Revised from 6th edition of Veterinary Ophthalmology, Chapter 19: Diseases and Surgery of the Canine Cornea and Sclera, by R. David Whitley and Ralph E. Hamor The cornea is a unique portion of the outer fibrous tunic of the eye. It is transparent and serves a major refractive function while maintaining an impermeable physical barrier between the ophthalmic structures and the environment. The transparency of the cornea enables it to perform two main functions: to refract light and to allow sufficient quantity and quality of light into the eye to form an image on the retina. In spite of its exposure to environmental hazards, the cornea can maintain a smooth outer surface necessary for retinal image formation by the continuous replacement of the surface epithelium and a healthy preocular tear film. Since most pathological corneal responses are associated with changes in transparency, many different corneal disorders can lead to opacification and loss of vision. Fortunately, most corneal pathology is obvious to the animal caregiver and usually amenable to medical or surgical therapy. The most important goals of corneal treatment are to preserve or improve the quantity and quality of light entering the eye (even in the presence of corneal opacities, e.g., eyes with scarring or dystrophy) and to promote corneal healing (e.g., eyes with ulceration or neoplasms). To achieve these goals, damage to normal corneal tissues should be avoided and therapies selected to induce as little trauma as possible. Minimizing corneal trauma reduces the likelihood and severity of scarring, and maintains maximal corneal transparency. This chapter provides an overview of the most common corneal and scleral disorders in the canine eye and their clinical management. The fibrous tunics of the canine eye consist of the sclera and the cornea, and the limbus is the transition zone between the cornea anteriorly and the sclera posteriorly. The canine cornea consists of the corneal epithelium externally, the corneal stroma, Descemet’s membrane, and corneal endothelial cells (Figure 9.1) (also see Chapter 1). Descemet’s membrane, the basement membrane underlying endothelial cells, becomes thicker with age as it is continuously produced. Canine endothelial cells are hexagonally shaped with a normal density of approximately 2500–3175 cells/mm2. These cells decrease in number with age, with the number of cells in older dogs being frequently below 2100 cells/mm2, resulting in an increased diameter per endothelial cell to compensate for the reduced number. Figure 9.1 The canine cornea consists of the corneal epithelium externally, the corneal stroma, Descemet’s membrane, and corneal endothelial cells. The peripheral cornea is thicker on average than the central cornea. In neonatal puppies, there is a decrease in corneal thickness until approximately six weeks of age; then it increases with age until approximately 30 weeks. In adult dogs, corneal thickness increases gradually with age. Mean corneal thickness, as measured by ultrasonic pachymetry (USP) and in vivo confocal microscopy, is 562 ± 6.2 and 585 ± 79 μm, respectively. Spectral‐domain optical coherence tomography in normal dogs demonstrated that the epithelial thickness was 72.3 ± 4.6 μm, nonepithelial thickness was 538.9 ± 42.5 μm, and central corneal thickness (CCT) was 611.2 ± 40.3 μm. A diurnal variation in CCT measured by USP was found in normal dog corneas with CCT values significantly lower in the evening. The corneal stroma consists primarily of collagen fibrils, keratocytes, nerves, and glycosaminoglycans. Corneal collagen fibrils exist in broad belts called lamellae that run approximately parallel to the corneal surface. Keratan sulfate, chondroitin sulfate, and dermatan sulfate are the predominant glycosaminoglycans in the cornea. In the equine cornea, chondroitin 4‐sulfate is more concentrated in the deep central, peripheral, and middle central layers of the cornea compared to chondroitin 6‐sulfate. The canine cornea is highly innervated by an average of 11.5 large “trunks” of the trigeminal nerve (cranial nerve V) that enter the midstromal region circumferentially at the limbus. These trunks course radially to the central cornea forming anterior and posterior nerve plexi in the anterior stroma. Subepithelial plexus formation and extensions into the basal epithelium with free nerve endings extending to the epithelial wing layers also occur. Axons from the subepithelial plexus give rise to the subbasal nerve plexus after penetrating the epithelial basal lamina. The nerve fiber density of the central subepithelial nerve plexus, as determined by in vivo confocal microscopy, was 12.39 ± 5.25 mm/mm2 in mesocephalic dogs and 10.34 ± 4.71 mm/mm2 in brachycephalic dogs. The nerve fiber density of the central subbasal nerve plexus was 14.87 ± 3.08 mm/mm2 in mesocephalic dogs and 11.80 ± 3.73 mm/mm2 in brachycephalic dogs. Corneal sensitivity, or corneal touch threshold (the minimum stimulation of the corneal surface by a Cochet–Bonnet esthesiometer to elicit a blink reflex), is higher in dogs with dolichocephalic skull types compared with dogs with mesaticephalic or brachycephalic (which had the least sensitive cornea) skull types. In general, the central corneal region was most sensitive, followed by the nasal, temporal, dorsal, and then ventral corneal regions. Dogs with diabetes mellitus have reduced corneal sensitivity in all corneal regions. Factors supporting transparency of the normal canine cornea include the absence of blood vessels and pigment, the absence of keratinization of the anterior surface epithelium, a well‐organized stromal collagen lattice, and the small diameter of the collagen fibrils. The collagen fibrils that comprise the corneal stroma are composed of parallel arrays of long collagen molecules held together by intermolecular bonds. The collagen fibrils in the cornea have a uniform diameter of approximately 25 nm. Some nonfibrillar collagens are also found in the corneal stroma, types VI and XII being the most notable. Studies suggest that corneal clarity may not be dependent only on the absolute size of the stromal collagen or spacing of the fibrils, but also the fibril volume fraction (i.e., the proportion of the stroma that is occupied by hydrated collagen fibrils) may also be a major factor in clarity. The corneal endothelium uses physiological pumps (i.e., water and ion transport systems) to remove and transport fluid from the corneal stroma into the anterior chamber. In this way, the corneal endothelium regulates hydration of the corneal stromal collagen matrix, which provides mechanical strength. Sclera is composed of collagen fibrils with various diameters ranging from 25 to 230 nm. Scleral collagen fibrils are arranged in irregular, nonparallel bundles that vary in width and thickness, intertwine with each other, and branch extensively The different stages of corneal healing are summarized in Table 9.1 as the outer epithelium bridges the defect to months later as the endothelium recovers. Fortunately, these events can be observed directly. The corneal epithelium is maintained by a constant cycle of proliferation of cells in the basal layer and shedding of cells at the surface. Renewal of basal cells also occurs by centripetal migration of stem cells from the limbus. An epithelial defect of the cornea heals rapidly (in the absence of sepsis) by epithelial sliding and mitosis. After a short lag period of approximately 1 h, the normal epithelium at the edge of the defect flattens, retracts, thickens, and loses its hemidesmosomal attachments to the basement membrane. Limbal stem cells appear to play an important role in the maintenance of corneal epithelial health and corneal clarity. The limbal epithelium has been studied in multiple species searching for stem cell crypts found in humans. While the limbal epithelium demonstrated invagination similar to humans, no crypt‐like structures were found in dogs. Canine corneal epithelial stem cells appear to reside in the limbus and give rise to proliferative cells in response to stimulation. Epithelial sliding and stromal replacement mainly accomplish healing of corneal defects that involve the epithelium and anterior stroma. Stromal replacement requires synthesis and cross‐linking of collagen, proteoglycan synthesis, and gradual wound remodeling, which requires several weeks. The stroma adjacent to the defect exhibits edema early, followed by an influx of neutrophils from the tear film (via the lacrimal gland and conjunctival blood vessels) within 1–2 h of injury. Regional keratocytes transform into fibroblasts that proliferate and rapidly synthesize collagen and other components of the extracellular matrix (ECM). Stromal fibroblasts produce fibronectin, an ECM glycoprotein that stimulates cell adhesion, cell migration, and protein synthesis. Shortly thereafter, fibroblastic proliferation begins in the stroma. Fibroblasts also arise from the stromal histiocytes, and as the fibrous reaction continues, the epithelium is displaced anteriorly to its normal surface level. New collagen fibers and lamellae are produced, but disorganized arrangement may result in opacity or corneal scarring. The main cell type involved in the corneal fibrosis and scarring is the myofibroblast. Table 9.1 Dynamics of corneal healing after corneal ulcerations. The endothelial cell monolayer is the inner limiting layer of the cornea. Endothelial cells normally form a hexagonal, mosaic pattern on Descemet’s membrane that can be visualized clinically. The hexagonally shaped canine endothelial cells tend to enlarge in size and decrease in number with age. In the young dog, the number of endothelial cells averages 2500–3175 per mm2. Injury to endothelial cells results in decreased cell density in dogs, suggesting a limited capacity for mitosis in the canine adult. Phacoemulsification, radiofrequency hyperthermia, and CO2 photokeratotomy and intraocular surgery usually result in damage to endothelial cells in dogs, but intraocular irrigation with various saline solutions, low doses of tissue plasminogen activator (25 μg/100 μl), and transcorneal diode laser iridal photocoagulation did not appear to damage the cornea endothelium Healing of a full‐thickness corneal laceration may be divided into approximately six phases (Box 9.1). This is about the most severe injury that the cornea can exhibit, and potentially recover from with vision. Healing of corneal wounds is a complex process involving the integrated actions of proteinases, growth factors, and cytokines produced by epithelial cells, stromal keratocytes, inflammatory cells, and the lacrimal glands (Table 9.2). Multiple autocrine and paracrine interactions occur between epithelial cells, activated stromal fibroblasts, and the exocrine actions of factors secreted by lacrimal gland cells into the precorneal tear film (PTF). Various proteinases, proteinase inhibitors, growth factors, and cytokines in the tear film and aqueous humor play a role in the natural turnover of the corneal cells and corneal wound healing. As a result of these discoveries, therapy of corneal ulcerations is now also directed at controlling these proteases as well as the antibacterial therapies. Maintenance and repair of the corneal stromal ECM require a tightly coordinated balance of ECM synthesis, degradation, and remodeling. Proteolytic enzymes (proteinases) perform physiological functions in the slow turnover and remodeling of the corneal stroma. Excessive degradation of normal healthy tissue is prevented by natural proteinase inhibitors in the PTF and cornea, such as α1‐proteinase inhibitor, α2‐macroglobulin, and tissue inhibitors of metalloproteinases. However, pathological degradation of corneal stromal collagen and proteoglycans occurs when the balance between proteinases and proteinase inhibitors favors the proteinases. The rapid degradation of the corneal stroma associated with some severe corneal ulcers is caused by proteolytic enzymes acting on the collagen, proteoglycans, and other components of the stromal ECM and is referred to as keratomalacia or “corneal melting” (Figure 9.2). Microorganisms, inflammatory cells (e.g., polymorphonuclear leukocytes and macrophages), corneal epithelial cells, and fibroblasts produce and release proteolytic enzymes. Endogenous proteinases are produced by host cells. Exogenous proteinases are secreted by infectious organisms. Examples of exogenous proteinases include the variety of proteases produced by Pseudomonas aeruginosa (e.g., alkaline protease, elastases A and B, protease IV, modified elastase, P. aeruginosa small protease), and serine proteinase production by Aspergillus and Fusarium spp. Extracellular enzymes of bacterial or fungal origin also contribute indirectly to corneal proteolytic activity by activating endogenous proteinases. Table 9.2 Types of corneal ulcerations in the dog. Figure 9.2 Keratomalacia in a dog with bacterial keratitis. Two important families of enzymes that affect the cornea are the matrix metalloproteinases (MMPs) and serine proteases. Neutrophil elastase, an abundant serine proteinase in tears, is synthesized by polymorphonuclear leukocytes and macrophages. It degrades native III and IV collagen as well as corneal ECM compounds such as laminin and fibronectin. Two MMPs (MMP‐2 and MMP‐9) are of major importance in the remodeling and degradation of corneal stromal collagen. MMP‐2 and MMP‐9 were identified by immunohistochemistry in both healthy and ulcerated corneas of humans, dogs, and a variety of other animal species. In most species, MMP‐2 is constitutively present in the unwounded corneal epithelium and stroma and is upregulated after wounding, while MMP‐9 is found only in the wounded cornea. In damaged corneas, proteinase activity increases in the tear film and is considered an important fundamental response of the mammalian eye to corneal injury. If infection is present, proteinases secreted by infectious organisms further contribute to corneal damage. In dogs with traumatic keratoconjunctivitis, PTF levels of MMP‐9 were significantly increased compared to clinically normal dogs. In dogs with P. aeruginosa ulcerative keratitis, PTF concentrations of MMP‐2 and MMP‐9 were significantly higher than contralateral unaffected eyes and clinically normal dogs. Protease levels subsequently decreased as corneal healing progressed following medical or surgical therapy. Corneal pigmentation is most commonly associated with chronic inflammation. Corneal pigmentation is found in disorders such as chronic superficial keratitis (CSK) (i.e., pannus) in the German Shepherd; the pigmentary keratitis syndrome in brachycephalic breeds (Figure 9.3); keratoconjunctivitis sicca (KCS); and scarring with ulcerative keratitis. Corneal pigmentation results from migration of melanocytes from the limbal and perilimbal tissues. Melanin pigment may accumulate within corneal epithelial cells, macrophages, and fibroblasts in the dog. Other signs of active keratitis, such as corneal vascularization, stromal inflammatory cell infiltration, and granulation tissue formation, usually accompany pigment cell migration. Melanin is transferred to the basilar or suprabasilar cells of the cornea and the anterior stromal tissue. Once present, corneal pigmentation is nearly impossible to eliminate! Only two previous studies that have investigated the histopathology of canine corneal pigment are available. Corneal epithelial melanin deposition usually is usually concurrent with presence of blood vessels and inflammatory cells. Ocular surface disease and signalment certainly play a role in the condition. Recent studies investigating corneal pigment in Pugs specifically identified a high prevalence in this breed, with approximately 70–82% of examined dogs affected. Both studies also identified a high prevalence of ocular comorbidities, including disorders of the lacrimal system and eyelids. A statistical association between KCS (keratoconjunctivitis sicca) and SCP (superficial corneal pigmentation) was reported in one study, but it was also noted that SCP developed in the absence of KCS in other dogs. In the other study, the absence of consistently identifiable inflammatory risk factors (ocular adnexal or tear film abnormalities) and the detection of SCP were considered suggestive of a hereditary epithelial or pigmentary dystrophy in the Pug, or pigmentary keratopathy. Several other brachycephalic dog breeds develop SCP commonly and without an identifiable underlying etiology and include the Boston Terrier, Lhasa Apso, Pekingese, and Shih Tzu. Figure 9.3 Superficial corneal pigment in a Pug with chronic pigmentary keratitis. Another less common source of corneal pigmentation is anterior synechiae (often after corneal perforations) and less common after the adherence of anterior uveal cysts to the cornea. Cysts of the anterior uvea may be either congenital or acquired (as the result of uveal inflammation or degeneration). The pigmented cells may arise from the pigment epithelium of the ciliary body, iridal stroma, and posterior iridal epithelium. Corneal edema or swelling (i.e., corneal hydration) may result from imbibition of fluid by the epithelium or stroma (Figure 9.4). Corneal transparency depends both on its physical structure and on mechanisms that prevent overhydration. The major barriers to edema are the endothelium and the epithelium. Removal of the epithelium in rabbits produces an average increase in corneal thickness of 200% in 24 h, whereas removal of the endothelium produced an increase of 500%. Alterations in endothelial cells (as in iridocyclitis) result in the cornea absorbing aqueous humor and becoming edematous. The endothelium maintains corneal deturgescence by an energy‐dependent sodium–potassium transport pump as well as by a physical barrier. The barrier function of the endothelium results from tight cellular junctions known as “zonula occludens.” Traditionally, corneal edema was regarded simply as increased corneal water content that results in increased thickness, increased scattering of light, and decreased transparency; however, corneal edema also involves loss of stromal glycosaminoglycans and water uptake. When the cornea swells, fluid is not uniformly distributed within the corneal stroma with its anterior stroma most affected. The posterior corneal lamellae are hydrated to a greater extent, possibly because of differences in the glycosaminoglycan content between the anterior and posterior stroma or presence of lamellar interweave in the anterior stroma that limits the extent to which these lamellae can swell. Corneal edema in the dog may be associated with a variety of causes, including endothelial dystrophy, age‐related degeneration, endothelial damage associated with persistent pupillary membranes (PPMs), mechanical trauma, toxic reactions, anterior uveitis, endotheliitis, glaucoma, neovascularization, and ulceration. Figure 9.4 Afghan Hound with diffuse corneal edema after canine adenovirus type 1 vaccination. Endothelial dystrophy occurs in several breeds, including Boston Terriers, Chihuahuas, Dachshunds, and German Shepherds. Light microscopic findings have included stroma edema, fibrous tissue proliferation on a thickened Descemet’s membrane, and endothelial cell hypocellularity. This condition is similar to Fuchs dystrophy in humans and is commonly bilateral (see more information later in this chapter). Corneal edema associated with endothelial changes is commonly seen with anterior uveitis in the dog. Intraocular inflammation results in corneal edema via an increase in endothelial permeability and a decrease in Na+/K+‐ATPase pump activity. Infectious canine hepatitis, which is an immune‐mediated, Arthus‐type reaction, develops in the anterior uveal tract and progresses to destruction of the corneal endothelium with resultant corneal edema, thus causing the “blue eye” appearance. Natural infections or vaccination with modified live canine adenovirus type 1 may result in the development of corneal edema (see Figure 9.4), but current vaccinations with canine adenovirus type 2 decrease the incidence to below 1%. Approximately 30% of dogs that develop corneal edema from adenovirus infections do not completely resolve. Traumatic endothelial damage may occur with anterior lens luxation. Trauma to the endothelium may also result from intraocular surgery, such as phacoemulsification, intracapsular lens extraction, and intraocular lens replacement. Irrigation solutions used in phacoemulsification also damage the corneal endothelium. Results of one study on the response of canine corneal endothelium to intraocular irrigation solutions indicated that irrigating fluid composition has a less deleterious effect on the corneal endothelium than the volume of fluid and time of irrigation (less than 100 ml of fluid for less than 20 min had the least damaging effect). There are a number of drugs that result primarily in corneal edema in dogs. As an example, chlorpromazine accumulates in the canine posterior corneal stroma, lens, and uveal tract. In addition to causing cataracts, it produces posterior corneal precipitates and pigmentation. Chlorpromazine is a phototoxic compound, and the cellular damage to endothelial cells occurs after light exposure. Bilateral corneal edema occurred in 3 of 12 dogs after long‐term treatment (>3 months) with tocainide, an antiarrhythmic agent. Because of the lack of inflammation, this was presumed to be a direct endothelial toxic effect of the drug. Corneal stromal vascularization is a nonspecific response to corneal injury or inflammation. The healthy canine cornea is avascular and the presence of blood vessels within the cornea represents pathological change. Vascularization is a normal component of the reparative response after injury in a variety of tissues; however, in the cornea, this process can result in disrupted corneal architecture, opacification, and reduced vision. Superficial highly branching blood vessels in the anterior stroma are associated with corneal diseases (often can be observed connected to conjunctival blood vessels) and the short fine blood vessels deep in the corneal stroma at the limbus (paintbrush vessels) are associated with anterior uveal diseases. The avascular state of the cornea is actively maintained by a balance of antiangiogenic and angiogenic factors. Corneal vascularization occurs when this balance is lost and the local corneal microenvironment favors angiogenic factors. The presence of vascular endothelial growth factor (VEGF) receptors 1 and 2 has been demonstrated in normal canine eyes. In the normal canine cornea, superficial and basal corneal epithelium, corneal endothelium, and limbal vascular endothelium contained VEGF receptor 1, while VEGF receptor 2 was found in the scleral vascular endothelium. Both VEGF receptors 1 and 2 were detected in pathological vascular endothelium and corneal neovascularization. Any corneal insult that induces inflammation or hypoxia may result in corneal angiogenesis. Figure 9.5 Superficial corneal vascularization in a dog with chronic KCS. Figure 9.6 Deep corneal vascularization in a dog with chronic anterior uveitis. Superficial vessels arise from conjunctival vessels and are bright red, fine, branch repeatedly, and can be observed to cross the limbus (Figure 9.5). Deep corneal vessels are located in the posterior stroma and suggest deep corneal or intraocular disease. Deep corneal vessels arise from anterior ciliary vessels and appear dark red, straight with few or no branches, and do not cross the limbus (Figure 9.6). Microcornea is a small cornea in an otherwise normal globe. The appearance in dogs is a cornea with a horizontal diameter of less than 12 mm. A small cornea may also occur with ocular or systemic conditions associated with multiple ocular anomalies; the most common is microphthalmia. Microcornea is reported as a feature of merle ocular dysgenesis in a variety of breeds, including Australian Shepherds and Dachshunds. The Collie, Miniature and Toy Poodle, Miniature Schnauzer, Old English Sheepdog, Saint Bernard, and possibly other breeds may be predisposed to microcornea and multiple ocular anomalies as well. Megalocornea is a cornea of greater than normal size, normal being approximately 16–18 mm in horizontal diameter. This is a rare, congenital anomaly in the dog and is usually concurrent with congenital glaucoma and buphthalmos (or megalophthalmos). A dermoid is a choristoma, or normal tissue in an abnormal position. Dermoids occur most commonly at the temporal limbus and can involve the eyelids, conjunctiva, nictitans, cornea, or a combination of these structures (Figure 9.7). Dermoids may contain keratinized epithelium, hair, blood vessels, fibrous tissue, fat, nerves, glands, smooth muscle, and cartilage. Dermoids are present at birth, but they may not be recognized clinically until the dog is several weeks old. If they are irritating from the long hairs extending from its surface or obstructing vision, dermoids can be treated by surgical removal. The procedure of choice for corneal dermoids is superficial lamellar keratectomy (see the next section). In the uncommon situation where a dermoid requires deep keratectomy, a conjunctival graft may be warranted. Surgical placement of canine amniotic membrane following excision of large dermoids is reported to enhance healing and reduce corneal scarring. Superficial keratectomies are the most frequent corneal surgery in the dog. Other superficial corneal lesions amenable to superficial keratectomy include indolent ulcers, corneal neoplasms, sequestrums, foreign bodies, corneal abscesses, inclusion cysts, bacterial and fungal keratitis (usually in conjunction with a conjunctival graft or flap), and corneal degeneration. The specific procedure or method for the superficial keratectomy is determined by the type of lesion. Before performing a superficial keratectomy, determining the depth of the lesion using biomicroscopy, high‐frequency ultrasound, confocal microscopy, or optical coherence tomography is important in planning the surgery. If the resulting corneal wound extends deeper than one‐half corneal thickness, use of a conjunctival pedicle flap or amniotic membrane graft is warranted to protect the cornea, to help prevent perforation, and to promote healing. Current observations suggest that corneal stromal tissue may not completely regenerate; the number of superficial keratectomies that can be performed at the same site is limited to two or three. Figure 9.7 (a) A dermoid, or choristoma, at the temporal limbus in a young dog. (b) A histological section of a dermoid after keratectomy. Note the hair follicles and glands that are typical of dermal tissue. (Hematoxylin and eosin stain.) Superficial keratectomy is most commonly performed in veterinary medicine using traditional microsurgical instruments; however, it can also be performed using carbon dioxide or excimer laser ablation. Magnification (e.g., an operating microscope) is essential to perform the surgery, and specialized surgical equipment (e.g., corneal dissector, dermatology punch, corneal trephine, and micrometer diamond knife) greatly facilitates the removal of corneal tissue and may improve the clinical outcome. There are two common methods to perform a superficial keratectomy: the complete and the partial incision keratectomy. In the first method, the complete incision keratectomy, an initial corneal incision is made that surrounds completely the lesion to be removed. The incision needs to be at appropriate depth to allow complete removal of the lesion. It is made using a corneal trephine, diamond knife, or microsurgical blade (Figure 9.8). In the second type of superficial keratectomy, the partial incision keratectomy, a small corneal incision is made adjacent to the lesion that is to be removed. This initial incision is made at the appropriate depth but only wide enough to allow insertion of the lamellar‐separating device (e.g., Martinez corneal dissector, microsurgical blade #6400 or #6900, and iris spatula) to be inserted. Using this separator instrument through the initial incision, the entire lamellar plane under the lesion to be removed is separated, thus undermining the lesion. Corneal section scissors are then introduced into the initial incision and used to complete the keratectomy. Following keratectomy, the cornea is treated much like a corneal ulcer with topical broad‐spectrum antibiotics to prevent infection and with topical atropine to decrease ciliary spasm and discomfort. A potentially devastating complication after keratectomy is corneal perforation, which generally results from infection at the surgical site. The potential for infection is exacerbated by deep, extensive keratectomies but is largely preventable by use of conjunctival flaps or other supportive surgeries. Reevaluations after surgery (with monitoring of healing by use of fluorescein dye application) and use of topical antibiotics should prevent most postsurgical complications. Corneal opacities are commonly classified by the degree of opacity and are described as a nebula, macula, or leukoma. A nebula is a minor, diffuse, hazy opacity with indistinct borders. A macula is a moderately dense opacity with a circumscribed border. A leukoma is a dense, white opacity. When iris tissue adheres to the posterior surface of the cornea beneath an area of corneal opacity, the condition is described as an adherent leukoma. Infantile corneal dystrophy, or puppy keratopathy, is a congenital, subepithelial, geographic corneal opacity that is nonhereditary, transient, and observed in puppies younger than 10 weeks. The condition slowly resolves and, in most cases, is absent by 12–16 weeks of age. There is no interference with functional vision and treatment is unnecessary. Figure 9.8 Complete incision superficial keratectomy. (a) The initial corneal incision, which may be round, square, or triangular, should completely surround the lesion to be removed and can be made using a corneal trephine, diamond knife, or microsurgical blade. (b and c) After the initial incision is made, the edge of the tissue to be removed is grasped by a forceps, and a corneal dissector (e.g., Martinez corneal dissector, Beaver #64 microsurgical blade, and iris spatula) is introduced and held parallel to the cornea. The dissector is used to separate the corneal lamella without penetrating deeper than the original incision. The cornea is then separated until the opposite incision line, or limbus, is reached. (d) Scissors may be needed to connect the dissection to the opposite incision or to remove the corneal tissue from the limbus. PPMs are congenital lesions that occur in many canine breeds and are known to be hereditable in some. Persistent pupillary tissue strands arise from the iris collarette and represent failure of normal embryonic vasculature structures to completely regress. Corneal and/or anterior lens capsule lesions can be associated with adherence of PPMs (Figure 9.9). Both focal and diffuse corneal opacities occur, but the former is more frequent. Focal lesions appear as punctate, linear, or round deep corneal opacities that may be pigmented or unpigmented. Larger, more diffuse corneal opacities also affect Descemet’s membrane and may result from generalized stromal edema. PPM‐associated leukomas may be isolated anomalies or a component of a more extensive anterior segment dysgenesis. Colobomas or staphylomas of the limbus or sclera are rare in the dog. The lesions are thin regions of the globe’s fibrous tunic lined by uveal tissue and appear as a tan, gray, or blue raised mass covered with conjunctiva. If strabismus is present, vision may not be present! Etiologies include congenital malformation and secondary to inflammation, glaucoma, neoplasia, trauma, or surgery. Corneal diseases may be categorized into inflammatory and noninflammatory causes. Inflammatory corneal disorders can be further classified into ulcerative and nonulcerative keratitis. Figure 9.9 Dog with PPMs adherent to the posterior cornea and resulting in a focal corneal opacity. Corneal ulceration, or ulcerative keratitis, is one of the most common ocular diseases in the dog. A corneal ulcer is present when there is a break in the corneal epithelium that exposes the underlying corneal stroma. Clinically, lacrimation, blepharospasm, photophobia, conjunctival hyperemia, corneal edema, and possibly miosis and aqueous flare are also present. The diagnosis of a corneal ulcer is made on the basis of these clinical signs and the retention of topically applied fluorescein dye by the corneal stroma (Figure 9.10). There are several types of corneal ulcerations (Table 9.2). Uncomplicated superficial ulcers usually heal rapidly, with minimal scar formation. Complicated deep ulcers, such as those with microbial infection, however, may lead to impaired vision because of corneal scarring or, when corneal perforation occurs, to anterior synechia formation. Severe ulcerative keratitis may lead to loss of the eye because of endophthalmitis, glaucoma, phthisis bulbi, or a combination of these. Corneal ulcers are classified by depth of corneal involvement and by their underlying cause. The first step in treating all corneal ulcers involves identifying and removing the inciting cause, which may be eyelid abnormalities (e.g., masses, lagophthalmos, distichiasis, ectopic cilia), foreign bodies, trauma, and KCS. Chronic, infected, or progressive corneal ulcers should undergo microbiological culture and antibiotic susceptibility tests and cytological examination of corneal samples. These diagnostic procedures help guide specific antimicrobial therapy. Figure 9.10 The diagnosis of a corneal ulcer is made on the basis of retention of topically applied fluorescein dye by the corneal stroma as observed in this superficial corneal ulcer. Epithelial and superficial stromal foreign bodies are not uncommon and may occur more frequently in hunting dogs and in the fall. They may be successfully removed with saline hydropulsion, a cytobrush, an ophthalmic spear sponge, or a Kimura spatula. This can generally be performed under topical anesthesia alone with excellent success rates. Stromal or penetrating foreign bodies, without lens involvement and without significant anterior uveitis, usually require general anesthesia for removal but have a good prognosis for vision retention after surgery. There is a report of a penetrating gunshot injury with lead shot entrapped within the choroid where the dog remained visual for 4.5 years after penetrating corneal and lenticular injury. If the pellet is ferrous (rather than lead), surgical removal should be attempted as iron or ferrous pellets are retinotoxic, and eventually can destroy the retina. Table 9.3 Antiproteolytic agents for topical treatment of melting corneal ulcers. MMPs require Ca2+ and Zn2+ as cofactor and stabilizing ion, respectively. a Note that doxycycline can also be administered orally (10 mg/kg, s.i.d.). b Easily made by the addition of 5 ml of sterile water to a commercial blood collection tube. c Serum stored in the refrigerator can be used for up to five to seven days. It should then be discarded because of the risk of bacterial contamination. Corneal ulcers are classified by the depth of corneal involvement and by their underlying cause. Depth of corneal involvement is reviewed first and includes superficial corneal ulcers, stromal corneal ulcers, descemetoceles, and perforations (see Table 9.3). Superficial corneal ulcers are further classified as uncomplicated, progressive, or refractory. For successful management of ulcerative keratitis, the inciting cause of the ulcer is identified and removed, the stage and severity of the ulcer is determined, and an appropriate therapeutic modality is selected. Identifying the cause or contributing factors requires a thorough ocular examination. Eyes should always be evaluated for eyelash abnormalities, eyelid structure and function, and preocular tear film disorders (e.g., Schirmer tear test, tear breakup time, and Rose Bengal retention). Uncomplicated superficial ulcers from direct trauma, shampoos, exposure while under general anesthesia, and other factors can resolve with only topical antibiotic therapy applied three to four times daily to prevent secondary bacterial infection. Combination ophthalmic preparations (e.g., neomycin, bacitracin, and polymyxin B), erythromycin, or oxytetracycline are frequently good antimicrobial selections that provide broad‐spectrum coverage. Stimulation of the abundant sensory receptors in the superficial cornea by ulceration results in a localized neurogenic reflex anterior uveitis associated with miosis of the pupil, iris hyperemia, and increased protein levels in the aqueous humor (i.e., aqueous flare). Therefore, a mydriatic agent (1% atropine or 1% tropicamide) is applied topically once or twice daily to control ciliary muscle spasm, a dilated pupil, and the ocular discomfort associated with the secondary uveitis. The ulcer should resolve in two to six days with limited or no scarring; if not, it should be reevaluated for an undetected, underlying cause or contributing factor. Corneal ulcers may be a complication of general anesthesia for nonophthalmic procedures in dogs, even those whose eyes were lubricated with topical lubricating gel. Evaluation of 199 canine eyes lubricated before general anesthesia demonstrated corneal ulceration in 1 eye and corneal erosion in 25 eyes. Spontaneous chronic corneal epithelial defects (SCCEDs) in dogs are chronic superficial ulcers that fail to resolve through normal wound‐healing processes. A variety of other terms include indolent erosions or ulcers, canine recurrent erosions, refractory corneal ulcers, Boxer ulcers, nonhealing erosions, persistent corneal erosions, recurrent epithelial erosions, and idiopathic persistent corneal erosions. SCCEDs are generally divided into the Boxer ulcer and superficial nonhealing ulcerations in old dogs of other breeds. Although originally reported as Boxer ulcers (due to its predilection for Boxers), subsequent larger studies document occurrence in almost every breed that are affected middle‐to advanced aged, overrepresented by the Boxer breed, and exhibit varying degrees of blepharospasm. The initiating event in dogs with SCCEDs is likely superficial corneal trauma. These epithelial defects result in variable amounts of ocular discomfort along with the potential for corneal neovascularization, fibrosis, and edema. Hallmark clinical and histological features of SCCED include a superficial axial or paraxial corneal ulcer that does not extend into the stroma, associated with redundant, nonadherent corneal epithelial borders that may be associated with an acellular hyaline zone in the anterior stroma, neovascularization, and, when not treated adequately, may persist for weeks to months. While the Boxer breed is overrepresented with this condition, comparison and inclusion of other breeds of older dogs has not determined whether their pathogenesis is the same or different. SCCED should be considered in any middle‐ and advanced aged dog with an erosion that has not healed in one to two weeks. An average age of eight to nine years is reported with these dogs (the Boxer breed may be younger dogs); therefore, young dogs with nonhealing erosions should be very carefully examined prior to a diagnosis of SCCED. Often in the Boxer breed, both eyes may be affected, but not at the same time. This condition may be divided into (i) the Boxer breed and (ii) aged dogs of any breed. Studies suggest possible defects in the basal epithelium and its basement membrane and/or defects in the anterior stroma. SCCEDs have a typical clinical appearance (Figures 9.11 and 9.12). A ring of loose epithelium surrounds a SCCED, resulting in a diffuse ring or halo of less intense fluorescein staining around the defect as fluorescein diffuses underneath the poorly attached epithelium. A SCCED is always superficial, with no stromal loss. Varying degrees of vascularization occur in SCCED (determined by the duration of the active ulcer) with studies reporting 58–64% of lesions exhibiting neovascularization. The degree of pain demonstrated by blepharospasm varies between dogs, but tends to be fairly high in the early stages of the disease but may decrease with chronicity. Figure 9.11 Large nonvascularized SCCED in a nine‐year‐old Boxer dog. Note the axial location, ring of loose epithelium, and the decrease in intensity of the fluorescein staining as it migrates under the loose epithelium surrounding the defect. Figure 9.12 Vascularized SCCED in a 10‐year‐old Boxer dog. Note the peripheral location of the erosion, superficial corneal vascularization, ring of loose epithelium surrounding the defect, and fluorescein leakage under surrounding loose epithelium. Most studies for medical treatment for SCCEDs include epithelial debridement of the loose epithelial lip of epithelium, and medical treatment leads to healing (Box 9.2). The most common therapy for the treatment of SCCEDs is epithelial debridement, used alone or in combination with other medical or surgical therapies. After application of topical anesthetic, epithelial debridement is performed using multiple dry cotton‐tipped applicators, beginning in the center of the erosion and working out to the periphery with radial strokes. Normal corneal epithelium cannot be removed with a cotton‐tipped applicator, so debridement should be continued until only firmly adhered epithelium remains. Debridement can also be performed with corneal burrs, excimer laser spatulas, scalpel blades, spatulas (Kimura and iris), or forceps. Typically, debridement can be repeated at 7‐ to 14‐day intervals. Success rates and time to healing vary between studies from 20% in 14 days to 84% in an average of 23 days. The number of debridements, the time between procedures and examinations, and the number treatments suggest the success rates of approximately 50%. It was noted that adding a soft contact lens or third eyelid flap increased healing rates after debridement to 58% and 64%, respectively. A number of treatment options have been reported for the treatment of SCCEDs. With all treatments, prophylactic antibiotics should be administered q 6 h to q 8 h to prevent secondary infection of the compromised cornea. A cycloplegic (e.g., atropine) to improve comfort and Elizabethan collar to prevent self‐trauma are usually indicated. Most studies of topical medications for the treatment of SCCEDs consist of small, nonrandomized, nonmasked, and/or uncontrolled clinical trials. The lack of controls and small sample sizes make interpretation of these results difficult, particularly since statistical power is often too low to detect a meaningful difference between treatment groups. A wide variety of medical therapies have been utilized in the therapy of SCCEDs. Treatment with topical PSGAGs resulted in healing of 82% of the treated dogs. A separate study evaluated aprotinin, with a resulting healing rate of 33%. Treatment with topical substance P alone or combined with insulin‐like growth factor resulted in healing of erosions in 70% and 75% of dogs, respectively. A chondroitin sulfate–antibiotic combination brought about healing in 81% of treated dogs, but treatment had to be continued for four weeks, which is longer than many other reported therapies. In a randomized, controlled clinical trial, dogs were treated with manual debridement and grid keratotomy followed by oral doxycycline (5 mg/kg q 12 h) and topical triple antibiotic (q 8 h), topical oxytetracycline ophthalmic ointment (q 8 h) and oral cephalexin (22 mg/kg q 12 h), or a control group of topical triple antibiotic ointment and oral cephalexin. Dogs treated with topical oxytetracycline ophthalmic ointment healed significantly faster (74% healed within two weeks) than dogs in the control group (10% healed within two weeks). Dogs treated with oral doxycycline healed more rapidly than dogs in the control group, but the difference was not statistically significant. The effects of topically applied heterologous serum versus isotonic saline were evaluated in 41 dogs with SCCEDs. Median time to epithelialization was not significantly different between serum‐ or saline‐treated eyes and was not significantly different between Boxer versus non‐Boxer breeds.
9
Canine Cornea and Sclera: Diseases and Surgery
Corneal Anatomy and Pathophysiology
Corneal Anatomy
Corneal Clarity
Corneal Wound Healing
Epithelial Healing
Stromal Healing
Tissue
Healing starts
Time to replace
Clinical monitoring
Epithelium
1 h
48–72 h
Very faint retention of fluorescein (new cell layer)
14 days
No fluorescein retention (multiple layers)
Corneal epithelial
Several weeks
Firm bond (epithelium cannot be dislodged) basement membrane
Corneal stroma
One to two days
Days to weeks
Stromal replacement requires local fibroblasts; occasional vasculature
Occurs under the healing epithelium
Descemet’s membrane
Regeneration depends on the endothelium (limited to very young animals)
Endothelium
Regeneration in young animals only
Endothelial Healing
Repair of Full‐Thickness Corneal Laceration or Perforation
Role of Proteases in Corneal Wound Healing
Proteinases and Proteinase Inhibitors
Major Proteinases in the Cornea and Their Origin
Clinical diagnosis
Corneal layers lost
Outcome
Superficial ulcer
Epithelium/basement membrane (BM) variable
Uncomplicated/progressive
Corneal erosion
Epithelium/BM
Refractory/recurrent
Shallow ulcer
Epithelium/BM/ ¼ – ⅓ stroma
Uncomplicated/progressive
Moderate ulcer
Epithelium/BM/ ½ stroma
Uncomplicated/progressive
Deep ulcer
Epithelium/BM/⅔ – ¾ stroma
Uncomplicated/progressive
Descemetocele
Epithelium/BM/stroma
Complicated/progressive
Iris prolapse
Epithelium/BM/stroma/Descemet’s membrane/endothelium
Complicated/progressive 
Proteolytic Activity in Healthy and Diseased Corneas
Corneal Pigmentation
Corneal Edema
Corneal Vascularization
Developmental Abnormalities and Congenital Diseases
Microcornea
Megalocornea
Dermoids
Superficial Keratectomy
Congenital Corneal Opacities
Infantile Corneal Dystrophy
Corneal Opacities with Persistent Pupillary Membranes
Limbal Colobomas and Staphylomas
Inflammatory Keratopathies
Ulcerative Keratitis
Corneal Foreign Bodies
Compound
Concentration used
Inhibitory activity
Inhibitory mechanism
Tetracyclines (doxycycline, oxytetracycline)
0.1%a
MMP inhibitor
Chelating agent (Ca2+ and Zn2+)
N‐Acetylcysteine
5–10%
MMP inhibitor
Chelating agent (Ca2+ and Zn2+)
Disodium ethylenediaminetetraacetic acid (EDTA)
0.2%b
MMP inhibitor
Chelating agent (Ca2+ and Zn2+)
Ilomostast (Galardin™)
0.1%
MMP inhibitor
Chelating agent (Ca2+ and Zn2+)
Serum (α2‐macroglobulin and α1‐proteinase inhibitor)
Undilutedc
MMP and serine protease inhibitor
Various entrapment of the protease
α1‐Proteinase inhibitor
0.1%
Serine protease inhibitor
Entrapment of the protease
Ulcerative Keratitis: Depth of Corneal Involvement
Superficial Corneal Ulcers
Spontaneous Chronic Corneal Epithelial Defects
Diagnosis
Treatment
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
