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

most of these cases hypertension was not suspected at the time of enucleation

■Ocular pathology of systemic hypertension in dogs and cats

–Lesions are bilateral but not necessarily symmetrical

–Hypertensive vasculopathy

Recognized clinically and grossly by the variations in caliber of individual retinal blood vessels, that may have sections of obliteration and sections of aneurysmal or saccular dilation

Vascular lesions are seen in the arterioles of the retina, choroid, or, less frequently, in the iris

Diseased arterioles have a thickened vascular profile with decreased luminal diameter

Vascular lesions are not consistent throughout the ocular tissues and their identification requires a PAS stain

Solid or lamellar PAS-positive deposits, effacing the vessel wall, are associated with fibrinoid necrosis

Retinal edema and retinoschisis may be recognized

Foci of retinal destruction, including RPE disruption, associated with hemorrhage, fibrin deposition, and neovascular proliferation are a common and distinctive feature of systemic hypertension in the dog and cat retina

–Intraocular hemorrhage may occur as a direct result of vascular damage

Hemophthalmos

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Intravitreal hemorrhage

Retinal hemorrhage

–Retinal detachment

Focal, multifocal or total bullous detachment is a very common feature that reflects hypertensive choroidopathy, with sub-retinal effusion or, in some cases, hemorrhage

Pre-iridal fibrovascular proliferation may result, and may contribute to neovascular glaucoma and to distortion of the iris profile

–Hypertensive optic neuropathy

Papilledema may rarely be recognized as a clinical feature in animals with severe hypertension

Optic atrophy may result from optic nerve ischemia, particularly in chronic hypertension

Hemorrhage in the optic disc secondary to vascular disease is common.

Comparative Comments

•The discussion of the retinal changes due to hypertension in dogs and cats is relevant to the human as well.

•It should be noted, however, that in the human, the pathophysiology of hypertensive retinopathy, optic neuropathy, and choroidopathy remain the focus of sharp controversy.

Comparative Comments (continued)

–Some say it is useful in some ways to classify hypertensive retinal lesions into vascular and extravascular, although such a separation is somewhat artificial

–Others, after reviewing experimental and clinical data, proposed dividing hypertensive retinopathy into vasoconstrictive, exudative, sclerotic, and complications of the sclerotic phase, and they have delineated the mechanisms underlying these phases.

Diabetic retinopathy (Fig. 11.26)

•Although previously thought to be uncommon, with longer survival times post-diagnosis, and routine surgical management of diabetic cataract allowing clinical visualization of the fundus, a relatively high incidence of retinopathy is now recognized in dogs with diabetes mellitus

•Spontaneous diabetic retinopathy is seldom associated with clinically apparent loss of vision in dogs

•While the more severe, proliferative form of retinopathy seen in diabetic humans appears relatively uncommon in dogs, ‘background retinopathy’ with micro-aneurysms in the retinal

vasculature and small, focal retinal hemorrhages is commonly seen

•Morphological features identified in dogs with spontaneous or experimentally induced diabetes include:

■Loss of capillary pericytes

■Thickening of vascular basement membranes

■Focal intraretinal hemorrhages

■Focal areas of degeneration of the neurosensory retina

•Diabetic retinopathy may be complicated by secondary hypertensive vasculopathy in some dogs.

Comparative Comments

•Diabetic retinopathy is of greater significance in human retinal vascular disease than retinal effects of hypertension

•Although the early changes can be induced in animal models, including dogs and rodents, the more advanced changes are limited to humans

•The progressive changes in diabetic humans include capillary basement membrane thickening, loss of capillary pericytes, the development of microaneurysms, intraretinal hemorrhages,

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Comparative Comments (continued)

macular edema, and finally the development of proliferative diabetic retinopathy, with glial vascular proliferation occurring as a response to retinal ischemia.

Anemia

Retinal hemorrhage is a recognized complication of profound anemia in cats.

Hyperviscosity syndrome (Fig. 11.27)

Hyperviscosity associated with monoclonal or polyclonal gammopathies, or rarely polycythemia, may lead to a range of ocular abnormalities that are similar to those seen in hypertension, including retinal detachment and retinal and intraocular hemorrhage, as well as secondary glaucoma.

The characteristic feature of hyperviscosity syndrome is pronounced tortuosity and distension of retinal blood vessels, with thrombosis and stasis of blood leading to extreme sacculation of blood vessels.

RETINAL DETACHMENT, RETINAL

SEPARATION

Retinal detachment is characterized by the focal or total separation of the neurosensory retina from the underlying RPE. Since the detachment essentially involves separation between the photoreceptor and RPE layers of the retina, rather than actual detachment of the retina in its entirety, including the RPE from the choroid, some prefer the more accurate term, retinal separation, over the more widely used term, retinal detachment.

Factors acting to maintain normal retinal attachment

•The tight junctions of the outer limiting membrane, and the tight junctions of the RPE cells

•The close anatomic relationship between photoreceptor outer segments and the RPE microvillous processes that surround them

•The gentle and widely distributed force exerted by the semi-solid vitreous body on the inner retina.

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Factors which can contribute to detachment (Fig. 11.28)

The following contributing factors either predispose to tearing of the retina (i.e. rhegmatogenous detachments), traction on the retina, or serous fluid or inflammatory exudates in the sub-retinal space:

•Advanced retinal degeneration and thinning

•Ocular trauma leading to tearing, necrosis, hemorrhage or vascular leakage

•Inflammation leading to sub-retinal infiltrates, vascular leakage or hemorrhage

•Congenital malformations of the posterior segment including retinal dysplasia, staphyloma and colobomatous lesions (see Ch. 3)

•Cellular bands in the vitreous, segmental vitreal degeneration or dysplasia (as in the Shih Tzu, see Ch. 3), or anterior vitreous prolapse, leading to active or passive traction exerted by the vitreous body on the inner retina

•Neoplasia involving the retina, choroid, anterior uvea, or vitreous cavity, that leads to hemorrhage, vascular leakage, retinal necrosis, or retinal traction

•Stretching of the globe leading to retinal tearing, as may occur in chronic glaucoma

•Toxic conditions that lead to vascular leakage or retinal degeneration

•Vasculopathy that may lead to hemorrhage, leakage or traction

■Systemic hypertension

■Diabetes mellitus

■Hyperviscosity syndrome

■Thromboembolic disease

Consequences of retinal detachment

•The detached retina ceases to function immediately

■Retinal metabolism is abruptly lowered

■The recycling of retinol by the RPE is interrupted

■The outer retina is separated from its blood supply in the choriocapillaris

■Gradually there is atrophy of the photoreceptor cells

•The hypoxic retina secretes vascular endothelial growth factor (VEGF), which promotes neovascular proliferation in the iris (pre-iridal neovascular membrane), ciliary body (cyclitic membrane), and optic nerve head. These neovascular membranes have further serious consequences for the function

of the eye, including hemophthalmos and secondary glaucoma (see Chs 5 and 9 for more detailed discussion).

Morphologic features of retinal detachment (Fig. 11.29)

•Hemorrhage, protein, inflammation, or other material in the subretinal space

■The most convincing evidence of pathological retinal detachment is the accumulation of material in the subretinal space, which normally appears optically clear in standard histopathological sections

•Hypertrophy of the adjacent RPE cells

■Enlargement of cell size along with an inward bulging of the RPE cell apices, often referred to as ‘tombstoning’

–Cell swelling without the characteristic ‘tombstoning’ can be seen in the absence of pathologic retinal detachment and this can be misleading

■Sometimes, in cats, the hypertrophied RPE cells will also form complex fronds associated with folding of Bruch’s membrane which then bulges into the subretinal space

–More commonly seen as a pronounced feature in cats

•Outer retinal atrophy

■Blunting and loss of photoreceptor outer segments

■Within a few days, apoptosis may be identified in the cells of the outer nuclear layer

■More profound outer retinal degeneration suggests chronicity, while inner retinal involvement may suggest secondary glaucoma

•Upregulation of vimentin and GFAP expression in the detached retina, beginning within hours of detachment.

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Morphologic features which suggest that retinal detachment is an artifact of tissue processing include:

•Absence of the features described in the previous section

■However, if one cannot detect the features described above in association with retinal detachment, pathologic detachment cannot be definitively excluded

•Photoreceptor outer segments still attached to the apices of RPE cells in the region of apparent detachment

■This feature indicates, without doubt, that the apparent retinal detachment is an artifact.

Comparative Comments

The discussion on retinal detachment in non-human species applies to human retinal detachments as well. As indicated in this discussion, retinal detachment corresponds to a separation between the RPE and the neuroepithelium at the junction between the two layers of the optic vesicle, where the embryonic cavity previously existed.

The attachment of the neurosensory retina to the RPE is a tenuous one, dependent on a number of mechanisms including intraocular pressure, vitreous support and pressure, gravity, interdigitation of photoreceptor outer segments and RPE apical microvilli, as well as the interphotoreceptor matrix and adhesion molecules.

The three major types of human retinal detachment are as follows:

1.Rhegmatogenous retinal detachment, the most common type, which results from a collection of vitreous fluid beneath the neural retina through a tear or a hole.

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2.Tractional retinal detachment, in which the neurosensory retinal is pulled by intravitreal membranes; this mechanism occurs in proliferative retinopathies such as diabetic retinopathy, sickle cell disease, and retinopathy of prematurity.

3.Exudative, transudative, or hemorrhagic retinal detachment, in which there is an accumulation of subretinal fluid from the choroidal or retinal vessels. This is a mechanism for retinal detachment in choroidal melanomas and inflammatory conditions.

In human eyes with retinal detachment, the principal histopathologic findings are as follows:

•Degeneration of the outer segments and eventual loss of photoreceptor cells

•Migration of Müller cells

•Proliferation and migration of RPE cells

•Development of cystic spaces in the detached retina.

Retinal tear

Many of the same factors that lead to retinal detachment can also lead to a retinal tear.

•Traumatic retinal damage is a leading cause of retinal tears

•Traction on the retina in association with vitreous liquefaction or the formation of contractile vitreous bands is another leading cause of retinal tears

■Degenerative vitreoretinopathy, as commonly seen in Shih Tzu dogs (discussed in detail in Ch. 3), is often associated with retinal tears

•Retinal necrosis in association with retinal vascular disease is a common cause of retinal tears

■Vasculopathy associated with systemic hypertension

■Diabetic vascular disease

■Atherosclerosis

■Thromboembolism or embolic metastatic neoplasia.

The Retina Chapter 11

there is extraor intracellular edema of the retina, with damage to the photoreceptor cells

•As discussed in regard to other species, direct trauma can lead to traumatic retinal holes, tears, dialysis, and detachment in the human retina.

The morphologic features of retinal tears include (Fig. 11.30)

•Retinal tears usually also imply local or total retinal detachment

•The torn ends of the retina are remodeled by gliosis, such that they take on a rounded and gliotic appearance

•The torn retina often rolls over on itself to adopt a scrolled appearance

■In the scrolled retina, the outer retina often is in apposition with the inner retina, a configuration that cannot occur unless there is a tear in the retina.

TRAUMA

Retinal contusion, blunt trauma (Figs 11.31, 11.32)

Trauma is frequently suspected as a cause of retinal atrophy, but is difficult to diagnose with certainty because there is seldom an accurate history of trauma.

See Chapter 5 for more detailed discussion of the effects of trauma on the retina.

The morphological features of peracute traumatic retinopathy

•Hemorrhage

•Disruption and fragmentation of photoreceptor outer segments

•Disruption and shattering of the lamellar organization of the retina

•Retinal tear.

The morphologic features of acute traumatic retinopathy

•Apoptosis

•Tissue necrosis or malacia

•Unsupported retinal blood vessels

•Retinal tear.

The morphologic features of chronic traumatic retinopathy

•Gliosis and atrophy

•Unsupported blood vessels

•Retinal tear.

Comparative Comments

•The retinal manifestations of trauma in humans have been extensively studied and categorized

•Direct blunt ocular trauma is the cause of commotio retinae, characterized by whitening of the outer retina. Histologically,

Lenticular metaplasia in the avian retina (Fig. 11.33)

Metaplastic lens-like differentiation is a common phenomenon in traumatized avian retinas.

Morphologic features of lenticular metaplasia

•Bladder cells or Morgagnian globules found within the atrophic neural retina or retinal pigment epithelium

•Metaplastic lens-like lesions may even demonstrate features consistent with lens capsule

•Gradual transformation from reactive Müller cells to bladder cells, with a change from GFAP to alpha A crystallin expression.

INFLAMMATORY DISEASES OF THE RETINA

Inflammatory disease of the retina seldom occurs in isolation, often being associated with uveal inflammation, due to its close proximity to the choroid, or with inflammatory disease of the central nervous system.

Retinal inflammation attributable to infectious agents

Systemic infections with a wide range of bacterial, viral, fungal, algal and parasitic pathogens may result in retinal inflammation. Many of these pathogens lead to retinal disease secondary to infection being established with the choroid, i.e. by extension of posterior uveitis, and are considered in Chapter 9.

Those pathogens for which the retina may be considered a target tissue are addressed below.

Canine distemper virus (Figs 11.34, 11.35)

•Canine distemper is a Morbillivirus (paramyxovirus) which causes a wide variety of systemic lesions when infecting susceptible dogs or other carnivores

•Retinal disease is seen in association with encephalitis and, although keratoconjunctivitis sicca and blinding optic neuritis may occur, frequently there are no ocular signs other than the typical ophthalmoscopic findings of multifocal retinitis or chorioretinitis

Morphologic features of canine distemper retinitis

■Grossly, there are multifocal, perivascular areas of retino-choroidal involvement which may appear pale, pigmented, or atrophic

■Histologically, in active infection, retinal disorganization, eosinophilic intranuclear or intracytoplasmic inclusion bodies, and multi-nucleate syncytia are observed

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A B

C D

■In chronic disease, retinal atrophy and gliosis are seen, along with migration of pigment epithelial cells into the neurosensory retina.

Bovine thromboembolic meningoencephalitis, Haemophilus somnus infection (Fig. 11.36)

•Haemophilus somnus is a Gram-negative bacterial pathogen of cattle, which can affect the urinary, reproductive, or respiratory tracts leading to serious disease

•The brain and the eye become affected as a result of widespread septic vascular thromboembolism

•Ocular signs, although striking, are generally a minor clinical concern because of the rapidly fatal nature of the embolic form of the disease

Morphologic features of retinal disease

–There is focal or multifocal acute hemorrhagic and necrotizing retinitis associated with septic vascular thromboemboli and vasculitis.

Herpes viral retinitis in camelids (Fig. 11.37)

•Infection with equine herpesvirus-1 can cause clustered outbreaks of encephalitis and retinitis in camelid species that are in contact with Equidae

The Retina Chapter 11

Figure 11.31  Trauma to the retina, fundus. (A) Beagle, 1.5 years old: this dog was still blind 1 week after being hit by a car. The photograph is of the tapetal retina. Linear areas of retinal edema (black arrow) and focal areas of abnormal pigment and edema (white arrows) are present. (B) Non-tapetal retina of the same eye as in (A) showing multiple areas of retinal edema (arrow).

(C)The tapetal retina of the same eye as in (A) taken 1 week later. Increased tapetal pigmentation is present. The tapetum is now hyperreflective in the areas of previous retinal edema (arrow).

(D)This is the non-tapetal retina of the same eye as in (A) taken 1 week later. Retinal edema has resolved, leaving areas of depigmentation and pigment clumping.

•Potentially fatal encephalitis is associated with neurologic signs and with vision loss in one or more animals

Morphologic features of retinitis in affected animals

■Acute necrotizing retinitis

■Eosinophilic intranuclear inclusion bodies.

Bovine virus diarrhea (BVD) virus in cattle (Fig. 11.38)

•Calves infected with BVD virus in utero, may be affected with a syndrome that includes cerebellar hypoplasia, microphthalmia, and retinal disorganization and dysplasia (see Ch. 3)

Morphologic features of retinal disease associated with pre-natal BVD infection

■Retinal folds or rosettes

■Loss of lamellar retinal organization

■Retinal gliosis

■Segmental loss of RPE cells or spindle cell metaplasia of RPE cells.

West Nile virus in raptors (Fig. 11.39)

•West Nile virus has a high morbidity in avian species, with a highly variable mortality between affected species

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•Raptors have a fairly high morbidity, and mortality is often associated with vision loss secondary to retinal or uveal infection

Morphologic features of West Nile Virus infection in the raptor eye

■Multifocal retinal or uveal lymphocytic infiltration

■Segmental retinal necrosis, or atrophy and gliosis.

Toxoplasmosis

•Active, disseminated infection with Toxoplasma gondii is reported to result in a characteristic multi-focal chorioretinitis in affected animals, however, there are no cases of chorioretinitis associated with toxoplasmosis in the COPLOW collection

•In contrast to humans, in which the retina appears to be a target tissue, in domestic species, retinitis tends to occur by extension of inflammation from the adjacent choroidal tissue

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•The pathogenesis of ocular toxoplasmosis is discussed in greater detail in Chapter 9.

Toxocara canis ocular larva migrans (Figs 11.40, 11.41) (see also Ch. 9)

Young dogs raised under conditions that promote a heavy exposure to infectious eggs, are at risk of developing inflammatory ocular disease associated with the migration of larval nematodes through ocular tissues, including the retina and uvea causing retinitis and uveitis, respectively.

Morphologic features of canine ocular larval migrans

•The hallmark feature of infestation is a migration tract with associated granulomatous inflammation which undulates through the uvea, retina, and vitreous

•The focal granulomas often need to be identified during gross examination with magnification, and the tissues embedded and