Ophthalmic Pathology Outline
This is a beginner's lesson in ophthalmic pathology, aimed at general pathologists or ophthalmology residents who are just starting their residency.
It is intended to give the essentials on general principles of pathology of the eye.
- Edema - stromal, epithelial (intra- and intercellular, vesicles)
- Inflammation - most moderate to severe keratitis will have reflex iridocyclitis (due to common blood vessels at limbus) - sometimes severe enough to get hypopyon; also get reverse (including corneal vascularization)
- Early - dilated limbal blood vessels; in 8-12 hrs get polymorphonuclear inflammatory cell (PMN) layering effect due to corneal structure - may get superficial or deep or both because of this layering (rather than diffuse; but, diffuse does occur)
- Later - in 12-24 hrs, get macrophages from limbus and corneal stromal cells
- Vascularization occurs if inflammation severe or have necrosis
- Stimulus unknown, but edema, leukocytes are factors
- From limbus - little tendency to migrate beyond injured tissue - also stratified according to depth of injury
- Descemet's membrane good barrier to bacterial or fungal penetration
- Vascularization with or without fibrosis
- Mineralization or fat deposits
- Hyperplasia or metaplasia of epithelium or endothelium
- Ulceration -- loss of tissue -- associated with edema, inflammation early; if allowed to continue, also have vascularization, melanosis, fibrosis
- Progressive stage - edema and PMN, epithelial cells swell and necrose, lamellae invaded by PMNs and necrose, may get posterior stromal abscess due to diffusion of toxins and inflammatory products
- Regressive stage - line of demarcation between normal cornea and infected area - necrotic tissue sloughs
- Healing stage - epithelium covers crater, blood vessels from limbus, keratocytes form scar tissue, stroma usually remains thinned; eventually get obliteration of small blood vessels, but larger ones remain (ghost blood vessels); some prominent scars may be due to slight irregularity of corneal fiber arrangement, others due to fibrosis
- Partial thickness--repair by filling in of defect by epithelial cells and by fibrovascular tissue
- Full thickness--as with partial, but also can have ingrowth of epithelial cells or fibrous tissue into anterior chamber
- Repair of corneal wounds
- Superficial - epithelial
- Within an hour, epithelial cells slide over to cover defect - if wound expansive, get mitosis (over usual amount seen)
- If at limbal area, conjunctival cells (including goblet cells) migrate - will assume corneal appearance in several weeks unless have vascularization in which case may take many months
- If not too deep, still get epithelial filling of wound
- Get fibroblastic transformation of stromal cells at edge of wound
- Endothelial cells migrate in from posterior cornea and meet the epithelial cells
- Chronic superficial keratitis (so-called pannus) of German shepherd dogs, dachshunds and terrier type canine breeds
- Subepithelial superficial stromal infiltration with fibrovascular tissue and mononuclear inflammatory cells (lymphocytes and plasma cells)
- Melanosis of epithelial cells and invasion of stroma by melanocytes (most likely derived from conjunctiva)
- Irregular increase in epithelial thickness (reactive hyperplasia) with marked thickening of basement membrane
- Mycotic keratitis
- Usually seen in horses
- Associated with traumatic break in epithelial barrier (as well as inappropriate topical medication of ulcers with steroids)
- Associated with intense edema and inflammation
- Descemet's membrane a temporary barrier to intraocular invasion
- Neoplasia - squamous cell carcinoma only one which may occur in clear cornea and not as extension from other tissues
Limited in its reaction to insults -- usually produces degeneration of lens fibers (cataract); artifacts of preparation are prominent.
Cellular events which represent cataract formation
- Posterior migration of epithelium
- Retention of nuclei in lens fibers beyond a certain point; posteriorly, the lens bow is the limit; anteriorly, the limit is less well defined, but the presence of nuclei in fibers beneath the epithelium at the anterior-most aspect of the lens would be abnormal
- 'Bladder cell' formation (swollen, nucleated posterior lens fibers)
- Vacuoles containing degenerated lens fibers
- Hyperplasia of lens epithelium, often with fibrous metaplasia
- Intumescence due to fluid intake difficult to document with routine histologic means
- Inflammation usually limited to conditions in which capsule has broken
- Mineralization occurs occasionally in old cataractous lenses
Pathogenesis of sugar cataract (from Kinoshita)
- Fluid (aqueous) around lens high in Na and low in K; opposite inside lens
- In most cataracts there is first osmotic swelling followed by degenerative changes
- With sugar cataracts: system becomes overloaded so that aldose reductase produces too much polyol (sugar alcohol, e.g., sorbitol), this leads to imbalance in pump-leak equilibrium because polyols do not leave lens; get increase in Na and Cl with resultant Donnan swelling
- With at least one heritable cataract (in mouse): have deficiency in Na-K ATPase which causes imbalance in pump-leak system, get increase in Na and swelling of lens
Lens-induced uveitis or endophthalmitis
- May also be called phacoanaphylactic endophthalmitis
- Controversy as to exact molecular cause; lens protein is not 'self,' and when released from capsule (especially in altered state as in cataract?), the eye reacts -- if the capsule is ruptured, the reaction may be violent
- Polymorphonuclear inflammatory cells surround lens cortex and nucleus; surrounding this is zone of mononuclear inflammatory cells many of which have been transformed into epithelioid cells
- The uveal tract, especially iris and ciliary body, is markedly inflamed
- Inflammation of this type usually will not respond to medical therapy and will eventually 'consume' the eye with phthisis bulbi the sequela
Congenital rupture of lens capsule
- Uncommon condition, but seen occasionally in rodents -- important from toxicologic study point of view (differentiate from effect of a drug)
- Rupture usually posterior; assume it must have occurred at a time when the body could recognize the protein as 'self' because little to no cellular reaction to extruded lens material
Sarcoma of globe in cats
Cats who have had ocular trauma resulting in phthisis bulbi appear to be at risk for developing intraocular sarcoma. Besides a history of trauma, a common feature in these cases is rupture of the lens. It may be that the lens epithelial cells undergo malignant transformation, or the neoplastic process may be from activated retinal epithelial cells.
These neoplasms can be aggressive and spread locally and grow into the brain along the optic nerve. Therefore, phthisical eyes in cats should be enucleated even if there appear to be no problems for the individual. This should be done as soon as possible after phthisis bulbi is recognized, and as much of the optic nerve as possible should be removed with the globe.
The syndrome of ocular sarcoma following trauma appears to be a problem primarily of cats. It has not been reported in dogs and other nonhuman animals.
- One of most important problems in ophthalmology
- Pathogenesis for new blood vessel development unknown (although new blood vessels okay elsewhere, but disastrous in eye)
- Difficult to manage clinically
- Because of the type of organ, microvasculature of eye most complex
- Almost every mature ocular tissue can be involved; especially in cornea, retina, optic disk and iris
- Once blood vessels form they do not leave
- Mediated by leukocytes (one school of thought)
- Reduction in concentration of normally present vascular inhibitor (another school of thought) - this inhibitor similar to that found in cartilage and aorta, and may be present in vitreous
- Termed rubeosis iridis
- Usually secondary to other ocular disease (e.g., acute iritis alone, iris atrophy and surgical trauma do not lead to neovascularization)
- Retinal vascular occlusive disease (e.g., diabetes mellitus) which is primarily venous or capillary
- Ocular posterior segment inflammation or panophthalmitis
- Intraocular neoplasia
- Fibrovascular membrane spanning the ciliary processes. Due to chronic uveitis, trauma or following lens rupture
- Not necessarily related to retinal neovascularization; may be due to chorioretinitis, trauma, aging or neoplasia
- Diabetes mellitus - areas of non-perfusion precede neovascularization
- Retrolental fibroplasia - excess O2 causes immature retinal blood vessels to undergo vasoconstriction; the blood vessels then undergo obliteration when placed in normal O2; get new blood vessel growth from tips of immature vessels (not from posterior mature vessels) - iris also can be involved
- Retinal vein occlusion
- Not seen with glaucoma and generally not with retinitis or chorioretinitis
- Death of retinal tissue does not lead to neovascularization, but hypoxia of retinal tissue does lead to neovascularization
Conveniently described as anterior (iris and ciliary body) or posterior (choroid) uvea.
- Usually involves either the anterior uvea (iritis, cyclitis or iridocyclitis) or the posterior uvea (choroiditis); can involve entire uvea (panuveitis)
- The basic inflammatory response is similar to other tissues although nonsuppurative lesions are more common
- Except in cases of granulomatous inflammation, the cause of the process usually is not determined unless there is an obvious insult (e.g., trauma to the globe); many or most of the inflammations may be related to hypersensitivity in which case the primary cause may be distant to the globe
- In many cases of anterior uveitis, the surrounding tissues are spared
- In most cases of posterior uveitis, the retina also is involved showing either degenerative changes (due to compromise of the choriocapillaris which is essential for outer retinal nourishment), direct extension of the inflammation, or perivascular cuffing
Sequelae to uveitis
- Most commonly on iris surface (rubeosis iridis); seen in chronic inflammation of the iris or of the ocular posterior segment, or with chronic retinal separation
- Occasionally with severe inflammatory or degenerative disease of the choroid, may get anastomoses of choroidal with retinal blood vessels, or frank choroidal neovascularization
- Adhesions of iris to cornea or lens (anterior or posterior synechiae, respectively)
- Fibrovascular membranes (those from iris span pupil; those from ciliary body, called cyclitic membranes, span ciliary body behind lens)
- Retinal separation due to exudation from choroid or contraction of cyclitic membrane
- Chorioretinal adhesions and retinal degeneration
- Ossification of the choroid
- Shrinkage and atrophy of the globe (phthisis bulbi)
- Glaucoma due to closure of the drainage angle
Equine recurrent uveitis
Most common cause of blindness in horses, ponies and mules. Characterized by variable degree of uveitis in one or both eyes; the inflammation is recurrent at variable intervals; the anterior uvea is more commonly affected. During the clinically quiescent phase, there is continuous 'smoldering' inflammation detectable histologically.
There most likely is a multiplicity of conditions which could produce this syndrome. This chronic, relapsing form of inflammation is a nonspecific characteristic of the uveal tract most likely due to delayed hypersensitivity to damaged uveal tissue.
- Acute stage
- Keratitis and conjunctivitis
- Fibrin and lymphocytes in anterior chamber
- Nonsuppurative iridocyclitis sometimes with choroiditis; the initial response is polymorphonuclear in the anterior uvea, but later is replaced by mononuclear cells
- Inflammatory exudate in vitreous
- Chronic stage
- All the changes seen in the acute
- Various sequelae to uveitis including retinal and optic disk involvement
- Quiescent stage
- Various sequelae to uveitis, but more of a degenerative than inflammatory nature
- Localized accumulations of lymphocytic and other mononuclear inflammatory cells in the uvea
This is the most common primary intraocular neoplasm.
- Usually arises from ciliary body or iris; also seen in the choroid
- Almost all have benign behavior; they rarely metastasize despite occasionally having extraocular extension into the orbit
- One exception is the diffuse iris melanoma seen in cats; there have been cases where there has been fatal metastatic disease despite removal of the eye
- Choroidal melanomas in humans are highly malignant; Callender described a histologic classification scheme which correlates the cytologic features with the degree of clinical malignancy; this scheme, however, seems to have no relevancy to the melanomas we see in nonhumans
Neoplasms such as medulloepitheliomas, ciliary body adenomas and adenocarcinomas occasionally are seen.
This is an increase in intraocular pressure which causes characteristic pathological changes in the eye. May be primary (no antecedent problem), but usually is secondary in our patients.
Some factors associated with or leading to glaucoma
- Closure of the ciliary cleft (drainage angle); this can be brought about by
- Peripheral anterior synechiae -- this is a very commonly observed histological change
- Posterior synechiae preventing flow of aqueous from posterior to anterior chambers -- get forward movement of iris with narrowing or closure of ciliary cleft
- Obliteration or 'clogging' of the trabecular meshwork by inflammatory exudate or tissue
- Idiopathic in which the angle is morphologically open, but intraocular pressure is increased; this is rare in nonhumans
Pathologic changes as a result of the increased intraocular pressure
The changes of major importance are in the optic nerve and retina.
- Optic nerve (because the ganglion cell axons form the optic nerve, they will be mentioned here)
- Ganglion cell death and loss
- Optic nerve axon degeneration and loss (best seen with Bodian stain); this change occurs early, before ganglion cell loss, and is especially evident in the optic disk area resulting in cupped appearance to disk; there is controversy as to its cause: some believe it is a mechanical effect on the axons as the lamina cribrosa shifts due to increase in intraocular pressure; others believe glaucoma results in compromise of the disk vasculature responsible for axon nourishment and in this manner causes axon degeneration
- Posterior bowing of lamina cribrosa; although not a true pathological change, its presence helps differentiate primary optic nerve degeneration from that due to glaucoma
- Buphthalmia (enlargement of the eye); results in marked distortion of ocular tissue relationships and degenerative changes
- Breaks in Descemet's membrane
- Atrophy of uveal tract; sometimes the ciliary body atrophy is sufficient to 'cure' the glaucoma so that the eye will be enlarged, but soft
- Lens luxation or subluxation due to tearing of stretched zonules
- Degeneration of the outer retinal layers; this can be a component of glaucoma without eye enlargement, but usually only if there is concomitant uveitis or other complications; characteristically, the tapetal retina is better preserved than the nontapetal retina; the reason for this is unknown
Development of the retina continues postnatally in cats, dogs, rodents. In the dog, photoreceptor inner segments begin forming on postnatal day 1; by postnatal day 16, the inner segments are 10 µm long, and outer segments are less than 3 µm; by 45-50 days, both inner and outer segments have reached their adult length of about 16 µm each. These figures hold for the posterior region of the retina: development proceeds from posterior to anterior (peripheral) so that at any stage, the posterior region is more developed than the peripheral region. This holds for developmental diseases as well, in which the posterior region of the retina shows more extensive changes than the peripheral region at early to intermediate stages of disease.
Similar to other tissues, but usually occurs as a complication of choroiditis in non-traumatic lesions. Scarring or gliosis of the retina is a sequela to inflammation and is associated with degeneration of the neural tissue and loss of vision for the area concerned (i.e., a focal lesion would be 'blind,' but surrounding normal areas would allow the individual continued vision).
Rarely seen clinically in nonhuman animals partly because it is unassociated with clinical signs until late in its course. It uncommonly is seen histologically as an incidental finding in various congenital and acquired anomalies, but usually is associated with severe intraocular inflammation.
In people, neovascularization of the retina is a frequent and disastrous complication in diabetes mellitus, retrolental fibroplasia and retinal vein occlusion. The exact stimulus for neovascularization is unknown. The iris also is involved, which implies that there may be a diffusable 'angiogenic' factor.
Known collectively as progressive retinal degeneration (PRD). This group of diseases also is known as progressive retinal atrophy (PRA).
This is a common problem in dogs in which it has been studied more extensively than in other domestic animals. Final appearance of the retina in the heritable retinal degenerations is similar. The sensory retina may be reduced to a thin, glial membrane with little recognizable components; the retinal epithelium may be completely gone although islands of hypertrophied or hyperplastic cells may remain, or there may be migration of these cells into the sensory retina.
Although the final outcome is the same in most cases, the early pathologic changes are often different and provide a useful classification scheme.
Seen in the Irish setter and collie. Rods and cones fail to develop normally; this is histologically evident as early as 20 days postnatally in appropriately prepared tissue.
Although rod nuclei and perikarya are present (outer nuclear layer), only a small number of inner segments and very little outer segment material forms; the rod outer segment material is disoriented and disorganized. Eventually, the outer nuclear layer thins due to pyknosis and loss of tissue. By 18 weeks or later, most outer and inner segment material has degenerated completely.
Cones do not develop normally in a functional sense, but a few appear to reach morphologic maturity. Most remain diminutive as with the rods. As the rod population decreases, the cone inner segments become broad and club-shaped probably due to loss of lateral support. With time, the cones degenerate completely.
Seen in the Norwegian elkhound and possibly in the miniature schnauzer. Rods fail to develop normally and cones degenerate secondarily.
The changes in rods are similar in extent and time-course to those in the Irish setter.
At about 47 weeks, a few cones begin to show disorganization of outer segment lamellae. This progresses slowly so that many years pass before there is complete degeneration of the cones.
Seen in miniature and toy poodles and various other breeds of dogs. Rods and cones appear to develop normally, but soon after morphologic and functional maturity, they begin to degenerate slowly. Degeneration of the photoreceptors may not be complete until the animal is 3-5 years or older.
This also is termed retinal detachment clinically. The site of interruption, however, is almost always at the photoreceptor outer segment-retinal epithelial junction. Because the retinal epithelium is part of the retina, the term separation may be more appropriate.
Usually caused by inflammation of the choroid which results in a breakdown of the blood-retinal barrier (retinal epithelial cells are disrupted). Any process which results in a breakdown of the blood-retinal barrier at this location can result in retinal separation. Some of the processes include systemic hypertension, renal disease and emboli or thrombi in the choriocapillaris.
There are many nonspecific degenerative changes which occur in the retinal epithelium and sensory retina due to the separation itself
- The retinal epithelial cells enlarge and round up; there may be hyperplasia with the formation of a multilaminar structure, or the cells may migrate to the sensory retina where they participate in phagocytizing degenerating photoreceptor cells; there will be degeneration of cytosol and organelles, sometimes with vacuolar changes; cells also may be lost
- The photoreceptor outer segments undergo vesiculation and there is disruption of their lamellae; they eventually are lost and degenerative changes occur in the inner segments; once the inner segments are degenerated, the process is permanent (up until then, there could be regeneration of outer segments and return of vision if the separation was corrected; this period is generally thought to be about 10 days, but may be as long as several months); eventually the remainder of the photoreceptor cells (outer nuclear layer and synapses in the outer plexiform layer) is lost; the inner retina may remain unaffected in holangiotic retinas
Light-induced retinal degeneration
Occurs in virtually every species studied: mice, rats, hamsters, rabbits, pigs, pigeons, primates and dogs.
In albino rats and mice, as little as 24 hrs of 'normal' room illumination can cause photoreceptor damage (this is reversible even after a few days of exposure as long as the inner segment remains intact); several days of continuous light can lead to permanent degenerative changes.
In melanotic rodents, degeneration can occur, but the light must be of higher intensity or the pupils must be artificially dilated to reduce the protective effect of the melanotic iris.
In primates, dogs and pigs, only relatively high intensity light sources have been studied and have included diagnostic instruments such as the indirect ophthalmoscope, strobe flash and slit lamp. All have produced marked, focal photoreceptor damage after exposures for as little as 15 min. at intensities commonly used in clinical settings.
The major pathological effects of visible light center around the photoreceptors and retinal epithelium. The inner retinal layers usually remain normal. This is in striking contrast to the full-thickness coagulation and necrosis seen with extremely high energy sources such as laser and xenon arc where the damage is caused by marked local rises in temperature. With common visible light, a rise in local retinal temperature is insufficient to explain the degeneration seen. There most likely is a combination of photochemical and thermal factors, the former playing a major role. It is known that light in the blue end of the visible spectrum is more damaging than other wavelengths; and rhodopsin, the major visual pigment residing in the photoreceptors, has peak absorbency in this range, supporting the photochemical theory.
Peripheral microcystoid degeneration
This is an age-related process seen in most species after middle-age. Histologically, there is a variable degree of degeneration of the retina near and including the ora serrata (ora ciliaris retina); tiny-to-large cysts may occur in the retinal layers; migration of retinal epithelial cells into the sensory retina is common. This condition is considered 'normal' in that it is universal; it rarely progresses further posteriorly than a couple millimeters from the ora serrata.
The intraretinal cysts contain acid mucopolysaccharide which is sensitive to hyaluronidase. The significance of this is unclear.
Some References for Ocular Pathology
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Retina and optic nerve
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