Eyelids: Like skin anywhere else, the defenses of eyelid against injury include both structural and cellular defenses, including hair, keratin, epithelial tight junctions, and a potent intraepithelial and superficial dermal immune system (see discussion on skin). Like skin, it becomes susceptible to infectious disease when those defenses are compromised by excessive moisture, metabolic disease, or mechanical injury. The eyelid is susceptible to all of the same infectious, nutritional, and immune diseases as skin in any other location.

Conjunctiva: The conjunctiva is protected from most physical and chemical injuries by the eyelids and by the tear film. It has tight junctions between the epithelial cells to prevent easy access by infectious or chemical agents into the underlying lamina 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. The resident mucosal immune system (MALT) functions similarly to immune systems in other mucosal sites, such as the upper respiratory tract, lungs (bronchus-associated lymphoid tissue [BALT]), and gastrointestinal tract (gut-associated lymphoid tissue [GALT]) (see Chapter 13).

Adaptive Cutaneous Metaplasia to Mild Persistent Irritation: The usual response of the cornea to persistent mild irritation is cutaneous metaplasia, which is a combination of keratinization, epithelial hyperplasia, epithelial pigmentation, subepithelial fibrosis, and vascularization (Figs. 20-59 and 20-60). In short, a cornea that is challenged to adapt to mild persistent irritation does so by recalling its genetic heritage as skin and comes to resemble skin in every way except for the acquisition of hair follicles. Not all examples of cutaneous metaplasia involve the entire range of adaptive changes; it is possible, for example, to have keratinization without pigmentation or epidermal metaplasia without accompanying stromal fibrosis and vascularization. It depends on the nature of the irritation. The most common causes for such adaptation include chronic desiccation and mechanical irritation from eyelid diseases such as entropion or anomalous placement or direction of eyelashes. Desiccation may result from defective production of tears as in keratoconjunctivitis sicca, from improper distribution of tears because of improper eyelid structure or function, or because of ocular enlargement that prevents the lids from closing. Because the cornea is permitted to exist in its privileged state only because it is constantly bathed in a protective and nourishing tear film, the partial or complete removal of that tear film represents a significant challenge to corneal homeostasis. If the change occurs slowly, the cornea successfully adapts by undergoing cutaneous metaplasia. If the desiccation occurs very rapidly, then the cornea will likely ulcerate.

Cutaneous metaplasia is a complex event that probably reflects the failure of conjunctival epithelial cells and stroma to acquire corneal phenotypes as they grow toward the center of the cornea to replace injured corneal tissue. The corneal epithelium has a finite number of replicative cycles. Persistent injury that exceeds the replicative ability of the corneal epithelium itself will require ingrowth of germinal cells that reside in the bulbar conjunctiva at the limbus. Similarly, injured corneal stroma often needs to recruit fibroblasts from the adjacent conjunctival lamina propria or sclera. Those chemical signals required to induce conjunctival or scleral tissue to undergo maturation into more appropriate “corneal” structure remain unknown.

Some of the lesions of cutaneous metaplasia are reversible, albeit only very slowly. Stromal fibrosis, however, is a permanent change, and the corneal stroma never again recovers complete transparency (see discussion on corneal wound healing). It is easy to think of corneal cutaneous metaplasia as an undesirable pathologic event, but in fact it is an eye-saving response to a pathologic change in the corneal environment. Failure to undergo cutaneous metaplasia would lead to corneal disintegration and subsequent destruction of all of the intraocular tissues.

Clinical entities characterized by corneal cutaneous metaplasia include pigmentary keratitis (corneal desiccation in brachycephalic dogs), keratoconjunctivitis sicca, band keratopathy secondary to eyelid closure defects, chronic keratitis secondary to irritation from eyelids or eyelashes, and chronic corneal desiccation as a consequence of chronic glaucoma.

Epithelial and/or Stromal Necrosis: Injuries to the cornea that occur too quickly or with too much severity to permit cutaneous metaplasia result in corneal necrosis. Because most of the injuries are from external insults, it is the corneal epithelium that is most commonly affected. The usual result is corneal ulceration. The causes are numerous, including rapidly progressing desiccation, severe mechanical injury, injury from exogenous chemicals, and a few niche-adapted infectious diseases such as herpesvirus infection in cats and Moraxella bovis infection in cattle.

After full-thickness epithelial loss, there is immediate osmotic absorption of water from the tear film into the anterior stroma, resulting in focal superficial stromal edema that is the clinical hallmark of corneal ulceration. The absorption of water increases the spacing between the stromal collagen fibers and results in increased scattering of light, which clinically appears as corneal opacity. Coloring the tear film with water-soluble dyes like fluorescein is a very common clinical diagnostic technique to accentuate the edema within the stroma. Within hours after injury, the early healing process begins and neutrophils from the tear film are also absorbed into the cornea (Fig. 20-61). In small “physiologic” numbers, they aid in defending the denuded cornea against opportunistic infection, provide growth factors for subsequent wound healing, and help with a small amount of corneal stromal débridement necessary for wound healing. If the wound becomes infected and the neutrophils migrate from the tear film and limbus in large numbers, their lytic enzymes create enough bystander injury to result in stromal destruction, known as suppurative keratomalacia (Fig. 20-62).

Corneal injuries of greater magnitude result in deep ulcers with substantial stromal loss, even to the point of disappearance of the entire stroma exterior to Descemet’s membrane. This is most commonly seen in rapidly progressing ulcers contaminated with bacteria, resulting in neutrophil-induced keratomalacia. These ulcers, known as melting ulcers, may progress over just a day or two to full-thickness stromal dissolution. Descemet’s membrane is the last barrier. It will bulge anteriorly into the defect created by the loss of the overlying stroma and epithelium to create a descemetocele (Fig. 20-63). In most instances, this fragile membrane (Descemet’s membrane) ruptures, resulting in a perforating ulcer, which leads to the loss of anterior chamber fluid and the strong probability of iris prolapse. Iris prolapse may also result from corneal perforation from trauma.

Keratitis is a common clinical term indicating inflammation of the cornea. Because the normal cornea is avascular, true inflammation cannot occur until later in the disease process, after the injured cornea has been vascularized as part of wound healing (see later discussion). Nonetheless, corneal ulcers are very susceptible to opportunistic infection from normal conjunctival flora or organisms from the environment. This is probably particularly true of mycotic keratitis in horses, particularly when the fungal infection is given an unfair advantage because of inappropriate use of antibiotics and/or corticosteroids in the management of minor corneal lacerations. The presence of such organisms within the cornea results in a marked acceleration of leukocyte immigration from the tear film and blood vessels of the limbus. Although these leukocytes may be effective in neutralizing the infectious agent, they usually create substantial bystander injury to the stroma or the epithelium, resulting in a delay in wound healing and an increase in scarring.

Repair (Wound Healing): Those injuries limited to just a portion of the epithelial thickness are rapidly repaired by epithelial sliding and eventual mitotic regeneration. Such injuries are unlikely to ever receive veterinary attention. Deeper defects that involve the full thickness of the epithelium and varying depths of stroma initiate a stereotypic series of events that are clinically significant, easily observed in clinical practice, and amenable to both medical and surgical intervention. Because the cornea is optically clear and readily accessible for continuous observation after injury, it is a favorite model for the in vivo study of the basic events of wound healing in mammalian tissue. From a pragmatic clinical perspective, the vast majority of corneal lesions encountered in clinical practice are already past the stage of initial injury and are at the stage of corneal wound healing. If healing is less than optimal, an array of antimicrobial agents, surgical procedures, and chemical agents to modify the wound healing response is commonly used.

Most models of corneal wound healing use a mild, controlled nonseptic epithelial injury. The sequence of events and the biochemical signaling involved in such injury are not necessarily the same as those in naturally occurring massive corneal injuries and subsequent infections seen in veterinary practice, but nonetheless these carefully controlled models provide the only information available.

After full-thickness destruction of a portion of the corneal epithelium, the sequence of events is depicted in Fig. 20-64. Briefly, the injured epithelial cells release cytokines, such as interleukin-1 and platelet-derived growth factor (PDGF). Within minutes of lethal epithelial injury, these chemical mediators cause necrosis and/or apoptosis of stromal cells within the very superficial corneal stroma. At the same time, injured epithelial cells at the margin of the ulcer release epidermal growth factor (EGF), keratocyte growth factor (KGF), and hepatocyte growth factor (HGF) to stimulate epithelial migration and proliferation. Additionally, the production of these growth factors is upregulated in the tear film. The increase in EGF and other growth factors results in flattening and sliding of viable suprabasilar epithelial cells from the adjacent intact epithelium. These cells dissolve their intercellular junctions and migrate across the exposed stromal surface, adhering to a temporary scaffold of fibronectin and other adhesion molecules (Fig. 20-65). As long as the underlying stroma is healthy enough to support epithelial migration, excessive numbers of neutrophils are not present, and if the event that caused the original corneal injury is no longer active, those epithelial cells slide with remarkable speed (as much as 1 mm per day) across the denuded surface in an attempt to close the defect. There are many other cytokines and adhesion molecules involved in corneal epithelial sliding and regeneration, suggesting that rapid sealing of the defect must be exceedingly important. Closure of the defect by even a thin layer of epithelium halts the continued recruitment of neutrophils, which are responsible for the keratomalacia, vision-impairing stromal fibroplasia, and vascularization from the limbus. Closure of the corneal defect also prevents further edema and limits access by potentially injurious infectious agents.

Lagging behind the epithelial activation and sliding, which occur within minutes to hours of injury, is rebuilding of the injured stroma, which starts within a few days. It is not clear how the cornea recognizes the need for stromal rebuilding. There are some cases in which even a deep stromal defect does not initiate ingrowth of fibroblasts and blood vessels to rebuild the stroma. Instead, the epithelium simply slides across whatever small amount of normal stroma remains. This results in an optically clear but precariously thin healed cornea (Fig. 20-66). Migration of neutrophils from the tear film and from the limbus into the corneal wound is a powerful stimulus for the recruitment of both blood vessels and fibroblasts from the limbus. Neutrophil immigration begins about 12 hours after mild injury in response to chemotactic factors released by injured epithelium and stroma. This delay in neutrophil recruitment presumably allows the epithelium to slide and seal small defects and thus prevents excessive immigration of neutrophils (and its negative consequences as outlined later). Additional stimulation of stromal fibroplasia and angiogenesis comes from release of growth factors, such as PDGF, vascular endothelial growth factor (VEGF), and transforming growth factor-β (TGF-β) from the injured epithelium, migrating neutrophils, and the injured stromal keratocytes. Not only does injury stimulate activation and migration of fibroblasts and angioblasts from the limbus, but it also changes the morphology and activity of the resident stromal fibroblasts (keratocytes). These cells undergo myofibroblastic metaplasia, become mobile and contractile, and produce increased amounts of various matrix proteins, growth factors, and metalloproteinases essential for stromal remodeling.

The histologic events of stromal rebuilding after significant injury are less complicated than the innumerable biochemical signaling interactions involved. Mild stromal injuries are repaired by in situ enlargement and sluggish proliferation of resident keratocytes, which undergo fibroblastic metaplasia. After significant stromal injury, however, repair using just local keratocytes/monocytes is not adequate. Such repair must await the arrival of reinforcements in the form of fibroblasts and blood vessels from the limbus. Histologically, enlargement and hyperchromasia of limbal fibroblasts and angioblasts is visible within a day or two of injury, but detectable migration is not evident until about 4 days. Fibroblasts and blood vessels, preceded by a halo of edema and stromal proteolysis, migrate with a maximum speed of 1 mm per day until they reach the site of injury (Fig. 20-67). Here, they rebuild the injured stroma to provide a scaffold suitable for the migration, adhesion, and eventual normalization of the epithelium. Over time, this fibroblastic-angioblastic matrix of granulation tissue matures to histologically resemble normal stroma. However, it is never able to replicate the very specific lamellar structure of normal stroma and even with optimal stromal wound healing, corneal clarity is permanently impaired.

It is worth mentioning here that a lamellar ingrowth of blood vessels from the limbus into the middle third of a perfectly normal corneal stroma occurs as a bystander effect of chronic uveitis (see the discussion on uveitis in the section on Delayed Responses to Injury).

To summarize, the epithelial and stromal events of wound healing are stimulated by a complex interaction of dozens of growth factors, adhesion molecules, and other chemical signals. It is far from understood exactly how these interact. It is clear that the cellular responses are greatly influenced not only by what chemicals are present but also by the context into which they are introduced. The action triggered by any of these mediators is influenced by other mediators in the environment, when the mediators are generated in relation to the wound healing process, and by what cells are targeted (Fig. 20-68).

Uveal Inflammation: The nomenclature of uveal inflammation is the same as that used in clinical ophthalmology (Box 20-12). Hypopyon is the accumulation of neutrophils and fibrin that settles ventrally within the anterior chamber (Fig. 20-69). Inflammation within the iris and ciliary body is usually referred to as anterior uveitis, although iridocyclitis is equally accurate. Inflammation limited to the choroid is choroiditis; inflammation limited to the vitreous is hyalitis; inflammation throughout the uveal tract is panuveitis; and inflammation involving the uveal tract and the adjacent ocular cavities (anterior chamber, posterior chamber, and vitreous) is endophthalmitis. Inflammation that spreads to involve sclera is known as panophthalmitis. Although these terms are widely used in clinical ophthalmology, in reality, the vascular tunic within the globe is a unified structure and virtually all examples of clinically significant uveal inflammation involve all portions of the uvea at least to some degree and have at least a little bit of effusion into the ocular chambers. Furthermore, the globe is a sealed sphere filled with fluid, so that inflammatory mediators or toxic products of infectious agents are likely to be widely disseminated within the globe. Thus from a purely histologic perspective, virtually all cases of uveitis can be correctly classified as endophthalmitis.

A further source of confusion between histopathologic and clinical terminology is a consequence of identification of the predominant leukocyte in the exudate. As is true of lesions in many other tissues, histopathologic examination underestimates the number of rapidly migrating granulocytes and is misled by the gradual accumulation of nonemigrating mononuclear leukocytes. Neutrophils rapidly accumulate within the aqueous or vitreous humors where they can be detected by clinical or cytologic examination. Unless bound up in fibrin, those leukocytes are washed away during histologic processing, leaving only the predominantly mononuclear population within the uveal stroma. This is not unique to the globe: An identical opportunity for confusion exists in correlating cytologic and histologic lesions in immune-mediated joint disease, chronic rhinitis, and pyometra (among others).

Causes of Uveitis: Uveitis can be initiated by a wide array of infections, immune responses, and trauma. Tissues of the globe usually act as an integrated unit, so injury to one part almost always has at least some influence on the health of other parts of the globe. The globe is filled with fluid, thereby allowing chemical messengers generated in one part of the globe to be absorbed by distant intraocular tissue. The iris stroma, in particular, is highly reactive because there is free communication between it and the aqueous humor. Any toxins, chemical mediators of inflammation, or growth factors secreted into the aqueous are absorbed by the iris, causing that portion of the uveal tract to react. (See later discussion on preiridal fibrovascular membrane in the section on Delayed Responses to Injury).

Most of the infectious causes of uveitis are ocular responses to systemic viral, bacterial, or parasitic diseases in which the uveal tract is only one of many tissues affected. Endophthalmitis as the sole manifestation of infectious disease is usually seen only 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. Aberrant migration of nematode or trematode larvae occasionally causes endophthalmitis, as does ocular colonization by a variety of protozoal parasites that cause systemic disease (toxoplasmosis and encephalitozoon in particular). Uveal involvement in systemic mycoses and protothecosis is particularly common in animals in certain geographic regions.

Immune-mediated uveitis is a particularly frequent finding. In only a few types is there a reasonable understanding of the pathogenesis, as in uveodermatologic syndrome and phacoclastic uveitis (see later discussion). In the great majority, there is a chronic lymphocytic-plasmacytic endophthalmitis with no demonstrable infectious agent and a moderately successful clinical response to immunosuppressive therapy (see the later discussion on idiopathic lymphonodular uveitis in the section on Diseases of the Uvea). The lesion is clearly the result of an immunologic response, but it is not known whether such a lesion reflects primary immune-mediated disease or simply a response to an elusive infectious agent that has long since disappeared.

Ocular trauma is a frequent cause of transient endophthalmitis. The uvea also responds to afferent neural signals and chemical factors released from an injured cornea, so that with any significant corneal ulceration or keratitis, one can expect to have at least a mild anterior uveitis.

1. Fragmentation and liquefaction of cortical fibers, creating spherical globules of denatured lens protein known as Morgagnian globules.

2. Hydropic swelling of cells, known as bladder cells, attempting but failing to regenerate.

3. Hyperplasia and fibrous metaplasia of lens epithelium; the epithelial hyperplasia may create plaque-like thickening with or without fibroblastic metaplasia.

4. Posterior lens epithelial migration; the lens epithelium migrates from the equator to lie under the posterior lens capsule; the normal adult lens has no epithelium posterior to the equator.

5. More variable changes include lens swelling in acute cataracts, lens shrinking with wrinkling of the lens capsule in advanced (“hypermature”) cataracts, and intralenticular mineralization.

1. Inflammation as a result of extension from endophthalmitis or encephalitis. Inflammation targeting the retina specifically is exceedingly uncommon. The character of the inflammation within the retina is exactly the same as it is within the brain: neuronal necrosis, perivascular cuffing, and gliosis. What is different about the retina, however, is its susceptibility to exudative retinal detachment. Fluid and cells escaping from inflamed retinal vessels are most likely to accumulate in the subretinal space and result in the separation of the photoreceptors from the RPE and the choroidal vasculature (Fig. 20-77). The photoreceptors are therefore likely to become necrotic, not only from the by-products of inflammation but also from ischemia and other forms of malnutrition resulting from their anatomic dislocation from the RPE (remember that the photoreceptors are entirely dependent on their intimate contact with the RPE and their proximity to the choroid for their nutrition). Serious photoreceptor damage occurs within days.

2. Noninflammatory photoreceptor degeneration from inherited metabolic disease, retinal detachment, or toxicity. Histologically, almost all of these photoreceptor diseases are indistinguishable from one another. The changes are the same regardless of whether the damage is from inborn metabolic errors (especially the innumerable inherited photoreceptor dysplasias of purebred dogs), excessive exposure to light or other radiation, or toxic chemicals.

3. Destruction of the neural elements of the inner retina (nerve fiber layer, ganglion cells, and inner nuclear layer) as a result of glaucoma. The pathogenesis of the inner retinal destruction and destruction of the optic nerve remain a source of great controversy and probably varies among species and with the type of glaucoma. Some of the damage is probably from pressure-induced collapse of retinal and even choroidal blood vessels, and some is probably the result of pressure-induced interference with the axoplasmic flow of nutrients within the optic nerve and nerve fiber layer (see the section on Glaucoma).

Retinal Detachment: The neurosensory retina (not including the RPE) is physically anchored only at the ora ciliaris and at the optic disc. It is held in apposition to the RPE partly by the physical presence of the gel-like vitreous and partially by the membrane forces related to the intricate interdigitations between photoreceptors and surface crevices in the RPE. 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 (sometimes referred to as retinal separation by those who correctly point out that the retina is never really attached at all) is a frequent and serious complication of many different ocular diseases. It may be focal or more diffuse. The distance of separation between the photoreceptors and the RPE may only be slight (so-called flat detachments) or the entire retina may be separated and suspended in the vitreous (Fig. 20-78), supported only by its durable attachments to the ciliary body and optic nerve (so-called morning glory detachment because of its resemblance to a tubular flower when viewed by clinical examination through the pupil).

The most frequent types of retinal detachment are as follows:

Retinal detachment is immediately significant because the image on the retina is out of focus, but more serious is the rapidity with which the photoreceptors are damaged. The outer segments of the photoreceptors, responsible for light absorption and electrical signal generation, are lost within 2 weeks after experimental saline-induced flat detachment (Fig. 20-80). Histologic and clinical evidence in natural disease suggests that this degeneration occurs much more rapidly (a few days at most) in the presence of toxic by-products of inflammation, or when the distance between the retina and the RPE is great. The inner segments of the photoreceptors and the cell bodies within the outer nuclear layer are much more resistant to injury and may remain viable for months (Fig. 20-81).

The retinal consequences of detachment probably vary by species, depending on how much intrinsic retinal vasculature is present. There is virtually no published information, but the almost avascular retina of horses should be much more susceptible to full-thickness ischemic injury than the well-vascularized retinas of dogs or cats (in which the inner half of the retina remains unaffected by detachment).

The detached retina in every species produces a variety of angiogenic growth factors presumably intended to increase its own blood supply. In species other than primates, however, there is little evidence of stimulation of retinal angiogenesis. Instead, these growth factors percolate through the vitreous and are absorbed into the iris stroma where they stimulate the production of a preiridal fibrovascular membrane. The result is a substantial risk of secondary glaucoma from either pupillary block or occlusion of the filtration angle (see the section on Glaucoma).

Eyelids: The responses of the eyelids to injury, the spectrum of potentially injurious agents, and the susceptibility to neoplasia are exactly the same as for skin and are not discussed further.

Although the responses of the eyelid itself to injury may be identical to those of skin elsewhere, there may be unique consequences for other parts of the globe, particularly the nearby conjunctiva and cornea. There may be direct spread of inflammation or neoplasia from the eyelid to the nearby conjunctiva or even to the cornea. Physical distortion of the eyelid from inflammation, scarring, or neoplasia may interfere with the ability of the eyelid to distribute the tear film, or to properly protect the cornea from injury. The abnormal eyelid may even cause mechanical injury by scraping the cornea that it was designed to protect.

There are only a few inflammatory diseases and neoplasms with a predilection for the eyelids, and these are discussed later under specific diseases. It is appropriate to be skeptical when attempting to prove an infectious cause for blepharitis in any species. There is a tendency to assume that whatever infectious agents are isolated from swabs of the eyelid margin or from expressed Meibomian secretion must be the cause of the blepharitis. This is flawed logic because ordinarily those same organisms are readily isolated from the conjunctival sac, or the eyelid margin, of perfectly healthy animals.

Conjunctiva: The reaction of conjunctiva to injury is the same as that of any other mucous membrane. It has a narrow spectrum of responses to injury and only seldom can an etiologic diagnosis be made by histologic examination of a conjunctival biopsy. The epithelium responds to acute injury with ulceration. With chronic mild injury, there is squamous metaplasia. In animals with pigmented conjunctivae, chronic irritation also stimulates hyperpigmentation, just as it often does in skin. If there is desiccation, the areas of squamous metaplasia are often keratinized.

The underlying lamina propria usually responds with a stereotypic lymphocytic-plasmacytic accumulation, with the development of hyperplastic lymphoid nodules if the stimulation is persistent. Neutrophils are seldom numerous within the tissue; if present at all, they are usually found migrating through the epithelium en route to the conjunctival sac where they will do battle with the infectious agents that might be present as opportunistic pathogens. Eosinophils are occasionally present in poorly defined allergic conjunctivitis in dogs, cats, and horses. They are present in greater numbers in the more discrete collagenolytic granulomas in horses with habronemiasis.

Looking for specific infectious agents in sections of conjunctiva is usually a waste of time. It is true that some of the viral diseases and chlamydial infections can leave specific footprints in the form of inclusion bodies, but these are usually present only very early in the course of these diseases, at a time before the lesion is assessed by conjunctival scraping or biopsy examination.

Orbit: There is nothing specific about the reaction of orbital tissues to injury. Each constituent (bone, fat, and muscle) reacts to injury in an identical fashion to that in the same type of tissue elsewhere. As has been a recurring theme in discussions of diseases in other parts of the globe and ocular adnexa, an event at one site almost always causes significant consequences for other parts of the globe, such as the following:

Glaucoma: Glaucoma is not a single disease but a group of diseases sharing specific physiologic and structural characteristics. It is a clinical syndrome characterized by a sustained increase in intraocular fluid 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 important. The syndrome is most prevalent in dogs, followed by cats and horses. It is rarely documented in other species but undoubtedly exists in all. Glaucoma is extremely prevalent as a cause for ocular pain and blindness in dogs, and it is by far 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 that species. Its frequency in horses may be greatly underestimated because of its variable clinical presentation in that species and because ocular pressure is not routinely measured in horses.

Theoretically, glaucoma may result from an increase in the production of aqueous humor or a decrease in its removal. In practical terms, however, all examples of glaucoma in domestic animals result from impairment of aqueous outflow. Glaucoma is usually divided into primary and secondary glaucoma. Primary glaucoma refers to those examples occurring without any known acquired intraocular disease to explain the increase in pressure. The great majority of these result from developmental errors in the structure and function of the aqueous drainage pathways. Secondary glaucoma refers to those examples in which there are changes, such as lens luxation, pupillary block, or intraocular neoplasia, to explain the impairment of aqueous humor outflow.

The aqueous humor that fills the anterior and posterior chambers is a low-protein transparent fluid just slightly denser than water. It is formed continuously by a combination of plasma filtration and active secretion by ciliary epithelium. Its chemical composition varies somewhat among species, but it always has a very low total protein concentration (about 5% of total plasma protein) but an amino acid concentration 50% higher than that of plasma. It contains glucose and electrolytes in concentrations roughly equivalent to those in plasma. The aqueous humor produced within the ciliary body circulates past the lens to provide nutrients to it and remove waste products, enters the anterior chamber through the pupil, circulates within the anterior chamber to nourish corneal endothelium and stroma, and then exits through slitlike spaces 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 blockage of the aqueous 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 rate of production varies from 2.5 µl per minute in dogs to 15 µl per minute in cats. The outflow pathway is through the iridocorneal angle and more specifically through a series of perforations in the connective tissue of the peripheral cornea, sclera, and iris stroma that makes up the trabecular meshwork. The microscopic anatomy of this outflow pathway varies by species, but all examples are quite similar in general design.

The trabecular meshwork is a series of mesenchymal sieves that occupies the iridocorneal angle and extends circumferentially around the globe. Embryologically, the trabecular meshwork is formed by rarefaction of the same mesenchyme that forms iris stroma. In carnivores this remodeling continues for several weeks after birth (Fig. 20-87). This area of perforated mesenchyme is referred to as the ciliary cleft. It is bordered externally by sclera, posteriorly by the muscles of the ciliary body, and internally by the iris stroma. Its anterior border, separating it from the anterior chamber, is formed by the pectinate ligament. With proper instrumentation (gonioscopy), the pectinate ligament is visible through the cornea as a series of cobweb-like branching cords (carnivores) or a fenestrated sheet (ungulates), stretching from the termination of Descemet’s membrane to the anterior portion of the iris root (Fig. 20-88).

Ultrastructurally, the trabecular meshwork is a series of connective tissue beams covered (completely or incompletely, depending on the species) by a single layer of trabecular endothelial cells connected to each other by delicate cytoplasmic tendrils. The cells are phagocytic and are probably important in regulating the outflow of aqueous humor. Most of that flow is probably by transcellular movement of pinocytotic vesicles across the cytoplasm of the trabecular endothelium.

In most species, the most functionally significant portion of the trabecular meshwork exists in the deep peripheral corneal stroma and inner sclera, and is known as the corneoscleral meshwork. Aqueous humor passing through this portion of the meshwork 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. A small percentage of the aqueous humor entering the filtration angle will exit via a more posterior route known as the uveoscleral meshwork, percolating into the veins of the ciliary body and choroid rather than into the scleral venous plexus (see Fig. 20-88). 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. Differences in the proportion of fluid leaving the globe by different routes might explain differing susceptibilities to different types of glaucoma among the domestic animals, and it also creates at least the potential for different types of therapeutic interventions.

These outflow pathways 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 endothelial cells lining the collagen beams within the trabecular meshwork, the glycosaminoglycans embedded in the matrix supporting those endothelial cells, and blood pressure within the scleral venous plexus.

The clinical (macroscopic) lesions of glaucoma are related to the secondary effects of increased pressure on various components of the globe. Although the increase in pressure is the result of obstruction of outflow in the anterior chamber, the pressure elevation is distributed throughout the fluid medium of the globe, and the effects are thus felt by all parts of the globe. These effects are the same, regardless of the pathogenesis of the glaucoma, and they vary with the rapidity of onset, the magnitude of the 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, corneal cloudiness because of edema, pupillary dilation, and excavation of the optic disc. The most frequent microscopic changes in glaucoma are listed in Box 20-13.

Corneal Anomalies:

Acquired Corneal Diseases:

Corneal Dystrophies and Depositions: Macroscopic examination of the cornea often reveals various types of colored or refractile stromal deposits. Some of these have already been discussed (superficial stromal pigmentation as part of cutaneous metaplasia or accumulation of leukocytes as part of stromal inflammation). Most other corneal deposits are composed of lipid and/or mineral. Among the domestic animals, they are most often seen in dogs. These deposits generally have characteristic clinical features (breed, age, exact anatomic location, and macroscopic appearance) that allow a diagnosis to be made without the need for histopathologic examination. They fall into two broad categories: inborn errors of metabolism known as corneal dystrophies and acquired corneal deposits, resulting from previous corneal disease or as incidental manifestations of systemic metabolic abnormalities that have “overflowed” into the cornea.

Genetically conditioned canine corneal stromal dystrophies include a seemingly endless array of lipid or mineral deposits somewhere within the corneal stroma. By definition, the defect is bilateral and congenital, even though the clinical or histologic manifestation of the abnormality may not be visible until later in life. The list of affected breeds grows daily. In each breed, the location, clinical character, and progression of the lesion are characteristic. In many, the exact nature of the deposit has not been characterized, but cholesterol, phospholipid, or lipid-calcium complexes, either alone or in combination, have been identified in some.

Corneal endothelial dystrophy is seen in several breeds of dogs as bilateral, diffuse corneal edema secondary to the progressive destruction of corneal endothelial cells. The edema is not accompanied by any evidence of inflammation or stromal fibrosis (Fig. 20-102) and usually begins at the lateral peripheral cornea and progresses over months-to-years to create diffuse edema. The microscopic lesion is extremely difficult to see because the corneal endothelial cells are generally not well preserved in histologic sections. Scanning electron microscopy and other specialized techniques demonstrate a progressive decrease in the number of corneal endothelial cells over time. The exact pathogenesis remains unknown.

Acquired corneal lipidosis (lipid keratopathy) results in milky or crystallin stromal deposits of serum lipids within the corneal stroma. The location depends on the pathogenesis. Any animal with an excessively high serum lipid concentration is predisposed to the deposition of neutral fat and cholesterol within the peripheral corneal stroma, reflecting an overflow from the limbal blood vessels. The lipid deposits become greatly accentuated if there is corneal inflammation because vascularization is increased and immature blood vessels are notoriously leaky.

The microscopic changes associated with corneal lipid deposition include the presence of the lipid material and variable degrees of reaction to those deposits. Stromal keratocytes may accumulate small lipid vacuoles, and clefts of cholesterol are usually found among the stromal fibers. In some cases there is virtually no inflammatory reaction, whereas in other dogs there is a well-developed granulomatous inflammatory reaction.

Uveal Anomalies: The epithelium on the posterior surface of the iris, the inner surface of the ciliary body, and the retinal pigment epithelium on the inner surface of the choroid are all derived from portions of the original optic vesicle. The bulk of the uvea is fibrovascular stroma derived from the periocular mesenchyme that originates from the neural crest (see Fig. 20-83). After outgrowth and later invagination of the primary optic vesicle to form the optic cup, the intraocular migration of this mesenchyme and its subsequent remodeling seem to be guided by soluble factors released from the neuroectoderm; failures of proper induction, remodeling, and eventual atrophy of portions of this mesenchyme are among the most prevalent of ocular anomalies.

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 20-3). 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. 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 (Fig. 20-103). 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 overlying sclera.

Acquired Uveal Diseases: There are in excess of 50 different etiologic types of uveitis in dogs alone, but in most of these the uveitis is only an incidental part of a systemic disease. The macroscopic or microscopic lesions within the globe are usually not distinctive, and diagnosis of the disease is rarely made on the basis of ocular lesions. Even when uveitis is the only clinical sign of disease, rarely is an etiologic diagnosis made. Many of the specific examples of uveitis listed in clinical textbooks are syndromes made distinctive by clinical features or by identification of a causal agent, rather than by distinctive histologic lesions. Listed next and in Table 20-4 are the most common and most important examples of uveitis that do have distinctive histologic features.

Idiopathic Lymphonodular Uveitis: Although not really a specific disease, idiopathic lymphonodular uveitis is by far the most common histologic pattern seen in uveitis. This may reflect in part a genuinely high frequency of immune-mediated uveitis. More likely, however, it is simply an indication of the chronicity of the uveitis because microscopic evaluation of globes with uveitis is usually done only in the chronic stages of disease, after all attempts at therapy have failed. Lymphonodular uveitis may therefore imply nothing more than a stereotypic endstage of uveitis that initially had a more distinctive and more variable histologic appearance. Lymphonodular uveitis was made famous by recurrent uveitis in horses. It is the only example of lymphonodular uveitis for which we have some insight into the actual cause, and for that reason it serves as the archetype for this group.

Equine Recurrent Uveitis: See the section on Disorders of Horses.

Feline Idiopathic Lymphonodular Uveitis: See the section on Disorders of Cats.

Canine Lymphocytic Uveitis: See the section on Disorders of Dogs.

Uveodermatologic Syndrome in Dogs (Vogt-Koyanagi-Harada Syndrome): See the section on Disorders of Dogs.

Systemic Mycoses: 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 saprophytic 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, except for the inexplicable predilection of cryptococcosis for cats. Ocular involvement is part of systemic disease, but fairly frequently, ocular disease is the only obvious clinical sign. Blastomycosis is by far the most prevalent example of an endophthalmitis caused by systemic mycosis, and it serves here as the prototype for this group.

Blastomycosis is the most frequently reported intraocular mycosis in dogs, but it is rare in cats. It is estimated that about 25% of dogs with the systemic disease have clinically obvious 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 disease is pyogranulomatous and very destructive. 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 yeast 4 to 20 µm in diameter, with occasional broad-based budding. The diagnosis can often be made by cytologic evaluation of subretinal exudates in eyes that are already blind because of retinal detachment (one would probably not dare to attempt aspiration of the subretinal space in a globe that still had vision). Other lesions in affected globes are those seen in any severe uveitis: intraocular hemorrhage, posterior synechia, preiridal fibrovascular membrane, or cataract. Spread into the optic nerve and even orbit is an infrequent complication.

Cryptococcosis is similar to blastomycosis in that the lesions are predominantly within the retina, choroid, and optic nerve. As mentioned earlier, ocular cryptococcosis is immeasurably more prevalent in cats than in dogs or 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 numerous and vary greatly in size and shape. 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 is more suppurative, more destructive, and more prone to progress to outright panophthalmitis. Involvement of the anterior uvea is perhaps more common than in the other systemic mycoses. The disease is seen only in animals that live in (or have visited) the very restricted geographic regions in which the organism is common. The great majority of cases are seen in dogs from the desert regions of the American Southwest (Fig. 20-112).

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 and lymphocytic choroiditis with little suppuration and without much of the destruction that characterizes blastomycosis and coccidioidomycosis. Organisms are usually very numerous and visible as small spherical bodies within the cytoplasm of macrophages.

Protothecosis is included here because the organisms can easily be mistaken for yeast and because the clinical and histologic features closely resemble those of the systemic mycoses described earlier. Prototheca are colorless saprophytic algae capable of causing enteric, cutaneous, or generalized granulomatous disease in a variety of mammalian species. Ocular lesions have been described only in dogs with the disseminated form of the disease. The lesions are essentially identical to those seen with blastomycosis and are distinguishable only by the detection of the pleomorphic algae (which usually are very numerous). In histologic section, the algae are free or within macrophages. The organisms are spherical to oval, from 2 to 20 µm in diameter, and have a refractile cell wall that stains with periodic acid–Schiff (PAS) reaction or Gomori’s methenamine silver stain. Prototheca reproduces by asexual multiple fission, so that multiple daughter cells form enclosed within a single cell wall. There is no budding as with blastomyces and cryptococcus.

Feline Infectious Peritonitis–Associated Uveitis: See the section on Disorders of Cats.

Bovine Malignant Catarrhal Fever–Associated Uveitis: See the section on Disorders of Ruminants.

Lens-Induced Uveitis: Phacolytic uveitis is an extremely common, mild lymphocytic-plasmacytic anterior uveitis that occurs in a large proportion of animals with cataracts in which the lens protein is beginning to disintegrate and leak through the intact lens capsule. Although seldom significant as the cause of clinical signs, it significantly reduces the success of cataract surgery, unless the surgery is preceded by a course of antiinflammatory drugs.

Phacoclastic uveitis is predominantly an immune-mediated disease in response to the release of large amounts of intact lens protein through a traumatically ruptured lens capsule. The severity and character of the reaction seem to be influenced by the amount of lens material lost, the speed of the loss, the age of the animal, and the species. The disease is most commonly seen in dogs because of their habit of running into sharp objects or having unpleasant encounters with the neighborhood cat. Lens rupture may also occur after blunt trauma, in which case the rupture is usually of the thin posterior capsule. Phacoclastic uveitis also occurs after spontaneous lens rupture not associated with trauma. This occurs in rabbits as a result of penetration of the lens by Encephalitozoon cuniculi and in dogs with rapidly progressing diabetic cataracts.

The clinical syndrome is quite distinctive: the initial clinical signs are related to corneal perforation and uveitis as direct consequences of the penetrating injury and/or subsequent sepsis. Those are often managed successfully with antiinflammatory and antibiotic therapy, and everything seems to be healing very well until the development of a severe and therapeutically refractory anterior uveitis that most commonly occurs about 2 weeks after the initial injury. Once the phacoclastic uveitis is initiated, the prognosis for saving the globe becomes poor.

There are two different types of lesions of phacoclastic uveitis, and these usually occur concurrently. The typical lesions in acute disease include rupture of the lens capsule, accumulation of intralenticular neutrophils, and a perilenticular inflammatory reaction that is initially neutrophilic. With time, it becomes progressively more granulomatous but remains distinctly perilenticular (Fig. 20-113). After a few days, the inflammatory reaction is accompanied by proliferation, fibroblastic metaplasia, and perilenticular migration of lens epithelial cells that have escaped through the site of perforation (Fig. 20-114). Because the perforating injuries causing phacoclastic uveitis may also implant bacteria or foreign material into the globe, it is not always possible to determine what part of the posttraumatic lesion is phacoclastic uveitis and what part is in response to a foreign body or infection. True phacoclastic uveitis is distinctly perilenticular, with minimal reaction in more distant portions of the uvea such as the choroid.

The pathogenesis of the inflammatory component of phacoclastic uveitis is probably an immunologic response to the release of large amounts of strongly antigenic lens protein into the aqueous humor. Although lens protein is not truly “foreign,” the body has tolerance for only small amounts of lens protein. The sudden release of large amounts following capsular rupture overwhelms this immune tolerance, resulting in a suppurative-to-pyogranulomatous reaction centered on the lens. This immune pathogenesis explains the lag between lens rupture and development of the phacoclastic uveitis. It also explains why small perforations might not cause the disease and why removal of the injured lens shortly after perforating injury prevents the development of the disease.

The fibrous metaplasia and migration of lens epithelium are critical prognostic events. This epithelium, once out of the lens, recognizes no barriers to its proliferation and causes pupillary block, occlusion of the filtration angle, and secondary glaucoma. In cats, probably it is this same epithelium that undergoes malignant transformation to the clinically significant and uniquely feline entity of posttraumatic primary ocular sarcoma (see discussion on neoplasia).

Phacoclastic uveitis can be a serious complication of cataract surgery in which too much lens material is left behind within the lens capsular bag. In most instances, complications arise primarily from the migration and fibroblastic metaplasia of this residual lens epithelium. This can result in opacification of the pupil (and of any artificial lens implant) and possibly pupillary block, causing secondary glaucoma.

Neoplasms of the Uvea: Primary uveal neoplasms are common only in dogs and cats, but they are exceedingly important in both species and vie with glaucoma as the most common reason for enucleation (Table 20-5). Primary tumors (melanocytic tumors and iridociliary epithelial tumors) are considerably more prevalent than metastatic tumors in the globe, with the possible exception of metastatic uveal lymphoma in cats.

In all species, melanocytic tumors are by far the most common of all ocular tumors. Those tumors predicted to be behaviorally benign are referred to as melanocytomas; those predicted to be malignant are classified as melanomas. As with melanocytomas and melanomas elsewhere, there is substantial variation in biologic behavior, depending on species and location. These site and species variables are more important in establishing the prognosis than are many of the histologic and cytologic features.

Canine anterior uveal melanocytoma is by far the most common primary intraocular tumor of dogs, arising from the melanocytes within the stroma of the iris or ciliary body. They ordinarily form a solid, deeply pigmented mass that protrudes into the anterior or posterior chamber. Growth is expansive rather than invasive (Fig. 20-115). The typical tumor has an inconspicuous germinal population of cytologically bland and poorly pigmented spindle cells, and a much larger proportion of huge ballooned “plump cells” distended with pigment (Fig. 20-116), which are assumed to be postmitotic endstage neoplastic melanocytes. These tumors have very little metastatic potential, and the few that are likely to metastasize can be identified by a notable increase in the numbers of mitotic figures. Sooner or later, all of these tumors grow large enough to cause obstruction of aqueous outflow and secondary glaucoma.

Histologically identical melanocytoma occasionally arises within the choroid as a slowly expanding subretinal mass. They are significant because they cause retinal detachment.

Feline diffuse iris melanoma has a distinctive clinical presentation: unilateral coalescing hyperpigmentation of the iris that slowly (often over many years) progresses to diffuse iris thickening and secondary glaucoma (Fig. 20-117). This is a uniquely feline disease. The tumor originates from the layer of melanocytes that forms the anterior border layer of the normal iris. The transformed cells have enlarged nuclei and hyperchromasia and proliferate slowly to replace the normal iris architecture. The fully developed tumor, as the name implies, results in a diffuse iridal infiltration by pleomorphic round-to-epithelioid melanocytes. Their appearance in cytologic preparations is extremely variable. Tumors vary from amelanotic to heavily pigmented, and from round cell to epithelioid to spindle cell (and mixtures of all of the above). Mononuclear gigantism is frequently seen (Fig. 20-118). None of these variables has any prognostic significance.

The prognosis has been the subject of great debate over the past 10 years. Retrospective studies that have attempted to establish histologic predictors of behavior have been thwarted by poor overall follow-up data (cats lost to follow-up, very few necropsies). Nonetheless, emerging from these studies is the general consensus that although these tumors are substantially more likely to eventually metastasize than are canine uveal melanomas, the overall risk of an affected cat developing clinical signs related to metastatic disease seems to be low. The probability that the affected eye will eventually develop glaucoma secondary to tumor infiltration of the trabecular meshwork is exceedingly high, although it may take years.

Rarely, cats develop canine-like nodular uveal melanocytomas (and dogs occasionally develop feline-like diffuse melanomas).

Iridociliary tumors vary from well-differentiated papillary adenomas to solid carcinomas. They all arise from the neuroectoderm of the posterior iris or ciliary body. The histologic distinctions have no apparent relevance to biologic behavior, because all of these tumors are benign. These are relatively common intraocular tumors in dogs (second in frequency only to melanocytoma), occasionally seen in cats, and infrequently seen in other species. They usually grow as discrete, expansile nodules that protrude into the posterior chamber and are thus visible through the pupil. They are populated by cuboidal and columnar epithelial cells resembling normal iridociliary epithelium and usually form cords and papillary structures reminiscent of disorganized ciliary processes (Fig. 20-119). Some have a more primitive cytologic and histologic appearance, but extraocular metastasis is so rare as to be nonexistent. Even small tumors may become clinically significant because they habitually produce fibroblastic and angiogenic growth factors that stimulate the development of preiridal fibrovascular membranes, causing secondary glaucoma or intractable hyphema.

Medulloepithelioma is a relatively rare congenital counterpart of iridociliary adenoma. It has the distinction of being the most common primary intraocular tumor of horses. The histologic appearance reflects its embryonic origin from primitive neuroectoderm still capable of both iridociliary and retinal differentiation. The tumor is populated by hyperchromatic cuboidal cells that make structures reminiscent of ciliary processes and sometimes tubular structures resembling the rosettes seen in retinal dysplasia. In horses, they often incorporate foci of cartilage, bone, and even brain tissue; these 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.

Feline primary ocular sarcoma (posttraumatic sarcoma) is a high-grade spindle cell neoplasm that probably arises from lens epithelial cells that have escaped through ruptures in the lens capsule. These cells routinely undergo fibroblastic metaplasia as part of ineffective wound healing (see discussion on phacoclastic uveitis), but the metaplasia progresses to outright sarcoma only in cats. The tumor begins as a distinctly perilenticular mass and then grows to fill the globe (Fig. 20-120). As with histologically similar postvaccinal sarcomas, these tumors may have fibroblastic, osteoblastic, or cartilaginous areas in the same tumor (Fig. 20-121). The interval between trauma and detection of tumor can be many years, but the key word here is “detection.” It is very common for cats with this tumor to be presented for veterinary attention only after the tumor has filled the globe. We do not know the rapidity of microscopic tumor development following injury. These tumors frequently invade the optic nerve and then extend into the brain. They are also capable of distant metastasis.

Neoplasms metastatic into the globe are much less frequent than tumors originating within the globe. Virtually any metastatic neoplasm can localize within the uveal tract and spread from there into other portions of the globe. Their histologic appearance is the same as that of the primary tumor. By far the most prevalent is lymphoma (lymphosarcoma), seen in many species but particularly prevalent in cats. It causes diffuse thickening and pallor of the iris and less frequently the choroid. It is clinically almost indistinguishable from severe idiopathic uveitis, and the distinction is usually made on the basis of additional clinical evidence.

Anomalies of Lens: 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, which will become corneal epithelium (see Fig. 20-83). 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.

Anomalies of the lens are of minor importance when contrasted with anomalies of other portions of the globe. 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 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), an abnormally shaped lens (lenticonus and lentiglobus), and a congenital lens luxation, which is presumably secondary to some congenital abnormality in the zonules.

Lens Luxation: Dislocation of the lens may be partial (subluxation) or complete (luxation). It may fall forward into 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. Anterior lens luxation (Fig. 20-122) is much more significant because it predisposes to glaucoma (see the section on Glaucoma). Lens luxation may be primary or secondary.

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 (notably terriers). The luxation is almost always bilateral, even if not simultaneous in onset. The ultrastructural and biochemical defect within the lens zonules have not been defined.

Secondary lens luxation is almost always a manifestation of blunt trauma that causes avulsion of the zonules, or excessive stretching of zonules within a globe that has become greatly enlarged secondary to glaucoma. It may also occur as a result of lysis of zonules by neutrophil enzymes or perhaps bacterial proteases in septic endophthalmitis.

The potential consequences of lens luxation are numerous, but the most significant is glaucoma. This is particularly frequent with anterior lens luxation. The pathogenesis may involve several factors including anterior dislocation of the vitreous causing pupillary block and accumulation of degenerate zonular material within the trabecular meshwork. It is sometimes impossible to decide whether the luxation caused the glaucoma, or the glaucoma caused the luxation.

Diabetic Cataract: Rapidly progressing bilateral cataracts develop in at least 70% of spontaneously diabetic dogs (but not in cats). Progression to complete cortical opacity usually occurs within a few weeks. The swelling may be so rapid that the lens actually ruptures. The pathogenesis of the cataract has traditionally been ascribed to the excessively high level of glucose within the aqueous. Glucose is normally the major energy source for lens fibers via anaerobic glycolysis. When the rate-limiting enzyme of this pathway, hexokinase, is overloaded with glucose, most of the excess glucose absorbed by the lens is shunted to the sorbitol pathway where it is transformed into the polyalcohol sorbitol, which is then slowly reduced to a ketose. Sorbitol may accumulate to very high concentrations within the lens where it osmotically attracts water, resulting in rapid swelling of the lens and disruption of its critical architecture. Sorbitol-induced osmotic disruption alone is not sufficient to explain all of the structural and metabolic changes in sugar-induced cataracts. The efficacy of antioxidants in slowing the progression of such cataracts, the nature of intralenticular biochemical alterations, and detection of increased intralenticular oxidants all point to some kind of oxidative damage as an additional promoter of cataracts.

Retinal Anomalies:

Acquired Retinal Disease (Tables 20-6 and 20-7):

Developmental Anomalies: Anomalies in the formation of eyelids, including the shape of the palpebral fissure, are exceedingly common in dogs because “eye shape” has been so extensively manipulated during the evolution of the various breeds. In some instances, the “anomaly” is even a required feature for the breed (e.g., as with ectropion in bloodhounds and Saint Bernards). Most of these anomalies are not examined microscopically because they are macroscopically obvious. They are important in clinical ophthalmology and are considered in much greater detail in clinical textbooks than they are here.

Acquired Diseases: Chalazion is sterile granulomatous inflammation in response to the leakage of Meibomian secretion into the surrounding dermis. It is much more common in dogs than in any other species. Although it can theoretically occur in response to any type of injury to the Meibomian gland, in almost all cases, the inflammation is found adjacent to Meibomian adenomas. Histologically, the inflammation is an accumulation of large foamy macrophages and multinucleated cells around the abnormal Meibomian gland. Some of the lipid may occur in the form of extracellular lakes of unstained free lipid, especially in cats. The macrophages contain distinctive slender, birefringent, intracellular crystals, which are readily visible under polarized light.

Idiopathic granulomatous marginal blepharitis is seen only in dogs as a series of coalescing nodules that eventually create a diffuse thickening of one or both eyelid margins. The histologic lesion is a coalescence of suppurating granulomas in the subconjunctival tissue of the eyelid margin, without any proven association with any particular adnexal structure, such as a Meibomian gland or hair follicle. The lesion is very similar to those of cutaneous sterile pyogranuloma syndrome and other idiopathic granulomatous panniculitides, for all of which the pathogeneses are unknown. No infectious agent has ever been identified.

Neoplasms of the Eyelids: Meibomian adenoma is by far the most common tumor of the canine eyelid, accounting for in excess of 80% of all eyelid tumors in that species. Eyelid tumors in any other species are infrequent to rare. The tumor is an exact counterpart of sebaceous adenomas seen elsewhere in skin: a smooth expansile growth populated by intermingled basal cells and mature sebaceous cells. The tumor usually retains well-developed lobular architecture and in some cases differs from a normal gland only by its much greater overall size (Fig. 20-129). Many are populated almost exclusively by basal cells with just a few foci of sebaceous differentiation. Many contain substantial amounts of melanin pigment. Behaviorally, they are benign and are easily cured by excision.

Melanocytoma is the second most common tumor of the canine eyelid. It is identical in all respects to superficial dermal melanocytomas found elsewhere in the skin, and it is universally benign (Fig. 20-130).

Other neoplasms affecting the eyelid with greater-than-usual frequency include nerve sheath tumors in dogs and cats, squamous cell carcinoma and mast cell tumors in cats, and sarcoids in horses. They are identical in histologic appearance and behavior to those tumors occurring anywhere else in skin.

Developmental Anomalies:

Acquired Conjunctival Diseases:

Neoplasms of the Conjunctiva: Squamous cell carcinoma is an exceedingly prevalent and economically significant neoplasm affecting the sunlight-exposed, nonpigmented epithelium of the eyelids, bulbar conjunctiva, usually at the lateral limbus and third eyelid of cattle living outdoors in sunny environments. The frequency is highest in areas in which livestock are likely to be exposed to ultraviolet radiation: areas with high altitude and lots of sunshine. Animals with poor pigmentation of eyelids and conjunctiva are particularly susceptible because this increases the risk of chronic cellular injury from solar radiation. 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. An identical tumor occurs in horses living in the same environments.

As occurs with sunlight-induced squamous cell carcinoma in other cutaneous locations, the ocular tumor goes through a series of precancerous changes in response to actinic injury. The sequence of lesions is squamous plaque (acanthosis), keratoses (localized foci of hyperkeratosis), squamous papilloma, dysplasia, squamous carcinoma in situ, and eventually invasive squamous cell carcinoma (Fig. 20-132). Keratoses can sometimes develop into cutaneous horns. These are usually conical, can reach a length of a few centimeters, and consist of compacted laminated keratin (Fig. 20-133). Occasionally, they are on the surface of a papilloma. Like actinic keratoses they are considered to be premalignant. The stepwise transition from acanthosis to eventual carcinoma in situ is characterized by increasing nuclear pleomorphism, hyperchromasia, and loss of polarity of the cells and maturational jumbling of cells within the stratum spinosum. The only absolutely unequivocal proof of malignant transformation is invasion by cords of malignant cells through the basement membrane into the underlying lamina propria (Fig. 20-132, C). The mass of invading cells is usually surrounded by an intense lymphocytic-plasmacytic inflammatory reaction, a reaction that is interpreted as an immune response to the developing tumor. Not all precursor lesions develop into carcinomas. The efficacy of the immune response in destroying precursor lesions and early carcinomas is unknown.

In cats, squamous cell carcinoma usually affects the skin of the eyelid itself rather than conjunctiva. Squamous cell carcinoma is inexplicably rare in either the eyelids or the conjunctiva of dogs.

Benign squamous papillomas with no inclination for malignant progression are frequent tumors of the bulbar conjunctiva of dogs. They are formed by multiple slender fronds consisting of conjunctival lamina propria covered by hyperplastic but otherwise orderly and mature stratified squamous nonkeratinized epithelium. There is often substantial melanin pigment within the basal cells and lamina propria, so these tumors can be mistaken on clinical examination for conjunctival melanomas. There is no evidence that these papillomas are caused by a viral infection.

Primary conjunctival melanomas arise within the epithelium of the bulbar conjunctiva of dogs and cats. In dramatic contrast to the benign melanotic tumors of the haired skin of the eyelid or those arising deeper within the stroma of the limbus (see later discussion), these are aggressively invasive with a high risk of metastasis. They resemble oral melanomas in histologic and cytologic appearance and in the frequency of being amelanotic. Microscopically, they form solid endocrine-like packets of 20 to 30 cells supported by a delicate fibrous stroma. Intraepithelial clusters (junctional activity) are often present. The cells generally are pleomorphic epithelioid cells with frequent nuclear gigantism and hyperchromasia. They are markedly invasive, a feature often visible in histologic sections. Postoperative recurrence is extremely frequent. Pigment, when present, is most frequently found in tumor cells within or near the epithelium.

Limbal melanocytomas are relatively common tumors in dogs. They are infrequent but not rare in cats. They arise from the pigmented cells within the limbus, which is the junction of the corneal stroma and sclera. They form a slowly expanding, heavily pigmented discrete nodule populated by heavily pigmented large plump cells identical to those seen in the more common anterior uveal melanocytoma. They have no metastatic potential, and surgical excision is curative. They may bulge outwardly to distend the overlying conjunctiva, but histologic examination reveals that they do not infiltrate the epithelium and are therefore easily distinguished from the more dangerous primary conjunctival malignant melanoma.

Hemangioma and hemangiosarcoma are vascular endothelial neoplasms arising within the conjunctival lamina propria at the lateral edge of the third eyelid, and in the lateral bulbar conjunctiva of dogs, cats, and (occasionally) horses. About 30% of canine cases are bilateral. The sites of predilection and the increased risk of disease in outdoor dogs in sunny climates and high altitudes suggest that this disease is probably triggered by chronic actinic radiation injury (as is true for at least some examples of cutaneous hemangioma and hemangiosarcoma in dogs). Those tumors that are well circumscribed and consist of bland endothelium are classified as hemangiomas, and those formed by hyperchromatic endothelium with at least moderate anisokaryosis and peripheral invasion are classified as hemangiosarcomas. However, there is a continuum in the histologic appearance from hemangioma to hemangiosarcoma. Many are intermediate, or even show a continuum of lesions from benign to malignant within the same tumor. Distinguishing benign from malignant is based primarily on the degree of peripheral invasion. At least in dogs (the species most often affected), this distinction appears to have no behavioral significance, as almost all are benign and surgically curable.

In horses, some (but not all) of the vascular tumors involving the third eyelid are solid primitive hemangiosarcomas. Some of these tumors are very invasive and have a high risk of metastasis to the regional lymph node.

Adenocarcinoma of the gland of the third eyelid is a tumor of very old dogs (rarely cats), which is usually seen as a well-differentiated, slowly expanding tubular adenocarcinoma at the dorsal margin of the third eyelid. It replaces the normal gland of the third eyelid but only slowly invades adjacent tissue. The risk of metastasis is very low.

Lymphoma (lymphosarcoma) occasionally arises within the lamina propria of the third eyelid in animals (most often in cats) that do not have any evidence of disseminated lymphosarcoma. The cells are similar in histologic appearance to those of lymphomas elsewhere, but it takes courage to make this diagnosis when the tumor appears to be present in only a single, unlikely location, such as the third eyelid.

1. Horses with high serum titers to Leptospira interrogans are 13 times more likely to have uveitis than horses with no such titers.

2. Antileptospiral antibodies rise during episodes of uveitis and decrease during quiescent phases.

3. The disease can be reproduced by infection of naive horses with Leptospira interrogans serovar Pomona. Not all infected horses developed uveitis, and the onset of ocular signs is usually delayed for a year or more after infection. In the original study, 22 of 36 of the eyes of Shetland ponies inoculated subcutaneously with small numbers of Leptospira interrogans serovar Pomona eventually developed classic recurrent uveitis. All ponies developed leptospiremia soon after inoculation, but none developed ocular disease until at least 50 weeks later.

4. There is cross-reaction between leptospiral antigens and various intraocular antigens, particularly those of the corneal endothelium and lens. This creates the possibility that the ongoing immune-mediated inflammation is not necessarily in response to persisting leptospiral antigens. Leptospirosis may cause the initial uveitis but may not be responsible for its perpetuation.