Chapter 4 General Pathology of the Eye
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.
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.
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.
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, 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 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 is defined as an increase in tissue mass because of an increased number of cells. It may or may not be accompanied 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 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).
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.
Figure 4-4 Photoreceptor atrophy in a canine retina. Only a clubbed vestige of the photoreceptors remains. This could be either inherited retinal atrophy or retinal atrophy secondary to prolonged detachment.
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 so-called atrophy is outright necrosis (as with viral retinopathies and those caused by light or toxins).
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 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 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.
Figure 4-5 Corneal cutaneous metaplasia in a dog with chronic corneal irritation from entropion. Irregular epithelial hyperplasia, keratinization, pigmentation, and superficial stromal fibrosis are present. This is a universal response of cornea to any type of prolonged, mild to moderate injury (e.g., chronic desiccation, any 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 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.
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.
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.
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.
Figure 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).
Necrosis within the retina, if extensive, may be detected as alterations in vision or as changes in the electroretinogram. Focal necrosis may be detected 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.
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.
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).
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 dèbridement 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 dèbridement 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 immune system to recognize and destroy a variety of infectious and noninfectious “foreign” agents.
The major mechanical and chemical events of inflammation do not differ among the various mammalian species. Considered here are those aspects of inflammation that have particularly important consequences for the eye or that are somehow modified by peculiarities of ocular anatomy or physiology.
When it works as it should, the inflammatory reaction is a beneficial physiologic reaction that is limited only to the immediate area of injury. It should persist only as long as is necessary for its defensive and dèbridement activities, and it should selectively recruit only those body defenses most effective in combating the specific injurious agent. Inflammation should thus exhibit a remarkable degree of moderation and specificity so that there is no undue injury to bystander tissues or to the overall health of the animal. This remarkable balancing act is achieved by the local release of a wide range of chemical mediators that reside within normal parenchymal tissue, within leukocytes or platelets, and within the plasma itself. It is not practical to attempt to list all of the inflammatory mediators, their origins, and their physiologic activity. Not only does this list grow almost daily, but such lists tend to reinforce the mistaken view that a given mediator has a specific, invariable biologic activity.
Like letters of the alphabet, each inflammatory mediator is a hormonelike member of a complex biologic alphabet. Each “letter” may thus have many different meanings, depending on the company it keeps and in what sequence the letters occur. These inflammatory mediators are part of a larger group of locally acting hormonelike messengers called cytokines, so named because they stimulate some kind of proliferative activity on the part of neighboring cells. These cytokines create the biologic language that carries the instructions for everything from coordinated embryologic development to orderly cell death (apoptosis). One must thus read the supposed activity of any given cytokine with substantial skepticism, because there is no guarantee that the activity that we have determined by in vitro testing of isolated mediators at arbitrary dosages has anything to do with their in vivo activity at physiologic dosages and in the company of many other members of the cytokine alphabet.
Although our understanding of the chemical mediation of inflammation and repair is still quite primitive and is largely limited to making lists of the chemicals involved, we know quite a lot about the mechanical events of inflammation. These events represent a stepwise, highly integrated chronologic sequence that involves changes in microvascular blood flow, endothelial permeability, leukocyte migration, humoral and leukocyte-dependent neutralization of foreign material, and tissue dèbridement preparatory to parenchymal and stromal repair.
The initial events of inflammation involve microvascular dilation (hyperemia) and endothelial cell contraction to increase the permeability of postcapillary venules to plasma solutes. This creates the redness and serous effusion that typify early inflammation, and that will continue as long as the active phase of inflammation persists. These early events are stereotypic: They are identical regardless of the stimulus, and they have no diagnostic specificity in terms of predicting what type of injury might have occurred. They occur in response to the rapid release of preformed chemical mediators such as histamine from mast cells or platelets within the region of initial injury. These short-acting vasoactive mediators are then reinforced by a wide variety of mediators that are synthesized de novo from parenchymal cells, leukocytes, and other cells at sites of inflammation.
This serous effusion that characterizes the very early stages of inflammation is beneficial, because it serves to flood the region with a substantial array of such activated humoral defenses as complement and some broadly acting antibodies as well as to engender the leakage of fibrinogen, which will then create the fibrin scaffold that will enhance both the migration and the phagocytic efficacy of the leukocytes that follow.
Within minutes of the initiation of the preceding changes in vascular permeability, leukocytes begin to settle out of circulation, bind to endothelial cells, migrate through the now-permeable endothelial junctions, and then move through the tissues in search of the cause of tissue injury. We have recognized for many years that the types of leukocytes recruited carry substantial diagnostic value, because certain types of infectious agents or immune responses habitually recruit specific types of leukocytes. As a rule neutrophil-dominated inflammation is equated with bacterial infection, eosinophils predict hypersensitivity reactions, especially to parasites, and macrophage-dominated (granulomatous) inflammation is restricted to cell-mediated immune events and to inflammation initiated by a relatively small group of poorly degradable infectious or noninfectious agents. Only recently, however, has the basis for that sometimes remarkable specificity become apparent.
Part of the answer lies in the mixture of mediators/cytokines that are triggered by certain types of infections, but there was always an inexplicable problem: Most described chemotactic mediators have a fairly broad range of activity, so that many of them attract neutrophils, eosinophils, and macrophages with almost equal avidity. How, then, could we explain the empiric observation of almost purely eosinophilic infiltrates in some parasitic diseases, or purely neutrophilic infiltrates in many bacterial infections? The answer seems to lie in a second level of leukocyte “screening” that occurs at the level of the endothelial cells themselves. The locally generated inflammatory mediators rapidly stimulate the expression of leukocyte-specific adhesion molecules on the surface of the venular endothelium, which will bind only to complementary receptors on the surface of stimulated leukocytes that have fallen under the influence of these same local mediators. Thus, although the general chemotactic stimulus may attract many different leukocyte types into the permeable venules, only those leukocytes that can pass this second screening test will actually be allowed to enter the tissue to take up the “search-and-destroy” mission.
The leukocytes that thus enter the tissue become intermingled with the serum and fibrin that may already have accumulated because of the previous increase in vascular permeability, and these mixtures form the inflammatory exudates that for years have formed the basis for the prediction of disease causation based on histologic or cytologic evaluation of such exudates. These exudates are not static but are constantly changing in amount and in cellular and humoral makeup according to the ever-changing nature of the battle between the injurious agent and the tissue defenses. In its simplest form these changes may be nothing more than a gradual reduction in the intensity of the vascular response and leukocytic recruitment as the humoral and cellular defenses accomplish their task of diluting and destroying the offending agent. On the other hand, the nonspecific humoral and cellular defenses may become modified by the addition of specific immune responses as the battle continues. These immune responses act, in general, to improve both the specificity and the efficacy of what at first are relatively broad and nonselective defensive strategies.
The purpose of these defenses is to confront and destroy the offending agent. In some circumstances this is a messy affair, with spillage of leukocyte contents or excessive diffusion of humoral cytotoxic chemicals (like complement fragments) into the local environment. The resulting bystander injury is a substantial and undesirable side effect of inflammation, and it is sometimes a justification for intervening with drugs to dampen the inflammatory response.
The eye seems reluctant to become involved in inflammatory disease, and for good reason: The visual function of the eye is easily disturbed and is sometimes destroyed by minor degrees of inflammation that would be considered inconsequential in most other tissues. The blood-ocular barrier, the protective presence of eyelids, the tear film, the bony orbit, and a carefully regulated system of intraocular immune tolerance all seem designed to spare the globe from the need to participate in inflammatory responses (inflammation is a second level of defense to be triggered in any tissue only when the primary structural barriers have failed). When the intraocular tissues do become involved in an inflammatory reaction, the outcome is strongly influenced by the following three unique factors: