Ординатура / Офтальмология / Английские материалы / Veterinary Ocular Pathology A Comparative Review_Dubielzig, Ketring, McLellan_2010

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Figure 2.20  Fibrosis in the globe.

(A) Low magnification photomicrograph of a canine globe with fibrosis in the anterior chamber (*) and cyclitic membrane (arrow). The uveal tissue is entrapped, but not fibrotic (trichrome stain). (B) Subgross photomicrograph of a canine globe showing extensive fibrosis in the vitreous, anterior chamber and posterior chamber. The entrapped uveal tissue is wrinkled, but not fibrotic.

Immunologic or tissue healing features unique to the eye

•The globe has no lymphatic drainage

•The anterior surface of the eye (i.e. cornea) has no blood supply and is dependant on the physical washing effect of the tear film as well as immunoglobulin and other antimicrobial factors present in tear film

•The tissues of the globe exhibit a deviant immunologic response termed the Anterior Chamber Associated Immune Deviation (ACAID)

■Soluble antigens injected directly into the anterior chamber impair the ability to develop a delayed-type immune response to that antigen

■This is associated with a systemic immune deviation, with suppression of the delayed-type hypersensitivity response to the specific antigen, or acquired specific immune tolerance

•Relative resistance of the uveal tract to fibrosis (Fig. 2.20)

■Fibrosis is often extensive in the anterior or posterior chambers or the vitreous body but not apparent within the uveal tissues directly

■When fibrosis is seen in the uvea, it is often because there is scleral rupture with fibrosis extending directly from the orbital tissue

•The eyes of neonatal animals subjected to penetrating injury or corneal perforation are remarkably resistant to the development of intraocular inflammation.

ABNORMALITIES OF CELLULAR OR TISSUE

DEVELOPMENT OR DIFFERENTIATION

Aplasia and hypoplasia (Fig. 2.21)

Definitions:

•Aplasia: complete failure of a tissue to develop

•Hypoplasia: failure of a tissue to achieve the expected size

•Coloboma: segmental aplasia of one or more of the layers of the globe, leaving a defect. In embryologic terms, typical coloboma occurs when there is a failure of closure of the fetal fissure.

Metaplasia

Definition: The abnormal transformation of one differentiated tissue into another. Examples include (Fig. 2.22):

•Osseous metaplasia in chronic trauma

•Squamous metaplasia of the corneal or conjunctival epithelium in response to chronic inflammation.

Dysplasia

Note that the word ‘dysplasia’ is used in different ways in different circumstances, which may lead to confusion. Two important definitions of dysplasia that are commonly encountered in ocular and general pathology are:

1.Abnormal or disorganized tissue differentiation or development

2.Atypical features of cellular differentiation suggesting neoplasia or a pre-neoplastic state.

Neoplasia

Definition: cellular proliferation with impaired growth regulation leading to distortion or destruction of the normal tissues (Fig. 2.23).

•Benign: a neoplastic lesion that does not carry a risk of metastasis or aggressive infiltration

•Malignant: a neoplastic lesion displaying aggressive local infiltration and causing extensive damage to tissues, disruption of perfusion or distant metastasis.

Aging

Many of the tissues of the eye are at particular risk with respect to the effects of aging because:

•Many ocular tissues are terminally differentiated and have a limited ability to respond to damage.

•By virtue of the function of the eye, ocular tissues are exposed to direct sunlight and, in the case of the retina, focused sunlight

•The outer retina is a highly oxygenated tissue with exposure to oxidative free radicals.

Examples of aging effects on the eye include:

•Progressive thickening of the anterior lens capsule and Descemet’s membrane

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•Deposition of cell-poor ‘glassy’ collagenous membrane adjacent to the ciliary epithelium

•Progressive iris atrophy

•Senile cataract

•Cystic degeneration of the neuroepithelia:

■Typically the peripheral retina in dogs

■More pronounced in the ciliary body pars plana in cats and horses

•Degenerative changes in Bruch’s membrane leading to choroidal neovascularization, an important step in the pathogenesis of age-related macular degeneration in humans.

CHAPTER CONTENTS

Objectives

General principles of ocular embryology in relation to spontaneous developmental ocular diseases

Abnormalities associated with infectious diseases or maternal intoxication

Cyclopia or, more correctly, synophthalmos, in lambs,

Veratrum californicum toxicity

Abnormal ocular development in cattle associated with maternal infection with bovine viral diarrhea

– mucosal disease (BVD-MD) virus

Retinal dysplasia associated with perinatal infections in dogs and cats

Abnormalities associated with specific animal breeds

Collie eye anomaly (CEA)

Merle and white spot coat color (merle ocular dysgenesis)

Congenital ocular anomalies in Rocky Mountain horses

Persistent hyperplastic primary vitreous (PHPV) and persistent hyperplastic tunica vasculosa lentis (PHTVL)

Retinal dysplasias

The vitreoretinopathies – vitreoretinal dysplasia Oculo-skeletal dysplasia syndrome

Congenital cataract (lens opacity) and other congenital abnormalities of the lens

Normal lens structure

Congenital lens abnormalities other than cataract Congenital cataract

Hereditary cataracts

Goniodysgenesis and other anterior segment dysgenesis syndromes

Peter’s anomaly and persistent pupillary membranes

Congenital failure in the formation of the anterior segment, anterior segment dysplasia or dysgenesis

34into the pathology and pathogenesis of clinically observed lesions

41■ Euthanasia or enucleation because of disfiguring eye

42disease

45■ Enucleation because of glaucoma

•Almost every species and breed of domestic animal has a list of

Figure 3.1  Schematic drawing of early embryogenesis of ocular tissues. The lens placode forms and then invaginates in response to the optic vesicle making contact with surface ectoderm. With the subsequent invagination of the optic vesicle to form the double-layered optic cup. (Adapted with permission from Inagaki S, Kotani T 2002 Examination of the rat eye at the early stage of development with osmium tetroxide staining.)

GENERAL PRINCIPLES OF OCULAR

EMBRYOLOGY IN RELATION TO

SPONTANEOUS DEVELOPMENTAL OCULAR

DISEASES (Figs 3.1–3.4)

•The optic vesicle bulges out from the primitive neural tube ectoderm, making contact with the surface ectoderm, thus stimulating the local ectoderm to form the lens placode (Fig. 3.1)

•Lens placode invaginates to form the lens vesicle which separates from the surface ectoderm (Fig. 3.2)

■Incomplete separation of the lens vesicle leads to developmental abnormalities of the anterior segment, involving the lens, cornea and anterior uvea.

•Invagination of the optic vesicle to form a bi-layered optic cup

■Failure of normal growth and invagination of the optic vesicle may lead to optic cyst, anophthalmia, microphthalmia, or combined abnormalities of the brain and eye.

•Invasion of vessels and associated mesenchyme into the optic cup to form the primary vitreous and tunica vasculosa lentis

■Failure of the primary vitreous and tunica vasculosa lentis to form can lead to microphthalmia

•Sprouting of the neuroepithelium from the anterior margin of the optic cup to form the double-layered ciliary and iridal epithelia (Fig. 3.3)

•Closure of the optic fissure separating the vasculature of the primary vitreous from the mesenchyme outside the optic cup, and establishment of a continuous inner neuroretina and an outer retinal pigment epithelium.

■Failure of optic fissure closure is one mechanism that can lead to the formation of typical scleral colobomata, usually in the dependant posterior globe

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Figure 3.2  Early embryonic eye. Photomicrograph of an embryonic goat eye showing the lens vesicle separated from the surface ectoderm and early stage retinal differentiation. The section passes through the optic fissure, through which mesenchyme enters the developing globe to form the earliest vitreous.

Primary vitreous

Figure 3.3  Late embryonic eye. Photomicrograph of a bovine embryonic eye showing the primary vitreous, and the forward budding of neural tissue at the margins of the optic cup to initiate development of the ciliary body and iris (box).

■Colobomatous microphthalmos may result from subsequent failure to establish the intraocular pressure that normally contributes to globe expansion

•Development of a multi-layered neuroretina, extension of retinal ganglion cell axons into the optic nerve, formation of ciliary and iridal epithelia, and the formation of lens fibers and eventually sutures (Fig. 3.4).

■Failures in the normal development of the retinal and/or uveal neuroepithelia, and lens fibers may be responsible for

retinal dysplasia, optic nerve aplasia/hypoplasia, uveal colobomas and congenital cataract, respectively.

•Establishment and remodeling of the stromal layers of the eye including the uveal, scleral, and corneal stroma

■Failure of this normal mesenchymal development may be responsible for goniodysgenesis, choroidal hypoplasia, persistent pupillary membrane, Peter’s anomaly, variations in uveal pigmentation, and some colobomatous lesions

•Regression of the hyaloid vasculature of the primary vitreous and tunica vasculosa lentis and formation of the secondary vitreous (Fig. 3.5)

■Abnormalities in this process are associated with persistent hyperplastic primary vitreous, persistent hyperplastic tunica vasculosa lentis, and persistent hyaloid artery, as well as vitreoretinopathies such as vitreoretinal dysplasia.

•Vascularization of the retina, and the continued development of retinal ganglion cells and their axons, which enter the optic nerve (Fig. 3.6)

■Failure of these processes leads to neovascular sprouting into the vitreous and optic nerve hypoplasia, respectively.

•The full development of a multi-layered retina with functional and differentiated photoreceptors (this process continues after birth) (Fig. 3.7)

■Failure results in retinal dysplasia or photoreceptor dystrophies.

Figure 3.6  Retinal blood vessel growth. Photomicrograph of a neonatal canine retina showing retinal blood vessel proliferation and differentiation. The arrow points to a newly formed vessel in the developing nerve fiber layer.

•Many of the ocular tissues continue to develop throughout the early post-natal period, or, as in the case of the lens, throughout life. Abnormalities of these processes can lead to diseases that are not manifest in young animals, e.g. many forms of inherited cataract, hence they will not be covered in this chapter.

Figure 3.7  The fully-differentiated feline retina in the area centralis. Photomicrograph of the normal, fully-differentiated feline retina sampled in the area centralis, the region with the highest density ganglion cells.

Comparative Comments

These general principles of ocular embryology apply to humans as well as other vertebrates. Specific congenital abnormalities in the human eye will be considered in the chapters which follow, discussing specific tissues within the eye and in the orbit and adnexa.

The various congenital anomalies arise because of variation in size, location, organization, or amount of tissue that represents a departure from normal.

A number of congenital abnormalities in humans fall under the classification of hamartomas or choristomas.

•A hamartoma is an excessive amount of mature tissue (hypertrophy and/or hyperplasia) occurring in a location in which that tissue is usually found. An example of a hamartoma would be any of the hereditary phakomatoses such as neurofibroma (a mass of mature neural tissue and fibroblasts) occurring in the orbit. No such collection of congenital disorders is described in animals

•A choristoma, in contrast, consists of normal, mature tissue in an abnormal location. Embryologically, this is a result of one or two germ layers forming mature tissue that is not normally found in that topographic location. An example of a choristoma is lens occurring in the lid (a phakomatous choristoma).

ABNORMALITIES ASSOCIATED WITH INFECTIOUS DISEASES OR MATERNAL INTOXICATION

Cyclopia or, more correctly, synophthalmos, in lambs, Veratrum californicum toxicity (Fig. 3.8)

•This is caused by consumption of alkaloids from the weed Veratrum californicum (Western False Hellebore) by the pregnant ewe on day 14 of gestation

•The 14 day embryo is undergoing gastrulation to form a neural tube with lateral symmetry

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Figure 3.8  Veratrum californicum induced teratogenesis. A neonatal lamb has toxic synophthalmos, caused by maternal ingestion of Veratrum californicum on day 14 of gestation. (Courtesy of Ron Riis, Diplomate – American College of Veterinary Ophthalmology).

•Affected lambs have numerous developmental anomalies of the face, including arhinencephaly characterized by a proboscis-like nose developed above the fused globes

•Arhinencephaly with synophthalmos in humans is associated with very similar facial and ocular anomalies but no single teratogenic association has been made.

Abnormal ocular development in cattle associated with maternal infection with bovine viral diarrhea – mucosal disease (BVD-MD) virus (Figs 3.9 & 3.10)

•Caused by a pestivirus

•In post-natal infection, the virus causes a necrotizing epitheliotropic disease characterized by diarrhea

•Infection of the fetus is associated with several syndromes

■Early maternal infections (before 40 days’ gestation) results in infertility, or fetal death and resorption

■Infections later may be associated with abortion

■Infection after 40 days gestation can result in normal, immune-deficient, or stunted calves that are immune-tolerant of the virus and remain persistent carriers of the virus. These calves are of great importance in the spread and control of the disease

■Some calves infected after 40 days’ gestation develop congenital abnormalities (Fig. 3.9)

–Cerebellar hypoplasia ‘dummy calf’

–Brachygnathia

–Ocular abnormalities, typically seen in calves

infected later than 76 days but before 150 days gestation, include:

Microphthalmos

Microphakia/cataract

Retinal detachment

Retinal atrophy/dysplasia

Spindle cell metaplasia of the retinal pigment epithelium

Immunohistochemistry for BVD-MD virus antigen shows staining in blood vessels and punctate staining in the outer plexiform layer (Fig. 3.10).

Retinal dysplasia associated with perinatal infections in dogs and cats

•In cats infected in utero with feline panleukopenia virus retinal dysplasia is frequently associated with cerebellar hypoplasia

•Retinal necrosis and dysplasia have been reported following experimental infection with feline leukemia virus

•Dogs surviving neonatal canine herpesvirus infection demonstrate retinal dysplasia, necrosis and degeneration, often associated with other ocular abnormalities related to panuveitis.

Comparative Comments

The principle infectious embryopathies in humans are congenital rubella syndrome (Gregg’s syndrome) consisting of cataracts, cardiovascular defects, mental retardation, and deafness; cytomegalic inclusion disease; congenital syphilis; and toxoplasmosis.

The major drug embryopathies associated with a variety of eye changes in humans are: fetal alcohol syndrome, maternal thalidomide ingestion during the first trimester of pregnancy, and

lysergic acid diethylamide (LSD) ingestion during the first trimester of pregnancy.

ABNORMALITIES ASSOCIATED WITH

SPECIFIC ANIMAL BREEDS

Collie eye anomaly (CEA) (Fig. 3.11)

•Although a common disorder in dogs, specimens are seldom submitted for histopathological evaluation. Only six cases are logged into the COPLOW collection

•A congenital, recessively inherited, ocular disease seen in Collies and Shetland Sheepdogs, and also in Australian Shepherds, Border Collies, Lancashire Heelers and other herding breeds. The genetics of the disorder are discussed in greater detail in Chapter 11

•Bilateral but not always symmetrical

•A wide spectrum of severity of phenotypic expression is recognized, including:

■All cases demonstrate a regionally defined area of choroidal hypoplasia and segmental tapetal aplasia lateral to the optic disc. In isolation, this lesion has no clinically appreciable effect on vision

■Tortuous retinal blood vessels, may be apparent, most obvious in the area of choroidal hypoplasia

■Segmental lamina cribrosa or scleral defect (coloboma) with outward bulging or ectasia

–Although usually adjacent to or involving the lamina cribrosa, the scleral coloboma can be slightly separate from the disc

–Often unilateral

–Atrophic or dysplastic neural tissue, rather than uvea, lines the staphyloma

■Retinal detachment

–Can be localized to the area of the optic disc, i.e. peripapillary, or complete detachment.

–Usually unilateral

–Usually associated with a large coloboma

–Vitreous within the sub-retinal space probably gains access through tears in the atrophic neural tissue within the coloboma

■Retinal dysplasia

–Solitary or multifocal folds, or disorganized development of retinal layers with dysplasia may be seen

–Many authors and clinicians make a point of distinguishing retinal dysplasia, which has a component of disorganization, from retinal folds, which are simply a fold or wrinkle affecting all layers

■Hemorrhage into the posterior segment

–The source of hemorrhage may be neovascular

sprouts from the choroid; the margins of the coloboma; the dysplastic retinal foci, or traction on existing

retinal vessels, however, the source is usually undetermined

■Pre-iridal fibrovascular membranes (PIFVM)

–This secondary abnormality may, in turn, lead to peripheral anterior synechia followed by secondary neovascular glaucoma.

Merle and white spot coat color (merle ocular dysgenesis) (Fig. 3.12)

•As with CEA, merle ocular dysgenesis is seldom submitted to the pathology laboratory, although the condition is relatively common in certain breeds, such as the Australian Shepherd,

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specimens are rarely submitted for evaluation. There are only three cases in the COPLOW collection

•The merle gene is a color dilution gene that lightens the coat color. Many breeds or mixed breed dogs have merle coat color variants

•A dog homozygous for the merle gene will have a lighter coat color than a heterozygous genotype. Merle-to-merle breedings are not recommended

•The merle gene does not affect white coat color or white spots

•The merle gene does affect the color of the eye, although associated abnormalities may affect eyes with brown as well as blue irides

•Dogs of any breed, or mixed breeds, with the merle color dilution (homozygous merle) and abundant white spots are at risk of congenital abnormalities in ocular development. These abnormalities include:

■Microphthalmos

■Iridal abnormalities

–Iridal coloboma, iris hypoplasia

–Asymmetric pupil size, shape, or position (dyscoria and/or corectopia)

–Persistent pupillary membranes

■Lens abnormalities

–Microphakia

–Cataract

–Abnormal lens shape (coloboma)

–Lens luxation/subluxation

■Scleral defects (coloboma / staphyloma)

–Colobomata are usually not located at the optic disc as in CEA, and are frequently equatorial in location

–Colobomata may be very large (coloboma with cyst). The clinical picture in coloboma with cyst might be that of a fluid filled cyst making it difficult to recognize other ocular structures

■Retinal defects

–Retinal detachment, associated with severe dysplasia or large colobomata/staphylomas

–Retinal dysplasia, characterized by inner retinal thickening and the formation of inner retinal rosettes

•Affected dogs are frequently also deaf.

Congenital ocular anomalies in Rocky Mountain horses (Fig. 3.13)

•An inherited complex of multiple ocular abnormalities has been reported in the Rocky Mountain horse and related breeds. In this dominantly inherited disorder, that may have incomplete penetrance, disease expression is linked to the silver dapple locus, responsible for the chocolate coat color with white or flaxen mane and tail

•Bilateral ocular involvement is seen in affected horses

•Heterozygous horses have large, translucent, temporal ciliary cysts and may also have retinal dysplasia

•Homozygous horses have a complex of abnormalities that may include the following:

■Microphthalmos

■Cornea globosa

–In some affected horses the radius of curvature of the cornea appears to be shortened, leading to excessive anterior corneal curvature and the appearance of protruding eyes. These horses have abnormally deep anterior chambers