Chapter 1
Pathologic Principles of Ophthalmic Disease
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An understanding of the underlying principles of fundamental processes can be extremely helpful to the ophthalmologist in dealing with novel clinical problems.

Pathologic processes are those that deviate from the normal function of cells and tissues, all of which are controlled at the molecular level by protein messengers or electrical signals. The clinical relevance of deviations in basic control systems is best appreciated at the cellular and tissue level. The tissue level of change can be observed clinically either by gross inspection or by using optical illuminating and magnifying tools (e.g., the slit-lamp, biomicroscopy, and indirect microscope). The cellular level can be appreciated at high magnification with clinical tools; using light and electron microscopy best demonstrate this level in detail. Thus, clinical abnormalities can be identified with clinical methods and understood at the cellular level, and then manipulated surgically at the tissue level or pharmacologically at the molecular level.

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After conception, the embryo implants in the uterine wall and creates a cellular plate between the yolk sac and the amnionic sac. The cells of the embryonic plate subsequently divide into three distinct cell lines: the ectoderm, the mesoderm, and the endoderm. The ectoderm and the mesoderm are influential in forming the eye and supportive tissue. The ectoderm further divides into the neuroectoderm and the neural crest. The neuroectoderm forms all of the light- sensitive structures of the eye; the neural crest forms the majority of the supportive structures of the eye and orbit. The surface ectoderm forms the primary, light-focusing elements of the eye; the anterior cornea; and the crystalline lens. The posterior corneal stroma, the anterior iris, and the filtration apparatus of the anterior chamber angle are formed by neural crest tissue (Table 1).


TABLE 1-1. Germ Layers, Structures Formed, and Abnormalities of Differentiation

Germ LayerMature Structures FormedAbnormalities of Differentiation
 Neural ectodermNeurosensory retinaPrimary anophthalmia
 Retinal pigment epitheliumCongenital hyperplastic retinal pigment epithelium
 Neural crestUveal tractMelanocytic nevus
 Trabecular meshworkReiger's syndrome
 Posterior corneaPeters' syndrome
 Surface ectodermCorneal surfaceCryptophthalmos
 Crystalline lensAnterior ulcer of von Hippel
MesodermVascular endotheliumHemangioma
EndodermNot represented in the eye 


The migration and the differentiation of cells are two of the critical processes in the development of the eye. Abnormalities of migration and differentiation can lead to specific clinical entities.

Failure of cells to differentiate at critical times during development (e.g., such as at uterine implantation) may cause loss of the developing embryo (spontaneous abortion). Failure of differentiation of cells of the primary eye fields in the neuroectoderm may result in primary anoplithalmia. Differentiation of neural crest-derived cells proceeds normally in anophthalmia, thus orbital structures such as the rectus muscles and orbital bones are represented.

Dendritic melanocytes normally originate in the neural crest and migrate to their final functional site in the basal layer of the surface ectoderm. If migration is impeded in the deep orbital tissues, abnormal melanocytes form a congenital “blue nevus.” If migrating melanocytes fall just short of the surface epithelium, usually in the skin adnexal units, a junctional nevus is formed (Fig. 1). Similarly, a limbal dermoid results from abnormal proliferation and differentiation of neural crest-derived cells in an abnormal location. Although the cells and their cell products are normal, the tissue has no functional role in the area.

Fig. 1. Neural crest tissue provides supportive tissue and melanocytes for the head and neck. The tissue must migrate from its site of induction adjacent to the neural crest over great distances to its final site of differentiation. Illustrated here is the migration of cells destined to be dendritic melanocytes in the surface epithelium of the skin. Abnormalities in migration patterns give rise to clinically observable abnormalities such as a deep blue nevus or a junctional nevus. Distinguishing between these two abnormalities is clinically important because the risk of malignant transformation of a junctional nevus is much greater than that for a deep blue nevus.

Peters' syndrome is a condition resulting from faulty separation of the lens vesicle (an ectodermally derived tissue) from the posterior cornea (a neural crest-derived tissue). Clinically, the hallmark is central, posterior corneal opacity; histologically, it is a defect of variable extent in Descemet's membrane and posterior corneal stroma (see Table 1).

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Trauma usually involves disruption of cells or disruption of cell structural support, which translates into disruption of tissue and loss of function. Entire organ systems may be lost because of extensive degrees of injury. Disruption of cell membranes may be either physical or biochemical.

The cell membranes of all cells are composed of phospholipids. The phospholipid membrane is the interface at which the cells responds to and influences its environment. Phospholipids are soluble at alkaline pH.

Alkali injuries are particularly destructive because alkali dissolves all cell membranes with which it comes in contact. Once the surface cells have been destroyed, alkali is free to diffuse deeper into the tissue, where it can lyse both surface and vascular endothelial cells (Fig. 2). Involvement of vascular endothelial cells compounds the injury by adding downstream ischemia. Diffusion continues until the pH is neutralized.

Fig. 2. Alkali agents dissolve cell membranes, allowing the alkali agent to diffuse into adjacent tissue, injuring other cells. Acidic agents coagulate proteins, causing the formation of a relative barrier to diffusion and limiting damage to the superficial tissue.

Acid injuries are usually more limited because acid causes denaturation and precipitation of cellular proteins. A diffusion barrier is thus created to limit damage to deeper tissues. (see Fig. 2)

Mechanical trauma may be focused, as occurs from a concentrated application of pressure (e.g., a steel knife cutting through tissue) or unfocused, as occurs from blunt trauma. Cell death is present on both sides of even the sharpest knife wound because of the transection of cell processes. The death of corneal keratocytes, which have extensively arborizing cellular processes, may extend several microns on either side of a corneal incision. Corneal opacification occurs in the area normally maintained by damaged or dead keratocytes.

Blunt trauma may cause simultaneous injury to cells in a large area, as occurs with a corneal abrasion; it may also deform large segments of tissue. The vulnerability of specific ocular tissues varies greatly (Table 2). Elastic tissue, such as Descemet's membrane, the crystalline lens capsule, the zonular fibers of the lens, and Bruch's membrane have a limited range of deformability; beyond it they will rupture. Tightly adherent structures, such as the iris root and the longitudinal ciliary muscle inserted into the scleral spur, concentrate pressure and may also rupture. Transparent structures, such as the cornea, crystalline lens, and retina must maintain homogeneity to maintain transparency. Trauma frequently results in dyshomogeneity sufficient to cause opacification. When hydrostatic pressure is increased suddenly, pressure is transmitted throughout the globe, seeking sites of relative weakness. These sites include the sclera at the limbus, which is relatively thin to accommodate the structures of the trabecular meshwork; the point of insertion of the rectus muscles, and the optic disc (see Table 2).


TABLE 1-2. Ocular Tissue Vulnerable to Mechanical Trauma

Elastic natureDescemet's membraneRupture (forceps injury)
 Lens capsuleRupture (traumatic cataract)
 Zonular fibersRupture, disinsertion (lens dislocation)
 Bruch's membraneRupture (choroidal rupture)
ThinLimbusRupture of limbus
 Rectus muscle insertionScleral rupture
 Superior oblique insertionScleral rupture
 Lamina cribrosaAvulsion of optic nerve
AnchoredIris insertionIridodialysis
 Scleral spurCyclodialysis (hypotony)
 Vitreous baseRetinal dialysis
TransparentCorneaCorneal opacity
 Crystalline lensCataract
 RetinaRetinal Opacity


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Inflammation is one of the body's active, or reactive, methods of protecting tissues and organs. Other and more passive protective mechanisms include keratinization of the skin, which prevents excessive tissue fluid loss and exposure to environmental antigens. Tears dilute and mechanically remove surface agents; they also contain active antibacterial agents (lysozymes).There are three levels of inflammation; each has a different function and outcome.

Acute inflammation is the most primitive level and usually results in destruction of material or of organisms sensitive to the numerous degradative enzymes and oxidative processes that characterize it. Enzymes are carried in protective packets within the cytoplasm of polymorphonuclear leukocytes; they are formed in the bone marrow and brought to the site of tissue abnormality through vascular channels. In the region of injury, the vascular endothelial cell membrane changes its normally nonadhesive surface to one that attracts white blood cells. Endothelial cells separate from each other to create spaces large enough for passage of the white blood cells from the vascular lumen to the extracellular matrix external to the vessel (diapedesis). White blood cells then follow a trail of protein or other signals emanating from the site of injury (chemotaxis). The polymorphonuclear leukocyte initially attempts to remove noxious agents by internalizing (phagocytosis) and degrading the material through controlled exposure to the destructive enzymes carried by the cell. If noxious material overwhelms the cell, it simply dissolves and externalizes the enzymes into the immediate environment, allowing uncontrolled action of the destructive enzymes. The end result may be destruction of extensive areas of tissue, including areas of normal adjacent tissue (Table 3).


TABLE 1-3. Characterization of Inflammatory Cells

Cell TypeCytologic CharacteristicsFunction
Polymorphonuclear leukocytesNucleus: multilobulatedDestruction of organisms and damaged tissue with proteolytic enzymes and oxidation
 Cytoplasm: spherical inclusions
EosinophilsNucleus: bilobedInfluence blood vessels function
 Cytoplasm: spherical inclusions 
BasophilsNucleus: bilobedProduce vasoactive amines
 Cytoplasm: coarse basophilic granules 
Mast cellsNucleus: central blandProduce vasoactive amines
 Cytoplasm: featureless 
LymphocytesNucleus: large, homogeneousMultiple roles in recognition and destruction of protein components threatening to cell function
 Cytoplasm: inconspicuous
Plasma cellNucleus: eccentric; “clock face”Product antibodies
 Cytoplasm: paranuclear “halo” 
Epitheloid histiocyteNucleus: single, central locationProcess antigens, macrophagic
 Cytoplasm: similar to epithelial cells 
Foreign body giant cellNucleus: multiple, randomReaction to foreign materials, fungi
 Cytoplasm: abundant, amorphous 
Langerhans giant cellNucleus: multiple, peripheralAssociated with tuberculosis
 Cytoplasma: abundant, amorphous 
Touton giant cellNucleus: multiple, midperipheralAssociated with lipid abnormalities
 Cytoplasm: peripheral lipid 


Other cell types active in acute inflammatory processes include eosinophils, mast cells, and basophils; they secrete vasoactive substances to influence blood vessel function during allergic reactions.

At the second level of inflammation, chronic nongranulomatous inflammation, lymphocytes and macrophages operate in a more sophisticated and less destructive manner. Although an acute inflammatory reaction ends with destructive chaos, a chronic inflammatory reaction initiates the reparative processes of all tissues of the body. Even though mature lymphocytes appear with light microsopy to be similar, the functions of lymphocytes are markedly diverse. Some cells are capable of producing antibodies; during this process they evolve morphologically to form plasma cells. Other cells retain their nondescript appearance but are capable of completely destroying the cell membranes of other cells. Still other lymphocytes are able to produce protein signals (cytokines) to influence fibroblasts, which, in turn, may influence other cells (e.g., superficial squamous epithelial cells). These end-user cells may then produce cytokines themselves to complete the feedback loop, resulting in a carefully controlled, nonchaotic system. However, the reparative tissue never regains the functional diversity or the specialization of the original tissue.

The final level of inflammation is the most specific of all. The small, so-called granules of reactive tissue noted grossly in specific inflammatory reactions led to the term, granulomatous inflammatory reaction. The granules, which represent accumulations of activated mononuclear inflammatory cells, have a generous amount of cytoplasm and resemble a simple surface epithelial cell; they are thus called epithelioid histiocytes. Activation usually occurs when the cells encounter large quantities of poorly digested antigens or of organisms that can proliferate intracellularly. In the presence of complex stimuli, epithelioid histiocytes duplicate nuclear material without the associated division of cell cytoplasm, resulting in the formation of multinucleate giant cells. There are three types of multinucleate giant cells: Langhans giant cells, which have a peripheral ring of nuclei (associated with tuberculosis); Touton giant cells, which have a midperipheral ring of nuclei surrounded by a peripheral ring of lipid (associated with xanthogranulomatous disease); and foreign body giant cells, which have randomly dispersed nuclei (associated with foreign material and fungi). The presence of granulomatous inflammation limits disease categories to a rather small number, such as infection with complex microorganisms (e.g., fungi) or complex foreign material (e.g., wood fragments).

In many clinical settings, the inflammatory process itself may be abnormal. Sarcoidosis is the disregulation of chronic granulomatous inflammation expressed as noncaseating granulomas in multiple organ systems, particularly in the hilar lymph nodes of the lung. Inappropriate phagocytosis or inability to process ingested material may produce skin lesions (e.g., as found in Xanthelasma) composed of histiocytes (tissue macrophages) filled with lipid material. Disruption or circumvention of intracellular mechanisms that usually destroy ingested bacteria may lead to diseases such as tuberculosis and lepromatous leprosy. Similar abnormalities are seen in acquired immunodeficiency syndrome (AIDS), in which organisms such as Mycobacterium avium-intracellulare accumulate and apparently proliferate within macrophages. Macrophages or lymphocytes may inadvertently transport viruses or other infective particles and cause diseases such as spongiform encephalopathy (Creutzfeldt-Jakob disease). Cell-mediated destruction may result in such clinically unfavorable outcomes as corneal graft rejection. Apparent shared antigens may also cause disease in completely separate organ systems, as occurs in Graves' disease, in which there is tissue stimulation of both thyroid follicles and of extraocular muscle tissue.

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Control of fluid movements and maintenance of fluids in compartments is essential to the function of the eye. The cornea maintains its transparency, in part, by control of the amount of water in proteoglycans within the corneal stroma to allow the precise, homogeneous spacing between collagen fibers that allows transmission of light. Similarly, control of fluid movements is necessary to maintain transparency in the lens and the retina. On a larger scale, the distance between the anterior surface of the cornea and the photoreceptor's outer segments must be maintained by control of the volume of water in the anterior chamber, the posterior chamber, and the vitreous. The aqueous is produced by the ciliary epithelium of the pars plicata; the vitreous is produced and maintained by the epithelium of the pars plana and the peripheral retina. The actual cytokines and other protein signals responsible for stimulation and feedback of the cells directly influencing water movements are not precisely known. For example, it is known that agents such as beta blockers and carbonic anhydrase inhibitors can influence the production of aqueous humor. The steady state of the gross movement of fluid in the eye depends on production and outflow. The major site of impeded drainage has been identified in the juxtacanalicular connective tissue dividing the trabecular meshwork from the canal of Schlemm.

Abnormalities leading to dysfunction of the corneal endothelial cells include Fuchs' endothelial dystrophy and direct damage to endothelial cells during cataract removal (pseudophakic bullous keratopathy). A major function of endothelial cells is maintenance of the corneal stroma in a state of dehydration, relative to the sclera. During endothelial pump failure, water accumulates in the proteoglycans of the corneal stroma; the spacing between the collagenous fibers increases and becomes dyshomogeneous, resulting in impaired transmission of light. This change is recognized clinically as diffuse translucency of the corneal stroma (corneal edema). With an increase in hydration, the surface epithelial cells loosen, allowing fluid to accumulate in the subepithelial space (subepithelial bullae). If the bullae become large enough to burst, the corneal stroma will be vulnerable to infection, and corneal ulceration, corneal perforation, and occasionally, spontaneous suprachoroidal hemorrhage with loss of intraocular contents, may follow.

Glaucoma is caused by an imbalance between aqueous production and outflow; the vitreous does not appear to play a role in the fluid shifts found in most cases of glaucoma. Most, if not all of the abnormalities leading to increased intraocular pressure, are due to abnormalities of outflow. The sclera of children is elastic enough to allow enlargement of the globe and to accommodate a net increase in intraocular fluid volume, resulting in buphthalmos. However, adults have lost sufficient elasticity of the sclera, and an increase in fluid volume increases intraocular pressure. As occurs in any hydrostatic system, the increased pressure is distributed evenly throughout its container. The region of the eye most vulnerable to increased intraocular pressure is the “rim” around the optic “cup” of the optic disc, which is composed of axons from retinal ganglion cells. Losses in axonal bulk can be identified clinically as a characteristic expansion of the central cup.

Abnormalities involving water accumulation and structural changes of blood vessels occur in diabetes mellitus. High concentrations of glucose and other metabolites in the aqueous lead to increased solute load within the lens because of fluid shifts across the lens capsule. Accumulation of fluid changes the shape of the lens, creating increased refractive power, which manifests as induced myopia. If the osmolality of the aqueous returns to normal, vision may return to normal.

The blood vessels of the body depend on insulin to maintain structural integrity. Blood vessels at the capillary level are composed of a lining of vascular endothelial cells arranged in an octagonal pattern. Like most surface cells, the endothelial cell produces a basement membrane as part of its structural makeup. The most active surface of the endothelial cells is its lumenal surface, which determines coagulation properties and adherence of circulating cells (see the earlier section on inflammation). Pericytes, which are found in the basement membrane of endothelial cells, control lumenal flow. The changes that occur with diabetes affect the relationship between the endothelial cell and the pericyte, resulting in a loss of structural integrity that is recognized clinically by the development of microaneurysms, edema, and exudes. Exudates are shifts of high-protein content fluid from the intravascular space to the intraretinal space. As within the corneal stroma, the presence of fluid within the retina disturbs the homogeneity of its cellular makeup and causes decreased transparency. Accumulation of fluid in the macula (diabetic macular edema) is especially detrimental to vision (Table 4).


TABLE 1-4. Structural Changes in the Diabetic Eye

TissueStructural ChangeClinical Consequences
ConjunctivaMicroaneurysmsNone known
CorneaAbnormal basement membraneRecurrent erosion
Crystalline lensIncreased soluteInduced myopia
 Epithelial cell damageCortical cataracts
  Posterior subcapsular cataracts
Anterior chamber angleNeovascularizationIntractable glaucoma
 Lacy vacuolization of the pigment epitheliumPigment dispersion
Ciliary bodyThickening of epithelial basement membraneNone known
 Fibrosis of ciliary processNone known
Posterior uveal tractThickening of choriocapillary basement membraneNone known
Neurosensory retinaLoss of capillary pericytes“Background retinopathy”
 Microaneurysms“Background retinopathy”
 Thickening of capillary basement membraneFocal retinal ischemia
   (nerve fiber layer infarcts)
 Intraretinal neovascularization“Proliferative retinopathy”
 Extraretinal neovascularizationVitreous hemorrhage
 Formation of fibroglial membranesTraction retinal detachment
Optic nerveIntraretinal atrophy and gliosisOptic atrophy


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Enlargement of the cellular mass of the system is essential for ocular development, maintenance, and repair. Not all cells are capable of dividing with the same ease. Surface epithelial cells are constantly being lost and replaced; these cells, such as corneal epithelium, are produced by “stem cells,” thought to be located at the limbus. The stem cells themselves remain relatively undifferentiated and are able to produce daughter cells easily (i.e., the cell type remains within the cell cycle). Certain other cell types, such as the fibroblasts of supportive tissues, are called on to proliferate. Fibroblasts respond to strong healing stimuli in wound healing to produce both additional cells and cell products, including collagen and mucopolysaccharides, known collectively as the extracellular matrix. Such cells can thus be forced back into the cell cycle. Certain other cells are incapable of responding to any type of stimulus to reproduce. Retinal cells cannot replace cells lost through normal attrition or injury (see earlier section on diabetes); they are permanently out of the cell cycle. A balance of stimulatory and inhibitory influences tightly regulates those cells able to proliferate; cellular growth is limited both in number and extent. The spread of new cells along a surface can be limited by “contact inhibition” with adjacent, healthy cells. The new cells are incapable of penetrating adjacent, healthy tissue and usually remain as a cohesive or well-defined group of cells.

In neoplasia, cell growth is uncontrolled, and cells that are normally highly differentiated, such as those of the central nervous system (gliomas), are observed to proliferate. In addition, the newly formed cells are not limited in their growth pattern and may insinuate (invade) normal adjacent tissue and spread to distant sites (metastasize) through preformed channels (lymph vessels, blood vessels, body cavities) to distant sites (Fig. 3). The number of cells in a tumor can increase through one of two mechanisms: production or retention. Examples of both mechanisms can be observed in common intraocular tumors. In retinoblastoma, the genetic controls of proliferation have been lost because of the absence or the dysfunction of a gene on chromosome 13. Retinoblasts accumulate because the so-called turn off mechanism is absent or abnormal. In choroidal melanoma, it is thought that the longevity of the tumor cells may be extended, allowing a net gain in the number of tumor cells. Few mitotic figures are observed in malignant melanoma, except in the most aggressive and undifferentiated types.

Fig. 3. Progression of successive generations of cells from normal to neoplastic to malignant.

In both instances, excess cells are a threat because they occupy extra space, and tumor cells that lose intracellular cohesiveness are able to spread through adjacent normal tissue and even to distant sites.

In retinoblastoma, tumor cells migrate posteriorly along the optic nerve toward the brain, similar to the migration of axons from retinal ganglion cells to the lateral geniculate during normal embryonic development. The migrating cell mass destroys the normal tissue it encounters, leading to organ dysfunction and death.

Melanoma uses a different route of egress. Malignant melanoma cells are able to breech blood vessel walls and enter the bloodstream. Neoplastic cells acquire unusual adhesive properties that allow them to congregate in specific distant body sites, such as the liver and lymph nodes that are locally destructive to the host organ. Tumor cells may also produce protein signals (e.g., tumor necrosis factor, which causes systemic abnormalities such as anorexia and weight loss).

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Cell renewal systems are imperfect; in fact, some cells are designed to exist for only a discrete time, programmed to die by a process known as apoptosis. One of the clearest examples of apoptosis occurs during the involution of the embryonic hyloidal vascular system during intrauterine development. Incomplete apoptosis can sometimes be identified clinically in retention of the hyloid vascular system, anteriorly as a persistent pupillary membrane or posteriorly as a vascular loop or a glial veil over the optic disc. Other cells appear to lose the ability to maintain a calcium concentration gradient across the cell membrane. Calcium accumulated intracellularly to the point of cell destruction occurs in the process of dystrophic calcification, in which serum calcium is normal but local biochemical conditions have been altered. This process occurs in collagenous structures subjected to repeated stress, such as the sclera anterior to the rectus muscles. Dystrophic calcification occurs in a relatively cell-free environment though processes that are incompletely understood to cause formation of a senile scleral plaque.

The vitreous body is not maintained throughout the life of an individual. At some point after the eye reaches mature size, the relationship between the type II collagen framework and the associated hyaluronic acid and water changes. The lamellar pattern of childhood breaks down to form pockets of free fluid (syneresis). The vitreous shrinks, causing retraction to its site of formation in the region of the ora serrata. The separation of areas of relatively weak attachment posteriorly may lead to bothersome floaters or occasionally, to retinal detachment with potentially serious visual consequences.

One of the most commonly encountered examples of age-related degeneration is formation of a nuclear sclerotic cataract. In this condition, transparency cannot be maintained because so-called spent lens fibers accumulate and degenerate, causing decreased transparency.

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Pathologic conditions are deviations from normal physiologic processes; in many cases, the pathologic process leads to a clinically recognizable pattern. The clinical advantage of knowing the natural history of a pathological process is being able to predict the next step and to plan meaningful intervention. For developmental abnormalities, it is important to be able to distinguish between abnormalities that are stationary and those that are progressive. It is also important to distinguish between ocular entities that are significant only for ocular function and those that may be associated with systemic abnormalities, including possible heritable neoplasia. For inflammatory conditions, it is important to be able to recognize the cause of inflammation and to control the extent of involvement of normal tissue and the ultimate wound healing process. For neoplastic conditions, it is important to determine which changes are local and which conditions threaten life itself.
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