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

Morphologic features of retinal diseases associated with increased lipofuscin in the RPE cells

•Lipofuscin appears as light brown granules in the cytoplasm of the RPE cell, that stain positively with PAS

•Lipofuscin granules demonstrate characteristic yellow autofluorescence when non-stained sections are observed under illumination with blue light

•On transmission electron-microscopy, lamellar membrane profiles are often observed within these lysosomal storage bodies

•Pathologic accumulation of lipofuscin in the RPE is a significant finding that can contribute to vision loss

■RPE cells are responsible for the continuous phagocytosis and lysosomal degradation of proteins and

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A B

C D

E

phospholipids in photoreceptor outer segment membranes throughout life

■This membrane degradation occurs in an environment that is exposed to light, which can contribute to oxidative damage to the tissues and favors lipofuscin formation.

Large amounts of lipofuscin in RPE cells

Large amounts of lipofuscin in RPE cells might be an indication of any of the following problems:

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Figure 11.12  Feline central progressive retinal atrophy, FCRD. (A) DSH, 8 years old: the small elliptical area of hyperreflectivity is located temporally in the area centralis. (B) DSH, 8 years old: in this right eye, the center of the elliptical lesion is hyperreflective due to the angle of light striking the retina and reflecting to the viewer. (C) Siamese, 14 years old: in the left eye, the center of the lesion appears dark and the margin appears hyperreflective. (D) DSH, 11 years old: photographed through a neutral density filter and a 28-diopter lens, this hyperreflective lesion is superior to the disc and extends nasally and temporally.

(E) Low magnification photomicrograph showing abrupt loss of the photoreceptors (arrow), while the inner retinal layers persist, typical of central retinal atrophy in cats.

•Absolute or relative deficiencies in vitamin E, or other antioxidants

■Absolute or relative dietary deficiency or malabsorption of vitamin E has been associated with retinal degeneration in a wide range of species, including dogs and horses

•Central progressive retinal atrophy, retinal pigment epithelial dystrophy (RPED) (Fig. 11.15)

■Although encountered in European populations of several dog breeds that include, most notably, the English Cocker Spaniel, Labrador and Briard, this is a rare condition in the United States

■Clinical features of RPED include:

–Brown or tan pigment foci that are visible throughout the tapetal fundus

–Slowly progressive retinal degeneration, with multifocal areas of increased tapetal reflectivity and pigment clumping within the non-tapetal fundus

–Progressive loss of vision

–In some affected dogs, signs of ocular disease are accompanied by neurological abnormalities including ataxia, proprioceptive deficits and muscle weakness

■Morphologic features of RPED include:

–Hypertrophy and degeneration of the RPE, with associated degenerative changes in the outer, neurosensory retina

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–Widespread accumulation of lipofuscin granules within the RPE

–Lesions are initially most severe at the posterior pole, spreading to involve the entire retina as the disease progresses

–Other lesions that may be seen in tissues of affected dogs if submitted for necropsy include:

Lipofuscin accumulation in brainstem nuclei

Central neuro-axonal dystrophy and degeneration, that is most prominent in the sensory relay nuclei of the brainstem

Lipofuscin accumulation in smooth muscle, in particular intestinal lipofuscinosis

■These abnormalities are essentially identical to those associated with dietary vitamin E deficiency in dogs

■Low plasma alpha-tocopherol values have been reported in affected dogs fed diets containing adequate vitamin E. Thus, this familial disease probably represents an ocular manifestation of systemic antioxidant deficiency. The disease appears to be due to abnormal metabolism or transportation of vitamin E, rather than a primary retinal disorder

•Equine motor neuron disease is frequently accompanied by a characteristic retinopathy

■Pigmented linear lesions are visible throughout the tapetal fundus, often forming a distinctive reticulated pattern

■Accumulation of lipofuscin in the RPE is associated with retinal degeneration

■Abnormal blood and tissue levels of vitamin E have been implicated in the development of retinal degeneration as well as neurodegenerative disease in horses

■Signs of neurological dysfunction are usually the presenting complaint

•Canine multifocal retinopathy (see earlier in this chapter)

•Increased exposure to ultraviolet light and blue light

■Continuous exposure to intense sunlight or high levels of artificial light may increase lipofuscin accumulation

■Much of the short wavelength light to which the eye is exposed is filtered by the lens, hence exposure to this ‘light hazard’ is increased in aphakic animals

•Increased or altered turnover of photoreceptor outer segments

■As may occur in association with photoreceptor degeneration

•Dietary exposure to factors which contribute to oxidative stress such as high concentrations of fats

•Accumulation of large amounts of lipofuscin in the retina can also result from specific intrinsic errors of metabolism, such as the neuronal canoid lipofusinoses (see earlier in one chapter and metabolic problems involving lipo formatting on breakdown)

Comparative Comments

•The deposition of lipofuscin in the RPE of non-human animal retinas is related to the entity of drusen seen in human eyes

•Drusen are localized deposits of extracellular material between the basement membrane of the RPE and the inner collagen layer of Bruch’s membrane. They are classified clinically and pathologically into several subtypes: hard, soft, diffuse, basal, nodular, mixed, and calcified regressing drusen

•The appearance of drusen is the first clinically detectable feature of age-related macular degeneration. It is not clear, however, whether the photoreceptor atrophy occurring in age-related macular degeneration is a primary abnormality of the photoreceptors or is secondary to the drusen and other underlying changes in the RPE and Bruch’s membrane.

Age-related degenerative changes

Peripheral cystoid degeneration (Fig. 11.16)

•The peripheral retina in older dogs is often distorted because of the formation of hyaluronic acid filled cysts at the junction between the peripheral retina and the pars plana of the ciliary body (the ora ciliaris retinae)

•This is an aging change that is very common and of no known clinical significance

•In cats, similar cysts are not located in the retina but in the pars plana epithelium of the ciliary body

•In horses, the cysts may be multiple, but are often solitary and arise at the pars plana.

The Retina Chapter 11

Accumulation of lipofuscin

•In the RPE (see previous section).

Equine senile retinopathy (Fig. 11.17)

•The aged horse has a peripheral retinal degeneration characterized by multifocal, neurosensory retinal atrophy and degeneration with pigmentary changes

•The peripheral RPE appears to be colonized by pigmented and non-pigmented cells from the ciliary body epithelium

•Areas colonized by pigmented cells demonstrate local hyperpigmented foci and neurosensory retinal atrophy

•Areas colonized by non-pigmented cells have neurosensory retinal atrophy with deposition of basement membrane matrix material in the degenerate retina

•Since the degeneration is generally confined to the periphery, this condition seldom results in clinically apparent reduction of vision.

Comparative Comments

A counterpart to peripheral cystoid degeneration, described in dogs, is seen in humans and generally termed ‘peripheral microcystoid degeneration.’ These are aggregates of microcysts occurring just posterior to the ora serrata, presumably due to degenerative occlusive disease in the peripheral retinal arterioles.

Peripheral microcystoid disease does not lead to visual signs and symptoms unless the cysts coalesce to form a retinoschisis in the outer plexiform layer.

Light-induced retinopathy, photic retinopathy (Fig. 11.18)

•Retinal phototoxicity with apoptosis of photoreceptors is well documented in dogs and rodents

•Depending on the duration, intensity and wavelength of light, and degree of ocular pigmentation, phototoxicity can be induced in many species

•Light-induced retinal damage is not commonly recognized, but may be a problem in surgical patients subjected to intense light from an operating microscope for extended periods

•Retinal phototoxicity is manifest as a disorganization and loss of photoreceptor cells in the outer retina

•Vacuolation of RPE cells may also be seen in focal areas of light-induced damage

•The retina overlying the tapetum is generally more severely affected than the retina within the non-tapetal fundus, where the RPE is typically heavily pigmented.

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Comparative Comments

•Although no exact counterpart of light-induced retinopathy is described in humans, light does induce photo-oxidative stress in the human retina, and photic retinopathy is a general term used for humans that describes various types of light-related damage to retinal cells, resulting from photochemical, photodynamic, photocoagulative, or even mechanical processes. Light toxicity, in fact, is widely cited as a major pathogenetic mechanism in the etiology of age-related macular degeneration

Comparative Comments (continued)

•Various researchers have emphasized the protective role of melanin granules in the choroid and RPE in preventing retinal damage.

Feline fluoroquinolone-induced toxic retinopathy (Figs 11.19, 11.20)

Acute onset of retinal degeneration has been documented in cats treated with the fluoroquinolone antimicrobial, enrofloxacin.

•After the manufacturer increased the label-recommended dosage of enrofloxacin to a variable range extending up to 20 mg/kg per day as a single or divided dose, reports of sudden blindness in cats started to emerge

■Since the recommended dose has been subsequently reduced, to no more than 5 mg/kg, the widespread reports of retinal toxicity have stopped

•Diffuse photoreceptor degeneration and acute loss of vision is generally recognizable in affected cats, within days of enrofloxacin administration

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•Toxicological studies focused on retinal pathology showed that enrofloxacin at 20 mg/kg per day is toxic to the retina of cats

•Subsequent studies of orbifloxacin have shown similar retinal toxicity but it has never become a clinically significant problem because the recommended dose has remained ‘safe’

•Toxicological studies indicate that retinal toxicity is doseand concentration-dependent. However, it should be borne in mind that animals with renal or hepatic impairment may show signs of toxicity, despite receiving fluoroquinolones at lower than the ‘safe’ doses established for healthy cats.

Morphologic features of enrofloxacin toxicity

•Acute toxicity is present within hours of a single toxic dose

•The target cell is the rod photoreceptor

•In acute toxicity there is swelling and cytoplasmic vacuolation and in chronic toxicity there is photoreceptor loss.

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Plant toxicity

Chronic ingestion of bracken fern (Pteridium aquilinum) by sheep in the UK causes diffuse retinal degeneration, termed ‘bright blindness.’

This syndrome has been reproduced experimentally and the toxic principle responsible for retinal degeneration shown to be ptaquiloside.

Retinopathy associated with Scrapie in sheep

•Scrapie is a transmissible spongiform encephalopathy, or prion disease, that leads to clinical signs associated with neurodegeneration in affected sheep

•Multifocal circular retinal lesions have been reported in sheep with naturally occurring Scrapie

•Outer plexiform layer atrophy, disorganization and loss of nuclei in both nuclear layers, and Muller cell hypertrophy have been identified in some sheep with naturally occurring Scrapie

•Intense accumulation of abnormal prion protein in the plexiform layers of the retina, and altered expression of immunohistochemical markers for several retinal cell types, in particular increased expression of GFAP, has been reported in experimentally infected sheep.

The retina in glaucoma

The general topic of glaucoma and its affects on the eye will be covered in more detail in Chapter 13 but it is appropriate to comment briefly on the retinal changes seen in glaucoma.

The canine retina in glaucoma (Fig. 11.22)

•The response of the canine retina to glaucoma differs from that seen in other species

■This is perhaps related to the acute and extreme nature of intraocular pressure elevation in many affected dogs

■The entire retina often undergoes necrosis and destruction in canine glaucoma, not just the ganglion cells and inner retina

■The superior retina is usually less severely affected than the inferior retina in canine glaucoma (so called ‘tapetal sparing’)

– This is true even in breeds lacking a tapetum

■In severe primary glaucoma in dogs, full-thickness retinal necrosis, and subsequent gliosis and atrophy, occurs very rapidly and can reach ‘end stage’ within a week of the owner first noticing disease in severe and rapidly developing cases. These are the type of cases that are likely to be enucleated.

General features of retinal morphology in glaucoma (Fig. 11.21)

•Glaucoma is a disease of the inner retina, particularly the ganglion cells.

■The pathogenic mechanisms that lead to ganglion cell loss in glaucoma remain unclear

–A number of different mechanisms have been proposed to account for loss of ganglion cells from the retina, including neurotrophin deprivation and excitotoxicity and an interruption of vascular perfusion in the optic disc

–An observation made in the COPLOW collection is that in cases where the retina is detached before the

development of glaucoma, the ganglion cells are relatively spared.

The retina in glaucoma in cats, and in species other than the dog

Cats, like all other species seen in the COPLOW collection, demonstrate a loss of ganglion cells but, even in chronic and severe glaucoma, the outer retina is generally spared from severe atrophy.

Comparative Comments

•Glaucoma is discussed in greater detail in Chapter 13

•In humans, as well as in most other species, glaucoma is in part a disease of the inner retina, and the discussion regarding the mechanism of ganglion cell loss in glaucoma applies to humans

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Comparative Comments (continued)

•The death of ganglion cells is associated with visual field loss and optic atrophy. It is also associated with the thinning of the nerve fiber layer

•Changes in the visual field, appearance of the optic nerve, and thickness of the nerve fiber layer are followed routinely in documenting the progression of glaucoma in human patients.

RETINAL VASCULAR DISEASE

Systemic hypertension

Systemic hypertension is a relatively common, yet probably underrecognized, cause of ocular disease in dogs and cats.

Causes of systemic hypertension in dogs and cats include:

•Secondary:

■To renal disease

–Renal disease may also be secondary to hypertension and the cause-and-effect relationship between systemic hypertension and renal disease remains undefined

A B

C D

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■To hyperthyroidism

■To diabetes mellitus

■To cardiac disease

■To hyperadrenocorticism

■To phaeochromocytoma

■To carcinoid tumor

■To hyperaldosteronism

•Primary:

■Idiopathic or essential hypertension

–An age-related increase in blood pressure has been documented in both dogs and cats, as well as in humans.

Systemic pathology of hypertension involves a number of target organs:

•Kidney

■Vasculopathy leads to poor renal perfusion

•Brain

■Vasculopathy leads to hemorrhage and ischemia

•Eye (Figs 11.23–11.25)

■The eye is frequently the first organ to manifest clinically apparent complications of systemic hypertension in dogs and cats

■Hypertensive vasculopathy was diagnosed in 145 canine cases in the COPLOW collection and in 43 feline cases. In

Figure 11.23  Hypertensive chorioretinopathy in dogs, clinical.

(A) Cocker Spaniel, 11 years old: intraretinal (black arrow) and a large preretinal hemorrhage (white arrow) are present. (B) Cocker Spaniel, 12 years old: this blind dog has a total inferior retinal detachment. Preretinal hemorrhage can be seen overlying the optic disc (arrow). Intraretinal hemorrhage was also present.

(C)Australian Shepherd, 6 years old: the inferior retina is totally detached (arrows) due to subretinal hemorrhage.

(D)Brittany Spaniel, 9 years old: the fundus is not visualized due to the massive preretinal hemorrhage.