are no actual cellular junctions. As such, the potential subretinal space where edema, hemorrhage, and inflammatory cells can accumulate is the remnant of the lumen of the primary optic vesicle and is delimited by the tight junctions between the RPE cells and the outer limiting membrane. The clinically termed "subretinal space" is technically within the retina, not subretinal. The RPE that overlies the tapetum lucidum (dorsally) is nonpigmented, and the RPE may also lack pigment in color-dilute animals. In the pig, which lacks a tapetum lucidum, the RPE is diffusely pigmented. The RPE supports photoreceptor function by reactivating spent photopigments. It also phagocytoses portions of the photoreceptor outer segments that are shed as part of normal renewal. The RPE transports nutrients to the outer retina and removes waste products. It also scavenges free radicals and has antioxidant properties.

In domestic species, the retina has a dual blood supply. Blood vessels within the retina supply the inner aspect, whereas the outer retina, specifically the photoreceptors, is supplied by the choroidal vasculature. The presence of blood vessels makes inner retinal ischemia quite rare, whereas ischemia of the outer retina, which depends on diffusion from choroidal vessels, is more common. In fact, it is expected with retinal detachment. The distribution of blood vessels within the retina varies considerably between species. In domestic ruminants, pigs, and carnivores, the retina contains blood vessels throughout most of the retina (holangiotic pattern). In horses only the area adjacent to the optic disc is vascularized; the remainder of the retina is avascular (paurangiotic pattern), increasing the dependence on choroidal supply. Histologically, blood vessels may be present within the nerve fiber, ganglion cell, and inner plexiform layers.

The optic nerve is the continuation of the nerve fiber layer of ganglion cell axons into the optic chiasm and brain and uses the preexistent tube formed by the embryonic optic stalk (Fig. 21-10 ). The portion of the optic nerve within the sclera that includes axons, myelin, and supporting glial cells forms the optic nerve head (optic disc [E- Fig. 21-2] ). The axons of the retinal ganglion cells exit the globe through a series of perforations, known as the lamina cribrosa, present within the sclera at the posterior pole of the globe. In most species, axons become myelinated just prior to or just after crossing the lamina cribrosa. In dogs, the myelin extends several millimeters within the sclera or internal to the lamina cribrosa, and this extension is responsible for the prominence of the optic disc in that species. The optic nerve is an extension of the brain rather than a true peripheral nerve. The myelin is produced by oligodendrocytes instead of Schwann cells (see Chapter 14).

The bony orbit surrounds most of the globe, except the cornea, and separates the globe from the brain. Along its posterior border are Corneal injuries that extend beyond the epithelium will also cause stromal necrosis, recognized clinically as keratomalacia. This is most commonly seen in rapidly progressing ulcers contaminated with bacteria or fungi but may also be observed in sterile wounds. Many organisms produce enzymes that cause stromal necrosis. Furthermore, neutrophils will migrate from the tear film and limbus in large numbers and release lytic enzymes also contributing to the stromal destruction and resulting in neutrophil-induced suppurative keratomalacia. These ulcers, clinically termed melting ulcers, will progress rapidly over just a few days. Corneal healing in those instances will require fibrotic repair. The most severe cases will cause full-thickness stromal necrosis exposing Descemet's membrane. Descemet's membrane may bulge anteriorly into the defect created by the loss of the overlying stroma and epithelium to create a descemetocele. In the absence of immediate medical intervention, this typically leads to rupture of Descemet's membrane (perforating ulcer), leakage of aqueous humor from the anterior chamber, and possibly iris prolapse.

Corneal edema (stromal edema) is the presence of excess fluid and alteration of glycoaminoglycans contents within the stroma leading to separation of lamellae and decreased transparency. The causes of stromal edema are numerous, and edema may be present with injury to the epithelium, the stroma itself, or the endothelium (Box 21-3). Any injury that results in interruption of the corneal epithelium may cause stromal edema from osmotic absorption of fluid from the tear film. The excess fluid should be removed by the actions of the endothelium after reepithelialization of the defect. Inflammation/ infiltration of leukocytes that reach stroma from the surface, conjunctiva, or anterior chamber may be accompanied by edema. Neovascularization of the stroma from ingrowth of blood vessels at the limbus often results in edema, as new immature vessels tend to be leaky. The corneal endothelium is critical to maintaining the stroma's dehydrated state. The endothelium uses energy-dependent sodium potassium transport pumps to transfer solutes in the anterior chamber (with fluid leaving by osmosis). Cellular tight junctions act as a physical barrier to prevent extension of fluid from the aqueous humor in the stroma. Any injury to the corneal endothelium may cause edema from absorption of fluid from the aqueous humor or decreased ability to respond to edema secondary to epithelial or stroma injury. Common causes of endothelial injury include contact between the lens and corneal endothelium from anterior lens luxation, glaucoma, and intraocular inflammation (leukocytic infiltration).

Corneal neovascularization (stromal neovascularization) is the ingrowth of blood vessels from the limbus in the corneal stroma.

The reaction of conjunctiva to injury is comparable to that of other mucous membranes. The normal conjunctival surface flora may be altered with conjunctival disease as well as corneal disease. The conjunctival epithelium responds to acute injury with necrosis leading to erosion or ulceration. Chronic injury may cause hyperplasia, squamous metaplasia and keratinization, decrease or increase in the number of goblet cells, and hyperpigmentation. The underlying substantia propria (conjunctival submucosa) typically responds to acute injury with edema and hyperemia. Neutrophils may be present if there is epithelial ulceration. Almost any cause of chronic conjunctival injury will result in the infiltration of lymphocytes and plasma cells in the substantia propria (nonspecific lymphoplasmacytic conjunctivitis). Lymphoid hyperplasia may be present in some chronic conditions, notably in horses, and those lymphoid nodules may become large and easily recognizable clinically. Eosinophils are a feature of hypersensitivity disease/allergic conjunctivitis and foreign body reactions in dogs, cats, and horses, and often numerous with parasitic infections (habronemiasis in horses and onchocerciasis in dogs and cats). Macrophages may infiltrate the conjunctiva with parasitic disease, foreign body injury, and some idiopathic inflammatory disease such as nodular granulomatous episcleritis in dogs. Fibrosis/scarring is the end result of some cases of severe conjunctival injury and healing, and it may interfere with eyelid function as noted previously depending on extent and location. Chronic sun exposure may cause solar elastosis and other forms of solar damage in the superficial substantia propria as it does in the dermis.

The cornea responds to injury in a variety of manners, but most diseases provoke a few common processes that may be seen in combination (Box 21-2).

Because most of the corneal injuries are from external insults, the corneal epithelium is most commonly affected. Epithelial necrosis is typically the result of acute injury from trauma, severe dessication, chemical burn, and less frequently infectious diseases. Minor injuries may cause only erosions, but more severe damage will cause fullthickness loss of epithelium (corneal ulcers). There is immediate osmotic absorption of water from the tear film in the anterior stroma after corneal ulceration, resulting in focal superficial stromal edema. Corneal ulcers imply the exposure of the underlying stroma, which can be detected clinically with the use of water-soluble dyes such as fluorescein. Neutrophils from the tear film will rapidly infiltrate the area to protect the cornea against opportunistic infection and provide growth factors for subsequent wound healing. Small uncomplicated lesions with minimal stromal involvement will heal by sliding and proliferation of the epithelium (see Corneal Wound Healing). 

Nonspecific Chronic Keratitis with Epidermalization. Nonspecific chronic keratitis with epidermalization (cutaneous metaplasia) is an adaptive response to mild but persistent corneal injury. These changes inevitably result in loss of corneal transparency; however, the purpose is to maintain corneal integrity and avoid eventual rupture as a consequence of chronic injury. The most common causes of mild chronic irritation are tear film abnormalities and mechanical irritation. Tear film abnormalities that result in desiccation include diseases such as keratoconjunctivitis sicca, improper distribution of tears because of abnormal eyelid structure or function, and any condition that prevents the eyelids from closing properly (lagopthalmos). Mechanical irritation may be secondary to eyelid diseases such as entropion or eyelid neoplasia, anomalous distribution/direction of eyelashes (distichiasis and trichiasis), or friction from the nasal skin folds. Unlike acute injuries discussed previously, mild persistent irritation does not cause necrosis. The corneal response to mild chronic injury is a stereotypical pattern of epithelial and stromal changes . The epithelial changes of nonspecific chronic keratitis consist of hyperplasia with rete peg formation, melanosis, and keratinization. The combination of these changes has been termed corneal epidermalization or cutaneous metaplasia because the corneal epithelium acquires features expected with the skin's epidermis. Corneal melanosis results from centripetal migration of limbal melanocytes and melanin accumulation within the corneal basal cells. The stromal changes of nonspecific chronic keratitis consist of superficial neovascularization and fibrosis. There may be infiltration of inflammatory cells, most often lymphocytes and plasma cells. There may also be significant pigmentary incontinence (leakage of melanin from the epithelial basal cells) resulting in superficial stromal melanosis from pigment accumulation in macrophages and fibroblasts. Not all examples of nonspecific chronic keratitis involve the entire range of adaptive changes; it is possible, for example, to have keratinization without melanosis or epithelial changes without accompanying stromal fibrosis and neovascularization. Some of the lesions of nonspecific chronic keratitis are reversible if the underlying cause can be removed, although there may be permanent loss of transparency. Clinically these changes may be recognized simply as "chronic keratitis" or "pigmentary keratitis" if the changes include melanosis. Nonspecific chronic keratitis that includes melanosis should not be Because the normal stroma is avascular, stromal neovascularization is always considered a pathologic response. Most instances of corneal neovascularization follow a predictable series of events (Box 21-4).

The potential causes of corneal neovascularization are wide ranging and include trauma (both accidental and surgical), inflammation, infection, degenerative conditions, and others. Corneal neovascularization is primarily mediated by vascular endothelial growth factor (VEGF) in most instances; however, other growth factors may play a role depending on the cause. Following the initiating event, there is a period of latency during which VEGF levels will increase. The latent period lasts approximately 24 hours. This is followed by dilation of limbal blood vessels, which can be recognized clinically and precedes corneal neovascularization. For vascular sprouting to occur there will be multifocal enzymatic digestion of the basement membrane of the limbal vessels accompanied by endothelial cell proliferation. The endothelial cells will then migrate in the direction of the initiating cause, usually dissecting parallel to the corneal stromal lamellae. The growing sprouts become tubes with a lumen followed by adjoining of nearby sprouts to form vascular loops with blood flow. Assuming the initiating cause persists, vessels providing both the afferent and the efferent blood flow will mature into recognizable small arterioles and venules. The process of corneal neovascularization can be interrupted if the initiating cause is removed or controlled. Conversely, the framework of corneal neovascularization may persist for an extended period of time after the initiating cause is removed and blood flow has ceased ("ghost vessels"). These remnant vessel walls may become easily engorged with blood with only mild stimulus and in the absence of new vessel formation. Clinically and histologically, corneal neovascularization is generally characterized as superficial, midstromal, or deep. The distribution of the vessels typically corresponds to the origin of the initiating cause (superficial vs. deep). Midstromal neovascularization can be seen secondary to uveitis, even in the absence of any other overt corneal disease. 

Neutrophils are typically the main leukocyte in acute keratitis. Almost any cause of chronic corneal injury will result in the infiltration of lymphocytes and plasma cells in the stroma. Eosinophils are uncommon in the cornea and are usually seen with specific conditions (see Eosinophilic Keratitis). the cornea responds to injury ( Fig. 21-12) . However, few examples in clinical veterinary medicine truly represent wound healing only by regeneration, and most clinical diseases that require intervention include some aspect of fibrotic repair (Fig 21-13 ). Sterile surgical corneal incisions (cataract surgery or other) are one example in which healing is expected by regeneration despite being a fullthickness corneal interruption. In addition, the response to corneal injury is not limited to the cornea itself. The tear film, for example, is intimately involved in the process contributing various growth factors and proteases, and it provides the means for leukocyte movement and removal of damaged cells. Posteriorly, the aqueous humor of the anterior chamber is the source of the fibrinogen needed to form a fibrin clot that seals a full-thickness interruption allowing the healing process to begin.

confused with pigmentary keratopathy of some brachiocephalic breeds such as the pug in which corneal melanosis occurs in the absence of persistent irritation.

Corneal Wound Healing. Skin has provided the model for most basic wound healing studies (see Chapters 3 and 17). Although some of the principles involved in skin wound healing can be applied to the cornea, there are significant differences. Some differences are mechanistic, but, more important, the desired outcome in corneal wound healing includes transparency. The dermis and corneal stroma are analogous, but the corneal stroma has unique and specialized properties, including the parallel lamellar arrangement of the small-diameter collagen fibrils, the low cell density, lack of blood vessels, and relative dehydrate state (see Box 21-1). These specializations are essential for corneal function and transparency. The requirement for such precise structural organization constrains the corneal stroma to undergo a more deliberate homeostatic remodeling than the dermis of the skin and most other collagenous tissues. Corneal stromal collagen is renewed at unusually slow rates compared to dermal collagen, and keratocytes exhibit slow replication. The cornea is much more resistant to stimuli that would initiate fibrotic repair responses in other tissues. In fact, many mechanisms and adaptations of the cornea aim to provide wound healing by regeneration rather than fibrotic repair in order to maintain transparency. The lack of blood vessels in the corneal stroma also significantly affects the healing process. In skin, platelets derived from the vasculature are a major source of fibrotic repair stimulating and modulating factors. The corneal healing response does not involve platelets, and other cells must provide the cytokines, growth factors, and other substances required. The epithelial response also differs between skin and cornea. Epithelial migration and wound surface closure in the cornea are much more rapid than in the skin. Furthermore, the corneal epithelium produces substances that substitute for those contributed by platelets.

The mechanisms that regulate corneal wound healing represent a complex series of events that are determined by the etiology and severity of the injury. The principles of corneal wound healing by regeneration provide the mechanistic framework to understand how Stromal healing initially results in irregular deposition of collagen fibrils and decreased corneal transparency. Remodeling over months to years can often at least partially restore transparency and tensile strength. Regenerative healing can be separated into three phases: keratocyte migration and secretion of growth factors, proteases, and extracellular matrix (ECM); differentiation in myofibroblasts that are contractile and nonmotile and remodel of the ECM; and wound closure and myofibroblasts apoptosis/necrosis. The persistence of myofibroblasts can result in overproduction of ECM and exuberant contraction leading to fibrotic repair and loss of transparency. The final outcome depends on the severity of the lesion, the cause, the contribution of the infectious agent, and the balance of mediators and matrix metalloproteinases. Endothelium and Descemet's Membrane. The corneal endothelial cells are postmitotic with minimal to no regenerative potential in most species. Defects in the corneal endothelium are healed by sliding and hypertrophy of the adjacent viable endothelial cells. Normal function can be restored by sliding within a few days if sufficient endothelial cell density remains (400 to 700 cells/mm 2 ). The endothelial cells may secrete a new basement membrane if there is damage to Descemet's membrane. This process is often imperfect and can lead to duplication of Descemet's membrane.

Healing. Cytokines, growth factors, and proteases all play significant roles in modulating corneal wound healing.

Cytokines released following epithelial injury contribute to corneal would healing by (1) stimulating epithelial migration, (2) influencing the production of epithelial growth factors and their release, and (3) initiating stromal responses. Epithelial injury induces the release of cytokines mainly interleukins 1 and 6 (IL-1 and IL-6) and tumor necrosis factor-α (TNF-α). IL-1 and IL-6 are released proportionately to the severity of the epithelial damage. IL-1 promotes wound healing in concert with epithelial growth factor (EGF), upregulates the release of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF [a member of the fibroblast growth factor {FGF} family]), and potentiates the effects of platelet-derived growth factor (PDGF). IL-1 also stimulates the stromal response including collagenase and matrix metalloproteinase (MMP) production by keratocyte, keratocyte apoptosis, and neutrophil recruitment. IL-6 mediates epithelial cell migration by upregulation of the integrin receptor for fibronectin. TNF-α promotes keratocyte apoptosis, neutrophils recruitment, and influences epithelial healing through transforming growth factor-β (TGF-β). IL-8, upregulated by IL-1 and TNF-α, promotes neutrophil recruitment and angiogenesis. Many other cytokines (RANTES, MCP-1, and others) play a role in corneal wound healing.

Growth factors released following epithelial injury and upregulation by cytokine action induce proliferation and migration of epithelial cells. EGF, HGF, insulin growth factor (IGF), and KGF increase epithelial cell proliferation. HGF and IGF also facilitate epithelial cell migration and inhibit apoptosis. Some members of the EGF family (heparin-binding EGF-like growth factor [HB-EGF] and transforming growth factor-α [TGF-α]) increase proliferation but inhibit corneal epithelial cell terminal differentiation. Nerve growth factor (NGF) and other neurotrophic factors promote both epithelial proliferation and differentiation. PDGF is released from the epithelium and enhances epithelial migration in the presence of fibronectin. PDGF also stimulates keratocytes migration and proliferation, in part by mediating the action of TGF-β. TGF-β is also released from the epithelium and inhibits the epithelial proliferation stimulated by EGF, KGF, and HGF. TGF-β will act on stromal keratocytes when the basement membrane is damaged and induces differentiation into fibroblasts/myofibroblasts, migration Corneal Epithelium. The corneal epithelium is constantly being renewed by centripetal migration of limbal stem cells to replace the basal cells. The basal cells are mitotically active, and surface maturation ends with apoptotic shedding of the superficial cells. When healthy, the corneal epithelium is completely renewed every 5 to 7 days. Corneal epithelial wound healing is divided into four phases. During the first phase, the latent phase, there is no proliferation or cell migration. Damaged cells undergo apoptosis and are shed in the tear film. There is polymerization of fibronectin over the injury site to form a temporary extracellular matrix scaffold that will facilitate cell movement. The injury will initially result in the arrest of mitotic activity, retraction and hypertrophy of the cells at the margins, and disruption of hemidesmosomal attachments to the basement membrane. The latent phase may last for several hours. The second phase is migration, in which basal epithelial cells at the margins of the defect will slide in a centripetal migration to cover the defect, in part under the influence of Slug, a member of the Snail family of transcription factors. The cells remain attached by desmosomes essentially forming a sheet of cohesive cells that can cover the denuded area. The sliding occurs in the absence of cell proliferation (E- Fig. 21 -5). The corneal epithelial can slide by as much as 1 mm per day. Once the defect is reepithelialized, the third phase of proliferation begins. Mitoses and maturation will resume restoring normal thickness. The fourth phase is attachment and consists of the formation of hemidesmosomes to provide a strong attachment to the basement membrane. If the basement membrane is damaged, repair may occur simultaneously with hemidesmosome formation. Continued alteration may occur until the integrity of the underlying superficial stroma is restored. Corneal ulcers with interruption of the basement membrane may be reepithelialized quickly, but normal function will be delayed until the basement membrane is repaired (weeks) (Fig. 21-14) .

Stroma. Stromal healing requires transformation of keratinocytes, production of matrix, and tissue remodeling (see Fig. 21 -12). Stromal injury initially results in edema, apoptosis of local keratinocytes, and infiltration of neutrophils from the tear film within 1 to 2 hours of the injurious event. Apoptosis of keratinocytes is a key event that serves to avoid a fibrotic repair response by removing the mediating cells. Adjacent stromal keratocytes transform to fibroblasts or myofibroblasts, proliferate, migrate to the site of injury, and synthesize collagen and extracellular matrix. Monocytes can also differentiate into fibroblasts to contribute to stromal healing. Figure 21 -5 Early Healing, Shallow Ulcer, Cornea, Dog. The corneal epithelium (arrow) is sliding along the surface of the denuded intact stroma that now has substantial staining pallor and separation of collagen fibers typical of edema. Numerous neutrophils have migrated into the stroma from the tear film. The neutrophils, although necessary in moderation, have the potential to cause enzymatic digestion of the stroma (keratomalacia) and are sources of fibroblastic and angioblastic growth factors. H&E stain. (Courtesy Dr. B. Wilcock, Ontario Veterinary College.) vitreous is hyalitis; inflammation throughout the uveal tract is panuveitis; and inflammation involving the uveal tract and the adjacent components (anterior chamber, posterior chamber, and vitreous) is endophthalmitis. Uveitis or endophthalmitis that extends in the sclera is known as panophthalmitis. As previously discussed, the histologic diagnosis of ocular inflammation usually implies the infiltration of leukocytes, whereas many of the clinical diagnoses of ocular inflammation often represent predominantly vascularmediated processes.

Uveal inflammation almost always involves all portions of the uvea at least to some degree and readily extends in the ocular media. Furthermore, inflammatory mediators and toxic products are likely to be widely disseminated within the globe. Thus from a purely histologic perspective, almost all cases of uveitis can be technically classified as endophthalmitis. For practical purposes, the terminology chosen typically represents the component(s) most severely affected or the known underlying pathogenesis.

Causes of Uveitis. Uveitis can be initiated by a wide array of infections, immune responses, and trauma. The response obviously varies depending on the cause and severity of the insult. The components of the globe usually act as an integrated unit, and injury to one component almost always extend to other parts of the globe. The iris stroma, in particular, is highly reactive because there is direct communication with the aqueous humor. Any toxins, chemical mediators of inflammation, or growth factors secreted into the aqueous humor are absorbed by the iris, causing that portion of the uveal tract to respond.

Most of the infectious causes of uveitis are ocular responses to systemic viral, bacterial, or fungal diseases in which the uveal tract is only one of many tissues affected. Endophthalmitis as the sole manifestation of infectious disease may be seen as a sequela to penetrating injuries or perforating ulcers that allow the entry of environmental organisms into the globe. There are no viral causes of endophthalmitis, although there are a few systemic viral infections that cause vasculitis or retinitis that result in a uveal inflammatory response (e.g., feline infectious peritonitis). Uveal involvement in systemic mycoses and protothecosis is common in animals in certain geographic regions. Aberrant migration of nematode or trematode larvae occasionally causes endophthalmitis, as does ocular colonization by a variety of protozoal parasites that cause systemic disease (e.g., toxoplasmosis and encephalitozoonosis). and proliferation of keratocytes, as well as alteration in the synthesis of extracellular matrix. Other growth factors play lesser roles in corneal wound healing.

Proteases (proteinases) promote and regulate epithelial cell migration and proliferation during corneal epithelial wound healing and are essential for remodeling of the corneal stroma. Some proteases, including serine proteases urokinase-type plasminogen activator (uPA) and plasmin, contribute to the disruption of epithelial attachments to the basement membrane facilitating migration. Proteases, mainly serine proteases and MMPs, are critical to remodeling the stroma. Injury to the cornea disrupts the physiologic balance of proteases and protease inhibitors that contribute to corneal maintenance and renewal. Corneal injury shifts the balance toward degradation and remodeling and reduces the role of protease inhibitors such as α 2 -macroglobulin, α 1 -proteinase inhibitor, tissue metalloproteinase inhibitors, maspin, serine protease inhibitors (serpins), secretory leukocyte protease inhibitor, and calpeptin. Proteases secreted by infectious organisms will further promote degradation. MMP-2 and MMP-9 are the most extensively studied of the MMPs. MMP-9 is produced by epithelial cells and leukocytes and is mainly localized at the leading edge of the wound. MMP-9 breaks down collagen and basement membrane proteins, modulates IL-1, and activates TGF-β. MMP-9 also degrades the temporary fibronectin matrix following wound closure. MMP-2 is produced by the corneal epithelium and keratocytes. It is involved in renewal of healthy corneas and increased following corneal injury to influence stromal remodeling. Unlike other MMPs involved in corneal wound healing, epithelial injury is not required for MMP-2 activation. MMP-1 and -7 modulate epithelial migration. MMP-3, -12, -13, and -14 regulate stromal remodeling.

Corneal Fibrosis/Scarring (Fibrotic Repair). Significant stromal injury that overwhelms the cornea's ability to heal by regeneration leads to fibrotic repair, permanently impairing transparency. Many corneal injuries in veterinary patients are beyond the globe's ability to heal in any manner that would allow a return to normal function. In those instances, fibrotic repair that maintains corneal integrity is preferable to corneal rupture. Factors that stimulate fibrotic repair include extensive corneal injury, deep or full-thickness corneal injury, infiltration of large numbers of neutrophils, and the presence of infectious organisms (see Fig. 21 -13; E-Figs. 21-6 through 21-10). Histologically, enlargement and hyperchromasia of limbal fibroblasts and angioblasts is visible within 24 to 48 hours of injury, but detectable migration is not evident until approximately 4 days. Fibroblasts and blood vessels migrate as much as 1 mm per day until they reach the site of injury. If the cause of the injury is removed or controlled so that corneal rupture is avoided, the process will evolve to form a bed of granulation tissue covered by epithelium. Remodeling over time may help restore some transparency; however, there will never be a return to completely normal structure and function. Surgical grafting usually serves to facilitate and accelerate fibrotic repair in order to maintain corneal integrity in patients at risk of corneal rupture, or to promote fibrotic repair of a previously ruptured cornea.

The nomenclature of uveal leukocytic inflammation is essentially the same as that used in clinical ophthalmology (Box 21-5). Hypopyon is the accumulation of neutrophils and fibrin that typically settles ventrally within the anterior chamber (E- Fig. 21-11 ). Inflammation within the iris and ciliary body is usually referred to as anterior uveitis (or less commonly iridocyclitis). Inflammation limited to the choroid is choroiditis; inflammation limited to the The macroscopic manifestations of uveitis detectable by clinical examination are as follows: • Aqueous flare: An increase in protein content within the aqueous humor increases light scattering • Iris swelling and color change: Iris stromal hyperemia, edema, leukocyte accumulation, and fibrovascular proliferation • Conjunctival reddening: Hyperemia of the superficial and deep conjunctival blood vessels in response to vasoactive chemicals generated by the nearby uveitis • Hypopyon: The accumulation of neutrophils and fibrin that settles ventrally within the anterior chamber • Keratic precipitates: Small aggregates of inflammatory cells adherent to the corneal endothelium • Peripheral corneal midstromal neovascularization: Persistent inflammation results in the generation of enough angiogenic growth factors to stimulate "accidental" migration of limbal blood vessels into the peripheral cornea On the right, at the site of a former deep corneal ulcer, the epithelium has healed by corneal epithelial cell migration (sliding) into the ulcer, with subsequent epithelial hyperplasia and return of the corneal epithelium to normal or even increased thickness. However, because there has been no replacement or remodeling of the stroma (right), the epithelium is positioned directly on the surface of Descemet's membrane instead of on a reconstituted fibrous stroma. This process is "unsuccessful" wound healing because the "healed" cornea, lacking stroma, is too fragile to survive. Cataracts are frequent sequelae to uveitis, likely from impaired nutrition. The avascular lens entirely depends on the aqueous humor for the delivery of nutrients and the removal of metabolic waste products. Uveitis results in altered composition and decreased production of aqueous humor. Furthermore, cataracts may result from diffusion of inflammatory mediators of inflammation and other toxic products in the aqueous humor of inflamed globes. In some cases, the cause-effect relationship may not be evident and history may be necessary to differentiate between cataracts secondary to uveitis and cataracts that cause lens-induced uveitis.

Retinal detachment is a common sequela to uveitis and endophthalmitis, either from exudation from the choroid or traction from the vitreous. Increased vascular permeability within the choroid results in effusion of fluid and leukocytes in the subretinal space, causing exudative retinal detachment. Because the normal neuroretina is not actually attached to the retinal pigment epithelium (RPE), there is a potential space termed the subretinal space where fluid leaving the choroid during inflammation can accumulate. Choroidal exudation occurs in the subretinal space because the fluid cannot diffuse through the thick sclera. Alternatively, fibrovascular proliferation within the vitreous may contract, causing tractional detachment.

Phthisis bulbi refers to a shrunken, disorganized end-stage globe. It is a sequela not only to uveitis, but severe uveitis is the most common cause. Fibrovascular Proliferation and Neovascularization. Fibrovascular proliferation (neovascularization) is often considered separately from uveitis involving infiltration of leukocytes. However, fibrovascular proliferation is part of the inflammatory and healing responses, and many of the forms of uveitis commonly diagnosed by clinicians reflect vascular-mediated processes rather than leukocytic infiltration. Fibrovascular membranes may be present with leukocytic uveitis but also with neoplasms, trauma, and tissue damage associated with hypoxia such as retinal detachment and glaucoma. In fact, fibrovascular membranes are present in approximately 75% of all enucleated canine globes and in 20% to 30% of the enucleated globes in other species. Fibrovascular membranes develop when the balance of angiogenic and antiangiogenic factors favors neovascularization. Of the many cytokines that contribute to fibrovascular proliferation, vascular endothelial growth factor (VEGF) is the most significant. Fibrovascular membranes include newly formed vessels, spindle cells compatible with fibroblasts and myofibroblasts, and collagenous extracellular matrix. The contribution of each component to fibrovascular membranes depends in part on cause and chronicity. Fibrovascular membranes are often described by their distribution: retrocorneal, preiridal, posterior iridal, cyclitic, and intravitreal. Retrocorneal membranes line the posterior aspect of the cornea, often effacing the corneal endothelium. Preiridal membranes are the most common form of fibrovascular proliferation in the eye . These fibrovascular membranes line the anterior aspect of the iris. The membranes arise from budding and migration of capillaries from the iris stroma and recruitment of fibroblasts and myofibroblasts, similar to a healing response in other organs. Contraction of preiridal fibrovascular membranes can cause distortion of the iris, most often retraction of the pupillary margin of the iris, either anteriorly (ectropion uveae) or posteriorly (entropion uveae). Preiridal fibrovascular membranes may be continuous with retrocorneal membranes or extend posteriorly. Posterior iridal membranes cover the posterior iris epithelium and may extend to cover the ciliary body. Cyclitic membranes extend from the ciliary epithelium along the anterior vitreous face and may extend to carpet the posterior lens capsule.

Ocular trauma is a frequent cause of endophthalmitis. The lesion may be transient with mild blunt trauma or noncontaminated penetrating trauma where the perforation is rapidly sealed. Conversely, introduction of bacteria in the globe or rupture of the lens will provoke massive endophthalmitis.

Immune-mediated uveitis is common and presents in various forms. These typically present as chronic conditions with nonspecific lymphoplasmacytic uveitis. In individual cases, it is not known if such a lesion reflects primary immune-mediated disease or simply a response to an infectious agent that is no longer present. Previous inflammation can cause the release of uveal-or retinal-specific antigens that are normally masked intracellularly, thus eliciting an immune response. There are only a few diseases for which the cause is known. Examples include: (1) uveodermatologic syndrome as a reaction to antigen associated with melanocytes and (2) lensinduced uveitis following exposure to normally sequestered lens protein.

The uvea responds to afferent neural signals and chemical mediators released from an injured cornea. Any significant corneal injury can elicit a mild anterior uveitis ("reflex uveitis").

Because the uveal tract is a vascularized tissue, the response to injury is similar to that in other organs. Furthermore, injury that overwhelms the barrier mechanisms will result in loss of immune privilege making the entire globe subject to immune and inflammatory responses similar to that of other sites.

Consequences of Uveitis. The inflammatory reactions in the uveal tract mimic those in other organs for both acute and chronic processes. The consequences of inflammation, both for the uveal tract and for other portions of the globe, are what make uveitis unique. Inflammation of the uveal tract can have injurious consequences for every other component of the globe. Uveitis may result in corneal neovascularization and endotheliitis, synechiae, fibrovascular proliferation, cataract, retinal detachment, and glaucoma.

Midstromal corneal neovascularization is commonly seen with chronic uveitis. The vessels grow inwardly from the limbus as the blood vessels of the limbus respond to angiogenic factors being produced within the globe as part of the ongoing inflammation and healing. Endotheliitis develops when leukocytes extend from the uveal tract in the aqueous humor to reach the corneal endothelium (E- Fig. 21 -12). Lymphoplasmacytic uveitis and feline infectious peritonitis are common causes.

Synechiae are adhesions between the inflamed iris and either the cornea or the lens (E- Fig. 21-13 ). Anterior synechia is an iridocorneal adhesion. The adhesions may be focal or diffuse, along the central cornea or peripheral. Central anterior synechia is most commonly seen as a sequela to corneal rupture with or without iris prolapse. Peripheral anterior synechia commonly accompanies preiridal fibrovascular membranes (see later discussion). Adhesion to the anterior capsular surface of the lens (in the normal globe, the iris lies against the lens capsule) is known as posterior synechia. Because of the proximity of the iris and lens, posterior synechiae are more common than anterior synechiae. The adhesion is initially fibrinous and often occurs when aqueous humor protein content is high. The adhesions may become a firm fibrovascular membrane if allowed to persist. If that adhesion is sufficiently extensive around the pupillary margin (i.e., approaching the full circumference of the pupil), there will be significant impairment of aqueous humor outflow from the posterior chamber to the anterior chamber (pupillary block) leading to secondary glaucoma. Increased pressure within the posterior chamber in the presence of a circumferential posterior synechia results in anterior bowing of the iris known as iris bombé.

The Eye E- Figure 21 -12 Corneal Endothelialitis, Cornea, Cat. Neutrophils (arrows) adhere to and have accumulated on and in the corneal endothelium. When numerous, they separate the corneal endothelial cells from the adjacent Descemet's membrane (arrowheads). This is a relatively frequent complication of anterior uveitis in cats and especially cats with feline infectious peritonitis. The leukocytes may be predominantly neutrophils or lymphocytes, depending on the pathogenesis and the duration of the uveitis. 

The lens can only respond to injury in limited ways. The lens is avascular, lacks any cells other than the lens epithelium, and prevents leukocyte infiltration through the capsule. The response to injury is usually limited to hydropic swelling or degeneration of the lens fibers and attempts at regeneration through proliferation and adaptation of the lens epithelium. The outcome is essentially identical, regardless of pathogenesis. The changes all result in variably severe cataract, broadly defined as an opacification of the lens. Because normal function of the lens requires transparency, any opacification, or cataract, is a pathologic change ( Intravitreal membranes typically originate from the pars plana ciliary body. Such membranes may be the cause of vitreal hemorrhage but may also be part of the response to chronic intravitreal hemorrhage. Retinal and epiretinal membranes seen in some human conditions are rare in domestic animals. The development of fibrovascular proliferation in the globe shares mechanistic features with granulation tissue in other organs. However, unlike granulation tissue elsewhere, intraocular fibrovascular membranes tend to have detrimental rather than beneficial effects on function. The newly formed vessels are fragile and prone to hemorrhage, and fibrovascular proliferation can also contribute to the development of glaucoma. Preiridal fibrovascular membranes may extend to cover and obstruct the iridocorneal angle or extend along the posterior cornea causing a peripheral anterior synechia resulting in secondary glaucoma. Preiridal fibrovascular membranes may also extend on the anterior lens surface contributing to posterior synechiae and pupillary block, which may cause glaucoma. Intravitreal fibrovascular membranes can cause traction within the vitreous resulting in retinal detachment.

Fibrovascular proliferation almost never develops within the uveal stroma itself. Only in instances in which there is massive leukocyte migration to the site. Low levels of tissue plasminogen activator in the vitreous also contribute to slow fibrinolysis. Some erythrocytes undergo extracellular hemolysis as a result of either lysosomal enzyme release by macrophages or autohemolysis secondary to the lack of required concentrations of oxygen and glucose. Hemolysis may be more important than phagocytosis by macrophages for clearance of vitreal hemorrhage. Some red blood cells will persist for months within the vitreous. These cells must possess a metabolism allowing survival in the altered vitreous and escape phagocytosis by macrophages. These intact cells may be fresh red blood cells that lack the opsonins recognized by macrophages on older red blood cells targeted for phagocytosis. Macrophages will infiltrate the vitreous within days, but the response is measured and will continue for months. The number of macrophages that respond to vitreal hemorrhage is significantly less than that in other organs. Some of the macrophages in the vitreous appear metabolically inert and will undergo cytolysis with phagocytosis by other cells. The measured response is a consequence of reduced chemotactic stimulation, including the lack of fibrin degradation products, and the vitreal properties of hyaluronate that impedes migration and inhibits phagocytosis. The purpose of this measured response may be to maintain ocular immune privilege and ocular function by avoiding a marked response leading to granulation tissue formation. Consequences of vitreal hemorrhage include liquefaction of the vitreous. The presence of ferric and ferrous iron, a decrease in the concentration of hyaluronic acid, and an increase in the concentration of chondroitin sulfate, as well as the effect of plasma proteases, account for the change. Normal viscosity is regained after several months.

The retina responds to injury in a manner similar to that of the central nervous system (see Chapter 14). The neuronal elements of • Hyperplasia and fibrometaplasia of lens epithelium. The normal lens epithelium is a single layer thick and any epithelial hyperplasia may create plaque-like thickening. In some instances, the lens epithelium may adopt a spindle cell phenotype with or without fibroblastic metaplasia and collagen deposition. • More variable changes include lens swelling in acute cataracts, lens shrinking with wrinkling of the lens capsule in advanced ("hypermature") cataracts, epithelial cell necrosis/apoptosis, and intralenticular mineralization. Cataracts are best classified by the clinician who can examine the entire lens. Such classification is most important in the clinical diagnosis of breed-related inherited cataracts in dogs. Cataract may still be classified histologically by extent, location, and cause. Extent can usually be categorized as incipient (<15%), immature (>15%, incomplete), mature (circumferential), and hypermature cataract with evidence of lens collapse or resorption. Cataracts may be cortical with liquefaction, Morgagnian globules and bladder cells, or subcapsular with epithelial hyperplasia, fibrometaplasia, and posterior extension. Cataracts may be inherited or acquired/secondary.

The vitreous has limited ways in which it can respond to injury. The vitreous is avascular and lacks cells other than hyalocytes. Injury, including inflammation and glaucoma, often results in altered composition and loss of viscosity, essentially liquefaction of vitreous. The vitreous is highly susceptible to hemorrhage, and chronic lesions may cause fibrovascular proliferation. The significance of vitreal injury lies on the possible effects on the retina: separation from the retina and increased risk of retinal tearing with liquefaction and traction and retinal attachment with fibrovascular proliferation.

Asteroid hyalosis is one form of vitreal degeneration. The lesion consists of numerous spherical bodies with irregular contours embedded within the collagen framework of the vitreous ( Fig. 21-18 ). Occasionally the asteroid bodies will be bordered by or within macrophages. The asteroid bodies are composed of phospholipid and calcium complexes. The change is nonspecific and can be seen with chronic inflammatory, degenerative, and neoplastic diseases. Asteroid hyalosis can also be an age-related change.

There are three main pathologic mechanisms for ocular hemorrhages: bleeding from normal vessels (trauma), bleeding from abnormal vessels (systemic hypertension and uveitis), and bleeding from newly formed immature vessels (fibrovascular membranes and neoplasia). Blood disorders (e.g., coagulopathies, anemia, anticoagulants) are a less frequent cause of intraocular hemorrhage. The basic principle of blood catabolism applies to ocular hemorrhage; however, there are features unique to the removal of blood in the eye. Blood in the anterior or posterior chambers is removed through the iridocorneal angle, assuming it is functional and unobstructed. Hemorrhage within the uveal tract is rare and is often associated with significant uveal destruction with breakdown of ocular defense mechanisms and immune privilege. Blood catabolism in those instances is similar to that in other tissues.

Vitreal hemorrhage catabolism is significantly different than hemorrhage removal in any other tissues (Box 21-7). Rapid clot formation is facilitated by the network of vitreal collagen, which enables platelet aggregation and promotes the intrinsic clotting pathway. The absence of polymorphonuclear leukocyte infiltration early in the process decreases fibrinolysis. In turn, the lack of fibrin degradation production limits stimulation of polymorphonuclear 

Box 21-7 Features of Vitreal Blood Removal vascular supply. As such, it is not possible to accurately age retinal detachments histologically. Hypertrophy of the RPE, so-called "tombstoning," is an indicator of retinal detachment and can be seen as early as 24 hours after retinal detachment (range, 1 to 3 days) . However, the change is not always present, and it depends in part on the health of the RPE itself, the health of the choroid, and the nature of the subretinal the adult retina do not regenerate; the outer segments of the photoreceptors, however, have a rapid turnover and have among the highest metabolic activity in the body. As long as the cell body within the outer nuclear layer remains viable, photoreceptors can be quickly regenerated. The inflammatory response within the retina is similar to that in the central nervous system: neuronal necrosis, perivascular cuffing, and gliosis. The retinal pigment epithelium (RPE) remains mitotically active throughout life. Like other epithelia, it repairs by sliding viable cells into the area where cells have been lost followed by mitosis. The RPE may undergo fibrometaplasia. The Müller glial cells are less sensitive to injury than retinal neurons and are capable of proliferation. Repair of most cases of retinal necrosis occurs primarily by proliferation of Müller cells, which eventually form a nonfunctional dense glial scar. Occasionally the astrocytes proliferate along the vitreal face of the retina, forming a preretinal fibroglial membrane. Subretinal membranes (between the photoreceptors and the RPE) of a similar microscopic appearance are seen occasionally with chronic detachments and originate from migrating Müller cells or from retinal pigment epithelium that has undergone fibrometaplasia.

The neurosensory retina (not including the RPE) is physically anchored only at the ora ciliaris retinae and at the optic disc. It is held in apposition to the RPE partly by the physical presence of the vitreous and partially by the membrane forces related to the intricate interdigitations between photoreceptors and surface crevices in the RPE. As such, the term retinal detachment, which is commonly used in both clinical and pathologic settings, may be more accurately described as separation between the neuroretina and RPE. It does not describe a disconnection between the RPE and choroid. The potential space between the photoreceptors and the RPE is the remnant of the lumen of the primary optic vesicle, and it persists throughout life. Retinal detachment is a frequent and serious complication of many different ocular diseases. It may be focal, multifocal, or diffuse. The distance of separation between the photoreceptors and the RPE may only be slight, or the entire retina may be separated and suspended in the vitreous. Retinal tears may develop along with retinal detachment.

The most frequent types of retinal detachment are as follows: • Exudative retinal detachment: Accumulation of serous, fibrinous, or cellular exudates within the subretinal space as a consequence of choroiditis, retinitis, or neoplasia. Hemorrhagic detachment may be seen with trauma, systemic hypertension, or neoplasia. • Rhegmatogenous retinal detachment: Leakage of liquefied vitreous into the subretinal space through traumatic or degenerative breaks in the retina. • Tractional retinal detachment: Vitreal or preretinal membranes that develop as a consequence of uveitis or chronic hemorrhage can pull the neuroretina from the RPE. Histologically, retinal detachment can be recognized by the presence of material within the subretinal space, atrophy of the outer retina, and hypertrophy of the underlying RPE (E-Figs. 21-18 through 21-21). The presence of serous, fibrinous, hemorrhagic, or cellular exudates within the subretinal space is the most diagnostically reliable feature of retinal detachment. Outer retinal atrophy is an expected consequence of retinal detachment. Within days, there will be atrophy of the photoreceptor layer. Atrophy of the outer nuclear layer suggests chronicity ( Fig. 21-19 ). The progression of outer retinal atrophy is highly variable and depends in part on the nature of the exudate, the presence of inflammatory cells and mediators, the extent of the detachment, and the integrity of the choroidal 

Portals of entry into the cornea are listed in Box 21-8. Desiccation is a common form of corneal injury that can be the result of insufficient or altered tear film production. Desiccation can also be caused by any condition that impairs proper eyelid movement and closure, such as exophthalmos, eyelid conformation defect, and eyelid masses. Some eyelid diseases can also cause trauma and chronic irritation if a mass or distorted eyelid directly contacts the corneal surface. Penetrating trauma, essentially foreign body injury, can damage the epithelium, extend in the stroma, or cause a fullthickness breach with intraocular extension. Cat claws, plant material, and, to a lesser extent, bite wounds are common sources of traumatic injuries to the cornea and globe. Chemical injury is rare but includes both accidental exposures to various chemicals and inappropriate administration of preparations not intended for the ocular surface (e.g., skin formulations). Extension of conjunctival disease in the cornea is uncommon but may include spillover of inflammation or neoplasia, or induction of nonspecific reactive changes (corneal hyperplasia, stromal neovascularization). Corneal disease from intraocular extension via damage to the corneal endothelium may be the result of endotheliitis or endophthalmitis, anterior synechia, anterior lens luxation, or glaucoma. The portals of entry for the sclera consist essentially of trauma, hematogenous, extension of intraocular disease, and, less commonly, extension of orbital disease.

Portals of entry into the uvea are listed in Box 21-9. Injury to the uvea may occur through the bloodstream (hematogenous), trauma, or by extension of disease elsewhere in the globe (aqueous humor, vitreous, sclera). Hematogenous entry is used by infectious agents, exudate. Less commonly, the RPE may be multifocally hyperplastic. Retinal detachment that develops prior to glaucoma may have a sparing effect on the inner retina; there may be no inner retinal atrophy despite significant elevation in the intraocular pressure. Histologically, retinal detachment must be differentiated from artifactual separation, which occurs frequently during processing. With artifactual separation, there is no material within the subretinal space; there is no outer retinal atrophy or hypertrophy of the RPE. The presence of photoreceptor segments on the apical surface of the RPE also indicates artifactual separation.

The immediate consequence of retinal detachment is loss of function-that is, loss of vision. The detached hypoxic retina produces angiogenic growth factors, mainly vascular endothelial growth factor (VEGF). This is presumably intended to increase the retinal blood supply; however, there is little evidence of stimulation of retinal angiogenesis in domestic animals. Instead, VEGF diffuses in vitreous and aqueous humor, resulting in vascular/fibrovascular membrane formation. These membranes may cause further damage to the globe because the new vessels may easily hemorrhage. The membranes may also cause secondary glaucoma as a consequence of obstruction of the iridocorneal angle or pupillary block.

The optic nerve responds to injury in a manner similar to that of the central nervous system (see Chapter 14).

The response to insult of the bone, adipose tissue, skeletal muscle, and glandular tissue that constitute the orbit is similar to that of the same tissue type elsewhere in the body. Such responses may have significant consequences for the globe and vision. Space-occupying lesions in the orbit, including neoplasia, cysts, inflammation, hematomas, and edema, may cause protrusion of the globe (exophthalmos), which may impair proper eyelid closure resulting in corneal exposure and desiccation. Space-occupying lesions, particularly neoplasia, may also compress the optic nerve causing atrophy and blindness. Extraocular myositis and other conditions that cause damage to the orbital muscle may result in abnormal positioning of the globe with possible eyelid trauma to the cornea or exposure of the cornea with desiccation. Injury to the lacrimal gland, either dacryocystitis or extension of orbital lesions affecting other tissues, can lead to altered tear film production and keratoconjunctivitis sicca. Although rare, severe emaciation with atrophy of orbital adipose tissue can cause the globe to be positioned deeper in the orbit with possible entropion and eyelid trauma to the cornea.

The outer surface of the eyelid is skin and therefore is susceptible to the same diseases as the skin elsewhere on the body. For palpebral skin, the portals of entry are the same as for skin at other sites: • Colonization of the skin's surface or adnexal glands by nicheadapted infectious agents • Penetrating injury • Hematogenous localization (immune-mediated diseases, infectious) • Contact injury (physical or chemical)

The conjunctiva is a mucous membrane similar in structure to other mucous membranes and is therefore susceptible to injury from the same range of physical and chemical injuries affecting any other Box 21-9 Portal of Entry Into the Uvea organisms in the absence of penetrating trauma. One rare exception in domestic mammals is the specific targeting of the lens capsule in some instances of systemic mycosis, typically aspergillosis. These fungi exhibit a tropism for basement membranes throughout the body, including the lens capsule. In rabbits, the lens is frequently affected by the microsporidian Encephalitozoon cuniculi, possibly from in utero infection. There are a few reports of E. cuniculi causing lenticular disease in cats. In fish, cataracts induced by the intralenticular penetration of fluke larvae are common. Several viral diseases including bovine viral diarrhea are occasionally associated with congenital cataracts as a consequence of systemic infection in utero before the establishment of the blood-eye barrier.

Portals of entry into the vitreous include penetrating trauma, extension of uveal disease, diffusion of inflammatory mediators and other chemicals from the aqueous humor, and extension of retinal disease.

Portals of entry into the retina are listed in Box 21-11. It is important to view this list in perspective. Despite the long list of potentially injurious stimuli and the innumerable routes by which such stimuli can impact the retina, retinal disease is overall infrequent. The vast majority of retinal lesions fall into the following four categories: 1. Destruction of the neural elements of the inner retina (nerve fiber layer, ganglion cells, and inner nuclear layer) as a result of increased intraocular pressure (see Glaucoma). The pathogenesis of the inner retinal destruction and destruction of the optic nerve remain a source of great controversy, and it probably varies among species and with the type of glaucoma (see Glaucoma). 2. Retinal detachment is a common consequence of inflammatory, infectious, and vascular disease. The photoreceptors are therefore likely to become necrotic from ischemia and malnutrition metastatic neoplasia, and, less frequently, toxins. Injury to the blood vessels themselves from thrombosis or occlusion by neoplastic emboli may cause ischemic damage. Traumatic injury may be the result of penetration or blunt force. Penetrating injury may cause direct injury or provide infectious agents entry into the globe and uveal tract. Blunt trauma may result in separation of the uveal tract from the sclera leading to traumatic angle recession or cyclodialysis. Blunt trauma may also damage blood vessels, causing hemorrhage. Corneal and scleral disease may extend to involve the uveal tract. Furthermore, chemical mediators of inflammation released from injured cornea, lens, or retina diffuse through the aqueous humor or vitreous, or directly in the uveal tract eliciting uveal damage as part of the inflammatory response.

Portals of entry into the lens are listed in Box 21-10. The lens is occasionally injured by a direct perforating injury or blunt trauma. In those instances, other ocular components are expected to be involved. The significance of the lens injury will depend on its severity as well as the severity of damage elsewhere in the globe. Electrocution, albeit a rare event, can cause degeneration of the lens. Many injuries to the lens reflect the lens' dependence on the aqueous humor. There may be inadequate delivery of nutrients because of defective flow of aqueous humor or chemically abnormal aqueous humor. Metabolic diseases that cause cataracts include excessive glucose levels in animals with diabetes mellitus and cataracts associated with systemic hypocalcemia. The aqueous humor may also contain damaging inflammatory mediators or cataractogenic chemicals including some drugs. Degenerative changes in the lens are also seen in dogs with inherited photoreceptor disorders caused by diffusion of toxic by-products of photoreceptor degeneration. Inherited cataracts in dogs are frequent, although the underlying biochemical pathogenesis has not been elucidated.

Light-induced lens injury is mostly relevant for laboratory animals but nonetheless a potential mechanism of lenticular damage in domestic animals. Similarly, therapeutic radiation is an uncommon cause of cataract in domestic animals.

Because the lens is avascular and surrounded by a dense collagenous capsule, it is relatively resistant to invasion by infectious Chapters 4, 7, 9, and 13) .

The ocular surface is an intricate integrated functional unit that includes the eyelids, lacrimal gland, tear film, conjunctiva, and cornea. Both innate and adaptive immune responses contribute to the defense of the ocular surface. The innate response is not antigen specific. The cornea is protected from most physical and chemical injuries by the action of the eyelids from several reflexes, the bony orbit, and by the constant flow of the tear film. Multiple reflexes are activated by mechanical stimulation of eyelids or the cornea. The blink reflex causes the eyelids to close when stimulated by contact with any solid material or strong airflow. The menace response causes the eyelids to blink when there is visual perception of a threat to the globe. The corneal reflex causes the eyelids to close when the cornea itself is irritated by external stimuli. Reflex retraction of the globe into the orbit, with subsequent passive sliding of the third eyelid to cover the cornea, occurs in response to corneal trauma.

The tear film is produced by the lacrimal gland and by the gland of the third eyelid, with contributions from conjunctival goblet cells, several accessory glands within the conjunctival substantia propria, and the meibomian glands. The tear film provides nourishment for the avascular cornea, a mucus layer to prevent evaporation of the protective fluid, soluble antibacterial chemicals, and a flushing action to protect the cornea against infectious agents and foreign material.

The production of mucins by goblet cells forms the innermost layer of the tear film and may be increased under the influence of cytokines including interleukin-6 and interferon-γ during inflammation and by several pathways including the nuclear factor-κB pathway during infection. Ocular surface mucins provide an anchor to bond the tear film and corneal epithelium, inhibit bacterial colonization, and help remove foreign material. Transmembrane mucins produced by the corneal and conjunctival cells may help the spread of the tear films and protect against bacterial adhesion. Furthermore, the corneal epithelium has junctional complexes (tight junctions, gap junctions, desmosomes, and hemidesmosomes) to prevent easy access by infectious or chemical agents into the underlying stroma, and it can shed and renew superficial layers that are compromised. Mature and immature dendritic cells are present at the periphery and immature dendritic cells are present in the central corneal epithelium. Toll-like receptors (TLRs) are expressed throughout the ocular surface and can trigger an immediate innate response to the pathogen and activate adaptive immunity. TLR regulation is also critical for ocular surface tolerance of antigen, including sparing of commensal flora.

The innate immune response also includes antimicrobial peptides such as lysozyme, lactoferrin, lipocalin, angiogenin, secretory phospholipase A 2 , secreted immunoglobulin A (IgA), complement factors, defensins, and others that inhibit the invasion of infectious organisms (Table 21-1) . Lysozyme binds to the outer membrane of the bacteria, creating a pore that leads to cell death. Lactoferrin binds divalent cations such as iron that many microorganisms require for function and growth. Tear lipocalin scavenges bacterial products and binds siderophores that transport iron in microorganisms. Angiogenin has multiple antimicrobial effects. Secretory phospholipase A 2 acts via its lipolytic enzymatic activity. IgA is produced by plasma cells in the lacrimal gland and neutralizes pathogens by preventing their attachment to host cells. IgA also binds to adhesion molecules on pathogens, causing their aggregation and facilitating clearance by the tear film. β-Defensins from epithelium and resulting from their anatomic dislocation from the RPE and decreased access to nutrients supplied by the choroidal vasculature. 3. Inflammation as a result of extension from endophthalmitis.

Inflammation targeting the retina specifically is rare and extension of encephalitis is uncommon. Retinal detachment is a frequent complication of inflammation involving the choroid. 4. Noninflammatory photoreceptor degeneration from inherited metabolic disease or, less frequently, toxicity. The inherited photoreceptor diseases vary considerably in pathogenesis but are indistinguishable from one another using routine histologic examination techniques. Less common causes of retinal injury include: (1) light and other types of radiation arriving through the cornea and lens, (2) hematogenous dissemination of chemical or infectious agents, and (3) objects penetrating through the cornea or through the sclera. Because the retina is an extension of the brain, it is susceptible to most of the infectious, degenerative, and metabolic diseases of the brain, including the storage diseases.

The main portals of entry in the optic nerve are extension of orbital disease and the effects of increased intraocular pressure (glaucoma). Trauma causing traction, with or without proptosis, may result in significant optic nerve damage. Extension of intraocular, retinal, and brain disease are less frequent causes of optic nerve injury.

Portals of entry into the orbit are as follows:

• External trauma resulting in orbital fractures • Penetrating injury through the skin, oral cavity, or nasal cavity • Direct extension of inflammatory or neoplastic diseases from the oral cavity or the nasal cavity • Direct extension of intraocular inflammatory or neoplastic disease through the sclera • Direct extension of inflammatory or neoplastic disease from the conjunctiva or eyelid • Hematogenous localization (immune-mediated diseases, infectious, neoplasia)

Eyelids Like skin at other sites, the defenses of eyelid against injury include barrier functions, resistance to mechanical force, and immunologic defense mechanisms (see Chapters 3, 5, 13, and 17). Features of note regarding the eyelids include the presence of modified hair (cilia and sinus hairs). Reflexive blinking does not protect the eyelids themselves but does protect adjacent structures.

The conjunctiva is protected from most physical and chemical injuries by the eyelids and by the tear film. The epithelial cells are joined by desmosomes and tight junctions to prevent easy access by infectious or chemical agents into the underlying substantia propria. It is capable of rapid replication in the event of injury and readily undergoes squamous metaplasia as an adaptive survival mechanism in response to chronic low-grade irritation of any type. Both innate and adaptive immune responses contribute to the defense of the ocular surface (see Cornea below). The resident mucosal immune system (MALT) of the conjunctiva (CALT) functions similarly to immune systems in other mucosal sites, such as the upper respiratory tract, lungs (bronchus-associated lymphoid tissue [BALT]), and between nonfenestrated endothelial cells of the iris blood vessels and tight junctions between adjacent epithelial cells of the inner nonpigmented ciliary epithelium. In the iris, large molecules such as large proteins are unable to pass the barriers of the blood vessels.

In the ciliary body, the blood vessels are fenestrated and allow passage of plasma proteins and molecules into the stroma as part of aqueous humor production. The barrier is thus located at the nonpigmented epithelium where tight junctions are part of junctional complexes that also include adherens and gap junctions. The tight junctions limit the diffusion of large molecules through the paracellular spaces and also prevent the backflow of aqueous humor. Small amounts of plasma-derived protein will reach the aqueous humor by diffusion from the ciliary stroma to the iris stroma and release in the anterior chamber. Ocular inflammation may result from the disruption of the blood-ocular barriers, resulting in increased vascular permeability, but significant inflammation can also be the cause of the disruption of the blood-ocular barriers. In both instances, the disruption allows infectious agents, inflammatory mediators, and leukocytes access to the uveal tract, including the stroma of the iris, followed by extension into the aqueous humor of the anterior chamber and throughout the globe.

Anterior chamber-associated immune deviation (ACAID) is a specialized immune response unique to the eye by which infectious agents and other antigens introduced into the anterior chamber induce only a highly controlled immune response that effectively eliminates the provoking antigen while limiting bystander injury. The process involves the absence of certain response mechanisms normally active in other organs as well as augmented tolerance of some antigens. ACAID is not the absence of an immune response but, rather, a vigorous immune response that favors specific effector mechanisms and a form of selective unresponsiveness. ACAID protects the eye from antigen-specific immune-mediated injury from delayed-type hypersensitivity and B lymphocytes that secrete complement-fixing antibodies. ACAID depends on a unique intraocular immune environment and a modified systemic response. Major histocompatibility complex (MHC) class I molecules are expressed on virtually all nucleated cells, with the exception of the neurons in the central nervous system, and the corneal endothelium and retina. The low expression of classical MHC class I molecules on the corneal endothelium and the retina prevents targeting by cytotoxic T lymphocytes. MHC class I molecules also regulate natural killer (NK) cell-mediated cytolysis. NK cells are programmed to destroy any cell that lacks MHC class I molecules, usually infected cells or neoplastic cells. To avoid NK cell-mediated destruction, corneal endothelial cells and retinal cells express nonclassical MHC class Ib molecules, which can interact with NK cells transmitting an "off" signal and prevent NK activation.

The aqueous humor benefits from multiple soluble and membrane-bound immunosuppressive molecules. These molecules are released or expressed by the corneal endothelium, the trabecular meshwork cells, the iris posterior epithelium, and the ciliary body epithelium. Transforming growth factor-β (TGF-β) is the most important molecular mediator of immune privilege. TGF-β-exposed antigen-presenting cells (APCs) promote the generation of regulatory T lymphocytes (Treg) that suppress immune responses. TGF-β modifies APCs by inhibiting the expression of interleukin 12 (IL-12) and CD40, molecules that support activated T lymphocytes. Soluble TGF-β also induces the expression of TGF-β and IL-10 by APCs. α-Melanocyte-stimulating hormone (α-MSH) also induces Treg generation and synergizes with TGF-β. Transforming growth factor (TGF-β 2 ), α-MSH, and calcitonin gene-related peptide (CGRP) α-defensins from neutrophils help protect against a broad spectrum of organisms through membrane permeabilization.

Antigen-presenting cells, namely the resident dendritic cells of the conjunctival and corneal epithelium, play a pivotal role linking the nonspecific innate response and the development of antigenspecific adaptive immunity. TLRs and other mechanisms also bridge the innate and adaptive immune responses.

The cornea is an immune privileged site. The purpose of this altered immune response as a defense mechanism is to minimize bystander injury. Factors that contribute to the immune privilege in the cornea include the lack of blood and lymphatic vessels and the blood-aqueous barrier (see section below) resulting in separation from circulating immune cells and lack of efferent transport for antigen-presenting cells (APCs). Furthermore, only immature APCs that do not express major histocompatibility complex class II are present in the central cornea. Although mainly relevant to corneal transplantation, the low immunogenicity of the stroma and endothelium and induction of anterior chamber-associated immune deviation (ACAID) by the endothelium (see Uvea) also contribute to the unique immune status of the cornea. The adaptive immune response is also modified by the presence of indolamine dioxygenase in keratocytes and to a lesser extent in the corneal epithelium and endothelium. This intracellular enzyme catabolizes tryptophan, an amino acid essential for the survival of T lymphocytes.

The uveal tract is protected from physical injury by the eyelids, fibrous tunic of the globe, and by the bony orbit. The uvea is critical to maintenance of ocular immune privilege. Immune privilege describes anatomic and molecular mechanisms of immune regulation that provide protection against inflammation-induced injury while maintaining protection against pathogens. Within the eye, the anterior and posterior chambers, the vitreous, and the subretinal space are immune privileged sites. Protecting ocular structures against bystander injury from inflammation is critical to maintaining vision. Corneal endothelial cells and some retinal cells, for example, have limited to no capacity for regeneration. Controlling inflammation also helps keep the ocular media clear of cells and molecules that could diminish or scatter light. Ocular immune privilege is dependent on the immunologic phenomenon known as ACAID as well as the blood-ocular barriers. The lack of true lymphatic vessels within the uveal tract also contributes to the unique immunologic status of the globe.

The blood-aqueous barrier, one of two main blood-ocular barriers along with the blood-retinal barrier, is created by tight junctions defense mechanisms at other sites, including the globe's immune privilege/anterior chamber-associated immune deviation (ACAID) and the blood-ocular barriers.

The vitreous is protected from physical injury by the eyelids, fibrous tunic of the globe, and the bony orbit. The vitreous also benefits from defense mechanisms at other sites, including the globe's immune privilege/ACAID and the blood-ocular barriers. The vitreous has minimal active defense mechanisms. The hyalocytes can dedifferentiate into fibroblasts as part of a healing response.

The retina is protected from physical injury by the eyelids, fibrous tunic of the globe, and the bony orbit. The retina also benefits from defense mechanisms at other sites, including the globe's immune privilege/ACAID. The retina contributes to the blood-ocular barriers. The blood-retina barrier includes two components: the retinal vessels and the retinal pigment epithelium (RPE). In the retinal vessels, there are tight junctions between nonfenestrated endothelial cells. There are also tight junctions between the cells of the RPE, acting as a barrier between the choroidal blood vessels and neuroretina. The retina has essentially no defense against infectious agents, radiation, chemicals, or inflammatory diseases that extend from other ocular sites. Ischemic injury is a major threat to retinal viability. The retina does benefit from an autoregulated vascular system that allows retinal perfusion to remain relatively normal despite wide fluctuations in systemic blood pressure. This system helps reduce the risk of ischemic injury. The injured retina also produces angiogenic growth factors and has a powerful system of scavengers to counteract the damaging effects of excitatory neurotoxins, nitric oxide, and other potentially damaging by-products of ischemia. The retina has no resident phagocytes or other cellular components of the immune system. The optic nerve is protected from physical injury by the eyelids and bony orbit. The meninges provide both support and protection. The cellular and molecular defense mechanisms in the optic nerve mimic those in the central nervous system (see Chapter 14).

The orbit is protected from most physical and chemical injuries by the eyelids and adjacent skin. The connective tissues and muscles of the orbit are also protected by the bones of the orbit. The innate and adaptive immune responses of connective orbital tissues are similar to those of other connective tissues. The lacrimal gland contributes to the production of the tear film and the defense of the ocular surface (see Cornea).

Ocular developmental anomalies are divided into failures of induction, failures in remodeling, and late failures in atrophy. Included in this section are only those anomalies in early induction that affect the eye as a whole. The anomalies that result from defects occurring later in remodeling or from atrophy typically affect one component predominantly and are discussed in the sections covering each component of the eye. inhibit innate immunity by interfering with nitric oxide production by macrophages. TGF-β, α-MSH, and vasoactive intestinal peptide inhibit interferon-γ expression by activated CD4 + T lymphocytes modulating helper T lymphocyte differentiation. The aqueous humor contains complement regulatory proteins that inactivate the complement cascade. The corneal endothelium, iris, and ciliary epithelium express membrane-bound molecules such as CD86, membrane-bound TGF-β, and thrombospondin-1 to induce the conversion of activated T lymphocytes into Treg by contact. In addition, ocular cell surface expression of programmed death ligand-1/2 (PD-L1/PD-L2) and the Fas ligand (CD95 ligand) can induce apoptosis of activated T lymphocytes. Some complement regulatory proteins are membrane bound.

ACAID can be separated into three phases: ocular, thymic, and splenic. The induction of ACAID begins with the ocular phase and the capture of antigen in the anterior chamber by macrophages serving as APCs. Ocular APCs act under the influence of soluble immune suppressive molecules, chiefly TGF-β. After capturing the antigen, the APCs begin to produce macrophage inflammatory protein-2 (MIP-2). Activated ocular APCs express CD1d. CD1d molecules have a similar structure as MHC class I molecules, but they present lipid antigens rather than peptides. Within 72 hours, the ocular APCs that have captured antigens migrate to and through the iridocorneal angle and enter the scleral venous plexus and the venous circulation. Mobilized ocular APCs leave the globe predominantly via the bloodstream to reach the thymus and the spleen.

The thymic phase of ACAID aims to provide natural killer T (NKT) lymphocytes required for the splenic phase. In the thymus, ocular APCs induce the production of a unique population of NKT lymphocytes (CD4-CD8-NK1.1 + T lymphocytes). Only APCs that express CD1d can initiate the generation of these specialized NKT lymphocytes. Thymic NKT lymphocytes will migrate to the spleen within 4 days of the initiation of ACAID in the globe.

The splenic phase begins when the ocular APCs that have captured antigens reach the spleen. Some of the unique features of the ocular APCs include the expression of CD1d and complement 3b receptor. These cells also show increased production of IL-10, IL-13, and MIP-2 but downregulation of IL-12. Furthermore, the ocular APCs migrate to the marginal zones composed of predominantly B lymphocytes rather than target areas dominated by T lymphocytes. Once established in the spleen, the ocular APCs secrete TGF-β, thrombospondin-1, and interferon-α/β, creating an immunosuppressive environment. They also secrete MIP-2, a chemoattractant for CD4 + NKT lymphocytes. These CD4 + NKT lymphocytes in turn produce RANTES, which interacts with the marginal zone B lymphocytes and recruits CD4 + T lymphocytes, γδ T lymphocytes, and CD8 + T lymphocytes that differentiate to become the end-stage ACAID Tregs. Thymic NKT lymphocytes are necessary to produce Tregs, although their exact role has not yet been determined.

One population of Treg cells is CD4 + , considered "afferent" because these cells suppress the initial activation and differentiation of naive T lymphocytes into effector cells. Afferent Treg cells of ACAID act in regional lymphoid tissue. The second population of Treg cells is CD8 + , considered "efferent" because this population inhibits the expression of delayed-type hypersensitivity. Efferent Treg cells of ACAID act in the periphery, including the eye.

The lens is protected from physical injury by the eyelids, fibrous tunic of the globe, and the bony orbit. The lens capsule prevents direct invasion of most infectious agents. In addition, the capsule protects the lens from leukocyte-mediated injury but not from inflammatory chemical mediators. The lens also benefits from 1287.e1 CHAPTER 21 The Eye

Autopsy (syn. necropsy) procedures should include visual assessment of eyelids, globe size and shape, corneal qualities, and identification of any mass lesion both before and after removal of the globe from the orbit. The postmortem sampling technique mimics surgical enucleation and can be performed using a transconjunctival or transpalpebral approach. Care must be taken to avoid accidental puncture of the globe. The optic nerve should be sectioned along the bony orbit to ensure sufficient tissue is included for evaluation. The globe should not be incised in any manner prior to fixation; gross examination of the intraocular contents will be performed post-fixation. Unless diseased, eyelids and orbital tissue can and should be separated from the globe prior to fixation and processed separately. Adequate fixation is provided by 10% neutral-buffered formalin. Larger globes may benefit from intravitreal injection of formalin with a small needle inserted though the sclera adjacent to the optic nerve. Davidson's and Bouin's fixatives are alternatives that confer more rigidity to the fixed globe facilitating sectioning, although both require special processing.

In domestic animals, standard sectioning is done along the dorsoventral (vertical) plane including the optic nerve and with care not to cause iatrogenic displacement of the lens. The long posterior ciliary artery extends in a horizontal plane from the optic nerve to the lateral and medial limbus; it is usually visible on the outer sclera and can be helpful to orient the globe. Standard sectioning is perpendicular to the long posterior ciliary artery. The plane of sectioning may be altered to include previously diagnosed lesions of interest. The bisectioned globe allows visualization of intraocular structures. Evaluation should include (but not be limited to) assessment of mass effects in the uveal tract, the presence of hemorrhage, location of the lens (lens luxation), viscosity of the aqueous humor and vitreous, and position of the retina (retinal detachment).

give birth to lambs with this ocular malformation in addition to others. Ingestion of the plant before day 14 may result in fetal death but no anomalies. Ingestion after day 14 results in various anomalies but not cyclopia/synophthalmia.

Coloboma is the least severe of the developmental abnormalities affecting the globe as a whole (Fig. 21-22 ). Many result in the failure of the optic fissure to close. The optic fissure normally closes in the last third of gestation, persisting longest near the posterior pole of the globe just ventral to the optic nerve. If it persists for too long, there is the possibility that the developing retina will grow outwardly through this defect. Some colobomas are secondary to defects in the uveal neuroepithelium or retinal pigment epithelium and failure to properly induce the differentiation of the neural crestderived uveal stroma. In Charolais cattle, bilateral but often asymmetric colobomas at or near the optic nerve are inherited as an autosomal dominant trait with incomplete penetrance. In Australian shepherds, colobomas have been shown to be the result of a primary defect in the retinal pigment epithelium (RPE) causing hypoplasia of the adjacent choroid and sclera. Similar colobomas occur in other merle breeds and have been described in cattle and cats exhibiting subalbinism.

Glaucoma Glaucoma is not a single disease but a diverse group of diseases sharing specific physiologic and structural characteristics. It is a clinical syndrome characterized by a sustained increase in intraocular pressure that is detrimental to the health of the optic nerve and the retina, resulting in loss of vision and eventual blindness. Glaucoma causes changes in virtually every tissue within the globe, but changes in the retina and optic nerve are the most clinically important because they lead directly to vision loss. The condition is more prevalent in dogs than in cats or horses. Glaucoma is a frequent cause of ocular pain and blindness in dogs. It is the leading reason for surgical removal of the globe (enucleation). It is relatively less common in cats, yet it is still the leading cause for enucleation in Anophthalmia is a very rare condition in which there is no detectable development of the globe. It is usually bilateral. The vast majority of the cases clinically diagnosed as anophthalmia are more accurately described as severe microphthalmia, and some remnant of the globe can be found within the orbit. Anophthalmia most often accompanies other developmental anomalies.

Microphthalmia is the presence of a small, disorganized globe in an orbit of relatively normal size (E- Fig. 21-24) . In some cases, the anomaly does not reflect a primary maldevelopment but, rather, involution after some type of exogenous injury to a globe that up to that stage was normal in its development. This includes in utero trauma, ischemic injury, and infection. Such globes can be remarkably small, presenting as a pigmented nodule embedded in the orbit tissue. In most instances, there is pigmented tissue that can be recognized as uveal tract and some neural tissue with features suggesting retina.

Cyclopia and synophthalmia present as a single midline ocular structure (Fig. 21-21) . They reflect failure of division of the optic primordium into paired symmetric optic stalks and vesicles, which therefore results in a single midline globe. Most resulting globes include duplicates of some intraocular structures and are properly termed synophthalmia. Cyclopia and synophthalmia usually accompany other craniofacial deformities and are rare conditions. Cases of induced cyclopia/synophthalmia have occurred in sheep as well as llamas and alpacas that have ingested the plant Veratrum californicum. The plant contains three steroid alkaloids: jervine, cyclopamine, and cycloposine. The alkaloids cause anomalies through the inhibition of the sonic hedgehog signal transduction pathway, which plays an important role in cell growth and differentiation including ocular development. Ewes ingesting the plant on day 14 of gestation 1288.e1 CHAPTER 21 The Eye E- Figure 21 -24 Microphthalmia, Globe and Orbit, Calf. Note that the orbit (right) remains relatively normal, probably indicating that the initial development of the globe was normal and that its current small size (on the scalpel blade, left) is a result of in utero injury and subsequent atrophy (indicating so-called secondary microphthalmia rather than a primary failure of ocular development). (Courtesy Dr. B. Wilcock, Ontario Veterinary College.) are not just passive conduits through which the aqueous humor can flow. There is an important physiologic resistance to outflow responsible for the maintenance of normal intraocular pressure. The exact anatomic and physiologic constituents of this outflow resistance remain incompletely defined but include important contributions from the trabecular cells lining the collagen beams within the trabecular meshwork, the glycosaminoglycans embedded in the matrix supporting those trabecular cells, and blood pressure within the scleral venous plexus.

The macroscopic lesions of glaucoma are related to the secondary effects of increased intraocular pressure on the various components of the globe. Although the increase in intraocular pressure is the result of obstruction of aqueous humor outflow, intraocular pressure elevation is distributed throughout the fluid medium of the globe, and the effects are thus felt by all components of the globe. These effects are the same, regardless of the pathogenesis of the glaucoma, and they vary with the rapidity of onset, the severity of the intraocular pressure elevation, and the duration of the elevation. They are also influenced by the age of the patient and by the species. The most obvious of the macroscopic changes include ocular enlargement (buphthalmos), corneal edema, pupillary dilation, and cupping of the optic disc.

Histologic Changes Associated with Glaucoma. The challenge for the pathologist is that many histologic changes that can be secondary to glaucoma can also contribute to the cause of glaucoma. The distinction is not always possible in individual cases. For example, primary lens luxation can lead to pupillary block and glaucoma; conversely, glaucoma causing buphthalmos can damage the zonular ligaments, resulting in lens luxation. As such, ocular changes must always be interpreted in light of history and clinical findings.

The most helpful and frequent histologic changes in the diagnosis of glaucoma are listed in Box 21-12. The changes listed are more frequently observed with chronic glaucoma because globes with acute glaucoma are unlikely to be submitted for histopathologic evaluation.

Buphthalmos is stretching of the globe secondary to increased intraocular pressure (E- Fig. 21-27) . It is most obvious in dogs and least obvious in horses. Histologically the sclera becomes thin. Buphthalmos is associated with activation of stretch receptors and pain. Chronic buphthalmos can lead to corneal dessication when the eyelids cannot close over the enlarged globe.

Corneal edema develops when the aqueous pressure exceeds the ability of the sodium pump within the corneal endothelium to dehydrate the cornea (in dogs, at approximately 40 mm Hg). More severe corneal edema then develops as a result of pressure-induced injury to that endothelium, and that injury may become permanent if the endothelial injury is so extensive that it exceeds the capacity of the corneal endothelium to repair itself. Corneal edema secondary to glaucoma is much more frequent in dogs than in cats. Corneal that species. Its frequency in horses may be greatly underestimated because of its variable clinical presentation in that species and because intraocular pressure is not as consistently measured during clinical examination in horses.

Theoretically, glaucoma may result from an increase in the production of aqueous humor or a decrease in its removal. However, there are no known conditions in domestic animals that result from pathologic overproduction of aqueous humor. All examples of glaucoma in domestic animals result from impairment of aqueous outflow. Glaucoma is usually categorized as primary or secondary glaucoma. Primary glaucoma refers to those examples occurring without any known acquired intraocular disease to explain the increase in intraocular pressure. The great majority of these result from developmental errors in the structure and function of the iridocorneal angle and aqueous humor drainage pathways. Secondary glaucoma refers to those examples in which there are acquired lesions responsible for the impairment of aqueous humor outflow such as fibrovascular proliferation, lens luxation, inflammation, or intraocular neoplasia. There are instances in which acquired lesions will occur in globes already predisposed to glaucoma because of developmental structural anomalies. It can be challenging in those instances to determine the relative significance of the developmental and acquired lesions and to characterize the glaucoma as primary or secondary.

The aqueous humor contained in the anterior and posterior chambers is formed continuously by a combination of plasma filtration, diffusion, and active secretion by the ciliary epithelium. The aqueous humor is secreted into the posterior chamber. It circulates near the lens to provide nutrients and remove waste products. The aqueous humor enters the anterior chamber through the pupil, circulates within the anterior chamber to nourish corneal endothelium and stroma, and then exits through the iridocorneal angle at the junction between peripheral cornea and iris. This iridocorneal angle extends circumferentially around the globe and normally has tremendous reserve capacity to accommodate fluctuations in aqueous production and to provide a substantial margin of safety against the development of glaucoma secondary to partial obstruction of aqueous humor outflow by accumulations of blood or inflammatory debris.

The maintenance of intraocular fluid pressure is a balance between aqueous production and outflow and in domestic animals is influenced primarily by resistance to outflow. The outflow pathway is through the iridocorneal angle-a series of perforations in the connective tissue of the peripheral cornea, sclera, and iris stroma that makes up the ciliary cleft and corneoscleral trabecular meshwork (E-Figs. 21-25 and 21-26; see Figs. 21-6 and 21-7). Embryologically, the ciliary cleft and corneoscleral trabecular meshwork are formed by rarefaction of the same mesenchyme that forms iris stroma. In carnivores this remodeling continues for several weeks after birth.

Aqueous humor passing through the iridocorneal angle then enters a network of large veins, known as the scleral venous plexus, which is embedded in the peripheral sclera. The aqueous humor entering these veins is then returned to the systemic circulation. An alternative to this "conventional" drainage pathway is the uveoscleral outflow or "unconventional" pathway. The uveoscleral outflow allows a small percentage of the aqueous humor to percolate through the iris root and ciliary body interstitium to reach the supraciliary space (between the ciliary body and sclera) or suprachoroidal space (between the choroid and sclera) to exit the globe. The proportion of aqueous humor leaving the globe by this more posterior route varies by species: 3% in cats, 15% in dogs, and a larger (but undetermined) percentage in horses. These outflow pathways Optic nerve head cupping is most frequently observed with glaucoma ( Fig. 21-24; E-Fig. 21-29) . Microscopic changes in the optic nerve include gliosis and degeneration of axons (Wallerian degeneration). Necrosis and malacia can be observed in acute cases. Optic nerve injury occurs more quickly and is more prominent in dogs than in other species.

Pathogenesis of Glaucoma. Glaucoma represents a heterogeneous group of diseases. The exact pathogenesis for the characteristic retinal and optic nerve changes probably varies among species and among different types of glaucoma, and it is the subject of much controversy. Retinal ganglion cell death occurs predominantly by apoptosis. Both the intrinsic, mainly proapoptotic Bcl-2 family members, and extrinsic pathways contribute. Necrosis causes ganglion cell death later in the disease, and likely in specific forms of glaucoma. Multiple mechanisms contribute to the death of retinal ganglion cells. Some of the contributing factors involved in the pathogenesis of glaucoma include the following: Pressure-induced ischemic damage: This occurs after collapse of blood vessels in the retina, optic nerve, or choroid in response to increased pressure in the vitreous. Pressure-related outward bowing of the lamina cribosa contributes to the altered blood flow. The ischemia and resulting hypoperfusion/hypoxia may contribute to retinal ganglion cell death through multiple mechanisms:

• Direct damage to retinal ganglion cells and the induction of apoptosis • Excitatory damage from glutamate release (see Excitotoxicity below) • Oxidative stress and damage • Mitochondrial dysfunction Impairment of anterograde and retrograde axoplasmic flow: This interferes with ganglion cell function and is caused by pressureinduced compression of the axons passing through the lamina cribrosa. The altered axoplasmic flow results in disruption of neurotrophic factors from the central nervous system. Neurotrophic factors promote neuron survival by inhibiting apoptosis pathways. Brain-derived neurotrophic factor, ciliary neurotrophic factor, and glial cell line-derived neurotrophic factor all have neuroprotective effects. Endogenous production of neurotrophic factors in the retina can initially protect ganglion cells. However, only neurons exposed to adequate levels of neurotrophic factors can escape apoptosis, and both endogenous neurotrophic factors and those from the central nervous system are striae (Haab's striae) are breaks in Descemet's membrane occurring secondary to corneal stretching. They are visible on clinical examination as curvilinear to branching tracts of deep corneal stromal opacity. Perilimbal corneal neovascularization is commonly seen secondary to release of angiogenic factors from the injured retina or uveal tract. Chronic keratitis with epidermalization may be present if there is corneal desiccation associated with buphthalmos. Collapse of the iridocorneal angle is present with almost all forms and almost all cases of glaucoma. The anterior chamber may be shallow. Atrophy of the iris and ciliary processes occurs late in the course of glaucoma, probably as a consequence of chronic pressureinduced ischemia. Atrophy of the ciliary processes eventually leads to normalization of intraocular pressure and even hypotony, seen as part of end-stage glaucoma.

Cataracts are common in glaucoma, presumably as a result of altered aqueous humor dynamics and composition. Lens subluxation or luxation results from stretching and eventual rupture of zonular ligaments secondary to buphthalmos. The luxation may be into the anterior chamber or vitreous. Vitreal liquefaction may be secondary to inflammation preceding the glaucoma, but it also occurs as a consequence of glaucoma.

Retinal atrophy (degeneration) is the most important secondary change in glaucoma. It is important because it causes blindness as a result of damage to the ganglion cells, which cannot regenerate, even if the intraocular pressure returns to normal levels. The degeneration characteristically causes atrophy of the nerve fiber layer and loss of ganglion cells (Fig. 21-23; E-Fig. 21-28 ). In dogs, there can be later loss of neurons from the inner nuclear layer. The Müller glial cells remain intact, although some functions may be altered. In glaucomatous retinal atrophy, the outer nuclear layer and photoreceptors can remain unaffected for extended periods of time. This pattern of "inner retinal atrophy" with sparing of the outer nuclear layer and photoreceptors is characteristic of glaucoma. Other forms of retinopathy, including inherited, nutritional, and toxic forms, target photoreceptors rather than the inner retina. In some instances, the outer retina may be damaged as part of glaucoma. Acute, severe increases in intraocular pressure can lead to necrosis and apoptosis of photoreceptors, likely as a response to pressure-induced collapse of the superficial choroidal blood vessels and ischemia. In dogs, chronic glaucoma can lead to full-thickness atrophy. In globes with glaucomatous inner retinal atrophy, the retinal degeneration may be more severe ventrally. This is termed "tapetal sparing" but can also be observed in atapetal globes. Tapetal sparing is most common and dramatic in dogs but can be seen in any species. correlates with the extent to which the iridocorneal angle circumference is involved, which must be evaluated clinically. Goniodysgenesis is invariably bilateral but not necessarily symmetric. The robust pectinate ligaments of horses and ruminants, and to a lesser extent pigs, should not be confused with pectinate ligament dysplasia/goniodysgenesis (see Fig. 21-7) .

Goniodysgenesis should be considered a risk factor for the development of glaucoma rather than a specific cause. In fact, only a small percentage of affected animals develop glaucoma, including only approximately 15% of the most severely affected dogs. Furthermore, although the lesion is present throughout life, dogs with this condition develop glaucoma as middle-aged to older adults. Dogs that do develop goniodysgenesis-related glaucoma in one eye are at high risk for glaucoma in the contralateral eye. It is likely that there are functional changes associated with goniodysgenesis that do not have a histologic correlate.

The reasons for the delay in the onset of clinical signs of glaucoma are poorly understood. Age-related changes may be contributing factors. Pigment dispersion as a result of contact between the pigmented posterior iris epithelium and the lens capsule has been hypothesized to play a role in the development of goniodysgenesisrelated glaucoma in some dogs. Mild uveitis or other minor acquired lesions that might not result in glaucoma in normal globes may be significant in globes with goniodysgenesis. It is possible that any change that decreases the aqueous humor outflow capacity increases the risk of goniodysgenesis-related glaucoma, perhaps in a cumulative manner. The triggering events are unlikely to be the same in each individual.

When goniodysgenesis-related glaucoma does develop, the earliest histologic findings include collapse of the corneoscleral trabecular meshwork, partial and gradual collapse of the ciliary cleft, disruption of the posterior iris epithelium with pigment dispersion, and neutrophilic infiltration within the iridocorneal angle. Early changes in the retina include edema, neutrophilic infiltration, and ganglion cell apoptosis/necrosis. There may be full-thickness injury with severe increases in intraocular pressure. There may be edema and neutrophils within the optic nerve head with eventual infiltration of Gitter cells.

Most globes are examined histologically during the chronic stages of the disease. With chronic goniodysgenesis-related glaucoma, there is complete collapse of the iridocorneal angle including required for long-term survival and function of retinal ganglion cells. Excitotoxicity: Damaged ganglion cells release excitatory compounds, primarily the neurotransmitter glutamate, which then induces apoptosis of previously uninjured ganglion cells. This can lead to a self-perpetuating cycle of neuronal cell death from excitotoxicity. Retinal injury is unlikely to result in massive glutamate release as the case with acute brain injury. Glutamate excess is more likely to only occur in microenvironments representing areas of localized retinal degeneration. Retinal glutamate receptors are located in the outer plexiform layer where glutaminergic synapses connect photoreceptors to bipolar and horizontal cells and in the inner plexiform layer that contains most of the glutaminergic synapses between retinal ganglion cells and bipolar and amacrine cells. Excitotoxic damage occurs when excess glutamate binds to ionotropic glutamate receptors triggering massive calcium influx and activation of proapoptotic pathways. Excitotoxic damage overrides the protective effect of endogenous and exogenous neurotrophic factors. Glial cells that maintain physiologic levels of glutamate are responsible for the uptake of excess glutamate via glutamate/aspartate transporters. As such, deficits in transporter function can contribute to retinal ganglion cell damage. Furthermore, excess glutamate may cause glial cells to exacerbate ganglion cell loss by releasing neurotoxic factors such tumor necrosis factor-α, nitric oxide, and α 2 -macromodulin.

Primary Glaucoma. Primary glaucoma occurs without any significant contribution from acquired disease elsewhere within the globe. Primary glaucomas are subdivided into those cases in which there is detectable maldevelopment of the trabecular meshwork (goniodysgenesis) and those cases in which there are no primary histologic lesions (open-angle glaucoma). A very small proportion of these are truly congenital glaucomas in which clinical signs of glaucoma are evident in the first few weeks of life. The vast majority, however, have no clinically detectable increase in pressure or clinical signs related to glaucoma until middle age or even older. The reason for this delay in clinical onset is unclear.

Goniodysgenesis. Goniodysgenesis refers to an abnormal and incomplete development of the iridocorneal angle and aqueous humor draining pathway. It is essentially a canine disease, although reports in other species exist. It mostly occurs as an inherited disease in purebred dogs. It is the result of incomplete remodeling of the solid mass of anterior chamber mesenchyme that gives rise to the stroma of the cornea and anterior uvea. In carnivores, most of this remodeling occurs in the first few weeks of life and involves rarefaction of what was previously a solid mesenchymal mass. The extremely severe cases of goniodysgenesis with essentially no rarefaction of the iridocorneal angle (so-called trabecular hypoplasia) can cause true congenital glaucoma.

The most common histologic anomaly is failure of the most anterior portion of the iridocorneal angle to be adequately remodeled, resulting in thickening of the pectinate ligament with pigmented iris stroma-like tissue that extends from the iris base to the termination of Descemet's membrane (pectinate ligament dysplasia) (Fig. 21-25 ; E-Figs. 21-30 and 21-31). Arborization of the termination of Descemet's membrane is a common finding, but is not specific for goniodysgenesis. The severity of the lesion may vary significantly along the circumference of the iridocorneal angle. Multiple areas of the iridocorneal angle should be examined histologically before excluding goniodysgenesis, as the lesion may not be recognizable in every section. The risk of developing glaucoma Aqueous Humor Misdirection. Aqueous humor misdirection (also termed malignant glaucoma or ciliary block) occurs when aqueous humor accumulates in the vitreous or between the vitreous and retina. This displaces the vitreous, lens, and iris anteriorly, resulting in a shallow anterior chamber and eventually collapse of the iridocorneal angle. Pupillary block develops often as the lens is forced against the iris. It is mostly seen in older cats.

Angle Recession. Angle recession develops following blunt trauma that alters the shape of the globe leading to separation of the ciliary body from the sclera (cyclodialysis). As the ciliary body reconnects with the sclera, there is posterior displacement of the iridocorneal angle. The anterior aspect of the pars plicata of the ciliary body may be thin and lacking ciliary processes. Assuming the aqueous humor outflow pathways remain functional and not obstructed by hemorrhage or fibrovascular proliferation in the immediate period after the trauma, glaucoma can develop later partly because of remodeling of the iridocorneal angle. Fibrosis may be recognized histologically in some cases.

A number of changes occur as the eye ages. In the cornea, Descemet's membrane becomes thicker while the corneal endothelium is sparser. Senile iris atrophy is common in older animals. Dogs may develop small cysts/cystic degeneration of the posterior iris epithelium. Sclerosis or hyalinization of the collagen at the base of the ciliary processes and pigmentary incontinence in the ciliary body become more prominent in the aging dog ( Fig. 21-26) . Older cats and horses may have cysts within the pars plana of the ciliary body. The lens capsule thickens and nuclear sclerosis is common in older domestic animals. Senile cataract is common. Older dogs commonly develop hyaluronic acid-containing cysts in the peripheral retina at the ora ciliaris retinae (also termed peripheral cystoid degeneration). Gradual loss of some retinal photoreceptors occurs in older animals. Lipofuscin accumulates in the retinal pigment epithelium as part of normal aging. Foci of mineralization can be found in the sclera of older horses.

Anomalies in the formation of eyelids, including the shape of the palpebral fissure, are common in dogs. In some instances, the "anomaly" is even a feature for the breed (e.g., ectropion in bloodhounds and Saint Bernards). Most of these anomalies are not the ciliary cleft and corneoscleral trabecular meshwork. Collapse of the iridocorneal angle can result in a crease at the junction of the pectinate ligament and iris stroma mimicking angle recession (occasionally termed falsely recessed angle or posteriorly displaced angle). The inner retina is atrophic and there may be full-thickness retinal atrophy in some dogs, with or without tapetal sparing. The optic nerve head is cupped, and the optic nerve is gliotic. Atrophy of the ciliary processes, thinning of the sclera, and other changes associated with chronic glaucoma may be present.

Primary Open-Angle Glaucoma. Primary glaucoma in dogs, cats, and horses can occur in globes in which there is no visible abnormality in the structure of the iridocorneal angle or other portions of the aqueous outflow pathways. These cases represent dysfunction of the iridocorneal angle rather than an anatomic alteration. The best known is heritable open-angle glaucoma described in beagles, and it has been used as a laboratory model of primary glaucoma in human beings. In the early stages of primary open-angle glaucoma, all portions of the aqueous outflow pathways are histologically and ultrastructurally normal. The genetic defect is an autosomal recessive trait that results in accumulation of abnormal extracellular matrix within the trabecular meshwork and resistance aqueous humor outflow. In cats, primary open-angle glaucoma can be unilateral/ asymmetric or bilateral. There are no histologic lesions in the iridocorneal angle, but some cases show edema/myxomatous change surrounding the vessels of the scleral venous plexus.

Obstruction of the Iridocorneal Angle. The open iridocorneal angle may be blocked by various exudates and cells. Neoplastic cells, hemorrhage/fibrin, and leukocytic infiltrates are the most common forms of open-angle obstruction. Such accumulations of cells and material within the iridocorneal angle are highly unlikely to cause glaucoma unless a significant portion of the iridocorneal angle circumference is affected. Hemorrhage and leukocytic infiltrates in particular will tend to settle ventrally, allowing aqueous humor outflow dorsally. As such, these tend to contribute to the development of glaucoma only in the presence of other lesions. Neovascular glaucoma is common and occurs when the iridocorneal angle is obstructed by a preiridal fibrovascular membrane. The membrane may also extend on the peripheral posterior cornea (peripheral anterior synechia) and contract to further cause obstruction (E- Fig. 21-32 ). Neovascular glaucoma is commonly seen with retinal injury, specifically retinal detachment. It is also common with intraocular neoplasia, uveitis, and trauma. Some of the underlying causes of neovascular glaucoma (neoplasia and uveitis) may also contribute directly to aqueous humor outflow obstruction.

Neoplasia often infiltrates the iridocorneal angle directly and can carpet the anterior surface of the iris to cover the iridocorneal angle (E- Fig. 21-33 ). In addition, tissue damage, uveitis, fibrovascular proliferation, retinal detachment, and lens disease may all contribute to glaucoma secondary to neoplasia. The neoplasms that most frequently cause glaucoma by direct infiltration of the iridocorneal angle are uveal melanocytoma, uveal malignant melanoma, and metastatic lymphoma in dogs and diffuse iris melanoma and metastatic lymphoma in cats.

Pupillary Block. The passage of aqueous humor through the pupil may be blocked or impaired by extension of a preiridal fibrovascular membrane, from adhesions between the iris and lens (posterior synechia) secondary to uveitis, lens luxation, or by massive swelling of the lens part of an intumescent cataract. In pupillary block, aqueous humor accumulates in the posterior chamber, which may result in anterior bowing of the iris (iris bombé), thus displacing the root of the iris and collapsing the iridocorneal angle anteriorly (E- Figs. 21-34 and 21-35) . whereas others consist only of vestigial hair follicles. Dermoids also occur in the cornea.

Acquired diseases that affect the cutaneous aspect of the eyelid are essentially those that affect the skin and those with a predisposition for the head or mucocutaneous junctions (see Chapter 17). Chalazion is sterile lipogranulomatous inflammation in response to the leakage of meibomian secretions into the surrounding dermis of the eyelid margin. It is much more common in dogs than in any other species. In most cases, the inflammation is associated with meibomian gland neoplasia, although it can also occur with other causes of meibomian secretions leakage such as meibomian adenitis. Histologically, the inflammation is an accumulation of macrophages and multinucleated cells bordering the meibomian neoplasm or meibomian gland (Fig. 21-27 ). In dogs, these cells often contain acicular cytoplasmic clefts that correspond to birefringent material. There may be accumulation of extracellular free lipids (lipid lakes). Similar inflammation with macrophages and multinucleated cells develops in cats (termed lipogranulomatous conjunctivitis). Lipid lakes tend to be prominent. Although feline lipogranulomatous inflammation can be associated with meibomian gland disease, it can also accompany other forms of neoplasia, including malignancies such as squamous cell carcinoma. As such, the lesion is not strictly limited to the eyelid margin and can occur in the bulbar or third eyelid conjunctiva.

Infectious Diseases. Onchocercosis causes conjunctival diseases in dogs, cats, and horses. The life cycle is likely similar for all Onchocerca spp., with black flies (Simulium spp.) or gnats/midges (Culicoides spp.) serving as intermediate hosts. In small animals, the disease is caused by Onchocerca lupi and has been reported in dogs and cats from the southwestern United States and dogs from Europe. The condition often presents as conjunctival or episcleral inflammatory nodules centered on adult filarial nematode worms ( Fig.  21-28) . Orbital nodules may be associated with exophthalmos. The inflammation is predominantly granulomatous. Eosinophils may be present in large numbers, and there may be fibrosis. In some cases, the parasites elicit minimal inflammation and are bordered only by a thin band of fibrous tissue. The paired uteri of the adult female worms typically contain microfilariae, which suggest patent infection. Onchocerca lupi must mainly be differentiated from Dirofilaria immitis. Oncocercha spp. have annular/circumferential cuticular examined microscopically because they are obvious macroscopically. They are important in clinical ophthalmology, and surgical correction of these anomalies is common, but histologic examination is very rare.

Eyelid Agenesis (Coloboma). There may be partial or complete absence of an eyelid. It occurs in all species but is most common in cats, involving the lateral aspect of the upper eyelid. Dermoids and lacrimal gland aplasia/hypoplasia may be present simultaneously with eyelid agenesis. The eyelid defects may result in inadequate dispersion of the tear film or excessive evaporation leading to chronic keratitis and occasionally corneal ulceration.

Premature Eyelid Separation. In carnivores, the eyelids are normally fused at birth (known as physiologic ankyloblepharon), which is essential to protect the immature cornea from infection and desiccation. Premature eyelid separation predisposes the eye to infectious keratitis, desiccation, and corneal rupture.

Conformational entropion is the inward rolling of the eyelid margin because of inadequate overall length. The usual result is irritation of the cornea by the eyelid cilia and/or hair. It is a common bilateral anomaly in purebred dogs that have been selected for breeding based partly on the shape of the palpebral fissure. It is also common in sheep. The extent and magnitude of the defect varies greatly among individual animals but tends to be relatively uniform within an affected breed. Depending on the severity of the irritation, entropion can lead to nonspecific chronic keratitis or progress to corneal ulceration. Entropion may also be acquired as the result of blepharospasm, scarring of the eyelid that is severe enough to cause changes in conformation, or lesions to the globe such as phthisis bulbi or microphthalmia. Surgical correction of entropion is a common procedure.

Ectropion is created by undue laxity of an excessively long eyelid, resulting in an eversion of the eyelid margin. As with entropion, its extent and severity vary greatly among individual animals and among breeds. The lower eyelid is more frequently affected. The anomaly has less significance than entropion because there is no direct corneal irritation, but it can result in chronic keratitis. Like entropion, severe scarring of the eyelid may cause acquired ectropion.

Cilia. Anomalies of cilia are prevalent in dogs, less so in horses, and uncommon in cats. They may or may not cause clinical signs; their significance lies in the corneal irritation they can cause. These conditions are best diagnosed clinically; there is no need for microscopic evaluation. Distichiasis is the presence of an ectopic cilia originating from the ducts of the meibomian glands. The defect is usually bilateral. Trichiasis is misdirection of the normal cilia so that they contact the cornea. Ectopic cilia are abnormally placed cilia within the lamina propria of the conjunctiva. Their emergence through the palpebral conjunctiva may result in profound corneal irritation and ulceration.

Conjunctival Dermoid. Dermoid is the only conjunctival developmental anomaly that is reasonably prevalent. The bulbar conjunctiva is most commonly affected. It reflects the failure of the fetal ectoderm to undergo complete corneal differentiation with the result that a portion of the conjunctiva remains as skin. Clinically, it is visible as a haired nodule. Histologically, it appears as a segment of conjunctiva that is more or less identical to normal skin. Some dermoids show complete development of skin and hair follicles, to be examined histologically. Histologic examination in chronic cases typically shows nonspecific lymphoplasmacytic conjunctivitis often including lymphoid hyperplasia but no elementary bodies to confirm the diagnosis. In ruminants and pigs, chlamydophilosis causes lesions in multiple organs and may include conjunctivitis. The infection can cause mucopurulent conjunctivitis and polyarthritis in lambs and kids.

Thelazia spp. are thin, rapidly motile nematodes 7 to 20 mm in length that inhabit the conjunctival sac and lacrimal duct of a variety of wild and most domestic animals. Only a small proportion of animals infected with the parasite have clinical disease. They are transmitted from animal to animal by flies, which ingest larvae present in host lacrimal secretions. They are of minor significance as parasites of horses and cattle and cause mild lymphofollicular conjunctivitis. In Asia and Europe, Thelazia callipaeda is a cause of conjunctivitis in dogs and cats.

Lymphoplasmacytic Conjunctivitis. Lymphoplasmacytic infiltration is the most common inflammatory response of the conjunctiva. This type of inflammation does not suggest a specific etiology and represents the end result of a variety of insults. Chronic or previous infection, physical trauma, immune reactions, chronic irritation, and so on are all possible initiating or contributing causes. Lymphocytes and plasma cells are the predominant cell types. Rare macrophages and mast cells may be present. Mild cases are usually perivascular and superficial in distribution, whereas more severe cases may be diffuse. Some degree of lymphoid follicular hyperplasia will accompany chronic cases. Lymphoid hyperplasia can be quite severe in horses. Lymphoplasmacytic conjunctivitis is typically nonulcerative. The diagnosis of lymphoplasmacytic conjunctivitis is especially common in biopsy submissions, a reflection of the fact that the conjunctiva is sampled late in the disease process and often after treatment using a variety of medications has been attempted.

Eosinophilic Conjunctivitis. Eosinophilic conjunctivitis is the conjunctival counterpart of the eosinophilic keratitis syndrome seen in cats and occasionally in horses (see Disorders of Cats). Rarely, there may be conjunctivitis in the absence of keratitis. Lesions may be unilateral or bilateral. Although eosinophils are required for the diagnosis, the proportion of eosinophils within the inflammatory infiltrate varies greatly between cases. Ulceration is common in severe cases. In chronic cases, especially those in which antiinflammatory medication was used, inflammation is likely to be predominantly lymphoplasmacytic with a scattering of eosinophils. In any species, eosinophils may be present with allergic/hypersensitivity disease and parasitic disease. Solar-Associated Lesions. As in the skin, chronic ultraviolet exposure results in degenerative lesions in the conjunctiva (see Chapter 17). Factors that contribute to the development of solarassociated lesions include high altitudes, low latitudes, lightly pigmented conjunctiva, and long duration of exposure. The lesions include solar elastosis, solar fibrosis, and solar vasculopathy (Fig.  21-30) . The most common and most easily recognizable change consists of solar elastosis. Solar elastosis develops in the superficial substantia propria and is recognized as thick, basophilic, and irregularly aligned fibers. These fibers are visible with standard hematoxylin and eosin staining and do not require special staining for elastin fibers. The fibers of solar elastosis represent mostly newly produced material rather than degeneration of preexisting fibers. The lesions are usually mild in dogs but can form plaques in horses and cattle. Solar fibrosis describes a band of hypocellular, sclerotic altered collagen located immediately underlying the epithelium. Solar fibrosis is not true fibrosis. Solar vasculopathy is uncommonly seen in the ridges that are visible in longitudinal section, whereas Dirofilaria spp. have longitudinal ridges that are visible in cross sections ( Fig.  21-29 ). In horses, the ocular lesions are caused by Onchocerca cervicalis and it is the microfilariae that cause the lesions, not the adult worms. In addition to conjunctivitis, there may be keratitis and uveitis.

Chlamydial conjunctivitis occurs in many species. Chlamydophyla felis is often associated with primary conjunctivitis in cats. The lesion is often unilateral initially. It may be seen concurrently with rhinitis and/or respiratory disease. The conjunctivitis is initially neutrophilic but progresses to also include macrophages, lymphocytes, and plasma cells. Early in the disease (between days 7 and 14), intracytoplasmic elementary bodies may be seen on cytology. Because the clinical signs are characteristic, these cases are unlikely Areas of cystic degeneration are common. Meibomian adenomas usually include haphazardly arranged ducts that vary in number and size. Meibomian epitheliomas have histologic features similar to cutaneous sebaceous epitheliomas. They are wellcircumscribed masses composed of densely packed sheets of small basal reserve cells with limited differentiation to lobules or single lipid-laden cells or ducts. The mitotic index is typically high, but nuclear atypia and pleomorphism are minimal. Epitheliomas should have a "preponderance" of basal cells. Many meibomian neoplasms are pigmented. Leakage of meibomian secretions can lead to severe granulomatous inflammation (chalazion). Papillary hyperplasia of the overlying epithelium is common.

Conjunctival Squamous Cell Carcinoma. Squamous cell carcinoma of the conjunctiva occurs in all species but is most common in cattle and horses ( Fig. 21-33 ; E- Fig. 21-37 ). In cattle, it is an economically significant neoplasm. The bulbar conjunctiva, especially at the lateral limbus, is commonly affected. Squamous cell carcinoma is the most common neoplasm affecting ocular structures in horses. The third eyelid and limbus are the most commonly affected conjunctival sites in horses.

In both cattle and horses, the pathogenesis includes a role for ultraviolet light-associated damage. Many/most neoplasms have altered p53 expression. Animals with minimal pigmentation of eyelids and conjunctiva are more susceptible. Actinic keratosis often precedes the development of neoplasia. Viruses, such as bovine papillomavirus and bovine herpesvirus 5, have been detected within bovine ocular squamous cell carcinomas, but their causal role has not been proven. As with sunlight-induced squamous cell carcinoma in the skin, the ocular neoplasms go through a series of precancerous changes in response to actinic injury. The sequence of lesions is as follows: hyperplasia, dysplasia, squamous cell carcinoma in situ, and eventually invasive squamous cell carcinoma. Not all precancerous lesions develop into carcinomas. Solar-associated lesions may be seen concurrently.

In cats, squamous cell carcinoma usually affects the skin of the eyelid itself rather than conjunctiva. Those that do occur in the conjunctiva but presents as thickened, hyaline, "smudgy" vessel walls with or without endothelial swelling. Epithelial changes often accompany solar lesions, including hyperplasia, hyperpigmentation, and keratinization. Solar-associated lesions are often seen concurrently with conjunctival squamous cell carcinoma or vascular neoplasia.

Meibomian Gland Neoplasms. Meibomian adenomas and epitheliomas are very common benign neoplasms and represent up to 70% of all canine eyelid neoplasms. Meibomian gland neoplasms appear clinically as tan, pink, gray, or black masses extending from the meibomian gland orifice or, less frequently, erupting through the palpebral conjunctiva (Fig. 21-31) . Histologically, meibomian gland adenomas are similar to sebaceous adenomas of the skin. They are well-circumscribed and often partially exophytic. They are composed of variably sized lobules of meibomian cells that show normal maturation from small basal reserve cells at the periphery to mature conjunctiva must be differentiated from conjunctival mucoepidermoid carcinomas, which show some glandular differentiation and are often papillary on the surface. Squamous cell carcinoma is uncommon in the conjunctiva of dogs. Granular Cell Tumor. Granular cell tumors can affect the eyelid of dogs at the medial canthus. The histologic features are similar to those affecting other sites. The neoplastic cells are characterized by abundant cytoplasm that contains numerous periodic acid-Schiff (PAS)-positive granules. Ultrastructurally, the granules are consistent with lysosomes. The cells show minimal pleomorphism, and mitotic activity is minimal to absent. Excision is usually curative.

Apocrine Cystadenoma. Apocrine cystadenomas (hidrocystomas) are benign lesions that affect the eyelids of cats, most often Persians. Grossly, the lesions present as multinodular to multifocal pigmented masses. Histologically, apocrine cystadenomas consist of multiple variably sized cysts lined by cuboidal to attenuated epithelium. The dark appearance of the nodules is the result of the brown secretions contained within the cysts. Macrophages may infiltrate the cysts. Excision is usually curative, but additional similar lesions may develop.

Adenocarcinoma of the Gland of the Third Eyelid. Adenocarcinomas of the gland of the third eyelid affect dogs and cats. They are expansile and variably infiltrative masses. Some are welldifferentiated and composed of tubules that resemble normal gland tissue, and others are mostly solid with only rare tubules. Squamous metaplasia is a common finding. Third eyelid gland adenocarcinomas in dogs tend to recur only with incomplete excision, and they only rarely metastasize. Despite similar histologic features, adenocarcinomas of the gland of the third eyelid are more aggressive in cats and metastasize more readily than in dogs.

Conjunctival Melanocytic Neoplasms. Primary conjunctival melanocytic neoplasia occurs mostly in dogs and cats. In both species, the vast majority of conjunctival melanocytic neoplasms are malignant (E- Fig. 21-38 ). In dogs, most occur on the third eyelid, whereas the bulbar conjunctiva is the most common site in cats. Conjunctival melanocytic neoplasms appear clinically as pink to lightly pigmented to darkly pigmented masses of the palpebral, bulbar, and third eyelid conjunctiva. Histologically, the cells are polygonal to spindle cells and form various growth patterns. Junctional activity, intraepithelial nests of neoplastic cells, is present in most masses where the overlying epithelium is intact. A mitotic index of at least 4 in 10 400× fields indicates malignancy, although the mitotic index is typically much higher. Foci of necrosis are common, and melanophages may infiltrate the neoplasms. Conjunctival malignant melanomas are invasive with a high rate of recurrence (30% in cats and up to 50% in dogs). Metastasis occurs in 20% to 30% of canine cases and approximately 15% of feline cases.

Conjunctival Vascular Neoplasms. Vascular neoplasms arise within the conjunctival lamina of dogs, cats, and horses. Hemangioma and hemangiosarcoma appear clinically as smooth, raised, pink to red masses on the conjunctival surface. Those tumors that are well circumscribed and consist of attenuated endothelium are classified as hemangiomas, and those with invasion formed by plump endothelium are classified as hemangiosarcomas. However, there is a continuum in the histologic appearance from hemangioma to hemangiosarcoma. Most conjunctival hemangiosarcomas are well differentiated, and distinction from hemangiomas is not always straightforward. Most of vascular neoplasms in dogs and cats are cured by complete excision, although there may be recurrence. The metastatic potential is minimal. In dogs and cats, the pathogenesis includes a role for ultraviolet light-associated damage, and solarassociated lesions may be seen concurrently. In horses, most vascular neoplasms are malignant. Most are poorly differentiated hemangiosarcomas (initially described as angiosarcomas); however, rare lymphangiosarcomas have been reported. These neoplasms are locally infiltrative and may metastasize.

Conjunctival Mast Cell Tumor. Conjunctival mast cell tumors in dogs present clinically as smooth, firm, and subconjunctival and are histologically similar to those in the skin. The conjunctival masses are typically small and well circumscribed, and most are composed of sheets of well-differentiated mast cells. Neither the grading systems nor the prognostic markers established for cutaneous mass cell neoplasia have been investigated in conjunctival masses. Complete surgical excision is reported to be curative for conjunctival mast cell tumors, and metastasis has not been described.

Conjunctival Papillomas. Benign squamous papillomas are frequent lesions of the bulbar conjunctiva of dogs. They are formed by papillary fronds of hyperplastic, often pigmented epithelium supported by fibrovascular stroma continuous with the conjunctival substantial propria. Their significance lies mainly as a differential diagnosis for malignant neoplasms such as squamous cell carcinoma and conjunctival malignant melanoma when pigmented. The vast majority of conjunctival papillomas are not associated with a viral infection; however, papillomavirus-induced lesions can affect the conjunctiva.

Conjunctival Lymphoma. Conjunctival lymphoma occurs sporadically in all species. The conjunctiva may be the primary site or may be part of systemic disease. Conjunctival lymphoma has histologic features and behavior similar to those in the skin.

Dermoid. Dermoid is the only corneal anomaly that is reasonably prevalent. As with conjunctival dermoid, the lesion is composed of ectopic hair follicles and adnexal glands within the cornea (Fig. 21-34 ; E- Fig. 21-39) . The ectopic tissue ranges from just a few scattered sebaceous glands to features of normal skin including mature hair follicle.

Defects). Indolent corneal ulcers mostly develop in dogs, but nonhealing ulcers have also been described in horses and cats. The condition describes superficial ulcers that failed to heal properly despite the absence of an underlying cause. The lesion is likely initiated by trauma. In affected areas, the basement membrane is absent or discontinuous and the stromal surface is covered by fibronectin. Slug expression and other factors involved in epithelial cell migration are absent or decreased at the margins of the ulcer. After ulceration and sliding of the epithelium, permanent adhesion requires the reformation of basement membrane, hemidesmosomes, and hemidesmosomal anchoring filaments, which extend through the basement membrane to anchor into the superficial stroma. If the stroma is abnormal, these filaments cannot anchor the regenerating stroma. Histologically, the lesion is recognized as large flaps of epithelium separated from the stroma (Fig. 21-35; E-Fig. 21-40) . The Fungal Keratitis). Histologically, there is ulceration of the epithelium, often abrupt loss of stromal lamellar organization, and infiltration of mostly degenerate neutrophils.

Corneal Dystrophies and Depositions. Among the domestic animals, corneal dystrophies and depositions are most often seen in dogs. The lesions may affect the epithelium, stromal, or endothelium. True dystrophies are bilateral and symmetric, often breed related, and occur in the absence of inflammatory or metabolic disease. These deposits often have characteristic clinical features (breed, age, exact anatomic location, and macroscopic appearance) nonadherent epithelium shows dysmaturation and loss of polarity. The epithelial edge tends to be rounded. The underlying superficial stroma is hyalinized and acellular, forming a thin band of pale collagenous tissue. The stromal changes may or may not be present in horses. A variety of corneal stromal diseases, including corneal edema, can, in some cases, cause separation of the corneal epithelium, resulting in a histologic lesion that mimics indolent corneal ulcers. Histologically, indolent corneal ulcers may need to be differentiated from artifactual separation of the corneal epithelium: With artifactual separation, the corneal epithelium maintains polarity and maturation, and the interruption in the epithelium is abrupt.

Corneal Sequestrum. Corneal sequestrum is mainly a condition of cats but it also occurs in horses and dogs (Fig. 21-36; E-Fig.  21-41) . The lesion often occurs after chronic ulceration, but the exact pathogenesis is not known. There is imbibition of browncolored pigment in the superficial stroma. This results in a very characteristic central corneal dark brown pigmentation that is the predominant and essentially pathognomonic feature of this disease. The origin of the pigment remains undetermined; there is evidence to both support and disprove the presence of melanin and iron/ porphyrins. Histologically, the lesion is a well-demarcated area where the stroma is devitalized and acellular . When present, the brown discoloration is evident histologically. There can be significant, usually neutrophilic inflammation that borders but does not extend in the sequestrum.

Suppurative Keratomalacia ("Melting Ulcer"). Neutrophils from the tear film and limbus can release lytic enzymes, and many organisms produce enzymes that cause stromal necrosis/malacia (Fig.  21-38) . Keratomalacia can occur in sterile lesions; however, ulcers that become contaminated with bacteria or fungi are especially prone to destructive suppurative keratomalacia. The most severe cases will progress to descemetocele and corneal perforation. In the absence of immediate medical intervention, this typically leads to rupture of Descemet's membrane (perforating ulcer), leakage of aqueous humor from the anterior chamber, and possibly iris prolapse. Gram-negative bacteria such as Pseudomonas spp. are most likely to cause suppurative keratomalacia. Contamination by opportunistic hyphal fungi (especially Aspergillus spp. and Fusarium spp.) is a particularly frequent cause of keratomalacia in horses (see Equine distribution, and tumors in older dogs may be particularly slow to progress. Surgical excision or photocoagulation may be considered for larger masses.

The epithelium on the posterior surface of the iris, the inner surface of the ciliary body, and the retinal pigment epithelium and the inner surface of the choroid are all derived from portions of the original optic vesicle. The uveal stroma is derived from the periocular mesenchyme that originates from the neural crest. After outgrowth and later invagination of the primary optic vesicle to form the optic cup, the intraocular migration of the periocular mesenchyme and its remodeling seem to be guided by soluble factors released from the neuroectoderm.

The anomalies of the uveal tract can be divided into those resulting from a failure of initial induction or migration, a failure of later remodeling, or a failure of eventual atrophy (Table 21 -2).

During early embryogenesis, there is a persistent gap between the anterior lip of the optic cup and the overlying corneal epithelium. Several waves of periocular mesenchyme migrate through this gap to form the corneal stroma and endothelium, the stroma of the anterior uvea, and the anterior portion of the perilenticular vascular tunic. The ingrowth of mesenchyme to form the iris stroma is guided by the infolding of the most anterior margin of the optic cup, which will form the two layers of the future iris epithelium (E- Fig. 21-44) . Later, papillary proliferation of that iris epithelium gives rise to the epithelium of the ciliary processes. Proper inward migration of the neuroectoderm at the anterior lip of the optic cup seems to be a prerequisite for the subsequent migration of the mesenchyme to form the stroma of the iris and ciliary body. Similarly, proper maturation of the future retinal pigment epithelium from the posterior neuroectoderm of the optic cup is required for the proper maturation of the retina, choroid, and sclera.

Iris Hypoplasia. Failure of ingrowth of the future iris epithelium results in iris hypoplasia, typically affecting only the stroma (E- Fig. 21-45) . Cases of extreme iris hypoplasia are clinically referred to as aniridia. This is relatively more frequent in horses than in other species. At least in some cases, it is inherited and may be associated with congenital cataracts.

Goniodysgenesis. Goniodysgenesis is maldevelopment of the iridocorneal angle and is exceedingly common as a cause of primary glaucoma in dogs, but it is much less frequent in other species. It results from incomplete atrophy of the mesenchyme at the base of the iris. Most of this remodeling occurs in the first few weeks of life. For reasons that are poorly understood, clinical manifestations of glaucoma attributed to this developmental anomaly are not usually detected until middle age or even later. Goniodysgenesis is described in more detail in the section on Glaucoma.

Persistent Pupillary Membranes/Persistent Primary Vitreous. Persistent pupillary membranes and persistent primary vitreous that allow a diagnosis to be made without histopathologic examination. Acquired corneal deposits result from previous corneal disease or as incidental manifestations of systemic metabolic disease.

Corneal epithelial dystrophy occurs mainly in dogs. These lesions are unlikely to be examined histologically but consist of abnormalities to the basement membrane of the corneal epithelium with dyskeratosis and necrosis of the epithelial cells. Corneal stromal dystrophies are rare but consist of lipid or mineral deposits within the corneal stroma. Corneal endothelial dystrophy is seen in several breeds of dogs as bilateral, diffuse corneal edema secondary to the progressive destruction of corneal endothelial cells (E- Fig. 21-43) . The edema is not accompanied by any evidence of inflammation or stromal fibrosis. The loss of endothelial cells is difficult to evaluate histologically, but subtle attenuation can be recognized. The lesion must be differentiated from acquired endothelial degeneration (e.g., uveitis, glaucoma, surgery, anterior lens luxation). Furthermore, formalin fixation can cause artifactual vacuolation of the endothelium.

Acquired mineral deposition may occur in the basement membrane of the epithelium or in the corneal stroma, usually in the superficial aspect (band keratopathy). Corneal inflammation and hypercalcemia are potential causes of secondary mineral deposition. In horses, it can be seen with uveitis and administration of corticosteroid and phosphate-containing topical solutions.

Acquired corneal lipidosis (lipid keratopathy) results in milky or crystalline stromal deposits of serum lipids within the corneal stroma. It can be seen with primary corneal disease or lesions in adjacent structures that can overflow in the cornea. Hyperlipidemia may be a contributing factor. The lipids are recognized histologically as clear spaces or cholesterol clefts between stromal lamellae. Stromal keratocytes may accumulate small lipid vacuoles. Macrophages may border the foci of lipid deposition. Affected corneas are typically well vascularized.

Corneal Squamous Cell Carcinoma. Corneal squamous cell carcinoma occurs predominantly in dogs and horses. In dogs, lesions are most often limited to the epithelium (squamous cell carcinoma in situ). The neoplasms tend to be exophytic rather than infiltrative. Corneal squamous cell carcinoma is most often seen in brachycephalic breeds and often associated with a history of chronic keratitis. In horses, corneal squamous cell carcinoma tends to diffusely infiltrate the stroma rather than form a distinct mass or an exophytic growth. Some of the corneal stromal invasive squamous cell carcinomas may originate from the limbus. The histologic features of these neoplasms are similar to those at other sites. Most corneal squamous cell carcinomas are well differentiated. Limbal (Epibulbar) Melanocytic Neoplasia. Limbal (epibulbar) melanocytic neoplasia occurs in dogs and rarely in cats. These neoplasms appear grossly as darkly pigmented masses arising from the limbus and expanding into the adjacent cornea and sclera. Limbal melanocytic neoplasms arise from the melanocytes that demarcate the limbus at the junction of the corneal stroma and sclera. Histologically, almost all are benign melanocytomas. These broad-based, nodular neoplasms are composed of discohesive heavily pigmented plump polyhedral cells often admixed with fewer pigmented spindle cells. There is no atypia, and mitoses are rare to absent. These masses grow by expansion and may extend intraocularly. Rare histologically malignant limbal malignant melanomas have been described, and some otherwise benign neoplasms may include areas with cells that are less pigmented or amelanotic and mitotically active. Limbal melanocytomas have bimodal age Anterior chamber

Ciliary process Lens mesenchymal spindle cells, the resulting anomaly is known as persistent hyperplastic primary vitreous. It has been described as a prevalent familial lesion in several breeds of dogs. The nonangiogenic mesenchyme undergoes notable fibroblastic proliferation, sometimes with cartilaginous metaplasia. Most affected dogs have concurrent anomalies, such as persistent pupillary membrane, microphthalmia, congenital cataract, and abnormal lenticular shape. Anterior Segment Dysgenesis. Anterior segment dysgenesis is a general term for a variety of rare anomalies in which there is a failure of remodeling of the periocular mesenchyme that normally becomes the corneal stroma, corneal endothelium, iris stroma, and the anterior portion of the tunica vasculosa lentis. The usual clinical observation is absence of anterior chamber and the apparent fusion of the iris stroma to the corneal stroma and no corneal endothelium or Descemet's membrane. True anterior segment dysgenesis must be differentiated from the lesions secondary to perinatal corneal perforation. Perinatal corneal perforation with iris prolapse can result in diffuse anterior synechia and loss of the anterior chamber.

Idiopathic Lymphoplasmacytic Uveitis. Lymphoplasmacytic uveitis is the most frequent histologic pattern of uveitis. Lymphocytes and plasma cells infiltrate the iris and ciliary body stroma and may also extend in the neuroepithelium. Choroidal involvement is variable but tends to be less severe than in the anterior uvea. Lymphoplasmacytic uveitis is not a specific disease but, rather, a histologic pattern that is shared by many different diseases. It is an indication of the chronicity of the uveitis because microscopic evaluation of globes with uveitis is usually done only in longstanding disease, after attempts at therapy have failed. Some cases may be immune-mediated, associated with trauma or lens disease (termed lens-induced uveitis or phacolytic uveitis), and a long list of infectious agents may be contributing factors. However, a specific cause is only rarely identified histologically. The diagnosis of lensinduced uveitis (phacolytic uveitis) is often made by exclusion and requires thorough history and clinical details (see below). In dogs, lymphoplasmacytic uveitis typically does not cause glaucoma by itself. In horses and cats, some cases of lymphoplasmacytic uveitis may cause glaucoma and warrant discussion as specific entities (see Disorders of Horses and Disorders of Cats).

Lens-Induced Uveitis. Lens-induced uveitis can be separated between phacolytic uveitis and phacoclastic uveitis. Phacolytic uveitis is a common cause of mild lymphoplasmacytic anterior uveitis that occurs in animals with cataracts in which lens proteins begin to disintegrate and leak through the intact lens capsule. The lesion tends to be mild, and in some cases it may be plasma cell predominant. Posterior synechiae often accompany the inflammation. However, even in globes with cataracts, the final diagnosis of phacolytic uveitis must be made in light of history and clinical findings. Neither the distribution nor the nature of the inflammatory infiltrate is specific to the condition because it mimics idiopathic lymphoplasmacytic uveitis.

Phacoclastic uveitis is an immune-mediated disease in response to the release of large amounts of intact lens protein through a ruptured lens capsule. Because the lens protein is sequestered from the immune system during embryologic development, the release of large amounts of strongly antigenic lens protein into the aqueous humor essentially elicits a foreign body reaction type of response. The histologic lesion is a lens-centric granulomatous endophthalmitis. Phacoclastic uveitis is also seen in dogs that have rapidly progressing diabetic cataracts; however, in those instances, the refer to abnormal persistence of portions of the perilenticular vascular tunic or the vascular network within the developing vitreous. Such anomalies are common in dogs. The embryonic lens is encased in a network of blood vessels known as the tunica vasculosa lentis (E- Fig. 21-46 ). This network is created by contributions from the same mesenchyme that forms the iris stroma and from vasogenic mesenchyme growing into the developing vitreous through the posterior portion of the slowly closing optic fissure. The latter vessels, growing in from near the optic disc, are the hyaloid artery system. Together with other nonangiogenic mesenchymal elements, these vessels form the primary vitreous. This embryonic hyaloid artery system creates a temporary vascular network along the surface of the developing retina and also joins with the anterior chamber vessels to complete the tunica vasculosa lentis. All portions of this elaborate vascular system undergo atrophy before maturation of the globe. Persistence of one or more portions is common. The most common is persistence of the anterior portion of the tunica vasculosa lentis. This is usually referred to as persistent pupillary membrane. Macroscopically, these are seen as fine threads originating from the minor arterial circle of the iris (Fig. 21-39 ; E- Fig. 21-47 ). They are usually bloodless but are often pigmented. They may be inserted into the anterior stroma of the iris, or they may contact the surface of the anterior lens capsule. Occasionally, in what is probably a more significant anomaly, they insert into the cornea. These membranes become clinically significant if they contact the lens or cornea, where they interfere with proper development of corneal or lens epithelium, or their associated basement membranes (Descemet's membrane and lens capsule, respectively). Histologically, persistent pupillary membranes are thin endothelial tubes accompanied by varying amounts of mesenchymal stroma (E- Fig. 21-48) . At sites of corneal contact, they may cause fibrous metaplasia of the corneal endothelium. Where they contact the lens, there is usually epithelial proliferation and dysplasia of the lens capsule, resulting in a focal cataract.

Persistence of various portions of the hyaloid artery system, with or without other portions of the primary vitreous, includes much less common anomalies known as persistent hyaloid artery (E- Fig.  21 -49) and persistent (hyperplastic) primary vitreous. When persistent blood vessels are accompanied by hyperplastic nonangiogenic numerous. The yeasts measure 2 to 10 µm within a capsule up to 30 µm in diameter with rare, narrow-based budding. In a few cases, the granulomatous reaction is much more severe and mimics that seen in blastomycosis. In such lesions, organisms are typically scarce. The ocular disease caused by Coccidioides immitis resembles blastomycosis but can be more suppurative, more destructive, and more likely to progress to panophthalmitis (Fig. 21-40; E-Fig. 21-52) . Organisms are often rare and widely dispersed. Involvement of the anterior uvea is more common than in the other systemic mycoses. The disease is seen only in animals that live in (or have visited) the restricted geographic region in which the organism is common. The great majority of cases are seen in dogs from the desert regions of the southwest of the United States and some regions in Central and South America. The organisms measure 20 to 30 µm and may contain endospores. There is no budding.

The lesions caused by ocular infection with Histoplasma capsulatum are distinctive and quite different from those of the other systemic mycoses. There is usually a diffuse granulomatous uveitis with little suppuration and without much of the destruction that characterizes blastomycosis and coccidioidomycosis. Organisms measure 3 to 6 µm and are usually very numerous and visible as small spherical bodies within the cytoplasm of macrophages. There is no budding. In cats, histoplasmosis may present as nodular granulomatous conjunctivitis.

Protothecosis is caused by colorless, saprophytic algae capable of causing enteric, cutaneous, or generalized granulomatous disease in a variety of mammalian species. The clinical and histologic features closely resemble those of the systemic mycoses described previously. Ocular lesions have been described only in dogs with the disseminated form of the disease. The lesions are similar to those seen with blastomycosis. In histologic section, the algae are free or within macrophages, and they are typically numerous. The organisms are spherical to oval, from 2 to 10 µm in diameter, and have a refractile cell wall that stains intensely with PAS reaction. Prototheca reproduces by asexual multiple fission, and multiple sporangiospores (endospores) may be present within a single cell wall. Unlike blastomycosis and cryptococcosis, there is no budding.

Leishmaniasis is caused by a protozoan parasite, Leishmania spp., and requires transmission by phlebotomine sandflies. Ocular disease usually develops as part of systemic infection, but it can be the granulomatous inflammation tends to be more diffuse and may carpet the uveal tract. Phacoclastic uveitis occurs in rabbits as a result of penetration of the lens by Encephalitozoon cuniculi (E- Fig.  21-50) . Phacoclastic uveitis may be a contributing factor in cases of severe endophthalmitis secondary to the penetrating trauma where there is rupture of the lens capsule (E- Fig. 21-51) .

True phacoclastic uveitis must be differentiated from lens septic implantation syndrome. The latter occurs after penetrating trauma where there is lens capsule rupture and seeding of the lens with microorganisms, typically bacteria. The initiating traumatic injury is often a cat scratch. The traumatic event is followed by a period of dormancy of multiple weeks' duration during which there may be a favorable response to treatment. A severe lens-centric suppurative to pyogranulomatous endophthalmitis with suppurative phakitis then develops. The suppurative component distinguish septic implantation syndrome from phacoclastic uveitis, which is predominantly granulomatous.

Systemic Fungal, Algal, and Parasitic Diseases. Systemic mycoses, such as blastomycosis, cryptococcosis, histoplasmosis, and coccidioidomycosis, are frequent causes of severe uveitis in those geographic areas where the organisms are common environmental contaminants. Immunodeficient animals may develop endophthalmitis as part of generalized disease caused by fungi such as Aspergillus spp. or Candida spp., but these cases are rare; these same agents occasionally cause endophthalmitis when introduced by penetrating plant foreign bodies.

The frequency with which endophthalmitis accompanies systemic mycosis is unknown. The majority of cases are found in dogs, with the exception of cryptococcosis in cats. Ocular involvement is part of systemic disease, but fairly frequently, ocular disease is the initial complaint. Blastomycosis is by far the most prevalent example of an endophthalmitis caused by systemic mycosis.

Blastomycosis is the most frequently reported intraocular mycosis in dogs; it is rare in cats. It is estimated that approximately 25% of dogs with the systemic disease have clinically apparent ocular disease: unilateral or bilateral endophthalmitis with a very high frequency of exudative retinal detachment. The microscopic lesion is severe diffuse pyogranulomatous endophthalmitis, which tends to be more severe in the choroid and subretinal space than in the anterior uvea. The greatest accumulation of both leukocytes and organisms is usually in the subretinal space. The organisms may be numerous or extremely sparse, probably depending on the duration of the disease and on therapy. They are either free or within the cytoplasm of macrophages and have the typical features of Blastomyces spp.: thick-walled spherical yeasts, 8 to 25 µm in diameter, with occasional broad-based budding. Some cases may have a predominance of dead organisms where only the thick empty capsule is recognized. The diagnosis can often be made by cytologic evaluation of subretinal exudates, most often performed in eyes that are already blind because of retinal detachment. Other lesions in affected globes are those seen in any severe uveitis: intraocular hemorrhage, posterior synechia, preiridal fibrovascular membrane, and cataract.

Cryptococcosis is similar to blastomycosis in that the lesions are predominantly within the posterior aspect of the globe because the target sites are the retina, choroid, and optic nerve. Ocular cryptococcosis is more prevalent in cats than in any other domestic animal. As is typical of cryptococcosis in other feline tissue, the granulomatous inflammatory response is often minimal. Large collections of poorly stained pleomorphic yeasts, surrounded by wide capsular halos, impart a typical "soap-bubble" appearance in hematoxylin and eosin (H&E)-stained sections. The organisms are usually glaucoma. Primary neoplasia is more prevalent than metastatic disease in the globe. In all species, melanocytic neoplasms are by far the most common of all ocular neoplasms. However, there are significant intraspecies differences that warrant consideration of melanocytic neoplasia separately for dogs, cats, and horses.

Canine Uveal Melanocytic Neoplasms. In dogs, benign uveal melanocytomas are most common in the iris and ciliary body, typically affecting both. Only 6% of uveal melanocytomas principally affect the choroid. Melanocytomas of the anterior uvea readily efface the iridocorneal angle. Many will expand along the corneoscleral meshwork, which extends anterior to the termination of Descemet's membrane and blends with the deep peripheral corneal stroma. Scleral extension is common for both anterior uveal and choroidal melanocytomas and is not a feature that is indicative of malignancy ( Fig. 21-42; E-Fig. 21-53 and 21-54) . All melanocytomas have a similar histologic appearance independent of their origin in the iris, ciliary body, or choroid. The neoplasms are composed of variable proportions of heavily pigmented spindle cells and discohesive heavily pigmented plump polyhedral cells. Uveal malignant melanoma is more common in the anterior uvea than in the choroid. Only 3% of uveal malignant melanomas are choroidal in origin. Approximately 25% of anterior uveal melanocytic neoplasms and 15% of choroidal melanocytic neoplasms are malignant. The mitotic index is the most reliable parameter in the diagnosis of malignant melanoma. A threshold of 4 mitoses in 10 high-power fields (HPF) is most widely used to establish malignancy in uveal melanocytic neoplasms (Fig. 21-43) . As with uveal melanocytomas, expansion along the corneoscleral meshwork, in the sclera, and in extrascleral tissues is common. Malignant melanomas are less pigmented than their benign counterpart and can be amelanotic. Neoplastic cells containing pigment should not be assumed to be melanocytes because any disruption of the uveal tract can result in pigment dispersion and phagocytosis by neoplastic cells. For any uveal melanocytic neoplasm, necrosis and infiltration of melanophages is common. Choroidal involvement often causes retinal detachment. predominant or presenting clinical complaint. In dogs, the disease is endemic in the Mediterranean basin as well as areas of Africa, India, and Central and South America. The disease is less commonly seen in cats, mainly in Europe and South America. Although uncommon, there are reports of both canine and feline leishmaniasis in North America. The ocular infection most frequently causes granulomatous nodular conjunctivitis and uveitis; however, the infection may be present in any of the ocular components or periocular tissues. Amastigotes measuring 3 to 5 µm long and 1 to 2 µm wide are found in macrophages.

Iridociliary Cysts. Acquired cysts of the posterior iris or ciliary body epithelium occur sporadically in all species. Most often incidental findings, they can become clinically significant if they are multiple and large and obstructive to flow of aqueous humor. Rarely, individual cysts may become dislodged and displaced in the anterior chamber.

In Golden retrievers, iridociliary cysts represent a specific entity, so-called pigmentary uveitis. The term uveitis derives from the presence of aqueous flare and aqueous debris recognized clinically, but histologically pigmentary uveitis is not associated with infiltration of leukocytes; instead, the condition presents as multiple cysts from the posterior iris or ciliary epithelium, often delimited only by a single cell layer of variably pigmented cells that may be producing a basement membrane (Fig. 21-41) . The cysts fill the posterior chamber, contact the lens, and may bulge through the pupil. The cases likely to be examined histologically are those in which secondary glaucoma develops. There is no infiltration of leukocytes, but there may be both preiridal and retrocorneal fibrovascular membrane formation. Posterior synechia is common. Release of pigment from ruptured cyst, obstruction of aqueous humor outflow, fibrovascular proliferation, and forward displacement of the iris are likely contributing factors to the glaucoma. In Rocky Mountain horses, ciliary cyst may be present as part of an inherited condition that includes other ocular anomalies.

Uveal neoplasms are common only in dogs and cats. In addition to their direct effect on ocular function, neoplasms are commonly associated with secondary changes such as dyscoria, hemorrhage, fibrovascular proliferation, lens luxation, cataract, asteroid hyalosis, and retinal detachment, and they are a frequent cause of secondary of iris hyperpigmentation. These areas histologically correspond to preneoplastic iris melanosis characterized by one to five layers of well-differentiated heavily pigmented melanocytes that cover the anterior surface of the iris. Iris melanosis may remain stagnant for years or slowly progress by increasing the number and/or size of the foci. Once the melanocytes extend in the underlying iris stroma, it is considered FDIM. The progression of FDIM is highly variable. Some cases can progress slowly over years without clinical signs, whereas others develop rapidly, causing glaucoma and spread to other organs. Almost all instances of FDIM follow a similar progression, albeit at different rates ( Fig. 21-45; E-Fig. 21-55) . The lesion begins as iris melanosis and then infiltrates and expands the iris stroma, followed by extension in the ciliary body (Fig. 21-46; E-Fig.  21-56) . The lesion then extends in the sclera and/or choroid, and some neoplasms infiltrate the scleral venous plexus. Rare cases infiltrate beyond the sclera into the conjunctiva or orbit. Despite this reproducible pattern of growth, the rapidity with which FDIM progresses is unpredictable. As such, there are no definitive criteria to I Ocular Melanosis. Ocular melanosis (pigmentary glaucoma) is a unique condition that must be distinguished from uveal melanocytomas and malignant melanomas in dogs. It is unclear if ocular melanosis is truly neoplastic. It is seen most often, but not exclusively, in Cairn terriers. In that breed, pedigree analysis suggests the trait has an autosomal dominant mode of inheritance. The melanocytes in ocular melanosis have a unique immunophenotype that differs from normal melanocytes with negative staining for Melan-A and S-100. Grossly, ocular melanosis appears as diffuse pigmentation of the uveal tract. Pigment may be visible through the sclera. Histologically, it is characterized by diffuse uveal infiltration of large plump pigment-laden cells without formation of a distinct mass (Fig.  21-44) . Both melanocytes and melanophages contribute to the uveal expansion. There may also be extension along the optic meninges. The condition is bilateral in Cairn terriers. In other breeds, it is usually unilateral at presentation, but it may eventually affect the contralateral globe. low. In cats, many neoplasms are predominantly composed of elongated cells in sheets, and some contain metaplastic bone; these neoplasms are often misdiagnosed as sarcomas. Iridociliary neoplasms typically express vimentin and neuroendocrine markers, but malignant neoplasms in dogs may also express cytokeratin.

Medulloepithelioma is a relatively rare congenital counterpart of iridociliary neoplasms, most commonly seen in horses. They arise most commonly from the ciliary body or optic nerve and less frequently in the retina. The histologic appearance reflects its embryonic origin from primitive neuroectoderm still capable of both iridociliary and retinal differentiation. The neoplasms are composed of small hyperchromatic stellate to round cells that form loose sheets and poorly organized multilayered rosette-like structures with a central cavity. True Flexner-Winterseiner and Homer-Wright rosettes may be present, and some areas may have features resembling ciliary processes or retina. In horses, they often contain heterotopic elements that are not normal derivatives of the ocular embryonic development, such as cartilage and bone. These variants are known as teratoid medulloepitheliomas. Although they are by definition congenital tumors, their growth is slow and they may not be diagnosed until many years later.

Schwannomas. Schwannomas (also termed spindle cell tumors of blue-eyed dogs or peripheral nerve sheath tumors) occur almost exclusively in dogs, but they have been described in cats. These neoplasms may not form a mass that is recognizable clinically. Histologically, they typically arise in the iris and extend in the ciliary body. The masses are nonpigmented and composed of interlacing bundles, streams, and whorls. Antoni A and B patterns are often recognized. Approximately half of the neoplasms are welldifferentiated with a low mitotic index. Metastasis is rare and has only been described in dogs.

Metastatic Neoplasms. Neoplasms metastatic to the globe are much less frequent than primary ocular neoplasia. Lymphoma is the most common secondary neoplasms in all species, but it is particularly prevalent in cats. There are two general patterns of metastasis to the globe. Leukocytic neoplasms such as lymphoma and histiocytic sarcoma will typically cause diffuse expansion and effacement of the uveal tract ( Fig. 21-47 ). Carcinomas and nonleukocytic sarcomas more often will form multifocal masses. Some will carpet the iris and ciliary body and occlude blood vessels. Mammary adenocarcinomas and pulmonary adenocarcinomas are the most common guide veterinarians as to the best time to enucleate. However, there is general agreement that globes with progressing pigmentation compatible with FDIM that develop glaucoma should be enucleated. Histologically, FDIM is composed of neoplastic melanocytes that may be predominantly spindle, polygonal, or round. The amount of pigmentation varies greatly, but very few are amelanotic. Although not prognostically significant, neoplastic cells often exhibit significant pleomorphism with karyomegaly and multinucleated cells. Intranuclear cytoplasmic invaginations may also be a prominent finding. The histologic features that have some prognostic value include extent of the tumor, vascular invasion, mitotic index, and the volume of necrosis within the tumor. FDIM limited to the iris typically does not cause glaucoma, and removal at that time is associated with survival times similar to those of unaffected cats with no risk of metastasis. FDIM with extension in the ciliary body and beyond is more likely to develop glaucoma and more likely to metastasize, especially with extrascleral extension. Vascular invasion typically occurs in the scleral venous plexus and is usually associated with advanced or extensive lesions. A high mitotic index is a poor prognostic indicator, and a threshold of 7 mitoses in 10 400× fields may be used as a guideline. The liver and lungs are the most frequent sites of metastasis. Metastases tend to develop slowly and in some cases may not be recognized for 1 to 3 years after enucleation. FDIM must be differentiated from the much less frequent feline atypical melanoma. Feline atypical melanoma forms multinodular masses in the uveal tract rather than diffuse expansion of the iris. It is composed of well-differentiated, heavily pigmented melanocytes with minimal pleomorphism and a low mitotic index. However, despite these features typically associated with a benign process, feline atypical melanoma may metastasize.

Equine Intraocular Melanocytic Neoplasia. Equine intraocular melanocytic neoplasia (EIMN) is associated with equine cutaneous melanoma. Most EIMNs (67%) are diagnosed in horses known to have cutaneous melanoma. As with cutaneous melanoma, most horses with EIMN are gray horses (85%). Histologically, the iris is often affected, with some cases involving the iris and ciliary body. Fewer cases expand the anterior uvea as well as the choroid and/or sclera. The cellular features of EIMN are similar to those of equine cutaneous melanoma. Almost all EIMNs are moderately to heavily pigmented. The cells are spindle to polygonal with minimal to no mitotic activity. Many masses are necrotic with infiltration of melanophages. Preiridal fibrovascular membranes and pigment within the corneal endothelium are common findings. Glaucoma, however, appears uncommon. The pathogenesis is unknown; however, the strong association with cutaneous melanoma suggests a genetic basis.

Neuroectodermal Neoplasms. Neuroectodermal neoplasia is second only to melanocytic neoplasia in frequency. Most are iridociliary adenomas or well-differentiated iridociliary adenocarcinomas. Medulloepitheliomas are rare. Iridociliary neoplasms arise from the neuroectoderm of the ciliary body or posterior iris. Grossly, they are recognized as nonpigmented to lightly pigmented pink discrete masses that can protrude into the pupillary aperture and displace the iris face anteriorly. The neoplasms are composed of cuboidal to columnar cells that form cords and nests with tubules and occasionally cysts (E- Fig. 21-57 ). Tubules and cysts may contain hyaluronic acid. Neoplastic cells produce periodic acid-Schiff (PAS)-positive basement membrane material. Most neoplasms include some cells that contain pigment, but heavily pigmented iridociliary neoplasms are uncommon. Approximately 15% invade the sclera and are considered malignant (adenocarcinoma), but the risk of metastasis is The distinction between lens luxation as a cause of glaucoma and lens luxation as a consequence of glaucoma is not always obvious in cases in which both lens luxation and glaucoma are diagnosed in the same globe. Lens luxation can cause glaucoma if there is posterior synechia and pupillary block, by obstruction of aqueous humor flow in the anterior chamber or by displacing the vitreous, which can be an obstruction and predispose to retinal secondary epithelial neoplasms in dogs and cats, respectively. Hemangiosarcoma, malignant melanoma, fibrosarcoma, and osteosarcoma are common nonleukocytic sarcomas that spread to the eye.

The lens is derived from the thickening of the ectoderm induced by contact with the primary optic vesicle. This lens placode then migrates inwardly to cause the optic vesicle to invaginate on itself to form the primary optic cup. As it does, the lens placode grows to become a lens vesicle and separates from the overlying ectoderm (see Fig. 21 -2). This vesicle initially is just a single layer of cuboidal epithelial cells surrounded by a very thin capsule. The epithelial cells along its posterior surface elongate to obliterate the lumen of this primitive vesicle, creating the primary lens fibers that persist throughout life as the lens nucleus. The subsequent development of the cortical fibers of the postnatal lens depends entirely on mitotic activity from the anterior lens epithelium. No epithelium remains along the posterior half of the lens any time after the stage of the primary lens vesicle.

The lens has a central inductive role in ocular development, so significant anomalies of the lens are almost always accompanied by multiple ocular anomalies such as microphthalmia. It is likely that many of the lens developmental anomalies reflect acquired degenerative changes (even if occurring in utero), resulting in regression of what was a normally developing lens. Such changes include an abnormally small lens (microphakia) or abnormally shaped lens (lenticonus and lentiglobus).

Dislocation of the lens may be partial (subluxation) or complete (luxation). The lens may be forced in the anterior chamber, or it may remain trapped in the posterior chamber . A completely dislocated lens is likely to develop a diffuse cataract, presumably because of its inadequate access to aqueous humor and nutrition. Anterior lens luxation is much more significant because it causes pain and also predisposes to glaucoma. Lens luxation may be primary or secondary. Care must be taken during the processing of globes not to cause iatrogenic displacement of the lens that could mimic lens luxation.

Primary lens luxation refers to that occurring without any known trauma or other ocular disease. It may be congenital or may be seen later in life. Congenital luxation is usually the result of a developmental error that causes abnormal or insufficient zonules. Much more prevalent are spontaneous luxations that occur in young adult dogs of specific breeds (terriers and others). The luxation is almost always bilateral. In many breeds, primary lens luxation is associated with a mutation in the ADAMTS17 gene. Some cases of primary lens luxation secondary to zonular ligament dysplasia can be recognized histologically. In these cases, there is acellular, hyaline, eosinophilic material that covers portions of the nonpigmented ciliary epithelium (Fig. 21-49 ). This material stains intensely with the periodic acid-Schiff (PAS) reaction, and the trichrome stain indicates increased collagen compared to normal zonular ligaments.

Secondary lens luxation is most often seen with excessive stretching of the zonular ligaments within a globe that has become greatly enlarged secondary to glaucoma, blunt trauma that causes avulsion of the zonular ligaments, or uveitis that affects the quality of the zonular ligaments. Displacement of the lens can also occur in the presence of space-occupying neoplasms. Severe cataract with intumescence or collapse can also result in excessive stretching of the zonular ligaments. The ciliary processes are covered by thick, hyaline, eosinophilic material. The material is tightly adhered to the nonpigmented ciliary epithelium and much thicker than normal zonular ligaments. H&E stain. (Courtesy Dr. P. Labelle, Antech Diagnostics.) cells will initially line the uveal tract, especially choroid. Eventually, the neoplasm effaces the uvea, and there may be extension in the sclera and optic nerve. In late cases, the globe is essentially filled by the neoplasm. The neoplastic cells are usually spindle with severe pleomorphism and a high mitotic index (E- Fig. 21-60) . Multinucleated cells may be present. In some areas of the neoplasm, the neoplastic cells may be separated by basement membrane-type material. A small percentage of neoplasms show osteoid and/or chondroid material deposition. In extensive neoplasms, the lens may only be recognized as fragments of lens capsule. FPTOS are highly infiltrative, and extension beyond the sclera is a poor prognostic indicator. Rare intracranial extension along the optic nerve and metastasis has been described. FPTOS has similarities with vaccine site sarcomas: traumatic initiating event, long period of dormancy between initiation and the development of a neoplasm, and similar histologic characteristics. However, there is no known association between these two entities.

There is a less frequent variant of feline posttraumatic sarcomas composed of pleomorphic round cells. These cases are also associated with previous trauma and lens capsule rupture, and most have a distribution typical of FPTOS. The neoplastic cells have features that most closely resemble pleomorphic lymphoma; however, the exact histogenesis of the round cell variant of FPTOS is unclear. In many cases, the neoplastic cells express both T lymphocyte and B lymphocyte markers.

Retinal diseases categorized by lesion are listed in Table 21 -3; retinal diseases categorized by pathogenesis are listed in Table 21-4. detachment. Lens luxation can be a consequence of glaucoma when there is buphthalmos that stretches and tears the zonular ligaments.

Diabetic cataract is the best-studied form of metabolic lens disease. Rapidly progressing bilateral cataracts develop in most diabetic dogs. After being diagnosed with diabetes mellitus, approximately half of the dogs will develop cataracts within 6 months and 80% within 16 months. Controlling the hyperglycemia and, by extension, the levels of glucose in the aqueous humor can delay the development of cataracts. Once the lesion develops, progression to complete cortical opacity and thus visual impairment usually occurs within days to weeks. The swelling may be so rapid that the lens capsule ruptures. The cataract develops because of high levels of glucose within the aqueous humor. When the hexokinase pathway is overloaded with glucose, the excess glucose absorbed by the lens is shifted to the sorbitol pathway, where it is transformed by the enzyme aldose reductase into sorbitol. This leads to accumulation of sorbitol, which creates a hyperosmotic effect, and the influx of fluid. The result is rapid swelling of the lens and disruption of its architecture. The osmotic stress also induces apoptosis of lens epithelial cells. The histologic features of the cataract itself are similar to those of any other severe cataract, making clinical history critical to the diagnosis. Some cases develop severe granulomatous endophthalmitis (phacoclastic uveitis) that tends to carpet the uveal tract rather than be centered on the lens. This form of inflammation associated with diabetic cataracts must be differentiated from asymmetric uveitis (see Disorders of Dogs). Rarely, diabetic cats can also develop cataracts, but the lesion is less severe than in dogs and appears to have limited clinical significance. Older cats have lower aldose reductase activity than dogs and young cats, which may provide protection by limiting the production of sorbitol.

Feline Posttraumatic Ocular Sarcoma. Feline posttraumatic ocular sarcoma (primary ocular sarcoma) (FPTOS) is the second most common primary ocular neoplasm in cats. The condition is almost exclusive to the cat, although a few cases have been described in rabbits. The initiating event is presumed to be ocular trauma or severe ocular disease. The neoplasms are recognized following a period of dormancy typically lasting multiple years following the initiating event (average 5 years). Morphologically, the neoplasm is a sarcoma and expresses vimentin. The neoplasm is believed to arise from malignant transformation of the lens epithelial cells. Some neoplasms are immunopositive for the lens structural protein crystallin αA, and lens capsule rupture is recognized in almost all cases. Neoplasms are initially centered on the lens, and neoplastic cells multifocally deposit lens capsule/basement membrane-type material that stains with PAS and is collagen type IV immunopositive. To a lesser extent, immunoreactivity to smooth muscle actin (SMA) is also consistent with lens origin because lens epithelial cells can express SMA especially in diseased states such as cataracts. Similarly, the occasional immunoreactivity to cytokeratin may reflect the origin of the lens epithelium from the surface ectoderm; cytokeratin expression is normally lost during embryogenesis.

Gross findings reflect the fact that most neoplasms are recognized late in the disease process. The globe is often almost filled by the neoplasm, and the lens may be collapsed (Fig. 21-50; E-Fig. 21-59 ). Scleral and optic nerve extension may be visible grossly. Histologically, early lesions may be recognized as streams of spindle cells bordering the lens in the area of lens capsule rupture. A characteristic feature of FPTOS is that as the neoplasm progresses, the spindle retina, which retains no mitotic capability, the developing retina can still react with at least some neuronal regeneration. Such regeneration is usually mixed with glial scarring and does not restore normal retinal organization.

The viruses that most often cause retinal dysplasia in domestic animals are bovine viral diarrhea and mucosal disease virus (BVD-MD) in cattle, bluetongue virus in sheep, herpesvirus and adenovirus in dogs, and parvovirus and feline leukemia virus in cats. The viruses typically cause necrosis or inflammation within the retina, and the attempt at regeneration results in retinal dysplasia (E- Fig. 21-62) . Retinal dysplasia only occurs if these viral infections damage the retina while its neurons still have proliferative capacity.

Retinal Dysplasia. Retinal dysplasia is a general term denoting an abnormal retinal differentiation characterized by disorganized retinal layers. Acquired retinal folds, which can develop secondary to retinal detachment and reattachment or following retinal scarring, should be considered as a separate entity.

Retinal dysplasia is a rare anomaly that results from improper induction of retinal maturation by the retinal pigment epithelium (RPE). Most cases of retinal dysplasia are seen in dogs as an inherited disease. Retinal dysplasia may also be one of multiple congenital malformations in severely affected globes. The details of the pathogenesis likely vary depending on the cause, but all involve separation or inadequate apposition between the neuroretina and RPE, or dysfunction of the RPE itself. The result is a retina with multifocal to diffuse disorganization of the retinal layers with variably organized rosettes, variation in thickness, and, in many cases, retinal detachment ( Fig. 21-51) . Retinal folding is commonly seen with retinal dysplasias (E- Fig. 21-61) . In some cases, the retinal folds are present without disorganization of the retinal layers, and those instances may not represent true retinal dysplasia. Those cases may represent a globe where the development of the retina has occurred more rapidly than the development of the supporting choroid and sclera. The implication is that such retinal folds are transient and will disappear as the animal ages and the support structures continue to grow.

In all species, retinal dysplasia may occur following retinal injury during retinal development. Viral infection is most common, but other causes include toxic injury, nutritional deficiencies, radiation exposure, and intrauterine trauma. This typically implies in utero disease. However, in dogs and cats, the period of susceptibility to some of these events extends for at least 6 weeks after birth, during which time the retina continues to develop. In contrast to the adult There is loss of nuclei from all retinal layers as a sequela to the in utero destruction of retinal neurons by BVD virus. In some instances, this loss is followed by efforts at retinal regeneration, resulting in disorganization that may be considered as a retinal dysplasia. H&E stain. (Courtesy Dr. B. Wilcock, Ontario Veterinary College.) found throughout the uvea. The affected arterioles have thickened hyaline walls with narrowed lumen . The walls are expanded by periodic acid-Schiff (PAS)-positive material that may be solid or layered concentrically, which represents fibrinoid necrosis of the tunica media. Retinal edema and hemorrhage, segmental retinal necrosis, retinal detachment with outer retinal atrophy, and intraocular hemorrhage commonly accompany the vascular lesions. There can be necrosis of the retinal pigment epithelium (RPE). In cases in which there is severe retinal hemorrhage and necrosis, the diagnostic vascular lesions may be most easily recognizable in the choroid. Fibrovascular proliferation secondary to the release of vascular mediators from the injured retina is present in most cases and often the cause of neovascular glaucoma.

Nutritional Retinopathies. Vitamin A deficiency as a cause for retinopathy has been reported in cattle, horses, and pigs receiving a ration deficient in vitamin A over an extended period of time. The ocular effects of hypovitaminosis A first involve photoreceptor outer segments, specifically rods, in which vitamin A (retinol) is a component of the photopigment rhodopsin. The lesion can slowly progress to diffuse photoreceptor atrophy, loss of the outer nuclear layer, and eventually to complete retinal atrophy. Early lesions can be reversed with vitamin A therapy.

Vitamin E deficiency in dogs and horses manifests as lipofuscin accumulation in various cell types including the RPE, consistent with oxidative damage. Accumulation in the RPE is greater than that expected with normal aging. Histologically, lipofuscin accumulation in the RPE is visible with standard hematoxylin and eosin staining and may be highlighted with PAS stain. The RPE may concurrently be hypertrophic. As a consequence of RPE dysfunction, chronic vitamin E deficiency eventually progresses to degeneration of the photoreceptors. Retinal pigment epithelial dystrophy/ central progressive retinal atrophy (RPED), recognized mainly in some populations of dogs in Europe, presents with histologic findings indistinguishable from vitamin E deficiency. With RPED, the lesions occur despite adequate vitamin E intake, suggesting an inability to properly metabolize vitamin E that results functionally in a deficiency at the cellular level.

Toxic Retinopathies. Toxic injury to the retina is a rare event. Locoweed poisoning affects cattle, sheep, and horses. The ocular lesions mimic those in the central nervous system and consist of Retinal scarring as a result of necrosis and mild inflammation may persist in some cases. The window of susceptibility for the development of retinal dysplasia depends on the species because retinal development varies with the species.

Infection of bovine fetuses with BVD-MD is the most frequent and the most studied of the virally induced retinal dysplasias. Infection between days 79 and 150 of gestation can result in postnecrotic retinal dysplasia. The initial ocular lesion is necrotizing lymphocytic endophthalmitis with random retinal necrosis. The inflammation gradually subsides, and there is often minimal inflammation in fetuses aborted later or in dead neonatal calves. The ocular components that are already well-differentiated at the time of the endophthalmitis, such as cornea, uvea, and optic nerve, may remain normal or exhibit some postnecrotic scarring. Only the retina, which is still developing, will exhibit unsuccessful attempts at regeneration. Because the peripheral retina remains mitotically active for several weeks after the central retina has matured, dysplastic lesions may be found only in the peripheral retina. Calves with BVD-MD-associated retinal dysplasia typically also have cerebellar hypoplasia.

Optic Nerve Hypoplasia. Optic nerve hypoplasia may be unilateral or bilateral. Primarily documented in dogs, optic nerve hypoplasia also occurs in cats, horses, cattle, and pigs. The lesion is not necessarily associated with visual impairment. It is the consequence of retinal ganglion cell maldevelopment, early loss of retinal ganglion cells, or failure of the axons to exit the globe. It is inherited in some breeds of dogs. Histologically, the optic nerve has a narrow diameter with increased connective tissue in increased numbers of glial cells. The retina has fewer retinal ganglion cells than normal, and the nerve fiber layer is thin. In cattle and pigs, optic nerve hypoplasia must be differentiated from optic nerve atrophy secondary to vitamin A deficiency. Vitamin A deficiency causes abnormal thickening of growing bones, including orbital bones. This results in compression atrophy of the optic nerve. In pigs, the deficiency can also affect the globe with lesions such as microphthalmia. Vitamin A deficiency causes retinal degeneration (see Nutritional Retinopathies).

Ischemic Retinopathies. Ischemic damage to the retina can be the result of occlusion of the retinal vessels or, more often, from interference with blood supply in the choroid. Thromboemboli, metastatic disease, and severe choroiditis may all interfere with proper vascular supply to the retina. Vasculitis in the retina or choroid is uncommon but can be seen with immune disease or infectious diseases such as thrombotic meningoencephalitis of cattle, Rocky Mountain spotted fever, or ehrlichiosis in dogs . Ischemia also contributes to retinal injury as part of retinal detachment and is one of the contributing factors to retinal atrophy in glaucoma. Microvascular disease associated with diabetes mellitus may be seen in dogs and cats, but it does not have the same clinical significance as diabetic retinopathy in human beings.

Systemic hypertension is a relatively common cause for retinal ischemic damage in dogs and cats. It is usually secondary to chronic renal disease but can also be associated with endocrine diseases such as hyperthyroidism, diabetes mellitus, hyperadrenocorticism, and pheochromocytoma, as well as cardiovascular disease. The clinical findings often include intraocular and retinal hemorrhage, retinal edema, and retinal detachment. The globes submitted for histopathologic examination are typically glaucomatous. The lesions are usually bilateral but may be asymmetric. The diagnostic histologic lesions are most obvious in the retina and choroid, but they may be discovered until they are large enough to cause an abnormality of the globe, such as exophthalmos or strabismus. Any of the connective, muscle, and bone components of the orbit may give rise to neoplasms such as multilobular tumor of bone (multilobular osteochondrosarcoma), osteosarcoma, fibrosarcoma, liposarcoma, rhabdomyosarcoma, and salivary-lacrimal adenocarcinoma. There may be direct extension from conjunctival or nasal neoplasia. Metastatic disease to the orbit also occurs on occasion.

Canine Lobular Orbital Adenomas. Canine lobular orbital adenomas arise from the lacrimal gland located dorsally or zygomatic salivary gland located ventrally. Clinically, lobular orbital adenomas present as exophthalmos or subconjunctival mass effect. The masses are soft and friable. Histologically, the neoplasms are multilobular and composed of nests and cords occasionally with acini. The lobules lack ducts, and this feature is essential to making the diagnosis of lobular orbital adenoma. The cuboidal cell population resembles normal tissue, and mitoses are absent. Local recurrence is common because complete excision is unlikely without exenteration.

Hibernomas. Hibernomas are benign neoplasm of brown adipose tissue and occur as subconjunctival or orbital masses. Ocular hibernomas have been described only in dogs.

swelling and vacuolation of retinal neurons as well as axon degeneration (see Chapter 14). The effects of braken fern toxicity are discussed in Disorders of Ruminants, and the effects of enrofloxacin/ fluoroquinolone toxicity are discussed in Disorders of Cats.

Retinitis is most often a consequence of direct extension of uveitis or endophthalmitis. Some cases of idiopathic lymphoplasmacytic uveitis also include perivascular cuffing in the retina. The presence of retinal disease in those instances does not provide clues as to the underlying etiology.

Systemic infectious diseases may affect the retina, and the lesions usually mimic those at other sites. The retina may be the target of viral infections such as canine distemper, rabies, pseudorabies, classical swine fever, Borna disease, and malignant catarrhal fever. Bacterial diseases such as canine ehrlichiosis, Rocky Mountain spotted fever, and bovine thromboembolic meningoencephalitis may cause retinal lesions as a consequence of vascular disease. Parasitic diseases of the retina include toxoplasmosis, neosporosis, and ocular larval migrans caused by the migration of the larvae of Toxocara canis and Baylisascaris procyonis.

Ocular Astrocytomas. Ocular astrocytomas have only been described in dogs. Clinically, astrocytomas appear as a discrete mass in the fundus or more frequently as retinal detachment with secondary vitreal hemorrhage, hyphema, and glaucoma. Astrocytomas may arise in the retina or optic nerve and often involve both. The histologic features and classification are similar to those in the central nervous system (see Chapter 14). The prognosis is good with complete excision; however, neoplasms with optic nerve involvement may extend intracranially.

Orbital Meningiomas. Orbital meningioma (optic nerve meningioma, retrobulbar meningioma) is a disease of dogs. Clinically, orbital meningiomas are associated with exophthalmos and vision loss. Orbital meningiomas likely arise from extradural nests of arachnoid cells. The neoplasms efface the orbital connective tissue (Fig. 21-53 ). The masses may compress but do not invade the optic nerve until late in the disease. Very rarely there may be extension in the sclera or choroid, or through the optic foramen into the calvarium. The histologic features of orbital meningiomas differ from those of intracranial/spinal meningiomas. The neoplastic cells are large with abundant eosinophilic "glassy" cytoplasm. The neoplastic cells form sheets and nests with subtle whorls. In most masses (>90%), there are foci of myxomatous, chondroid, and/or osseous metaplasia. Only rare orbital meningiomas have features typical of intracranial/ spinal meningiomas. Optic nerve atrophy and degeneration and retrograde retinal atrophy with loss of ganglion cells are frequent secondary findings. Larger masses may cause bone remodeling.

Orbital cellulitis is not a specific disease but inflammation of soft tissue in response to infectious agents introduced via a penetrating wound, a migrating foreign body, or an inflammatory focus from adjacent tissues (e.g., tooth root abscess). Only rarely does panophthalmitis extend into the orbit to cause orbital cellulitis because the sclera is generally an effective barrier to the migration of leukocytes and infectious agents.

Orbital neoplasms are overall infrequent, perhaps with the exception of orbital lymphoma in cattle. Most orbital neoplasms are not 

Eosinophilic keratitis occurs predominantly in cats and occasionally in horses (see Disorders of Cats).

Immune-mediated keratitis (IMMK) represents a diverse group of nonulcerative, noninfectious corneal diseases. IMMK occurs in the absence of uveal disease. The lesions may be epithelial or stromal (superficial, midstromal, or endothelial). The etiology or initiating cause likely varies between cases, but all are presumed to be at least in part immune-mediated. Histologically, the findings are those of chronic keratitis and include stromal fibrosis and neovascularization with inflammatory infiltrates composed of predominantly lymphocytes and plasma cells. There is a predominance of T lymphocytes, including both CD4 + and CD8 + cells.

Equine recurrent uveitis (ERU) is a worldwide disease and is the most common cause of glaucoma and blindness in horses. Clinically, it is a complex syndrome defined by repeated episodes of uveitis. The periods of active inflammation alternate with periods of quiescence during which there is little or no recognizable intraocular inflammation. The episodes of uveitis tend to increase in frequency and severity over time, causing cumulative damage. Early lesions of ERU are unlikely to be examined histologically but consist of neutrophilic infiltration of the iris and ciliary body with a rapid transition to lymphocytes and fewer plasma cells and macrophages. Exudation of fibrin and proteinaceous material is a feature of the early disease.

The histologic features of the chronic disease are listed in Box 21-13. The histologic lesions that characterize the chronic disease include variably severe infiltration of lymphocytes and plasma cells in the uveal tract. The infiltrate tends to be most severe in the iris and ciliary body, but there is almost always some degree of choroidal involvement (panuveitis). The inflammation most often includes the formation of lymphoid follicles that become increasingly organized with chronicity (E- Fig. 21-68) . During periods of quiescence, the lymphoplasmacytic infiltrate is milder and predominantly perivascular. Many of the diagnostic changes involve the nonpigmented ciliary epithelium. Lymphocytes and/or plasma cells infiltrate the Histologically, the masses are variably encapsulated and composed of lobules of often vacuolated cells that show mild pleomorphism and minimal mitotic activity. Ultrastructurally, the neoplastic cells have fairly distinct basal laminae, and the cytoplasm contains numerous mitochondria and lipid droplets. The main differential diagnosis is well-differentiated liposarcoma, and distinction may not always be possible without history, especially in incisional samples. Hibernomas are immunopositive for uncoupling protein 1 (UCP1) normally expressed in brown adipose tissue.

Habronemiasis Habronemiasis (summary sores) causes nodular inflammation most often in the medial canthus as the response to infection by larvae of nematodes Draschia megastoma, Habronema muscae, and Habronema majus. The adult nematodes infect the gastric mucosa. The larvae are excreted in feces, ingested by fly maggots, and transferred to the periocular skin and conjunctiva by fly bites. The gross lesion is a firm nodule with yellow caseous debris in the center. Histologically, the lesion is similar to that anywhere in the skin and consists of chronic eosinophilic and granulomatous inflammation targeting live or dead larvae that are often difficult to identify in histologic sections (E- Fig. 21-66) . Conjunctival lesions may abrade the cornea and cause keratitis.

Fungal keratitis (keratomycosis) occurs frequently in horses and is reported mostly during warmer weather and in warm, humid climates. Similar infections occur much less frequently in dogs, cats, and other species. It is suspected that the use of topical antibiotics is a predisposing factor for fungal keratitis as the result of changes in the normal bacterial microflora with decreasing numbers of Gram-positive organisms and increasing numbers of Gram-negative bacteria. The normally predominant Gram-positive bacteria produce antimicrobial substances including the antifungal natamycin. Topical administration of corticosteroids may also be a predisposing factor, and it can exacerbate the effect of proteases and impair corneal healing. The pathogenesis involves disruption of the corneal epithelium secondary to erosion, ulceration, or penetrating trauma. The epithelial injury allows fungal organisms from the environment or those from the normal microflora to anchor, colonize, and invade. The release of proteases by the organisms and by inflammatory cells contributes to stromal injury and provides access to the deep cornea. Some fungal organisms also produce metabolites that inhibit angiogenesis, altering the cornea's healing response. Aspergillus spp. are the most common agents isolated. Fusarium spp. and others also cause fungal keratitis. Fungal keratitis typically elicits a suppurative response with keratomalacia (see Fig. 21-38) . The inflammation may be superficial but there is most often involvement of the deep stroma, and many fungal organisms show a tropism for the deep stroma and Descemet's membrane (Fig. 21-54; E-Fig. 21-67) . These organisms may have an affinity for glycoaminoglycans that are abundant in those areas. Inflammation that is predominantly deep can form a stromal abscess, which may protrude in the anterior chamber. Untreated or unresponsive cases can progress to corneal rupture. Despite extension to and involvement of Descemet's membrane that essentially provides access to the anterior chamber, fungal keratitis does not progress to endophthalmitis in the absence of corneal rupture. Many of the details of the pathogenesis have not yet been elucidated; however, ERU is generally regarded as a multifactorial immune-mediated disease. The majority of the infiltrating cells are CD4 + T lymphocytes and include helper T lymphocytes that secrete IL-2 and interferon-γ. There is also secretion of IL-17 likely by helper T lymphocytes 17, indicating a role for autoimmunity. Many cases of ERU show immune responses to ocular proteins, most often retinal antigens such as interphotoreceptor-binding protein, S-antigen, and cellular retinaldehyde-binding protein. Some horses develop lymphocytic inflammation in the pineal gland, which shares antigens with the retina, including the S-antigen. Furthermore, the disease is associated with specific equine major histocompatibility complex haplotypes.

Infectious agents have been implicated in the development of the disease, and there is some correlation between infection with Leptospira spp. and ERU. Antibodies against Leptospira spp. are detected in the serum, aqueous humor, and vitreous of some clinically affected horses, and leptospiral organisms have been cultured or identified by polymerase chain reaction in some ERU globes. The disease has also been reproduced experimentally by exposing ponies to L. interrogans serovar pomona; the ponies recovered from the systemic infection but developed ocular lesions within the following months. Antibodies against Leptospira spp. cross-react with the equine cornea, lens, ciliary body, and retina, suggesting that molecular mimicry contributes to the pathogenesis of the ERU. It is therefore possible that beyond the uveitis that occurs as part of systemic leptospirosis, exposure to leptospiral organisms also stimulates autoimmunity.

The mechanisms by which repeated episodes of uveitis develop remain unclear but likely involve epitope spreading. In ERU, there is evidence for both intramolecular and intermolecular epitope spreading. Epitope spreading occurs when immune-mediated damage to the tissue exposes antigens previously unrecognized by the immune system that can now be the target of additional injury.

Congenital stationary night blindness in horses predominantly affects Appaloosas, although it has been reported in other breeds. In Appaloosas, it is associated with the leopard complex gene nonpigmented ciliary epithelium. The nonpigmented ciliary epithelium is covered/expanded by acellular hyaline eosinophilic material compatible with amyloid ( Fig. 21-55 ). The eosinophilic material stains positive with Congo red and shows apple green birefringence under polarized light. It demonstrates immunoreactivity to antibodies specific for AA amyloid, and mass spectrometry indicates a predominance of serum amyloid A1 protein. The cytoplasm of some of the nonpigmented ciliary epithelial cells contains eosinophilic linear inclusions (Fig. 21-56) . These inclusions are crystalline arrays of protein that appear to develop within mitochondria. Masson's trichrome staining facilitates their identification. Although typical of the disease, the mechanisms involved in the amyloid deposition and formation of the linear eosinophilic inclusions are unknown.

There are a number of secondary lesions that can develop as a consequence of ERU and that may or may not be present in every case. ERU is the most common cause of cataract in horses. Retrocorneal and preiridal fibrovascular membranes are frequent and may lead to anterior or posterior synechiae. Many cases show retinal detachment secondary to choroidal disease, which can include thickening of choroidal vessels. The optic nerve may be infiltrated by lymphocytes and plasma cells or exhibit glial scarring. Many of the changes are nonspecific and secondary to the effects of glaucoma. The disease eventually leads to phthisis bulbi.

Infectious keratoconjunctivitis in sheep and goats has similar clinical and histologic features to the bovine disease with the same name, but the condition can be caused by a wide range of organisms. Chlamydophila pecorum and Mycoplasma spp. account for most cases. The lesions initially present with conjunctival edema and congestion, followed by serous to mucopurulent conjunctivitis, and, with chronicity, lymphoid follicular hyperplasia.

Malignant catarrhal fever is a sporadic, highly fatal systemic infectious disease that affects cattle and, less frequently, other ruminants and pigs. It has a worldwide distribution and is economically significant. The disease is caused by herpesviruses of the gamma herpesvirus family. The sheep-associated form has a worldwide distribution and is caused by ovine herpesvirus 2 (OvHV-2). It is transmitted by sheep and goats to cattle and other susceptible hosts. The wildebeest-associated form is caused by Alcelaphine herpesvirus 1 (AHV-1) and is transmitted by wildebeest. This form occurs mainly in Africa, but it also occurs in wildlife facilities housing wildebeest. The majority of cattle with malignant catarrhal fever have prominent ocular lesions including corneal edema, corneal neovascularization, and anterior uveitis. These lesions can distinguish this disease from bovine viral diarrhea and mucosal disease. In the eye, the lesion consists of necrotizing vasculitis with perivascular cuffing. CD8 + T lymphocytes predominate. The vasculitis is most often identified within the iris, but it can be found anywhere within the uveal tract or retina. Peripheral corneal stromal neovascularization and corneal edema are often marked. Lymphocytic corneal endotheliitis may also contribute to the corneal edema. The pathogenesis of the disease is unclear. A cellmediated cytotoxic lymphocytic process was initially suspected, but a pathogenesis of direct virus-cell interactions or immunemediated responses directed against infected cells has also been proposed.

responsible for the white spotted coat patterns. There is abnormal transcription of the gene coding for a cation channel (TRPM1), which is required for normal signaling between rods and bipolar cells. This results in visual deficits, most notably night blindness (nyctalopia). The abnormality does not cause histologically recognizable lesions.

Infectious bovine rhinotracheitis is caused by bovine herpesvirus type-1 (BoHV-1), a member of the alpha herpesvirus family. The various strains of the disease can cause lesions in multiple organ systems. The ocular signs of the disease include serous to mucopurulent conjunctivitis. The acute lesion consists of serous to mucopurulent conjunctivitis, whereas the chronic disease typically presents as severe follicular lymphoid hyperplasia recognizable both grossly and histologically. Following infection, the main site for BoHV-1 latency is in the neurons of the trigeminal ganglia.

Infectious bovine keratoconjunctivitis (also known as pink eye) is a worldwide contagious disease of considerable economic importance. It is caused by the Gram-negative coccobacillus Moraxella bovis. The disease is transmitted from animal to animal by mechanical vectors such as flies, by direct contact, and by fomites. Natural outbreaks occur most often during the summer, and the face fly (Musca autumnalis) appears to be the most important vector. Ultraviolet light is a contributing factor possibly through damage to the corneal epithelium facilitating colonization by the bacteria. Concurrent infection with bovine herpes virus type-1 (infectious bovine rhinotracheitis) increases the severity of the disease. Other infectious agents that may contribute include Moraxella ovis, Mycoplasma spp., Listeria monocytogenes, and Thelazia spp.

The disease initially presents as conjunctival edema and congestion. Within 24 to 48 hours, shallow corneal ulcers develop, likely the result of epithelial cytotoxins produced by the bacteria. Numerous neutrophils infiltrate the affected area, and some may phagocytize the organisms. Keratomalacia is associated with collagenase release from the corneal epithelium, keratocytes, and neutrophils . Moraxella bovis does not produce collagenases but produces a cytotoxin that damages neutrophils in a dose-dependent manner. The cytotoxin and the release of enzymes by neutrophil contribute to stromal injury. The lesion induces prominent and rapid corneal stromal neovascularization, which reaches and surrounds the affected cornea within 7 to 9 days. Most cases will significantly improve within a few weeks, leaving only mild corneal scarring. In severe cases, the corneal ulcer may progress to corneal rupture with iris prolapse and, in some cases, phthisis bulbi.

Moraxella bovis exhibits several virulence factors, but only the presence of fimbriae (type IV pili) on the bacterial cell surface and the secretion of a β-hemolytic, corneotoxic, and leukotoxic cytotoxin impact clinical disease. Only piliated strains cause clinical signs: The Q pili facilitates the attachment of the organisms to the cornea, and the I pili enables maintenance of an established infection. Hemolytic Moraxella bovis strains produce a pore-forming cytotoxin (cytolysin/hemolysin) that induces corneal ulcers by lysis of corneal epithelial cells and neutrophils. Nonhemolytic strains of Moraxella bovis are not pathogenic for cattle. Other virulence factors that some strains or isolates may exhibit include phospholipases, hydrolytic and proteolytic enzymes, and iron acquisition systems. 

Goniodysgenesis See Disorders of Domestic Animals, Diseases of the Globe as a Whole, The Classification of Glaucoma, Primary Glaucoma, Goniodysgenesis.

See Disorders of Domestic Animals, Diseases of the Eyelids and Conjunctiva, Developmental Anomalies, Entropion and Ectropion.

Idiopathic granulomatous marginal blepharitis is seen only in dogs as a nodular to multinodular to diffuse thickening of one or both eyelid margins. The histologic lesion consists of coalescing nodules of macrophages and neutrophils with variable numbers of lymphocytes and plasma cells in the subconjunctival tissue of the eyelid margin. Distinct granulomas and pyogranulomas characterize the lesion. The histologic presentation is similar to that of idiopathic sterile granuloma and pyogranulomas (see Chapter 17). The inflammation is not associated with hair follicles or glands. Microorganisms are never identified.

Prolapse of the gland of the third eyelid ("cherry eye") is common in dogs and is thought to be the result of laxity in the connective tissue anchoring the third eyelid to the periorbital tissues. The gland is histologically normal, although there may be secondary inflammatory changes.

Nodular granulomatous episcleritis (NGE) is a common nodular lesion of the conjunctiva. The lesion is most often solitary and presents as a smooth, tan to red, subconjunctival mass. As the name reflects, the vast majority of cases occur at the limbus, but the lesion may be seen in other conjunctival sites and rarely in the orbit. NGE has distinct histologic features consisting of a wellcircumscribed nodule composed of spindle and epithelioid macrophages in variable proportions admixed with lymphocytes and plasma cells (Fig. 21-58 ). Some spindle cells may be myofibroblasts.

Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative disorders caused by infectious protein particles (prions) (see Chapter 14 for general discussion and lesions in the central nervous system). In addition to the lesions in the central nervous system, including some affecting the visual pathway, TSEs also target the neural tissue of the globe. Ovine spongiform encephalopathy (scrapie) causes atrophy of the inner and outer nuclear layers with atrophy of the outer plexiform layer. The outer limiting membrane is less easily defined, and there can be vacuolation of the photoreceptor layer. Müller cells are hypertrophic, and there is increased glial fibrillary acidic protein (GFAP) immunoreactivity. Prions can be detected in the retina of most affected sheep. There can be optic nerve degeneration with vacuolation, Wallerian degeneration, gliosis, and infiltration of Gitter cells. Histologically, the lesion of bovine spongiform encephalopathy includes displacement of nuclei from the outer and inner nuclear layers into the photoreceptor and inner plexiform layers. There can also be loss of retinal ganglion cells. Rare vacuolation/spongiform change can be seen. Prions can be detected in the retina of most affected cattle.

Braken fern (Pteridium aquilinum) toxicity is a potential cause of retinal degeneration in sheep in the United Kingdom. In addition to its effect in other organ systems, the toxin ptaquiloside causes degeneration of the photoreceptor layer that eventually progresses to full-thickness retinal atrophy. Because the severely affected animals are blind and present with dilated pupils and tapetal hyperreflectivity, the condition has been termed bright blindness.

In pigs, conjunctivitis is often a manifestation of systemic diseases. Hog cholera can cause severe conjunctivitis. Pseudorabies, African swine fever, swine influenza, porcine reproductive respiratory syndrome, swine pox, rubulavirus, chlamydophylosis, and mycoplasmosis are also potential causes of conjunctivitis. Some of these conditions may cause keratitis in addition to conjunctivitis. In addition to surface lesions, diseases such as hog cholera and pseudorabies may cause intraocular lesions in some cases. In almost all instances, conjunctivitis is not the most significant clinical sign or lesion.

Blue eye disease is caused by porcine rubulavirus, a member of the paramyxovirus family. The disease has been reported only in Mexico; however, closely related paramyxoviruses have been identified in other countries. The virus mainly causes encephalitis, pneumonia, and reproductive failure, as well as ocular disease. The effects of the virus vary by age. Suckling piglets younger than age 21 days are most susceptible. Mortality among affected piglets can be as high as 90%; however, less than half of the piglets within a litter and approximately 20% of litters will be affected during an outbreak. Despite the name of the disease, only a small percentage of piglets develop corneal opacity corresponding to severe corneal edema. Many cases also have mild anterior uveitis, and some present with conjunctivitis. Older pigs tend to develop transient nonfatal disease that can include corneal disease. 

Uveodermatologic Syndrome (Vogt-Koyanagi-Haradalike Syndrome) Uveodermatologic syndrome is relatively frequent in dogs. Clinically, the disease is most often seen in Akitas, Siberian huskies, Samoyeds, and Australian shepherds, although many other breeds are affected. The globes from less commonly affected breeds are more likely to be examined histologically, perhaps because the disease is less readily recognized clinically. The clinical syndrome of dermal depigmentation and severe bilateral uveitis is distinctive. Ocular lesions typically precede skin lesions. In Akitas, specific dog leukocyte antigen (DLA) class II alleles predispose to the development of the disease. DLA are part of the major histocompatibility complex (MHC). The pathogenesis of the lesion involves immunemediated inflammation targeting a protein involved in melanin production in melanocytes, likely tyrosinase or tyrosinase-related proteins. Histologically, the lesion consists of severe granulomatous panuveitis with prominent pigment dispersion (Fig. 21-59) . The iris, ciliary body, and choroid are typically all affected, but the inflammation may not be as severe diffusely. The inflammation is strikingly uveocentric with very little extension in other parts of the globe. Retinal detachment and glaucoma are common secondary findings.

Asymmetric uveitis describes a condition in which injury to one eye causing a specific pattern of inflammation predisposes the contralateral globe to similar inflammation even in the absence of the initiating cause. The vast majority of cases are thought to be initiated by penetrating trauma to one globe. The lesion consists of granulomatous to pyogranulomatous endophthalmitis where the leukocytes carpet the uveal tract, posterior cornea, and/or inner retina ( Fig.  21-60) . Retinal detachment and necrosis are common. Usually within weeks, the contralateral globe will develop inflammation with similar distribution and composition without trauma. However, it is not possible to accurately predict if or when the contralateral globe will be affected. Clinicians should be made aware of this risk so that the contralateral globe can be closely monitored and early treatment can be administered. The pathogenesis has not been elucidated in dogs, but asymmetric uveitis may represent a T lymphocyte-mediated delayed-type hypersensitivity reaction targeting a uveal antigen. Clinical information is often required to differentiate asymmetric uveitis from phacoclastic uveitis associated with diabetic cataracts. Unlike uveodermatologic syndrome, in Multinucleated giant cells and eosinophils are occasionally admixed with infiltrate. Distinct granulomas are not a feature of the condition. It is likely that the histologic lesion represents a reaction to different stimuli rather than a specific disease. NGE is presumed to be an immune-mediated reaction, and most cases respond to immunomodulation.

Ligneous conjunctivitis is a rare entity seen predominantly in Doberman pinschers and Golden retrievers and described in other breeds. Grossly, the conjunctiva is bilaterally firm with a pseudomembranous exudate. Histologically, the main finding is the presence of abundant poorly cellular hyaline eosinophilic matrix in the substantia propria. The matrix is positive with phosphotungstic acid-hematoxylin (PTAH) staining and negative for Congo red, indicating fibrin. Similar material may be deposited at other sites. In some dogs, the disease is caused by a plasminogen deficiency.

Chronic superficial keratitis (CSK) is a clinically distinctive superficial keratitis seen primarily but not exclusively in German shepherd dogs and sighthounds. The underlying mechanism appears to be an immune-mediated response targeting cornea-specific antigens that have been altered by environmental factors such as ultraviolet light. There is a genetic component to the disease, and an MHC class II risk haplotype has been identified in German shepherds. Dogs homozygous for the risk haplotype are eight times more likely to develop CSK. The disease usually begins at the lateral limbus as red conjunctival thickening. The lesion spreads toward the axial cornea as a superficial, fleshy, vascularized stromal infiltrate, involving both globes although not always symmetrically (E- Fig. 21-70) . Chronic lesions become intensely pigmented, and eventually the entire superficial stroma may be vascularized, fibrotic, and pigmented.

Histologically, the lesion is a dense lichenoid lymphoplasmacytic stromal keratitis with stromal fibrosis and neovascularization. Cases with pigmentation are likely to show pigmentary incontinence. The corneal epithelium is likely to be hyperplastic, pigmented, and keratinizing. There may be single cell necrosis/apoptosis within the corneal epithelium. In commonly affected breeds, the lesion is likely to be recognized clinically, and most cases respond to long-term immunomodulatory therapy. A condition similar in signalment, histopathology, and likely pathogenesis targets the third eyelid (plasmacytic conjunctivitis/plasmoma). The histologic lesion of CSK overlaps with nonspecific chronic keratitis, and the distinction may require clinical information.

Granulomatous scleritis (necrotizing scleritis) is a condition of unclear pathogenesis. It is suspected to be an immune-mediated disease but is not associated with immune-mediated diseases affecting other sites. The inflammation does not form nodules and is always predominantly centered on the sclera. There may be extension in the adjacent uveal tract or anteriorly in the cornea in severe cases. The histologic lesion consists of macrophages with lymphocytes and plasma cells. Rare multinucleated giant cells may be present, and some cases may include neutrophils. Collagenolysis and vasculitis are inconsistent findings. Retinal detachment is common in cases with extension in the choroid. The lesion can be unilateral, but in many cases the contralateral globe will eventually develop a similar lesion. progressive degeneration of photoreceptors that leads to blindness, in the absence of an inflammatory or toxic cause. The underlying genetic and biochemical alterations vary greatly, but these disorders share clinical and histologic features. The molecular work in various breeds does not translate to specific histologic findings. This group of diseases includes early onset photoreceptor dysplasias in which photoreceptors fail to develop normally as well as late-onset degenerations that most often become significant in adults. Most of the breed-specific conditions included under the broad term progressive retinal atrophy are autosomal recessive diseases. Many of these conditions initially target rods, and night blindness (nyctalopia) is a common presenting complaint.

Because the initial retinal degeneration does not cause glaucoma, affected globes are only evaluated histologically in the very late stages of the disease or as part of the evaluation for other ocular disorders. At that time, the changes include multifocal loss 

Intraocular xanthoma is a rare condition mostly seen in Miniature Schnauzers. Grossly, the entire globe is filled with tan material mimicking a mass. Histologically, the material consists of massive numbers of vacuolated "foamy" macrophages and multinucleated giant cells. There are extracellular deposits of lipid presenting as birefringent crystals and clefts. Idiopathic primary hyperlipidemia, diabetes mellitus, and lens-induced uveitis may all be contributing factors.

Collie eye anomaly (CEA) is a bilateral, congenital, recessively inherited syndrome. It is most commonly seen in rough and smooth collies, Shetland sheepdogs, Australian shepherds, border collies, Lancaster heeler, as well as other breeds. The pathogenesis of the defect is thought to be a failure of the outer layer of the optic cup, which eventually becomes the retinal pigment epithelium (RPE), to induce the proper development of the neural crest-derived choroid, tapetum lucidum, and sclera. Molecular signaling between the RPE and periocular mesenchyme is required for melanocyte differentiation and choroidal vasculature development. For example, VEGF from the RPE is required for the development of the choroidal vasculature. The underlying genetic mutation of CEA is an intronic deletion in the NEHJ1 gene.

The histologic findings always include some degree of choroidal hypoplasia (Fig. 21-61 ). There is choroidal hypopigmentation as a result of a decrease in the number of melanocytes as well as segmental tapetal aplasia/hypoplasia. The choroidal hypoplasia tends to be more pronounced lateral to the optic disc, near the junction of the tapetal and nontapetal choroid. Posterior polar colobomas at or near the optic disc may be unilateral or bilateral and reflect a defect in the lamina cribrosa or sclera adjacent to the optic nerve (E-Figs. 21-71 and 21-72; see Fig. 21-22) . The colobomas are lined by retinal/neural tissue. Other findings may include retinal detachment, retinal dysplasia, and intraocular hemorrhage. Of interest, choroidal hypoplasia by itself does not lead to impaired vision.

Canine progressive retinal atrophy describes a group of inherited or suspected inherited photoreceptor disorders of dogs. It is a bilateral 

Feline herpesvirus 1 (FHV-1), a member of the alpha herpesvirus family, has a worldwide distribution and causes a combination of upper respiratory disease, conjunctivitis, and keratitis that predominantly affects kittens. The virus causes epithelial cell cytolysis, which can predispose to secondary bacterial infection. The conjunctivitis can also lead to symblepharon, adhesions between the cornea and conjunctiva. Intranuclear inclusion bodies are present only during the early stages of the disease and are therefore almost never seen histologically. After recovery, most kittens develop latent infection primarily in the trigeminal ganglia. FHV-1 is the most commonly clinically diagnosed cause of keratitis in cats, presumed to represent recrudescent disease in most adult cases. However, the causative effect of FHV-1 is difficult to document in clinical cases. Proving FHV-1 as the cause of keratoconjunctivitis is problematic because greater than 95% of cats show serologic evidence of exposure and up to 50% of clinically normal cats contain FHV-1 DNA in the cornea. Clinically, the disease may present as ulcers, either dendritic ulcers considered pathognomonic for the disease or geographic ulcers. FHV-1 can also cause a chronic stromal keratitis with nonspecific infiltration of lymphocytes and plasma cells. Based largely on the presence of viral DNA, some have also proposed a role for FHV-1 in feline corneal sequestrum and feline eosinophilic keratoconjunctivitis. Herpesvirus keratoconjunctivitis is essentially a clinical diagnosis, and affected corneas are unlikely to be examined by a pathologist. Samples that are examined histologically do not show intranuclear inclusions, nor do they demonstrate changes that can be specifically attributed to the cytopathic effect of the virus. It is therefore not possible to confirm FHV-1 infection histologically.

Eosinophilic keratitis is a unique disease that occurs predominantly in cats but also occasionally in horses. The pathogenesis has not been determined in either species. The clinical presentation varies, but the condition has similar histologic features in both species. In cats, the typical clinical presentation consists of white to pink proliferative plaques, most often involving the lateral cornea initially ( Fig. 21-63 ). Many cases have similar lesions in the adjacent conjunctiva, and in a few cases the lesions are exclusively conjunctival. The disease can be diagnosed by demonstrating the presence of eosinophils on cytology. Histologically, eosinophils are always a component of the inflammation but may not be the predominant cell type (Fig. 21-64 ; E- Fig. 21-73) . Because most cases sampled are chronic, the infiltrate is often predominantly lymphoplasmacytic with variable numbers of eosinophils. Mast cells and macrophages can be present in variable numbers. Some cases present with a band of granular hypereosinophilic material near or at the epithelial basement membrane presumed to represent eosinophilic degranulation. The overlying epithelium is often intact. The histologic diagnosis of eosinophilic keratitis is usually made in keratectomy samples. The disease usually responds favorably to medical treatment, and there is almost never an indication for enucleation, although the disease can be recurrent. The cause and pathogenesis are unknown. There is no known association with cutaneous eosinophilic granuloma complex or systemic diseases. A causative role for feline herpesvirus 1 has not been established.

Acute bullous keratopathy occurs almost exclusively in cats, but it has been reported in horses. The condition describes a specific form of photoreceptors that progresses to diffuse involvement and eventually includes the outer nuclear layer. As the disease progresses, there is blending of the outer and inner nuclear layers and unaffected ganglion cells may "drop" within that layer ( Fig. 21-62 ). Invariably the disease proceeds to full-thickness retinal atrophy and glial scarring. Complications of chronic progressive retinal atrophy include retinal detachment and cataract, both of which may lead to glaucoma. Only the early multifocal distribution can be helpful to suggest progressive retinal atrophy by histology. Once the lesion diffusely affects the photoreceptors, it is indistinguishable from any other cause of photoreceptor degeneration.

Sudden acquired retinal degeneration (SARD) is a common cause of acute, rapidly progressing, permanent photoreceptor degeneration. Blindness occurs within days to weeks. Affected dogs are adult, and the disease can affect any breed or crossbreed. The lesion is bilaterally symmetric and diffuse across the retina. The cause is unknown. Some dogs are otherwise healthy, whereas others show clinical signs suggestive of metabolic disease, such as weight gain, polyuria, polydipsia, polyphagia, and blood work that at times suggests adrenal dysfunction. Histologically, the lesion begins as thinning of the outer plexiform layer. The lesion progresses to a uniform diffuse loss of photoreceptors and eventually to diffuse full-thickness retinal atrophy. Once the lesion diffusely affects the photoreceptors, it is indistinguishable from any other cause of photoreceptor degeneration. There can be lymphoplasmacytic retinitis; however, the change is histologically minimal. Because the retinal degeneration does not cause glaucoma, affected globes are only evaluated histologically in the very late stages of the disease or as part of the evaluation for other ocular disorders.

Orbital extraocular polymyositis affects all the extraocular muscles except the retractor bulbi muscle. It is a rare disease, typically affecting young dogs. Clinically, the condition presents as bilateral and variably symmetric exophthalmos, retraction of the upper eyelid, and mild chemosis. In the chronic disease, there is enophthalmos (retraction of the globe into the orbit) and strabismus. Histologically, the lesion is a CD3 + predominant lymphocytic myositis that results in myonecrosis, followed by attempts at regeneration and eventually muscle atrophy and fibrosis. An immune-mediated attack directed specifically against the extraocular muscles is suspected to be the cause of this disorder. Because the extraocular muscles are a difficult site from which to obtain a biopsy, diagnosis is generally based on the clinical findings. antiinflammatory or immunosuppressive therapy has been proposed.

Feline lymphoplasmacytic uveitis is the most frequent histologic pattern of the uveitis in cats. It is not a specific disease but, rather, a common reaction to a variety of insults, including trauma, infectious diseases, and neoplasia. It is presumed to be an immunemediated disease; however, the cause and pathogenesis likely vary considerably between individual cases. Histologically, there is infiltration of lymphocytes and plasma cells predominantly in the iris, iridocorneal angle, and ciliary body (Fig. 21-65 ; E- Fig. 21-74) . The infiltrate may extend in the posterior iris and ciliary epithelium. Choroidal involvement is variable but tends to be mild. There can also be perivascular infiltration of lymphocytes and plasma cells in the retina, which does not provide any clues as to the initiating cause. Chronic and severe cases often include formation of lymphoid follicles within the iris, iridocorneal angle, or ciliary body. The lesion indicates chronicity, and the initiating cause is almost never recognized histologically. The lesion may be unilateral or bilateral, likely a reflection of the numerous potential causes. The significance of lymphoplasmacytic uveitis is that it is a common cause of glaucoma in cats. The mechanism by which the uveitis causes the glaucoma is unclear. Obstruction and functional distortion of the iridocorneal angle by the inflammation are likely contributing factors. Severe lymphoplasmacytic uveitis may clinically mimic uveal lymphoma.

Feline infectious peritonitis (FIP) has a worldwide distribution. The FIP virus is a strain of the feline coronavirus (FCoV) that has acquired virulence, possibly through a mutation that allows replication in macrophages (see Chapters 4, 7, and others). FIP is a common cause of uveitis and endophthalmitis in cats, most often in young cats. Ocular disease may be present with or without obvious systemic signs. Gross lesions include accumulation of highly proteinaceous material within the anterior chamber and/or vitreous. The histologic presentation is highly variable. In most cases, the disease is most severe in the anterior uvea with extension into adjacent anterior and posterior chambers. The inflammation tends to be predominantly neutrophilic with areas of pyogranulomatous or granulomatous inflammation (Fig. 21-66 ; E- Fig. 21-75 ). Some cases are plasma cell predominant. Neutrophilic or lymphoplasmacytic endotheliitis is common. Vasculitis may or may not be present.

of bullous keratopathy that develops within hours. Acute bullous keratopathy develops in the absence of preexisting corneal disease. Grossly, there is marked corneal edema and formation of stromal bullae. Histologically, there is a relatively well-circumscribed severe expansion of the corneal stroma. There is no associated inflammation. The cause of the lesion appears to be rupture of Descemet's membrane, which may be recognized histologically. Unlike most causes of corneal edema, there is no evidence of injury to the corneal epithelium or corneal endothelium. The underlying pathogenesis is unknown; however, an association with administration of systemic photoreceptors and loss of neurons from the outer nuclear layer. Late in the disease, there is complete loss of the outer segment of the photoreceptors with loss of some inner segments and thinning of other retinal layers. During all stages of the disease, the central retina is less severely affected.

Taurine deficiency (also known as feline central retinal degeneration) causes photoreceptor degeneration in cats. Unlike other domestic animals, cats have only limited capacity to synthesize taurine from the precursor amino acid cysteine because of low levels of the enzyme cysteine sulfinic acid decarboxylase. Cats depend on dietary intake to maintain normal tissue concentrations. All ocular components contain taurine, but the concentrations are highest in the retina and even more so in the photoreceptors. Taurine plays a critical role in normal development and function of the retina and also of the visual cortex of the brain. The exact functions of taurine are not clearly defined, but it does provide cytoprotection through its antioxidant properties and also modulates neuronal activity in a neurotransmitter-like manner. In taurine-deficient cats, the earliest lesions consist of cone disorganization. Cones are more sensitive than rods to taurine deficiency, and the rods of the peripheral retina are the last to degenerate. Initially, the histologic lesion is photoreceptor degeneration in the area centralis that progresses to more widely affect the retina dorsal to the optic nerve. In some cases, diffuse retinal atrophy develops, leading to blindness. The cardiac changes associated with taurine deficiency are described in Chapter 10.

Fluoroquinolone toxicity causes photoreceptor degeneration in cats. The lesion develops acutely and can even be seen in cats receiving a single inappropriately high dose. Histologically, there can be swelling and vacuolation of the photoreceptors within the hours of exposure to a toxic dose. Diffuse photoreceptor degeneration is recognizable within days. The susceptibility of cats to fluoroquinolone toxicity has a genetic basis. There are specific amino acid changes to the transport protein ABCG2 at the blood-retinal barrier compared to other species. These changes allow accumulation of fluoroquinolone within the retina. Fluoroquinolones are photoreactive, and exposure to light can generate reactive oxygen species that damage lipid membranes.

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Inflammation in the choroid tends to be lymphoplasmacytic, and there can be retinal perivascular cuffing. Retinal detachment is common. The inflammation may also extend in the optic nerve and/ or optic meninges. In enucleated globes from patients that do not manifest overt systemic signs and present for chronic unresponsive uveitis, the inflammation tends to be plasma cell predominant. Although the changes in the globe are often highly suspicious for FIP, an absolute definitive diagnosis is rarely possible based on ocular histopathology alone.

Inherited retinal dysplasias and degenerations have been reported as sporadic occurrences in a variety of cat breeds. Two separate diseases have been described in the Abyssinian. One is an early onset rod-cone dysplasia with clinical signs of slower pupillary light reflexes, mydriasis, and nystagmus developing as early as 4 to 6 weeks of age. It has an autosomal dominant mode of inheritance and is the result of a single base deletion in the CRX gene. Both cones and rods show abnormal and retarded development. The photoreceptor degeneration begins in the central retina and progresses toward the periphery. Cones are more severely affected than rods. By 1 year of age, the disease is advanced and cats are blind. In contrast, the lateonset retinal degeneration is inherited as an autosomal recessive trait, and affected cats usually show no clinical signs until approximately 2 years of age. There is variable progression to full-thickness retinal atrophy over 2 to 4 years. Rods are more severely affected than cones. The earliest histologic lesions are disorganization of the 

Note the fleshy gray-pink superficial stromal ingrowth (arrow) from the lateral limbus (right) into the anterior stroma of the cornea. This appearance is classic for chronic superficial keratitis (pannus). (Courtesy Dr

Anterior Uvea, Cat. The iris and ciliary body contain numerous coalescing perivascular lymphocytic-plasmacytic nodules (arrows). H&E stain. (Courtesy Dr

Feline Infectious Peritonitis, Ciliary Body, Cat. Lymphocytes and plasma cells tend to predominate within the uveal stroma (left), whereas neutrophils, fibrin, and macrophages predominate within the adjacent aqueous humor of the posterior chamber (right)

Current concepts in the pathophysiology of glaucoma

The molecular basis of retinal ganglion cell death in glaucoma

Corneal injuries and wound healing: Review of processes and therapies

Veterinary ocular pathology: A comparative review

Veterinary ophthalmology

Canine ocular neoplasia: A review

Immunohistochemical characteristics of normal canine eyes

Fundamentals of veterinary ophthalmology

Ocular immune privilege sites

Special senses

Ophthalmic immunology and immune-mediated disease

Control of scar tissue formation in the cornea: Strategies in clinical and corneal tissue engineering