Ординатура / Офтальмология / Английские материалы / Slatter's Fundemental of Vetrinary Ophthalmology 4th edition_Maggs, Miller, Ofri_2008

Germicides

Germicides are used for disinfection of instruments, for preoperative preparation of the lids and ocular surface, and as preservatives in eyedrops. A number of solutions have been used as topical antiseptics or germicides for the eye. However, many are toxic to the corneal and conjunctival epithelium and should not be used. Povidone-iodine solution is a reliable and nonirritating agent for destruction of bacteria, fungi, and viruses on the ocular surface and periocular skin before surgery, and is the preferred product for this purpose. It is mixed with normal

saline to form a 2% solution. Povidone-iodine solution, not surgical scrub, must be used. Benzalkonium chloride is a wetting agent that enhances corneal penetration of certain drugs as well as acting as a preservative. It is no longer usedfor surgical preparation of the patient or for sterilization of instruments. Other solutions, such as hexachlorophene, cresol, and mercuryand silver-containing compounds, can be very irritating to the ocular surface, and their use is contraindicated. In particular, silver nitrate applicator sticks (used for hemostasis after nail trimming in dogs) cause severe keratitis and epithelial sloughing in dogs and must not be used near the ocular surface.

Astringents and Cauterants

Astringents are locally acting protein precipitants; cauterants are severe protein-precipitating agents that cause local tissue destruction. Examples are copper sulfate, trichloracetic acid, phenol, iodine, and zinc sulphate. Such agents have historically been used (sometimes indiscriminately) to treat a variety of ocular diseases. However, identification and removal of the cause or more modern medical and surgical approaches usually achieve a better result in a more controlled manner, and astringents and cauterants are no longer recommended for ocular use.

Vitamins

Various vitamins have been advocated for their supposed therapeutic efficacy in the treatment of ocular disorders of animals. In the absence of a specific vitamin deficiency (e.g., vitamin A deficiency causing nyctalopia in cattle or conjunctivitis in turtles) there usually is little to be gained from such local therapy. The exception is systemic and ocular signs of warfarin poisoning, which are treated with vitamin K and its analogues.

Antiparasitic Agents

OCULAR PHARMACOLOGY AND THERAPEUTICS 59

body, iridal, retinal, and lenticular) cells. From this list it is clear that the effects of inadvertent or intentional irradiation of the eye are potentially wide-ranging. Two forms of radiation are commonly used for the treatment of ocular disease— b-irradiation and x- or g-irradiation. Because of safety precautions, licensing, and expense, treatment tends to be limited to larger veterinary hospitals, and referral of cases requiring such therapy is advocated.

b-Irradiation

b-Rays are low-energy electrons that penetrate tissue to 3 to 4 mm. Therefore they are used to treat superficial lesions only. b-irradiation for ophthalmic use is obtained from a strontium90 ophthalmic applicator. This therapy is used to control corneal neovascularization and pigmentation seen with chronic superficial keratitis (“pannus”) in dogs and to treat malignant ocular neoplasms, including squamous cell carcinoma of the lids, third eyelid, and conjunctiva in cattle, cats, and horses especially. Because of shallow penetration, b-irradiation from an applicator applied to the limbus does not reach the equatorial zone of the lens (Figure 3-12).

g- and X-Irradiation

Ivermectin is now used, almost to the exclusion of all older parasiticides, for treatment of parasitism such as habronemiasis and onchocerciasis in horses and ocular filariasis in small animals. When it is used at excessive doses or at normal doses in a susceptible individual such as a collie, ocular signs of ivermectin toxicity may be seen. They include mydriasis, reduction or absence of pupillary light reflexes, blindness, and retinal folds or edema. These signs are typically temporary.

PHYSICAL THERAPY

Contact Lenses

Therapeutic soft contact lenses (TSCLs) have been used in veterinary patients as bandages to protect the cornea during healing or sometimes as vehicles for delivery of hydrophilic drugs. Degradable collagen shields are also available; however, these typically degrade more rapidly than preferred (usually within 72 hours). Both lens types must be placed behind the leading edge of the third eyelid to reduce the chance of being dislodged. Many ophthalmologists recommend also placing a partial temporary tarsorrhaphy over the TSCL, a maneuver that requires general anesthesia or sedation and regional anesthesia. A temporary tarsorrhaphy will continue to provide a “bandage” effect even if the TSCL is dislodged. Hydrophilic TSCLs may be soaked in a concentrated solution of some drugs before being placed on the eye to afford some depot effect.

Irradiation

g-Rays and x-rays have similar wavelength, energy, and penetrating properties but differ in origin. g-rays emanate from the nucleus, and x-rays from the extranuclear portion, of the atom. Both penetrate deeply and are used for lesions inaccessible to b-irradiation. Superficial, orthovoltage, and megavoltage radiotherapy, cobalt 60, cesium-135, and radon and gold implants (brachytherapy) have all been used. Penetrating (x and g) irradiation may interfere with cell division in the equatorial region of the lens, especially in young animals, resulting in partial or complete “radiation cataract.” Higher doses result in keratitis (41%), conjunctivitis (mild,

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Irradiation may be used therapeutically for several ophthalmic diseases but also produces ophthalmic disease if the eye must be placed in the field during irradiation for other diseases such as nasal or orbital neoplasia. Radiation exerts its effect on rapidly dividing cells, which in the eye include lymphocytes, vascular endothelium (uvea, conjunctiva, eyelids, retina), and epithelial (eyelid, lacrimal gland, corneal, conjunctival, ciliary

FIGURE 3-12. Graph indicating the decrease in intensity of b-irradiation emitted from a strontium-90 ophthalmic applicator as a function of tissue depth. By 1-mm tissue penetration, the radiation intensity has decreased to 50%. The diagram of the eye is drawn to scale to show the relationship of decreasing intensity to various structures of the eye. (Modified from Gillette EL [1970]: Veterinary radiotherapy. J Am Vet Med Assoc 157:1707.)

FIGURE 3-13. Radiofrequency hyperthermia handpiece.

34%; severe, 28%), cataract (28%), and keratoconjunctivitis sicca. In one study, progression to corneal perforation occurred in 24% of patients, and 63% of cases of conjunctivitis and keratitis were refractory to treatment.

Hyperthermia

Hyperthermia (local induction of heat within a tissue) is used to treat squamous cell carcinoma and some other tumors of the eye and adnexa in horses and cattle. The temperature of the tissue is increased to 50° C for 30 sec/cm2 by the local passage of radiofrequency current through the tissue (Figure 3-13).

Lasers in Veterinary Ophthalmology

Lasers have been described for cyclophotocoagulation (glaucoma), retinopexy (retinal detachment), rupturing of iris cysts, correction of entropion, and ablation of intraocular and adnexal neoplasms. However, their advantages (if any) over standard surgical approaches have not been investigated or proven in most of these diseases. Diode, neodymium:yttrium- aluminum-garnet, and CO2 lasers are used most commonly in veterinary ophthalmology.

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Ocular pathology is relevant to those interested in clinical veterinary ophthalmology because examination of the eye is the direct observation of its gross pathology; even the ophthalmoscope is a low-power microscope. There is a strong correlation between the observations made on clinical examination and the results of microscopic examination. Clinicians and pathologists use exactly the same terminology—a welcome accord that is almost unique among medical specialties and is further testimony to the inseparability of clinical ophthalmology and ophthalmic pathology.

The widely held perception that ocular pathology is so complicated and so different from the pathology of other tissues that it must forever remain the realm of the specialist is untrue. The fundamental pathologic events in the eye are identical to those occurring in other tissues. The outcomes of these events may be quite different because of the following three important principles of ocular pathology.

First, the globe is a closed, fluid-filled sphere that is relatively impervious to events occurring in other body systems but highly sensitive to events occurring elsewhere within the eye itself. The internal environment of the eye is separated from general body circulation by a series of intercellular tight junctions (the blood-ocular barrier). At the same time the fluid aqueous and vitreous allow diffusion of soluble nutrients and growth factors throughout the eye. This fluid environment permits structures like lens, cornea, and (in some species) even retina to exist with a degree of avascularity critical to proper optical function. The disadvantage of this closed system is that potentially injurious chemicals, such as inflammatory mediators, cell breakdown products, and chemical promoters of fibroplasia, are also retained and distributed throughout the globe. In nonocular settings, such chemicals are rapidly diluted, deactivated, or destroyed as they leave the immediate vicinity of their generation.

Second, proper ocular function requires precise anatomic relationships among many constituent parts. Many portions of the eye are uniquely unforgiving of the presence of even minor changes in microanatomy or physiology that occur during inflammation and wound healing. A good example is serous retinal detachment, in which serous inflammation, ordinarily a minor event, causes blindness as it elevates the retina out of visual focus and leads to eventual ischemic retinal necrosis because it separates the retina from its choroidal source of oxygen and other nutrients. Similarly, something that is usually as harmless as edema can, within highly regimented tissues like cornea or lens, critically alter the passage of light to the point of causing blindness.

Third, some of the most important ocular tissues (retina, corneal endothelium, most of the lens) are postmitotic and thus have limited capacity to regenerate after injury. In these optically sensitive tissues the types of repair phenomena (e.g., fibrosis) that might return other organs to acceptable function often do not restore (and might even worsen) ocular function. The repair of a skin wound by fibrous scarring is a familiar and useful phenomenon, but scarring of similar magnitude would be blinding in the cornea. Development of relatively minor amounts of granulation tissue, which would be helpful or inconsequential elsewhere, can create occlusion of the pupil or of the trabecular meshwork, leading to glaucoma.

OCULAR INJURY

The basics of tissue reaction to injury are the same within the eye as within other tissues, and it is not the purpose of this chapter to review what is amply discussed in any textbook of general pathology. Presented here is a brief overview of those responses, with a particular emphasis on those aspects that are different, or have a different significance, within the eye from those in other tissues.

Causes of Ocular Injury

Ocular injury can be attributed to a wider diversity of noxious stimuli than is true of any other tissue. Most organs are injured by only one or two types of agents on a regular basis, and suffer injury only infrequently from other types of processes. The eye is quite commonly injured by such a wide diversity of agents as ultraviolet irradiation, nutritional excesses and deficiencies, toxicities, infectious agents of all types, physical trauma, desiccation, genetic disorders, immune-mediated phenomena, and neoplasia.

Although diseases that initially affect the eye rarely result in disease in other tissue, the converse is not true. The eye may be affected by disease in other tissues when its structural or physiologic barriers (i.e., the blood-ocular barrier, retinal vascular autoregulation) are insufficient to maintain ocular homeostasis. Examples are ocular manifestations of systemic infectious disease, metastatic neoplasia, hypertension and diabetes, and systemic nutritional deficiencies and toxicities.

Consequences of Ocular Injury

At the cellular level the reaction of ocular tissue to injury is the same as elsewhere, and depends on the nature, duration, and severity of the insult. The response to the injurious stimulus is

one or more of the following: resistance, adaptation, injury, containment, and repair.

Like any other tissue, the various ocular tissues are not without intrinsic resiliency and may successfully resist mild and transient injury. Alternatively, mild injury may simply be absorbed without any detectable change in ocular homeostasis. More substantial injury, particularly if prolonged, will likely trigger one or more adaptational changes, and even more severe/persistent injury may cause cell death (necrosis). In most instances such necrosis is then followed by some form of inflammatory reaction intended to neutralize or otherwise contain the injurious agent. Such containment is then followed by tissue repair, ordinarily including varying proportions of fibrosis and parenchymal regeneration.

The various ocular tissues continuously interact with innumerable internal and external environmental stimuli. The outcome of that ongoing interaction is the dynamic equilibrium that we casually refer to as “normal.” The definition of “normal” is always subjective and is greatly influenced by the sensitivity of the techniques we use to detect abnormalities.

When faced with an environmental challenge that exceeds their resistance (yet is not severe enough to cause outright necrosis), the various parts of the eye respond with gradual transformation into one or more adaptational states: hypertrophy, hyperplasia, metaplasia, dysplasia, and atrophy. A stimulus that exceeds adaptational capacity triggers degeneration and, if severe, necrosis. The same stimuli, if applied to the globe during its prenatal or postnatal development, can result in various degrees of developmental arrest known as agenesis, aplasia, or hypoplasia.

Agenesis, Aplasia, Hypoplasia

Agenesis, aplasia, and hypoplasia reflect varying severities of developmental arrest in which the organ primordium is absent (agenesis), has failed to develop beyond its most primitive form (aplasia), or has failed to complete its development (hypoplasia). Because the eye of some species (notably, dogs and cats) continues to develop for many weeks after birth, there is ample opportunity for hypoplasia to occur in response to postnatally acquired stimuli. In the eye one must therefore always be careful to distinguish truly congenital (present at birth) from developmental (occurring at any time during development) stimuli.

Hypertrophy

Hypertrophy is defined as an increase in tissue mass because of an increase in cell size. It is most commonly encountered as hypertrophy of the retinal pigment epithelium (RPE) subsequent to retinal detachment of more than a few hours’ duration. It is a rapid, reliable, and more or less specific change that allows one to separate genuine detachment from artifact (Figure 4-1). Hypertrophy is also seen in many other ocular tissues as a prelude to replication, such as occurs with hypertrophy of iris endothelium preparatory to the development of a preiridal fibrovascular membrane, hypertrophy of corneal stromal fibroblasts in the early stages of stromal repair, and hypertrophy of lens epithelium at various stages of cataract formation.

Hyperplasia

Hyperplasia is defined as an increase in tissue mass because of an increased number of cells. It may or may not be accompanied

FIGURE 4-1. Focal hypertrophy of the retinal pigment epithelium at a site of serous retinal detachment. Degeneration of the photoreceptors and of the neurons within the outer nuclear layer indicates that this detachment has been present for at least several weeks.

by hypertrophy of the same cells. In general, hyperplasia is the more efficient response to a need for more tissue mass in all tissues that are capable of mitotic replication. It is seen under many of the same circumstances as hypertrophy, and is relatively less common in the eye than it is in most other tissues because so many of the ocular tissues have limited or no proliferative capability. Many of the most dramatic examples of hyperplasia within the eye are combined with metaplastic changes, as described later. In most instances hyperplasia within the eye is seen as a transient phase of tissue regeneration that precedes eventual normalization of the reparative tissue mass. It is seen in conjunctival and corneal epithelium following any kind of injury and may remain in a permanently excessive state in the form of an epithelial facet (a plaquelike corneal epithelial thickening). Similarly, it may remain as a plaque of hyperplastic lens capsule epithelium in the form of an anterior capsular or subcapsular cataract (Figure 4-2).

Atrophy

Atrophy implies the reduction of tissue mass at some point after the tissue had reached its full development. Causes are as diverse as ischemia, denervation, lack of hormonal or other trophic stimulation, disuse, and loss of mass due to degeneration or necrosis. Within the eye “atrophy” is used most frequently to describe senile iris atrophy and pressure-induced glaucomatous atrophy of ciliary processes, retina, and optic nerve, and as a relatively imprecise umbrella for a group of so-called retinal atrophies (Figures 4-3 and 4-4).

The retinal atrophies comprise a very mixed group of syndromes that can be called “atrophies” only in the most superficial way. They include several congenital photoreceptor dystrophies, in which the clinical and histologic lesions are delayed in onset, and others in which the mechanism of socalled atrophy is outright necrosis (as with viral retinopathies and those caused by light or toxins).

Metaplasia

Metaplasia is the conversion of one adult tissue type into another, related and more durable, tissue type. The most prevalent examples are conversion of fibrous tissue into bone, or columnar

FIGURE 4-3. Normal canine retina. Note the density of the outer nuclear layer (ARROW) and the long, slender photoreceptors that contact the surface of the inconspicuous cuboidal cells that represent the retinal pigment epithelium (RPE). The tapetum (T) and pigmented choroid are shown external to the RPE.

mucosal epithelium into stratified squamous epithelium. The usual stimulus seems to be the need to adapt to a more hostile environment by acquiring a more durable cellular phenotype. Metaplasia is a relatively uncommon reaction in most tissues, but it is a particularly prevalent and clinically important reaction within the eye. Common examples are so-called cutaneous metaplasia of the cornea in cases of chronic keratoconjunctivitis sicca or exposure keratitis, under which circumstances the cornea seems to recall its embryologic origins as skin, and thus undergoes keratinization, pigmentation, and vascularization (Figures 4-5 and 4-6). In this instance metaplasia is a protective

FIGURE 4-6. Clinical counterpart of corneal cutaneous metaplasia, in a dog with chronic keratoconjunctivitis sicca.

adaptation, because the epithelium shifts to a phenotype more able to withstand dryness or chronic abrasion. Similarly, conjunctiva commonly undergoes metaplasia to a stratified squamous (and sometimes keratinized) epithelium in response to chronic irritation.

Other important examples of metaplasia occur inside the eye as fibrous metaplasia of corneal endothelium, lens epithelium, ciliary and iris epithelium, and RPE. All of these tissues are capable of fibrouslike metaplasia and quite substantial proliferation, creating retrocorneal, transpupillary, cyclitic, and retroretinal fibrous membranes. The significance of these membranes varies with location: Those crossing the pupil create the risk of blocking the outflow of aqueous humor and thus can cause glaucoma, whereas in other locations they may impair the passage of light or the diffusion of nutrients.

The most remarkable example of metaplasia is the development of lens fibers within injured bird retina (lentoid bodies). Such dramatic metaplasia defies our current understanding of ocular embryology, in that lens supposedly is of purely epithelial origin and theoretically cannot arise as a metaplastic phenomenon within the neuroectodermal retina.

Dysplasia

Dysplasia means disorderly proliferation. The term can be used in an embryologic context to signify disorderly development of a tissue, in the context of wound healing to imply a transient jumbling of tissue organization that precedes normalization, or in a neoplastic context to describe the state of disordered proliferation that is a prelude to malignant transformation. In ocular pathology we use it in all three contexts. Familiar examples are jumbled retinal development that may be inherited or may follow viral or chemical injury to the developing retina (Figures 4-7 and 4-8), conjunctival or corneal epithelial dysplasia that is a prelude to actinic squamous cell carcinoma, and nonneoplastic jumbling of corneal epithelium in any healing corneal ulcer (see Figure 4-5).

FIGURE 4-7. Disorderly repair within a neonatal canine retina injured by canine distemper virus infection. Although this is technically a postnecrotic retinal “dysplasia,” the appearance is completely different from that of the retinal folds and rosettes seen in the idiopathic inherited dysplasias that occur in many breeds of dogs.

FIGURE 4-8. Disorganized retinal development in a dog with inherited retinal dysplasia. The rosettelike structures most often represent transverse sections through retinal folds, which in turn probably represent redundant retina in a globe with an imbalance between retinal and choroidal/scleral growth.

Dystrophy

The much-abused term dystrophy is strictly defined as degeneration caused by tissue malnutrition, but hardly anyone uses it in that fashion. It tends to be used to describe a variety of juvenile or adult-onset degenerative diseases that have a presumed congenital basis. Ocular examples are several degenerative corneal diseases characterized by adult-onset stromal deposition of lipid or mineral, and unexplained progressive degeneration of corneal endothelium that is clinically observed as progressive diffuse corneal edema (corneal endothelial dystrophy). Using this definition, one should classify many of the inherited photoreceptor atrophies (so-called progressive retinal atrophies) as dystrophies.

Necrosis

Any tissue subjected to an injurious environmental stimulus beyond its adaptational range will undergo lethal injury, termed necrosis. Most such injuries affect cell membranes and result in defective regulation of transmembrane ion exchange. Particularly critical is an influx in calcium from the calcium-rich extracellular fluid. When present in excess within the intracellular environment, calcium is a powerful cytotoxic agent that, among many other activities, disrupts oxidative phosphorylation within the mitochondria and triggers hypoxic cell death. The morphologic outcome of the membrane damage and energy paralysis is cellular swelling, hydropic disruption of the cytocavitary network, irreversible mitochondrial swelling, and eventually, irreversible damage to nuclear chromatin that manifests as the familiar histologic hallmarks of necrosis: nuclear pyknosis, karyorrhexis, and karyolysis.

Although necrosis is obviously a significant event because such dead cells lose all function, we are often more able to detect the sequelae of necrosis than the actual necrosis itself. These sequelae may relate to the loss of barrier function, electrical activity or secretory function, or to the initiation of inflammation and healing.

LOSS OF BARRIER FUNCTION. Normal ocular function depends on the preservation of numerous critical barriers to maintain ocular clarity. For example, we ordinarily detect corneal

epithelial necrosis only because the underlying hydrophobic collagenous stroma osmotically imbibes the water from the tear film, resulting in rapid localized corneal opacity (Figures 4-9 and 4-10). Staining of the defect by fluorescein to facilitate clinical detection operates on exactly the same principle, as this hydroscopic dye binds to the now-exposed collagenous stroma. Similarly, necrosis of corneal endothelium results in deep corneal stromal edema, and necrosis of lens epithelium results in hydropic swelling of the normally dehydrated lens fibers, which we detect as cataract (see Figure 4-2). Loss of the endothelial tight junctions (as in vascular hypertension, infection with such organisms as the rickettsiae of Rocky Mountain spotted fever) within the iris or choroidal blood vessels results in serous effusion or even hemorrhage, which interferes with the clarity of the ocular media, or more serious consequences of retinal ischemia.

LOSS OF ELECTRICAL ACTIVITY. Necrosis within the retina, if extensive, may be detected as alterations in vision or as changes in the electroretinogram. Focal necrosis may be detected

4-9. Diffuse corneal edema in a horse. The absence of conjunctival vascular reaction suggests that the cause is probably diffuse corneal endothelial disease (lens luxation, glaucoma, or immune-mediated injury).

FIGURE 4-10. Histology of corneal edema. The normal stroma is diluted by the accumulation of fluid, changing the refractive index of the cornea and causing the characteristic gray opacity noted on clinical examination.

only by noting an increase in the tapetal reflex, because the necrosis (especially if it involves the outer nuclear layer and photoreceptors) causes a focal thinning in the light-absorbing retina. Necrosis of the tapetum itself would create a focal fundic black spot as the normally hidden pigmented choroid becomes exposed.

LOSS OF SECRETORY FUNCTION. Damage to the ciliary epithelium results in a profound reduction in the production of aqueous humor. This reduction explains, in part, the routine observation of transient ocular hypotension during uveitis of any cause. We use it to our advantage in the management of glaucoma when we attempt to selectively destroy ciliary epithelium by transscleral application of cold or laser energy to the ciliary body.

INITIATION OF INFLAMMATION: THE FIRST STEP TOWARD NORMALIZATION. It is paradoxical that our first clinical clue that there is something wrong with the eye is often the detection of inflammation because, in fact, inflammation is actually the first step in the repair process. In any tissue, cell death triggers a localized inflammatory reaction intended to ingest and remove the dead tissue. The mechanisms by which cellular injury triggers inflammation are several: release of chemicals from injured cell membrane (particularly prostaglandins) that act as direct inflammatory mediators, release of inflammatory mediators from other cells within the neighborhood (particularly mast cells or platelets), and activation of latent mediators within the plasma that frequently pools in areas vacated by recently destroyed parenchymal cells. In addition to the generation of chemicals intended to trigger the inflammatory response, these same events usually generate locally acting growth factors that stimulate parenchymal regeneration and fibrovascular stromal repair once the hostile events of inflammation have subsided. During the interval between necrosis and eventual repair, the injured tissue is frequently involved in profound inflammation that may be much more obvious, and more significant, than the tissue injury that triggered it. Although it is true that necrosis of any cause will trigger some inflammation, necrosis is not the only trigger. In fact, in most situations it is not the most potent initiator of inflammation (infectious agents and immune phenomena are more prevalent and more potent causes).

Ocular inflammation and subsequent repair are of such importance that they deserve specific consideration as separate topics.

OCULAR INFLAMMATION

Philosophically, inflammation should be considered a transient, controlled vascular and cellular response by living tissue to injury of almost any type. That response should be qualitatively and quantitatively appropriate to the nature of the tissue injury, and it should serve to neutralize and remove the injury’s stimulus while also laying the groundwork for parenchymal and stromal repair. In evolution, inflammation probably first appeared as a débridement phenomenon, whereby macrophages or their equivalent would move into injured tissue, clear up the debris, and prepare the way for healing to occur. We now know that this débridement itself consists of at least two simultaneous phenomena, namely, the removal of tissue debris and the production of various growth factors that initiate the subsequent tissue repair. Later in evolution the inflammatory process assumed a more defensive role, tightly integrating with the