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

THE CANINE GLAUCOMAS

Goniodysgenesis associated glaucoma (primary glaucoma, acute primary angleclosure glaucoma, primary open-angle closed-cleft glaucoma) (Figs 13.3, 13.4)

•The defining features of goniodysgenesis (pectinate ligament dysplasia, mesodermal dysgenesis)

■This is a familial, breed-related, congenital abnormality in the structures of the irido-corneal angle (ICA) and aqueous outflow apparatus

–Commonly affected breeds include the Bassett Hound, English and Welsh Springer spaniel, Flat-coated retriever, Great Dane, Samoyed, Sheba Inu and Siberian Husky

■Goniodysgenesis is characterized, morphologically, by the following features:

–A solid iris-like sheet of uveal stroma extending from the iris base to the arborized termination of Descemet’s membrane (pectinate ligament dysplasia)

–The abnormal sheets of uveal tissue are intermittent, and width of the irido-corneal angle and opening of the ciliary cleft can vary considerably throughout its circumference

The extent of goniodysgenesis is therefore best assessed by clinical observation of both the width of the opening of the ciliary cleft and the appearance of the pectinate ligament, using a special lens placed on the cornea (gonioscopy)

The glaucomatous eye cannot be used to observe the extent of goniodysgenesis because the cornea becomes cloudy with edema and the irido-corneal angle is

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narrowed by elevated IOP. The unaffected contralateral eye is used to evaluate the extent of affected angle

Severity or grade of goniodysgenesis appears to be heritable

The greater the extent of circumferential involvement of the drainage angle, the greater the chances of developing glaucoma

■Severe goniodysgenesis is clearly a risk factor in the development of glaucoma but most dogs affected by goniodysgenesis do not develop glaucoma

–Although gonioscopy may reveal goniodysgenesis or pectinate ligament dysplasia (PLD) in a significant number of dogs within certain breeds, only some of these animals will actually go on to develop glaucoma. The pectinate ligament is clearly not the most important source of resistance to aqueous outflow

–However, goniodysgenesis may signal the existence of other developmental abnormalities within the structures of the ciliary cleft or may have implications in the way the iris is positioned during miosis and mydriasis perhaps predisposing to pigment dispersion

–The limitation of gonioscopy in our clinical evaluation of the canine aqueous outflow pathway has been highlighted by histopathological identification of goniodysgenesis and ciliary cleft collapse in Norwegian elkhounds, a breed previously classified as affected by a chronic, slowly progressive, ‘open-angle’ glaucoma

■A dog with goniodysgenesis-related glaucoma in one eye is highly likely to develop glaucoma in the second eye

–For this reason there is a lot of interest in ‘prophylactic’ treatment which might delay or prevent glaucoma development in the second eye

•From ‘at risk’ to acute glaucoma – pathogenic mechanisms in dogs with goniodysgenesis

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■In dogs with goniodysgenesis, the progression to an acute glaucomatous crisis characteristically does not occur until middle age or later in life

–There is a suspicion that in many affected dogs, transient episodes of IOP elevation, with subsequent spontaneous resolution, precede confirmed glaucomatous crises. There are competing hypotheses which attempt to explain the increased intraocular pressure

–Elucidating the mechanisms that precipitate acute IOP elevations in dogs with goniodysgenesis will greatly enhance our ability to treat, and hopefully prevent or delay the onset of, glaucoma in ‘at-risk’ eyes

■Severe goniodysgenesis, narrow ICA, relatively anterior lens position, thick lens, and shallow anterior chamber, may all be considered as anatomic risk factors, i.e. markers indicating predisposition to glaucoma

–Similar anatomic risk factors may predispose human and canine subjects to primary angle closure glaucoma. However, only a small proportion of individuals with these characteristic risk factors go on to develop glaucoma

■Age-related changes in morphologic features such as lens thickness and narrowing of the irido-corneal angle may, at least in part, contribute to angle closure and the development of glaucoma in middle-aged and older

dogs

■Acute pupil block is a dynamic process that has also been put forward as a factor contributing to acute glaucomatous crises. It has been proposed that a very small segment of the iris, right at the pupil margin, is held in apposition against the anterior lens capsule by a complex dynamic mechanism that involves ‘iris stretch’ and combined ‘blocking forces’ generated by both the sphincter and dilator muscles.

–A role for ‘iris touch’, i.e. iris-lens contact, in the pathogenesis of IOP elevation in dogs with

goniodysgenesis-related glaucoma is supported by the finding of pigment dispersion in affected eyes

■Significant uveal inflammation was also identified in canine eyes with acute glaucoma. Whether uveitis plays a role in precipitating episodes of glaucoma due to iris thickening or miosis, or whether inflammation is a secondary phenomenon in dogs with primary glaucoma remains unclear

–Resistance to the flow of aqueous caused, in some way by the abnormal uveal membranes or by matrix deposited by the membrane

–Obstruction of aqueous drainage at the level of the pupil associated with contact between the papillary margin of the iris and the lens

–Degeneration of the filtration apparatus secondary to entrapment of released melanin

–Any combination of mechanisms

■Histopathological studies are associated with important limitations, including the tendency to examine only globes obtained at a late stage in the disease process

■Disease progression in canine goniodysgenesis-associated glaucoma begins with the sudden development of severe disease. Morphologically, the disease progresses in a stepwise manner, consistent with a rapidly progressive disease course following a dramatic initiating event

Sequential changes in the drainage angle following acute IOP elevation in goniodysgenesis-related glaucoma

The first 24 h (Fig. 13.5)

•Atrophy of the corneoscleral trabecular meshwork

■The identification of this change, so soon after the apparent onset of acute glaucoma, suggests that there is latent disease building up to the glaucomatous crisis

•Incomplete collapse of the ciliary cleft

•Disruption of the posterior pigmented epithelium of the iris near the pupillary margin

•Free pigment granules within the anterior chamber and in the angle and trabecular meshwork

•Neutrophilic inflammatory cell infiltrate in the anterior chamber, irido-corneal angle, ciliary cleft and the limbal sclera

•Nuclear enlargement and increased mitotic activity involving stromal fibroblasts and endothelial cells at the limbus

1–5 days (Fig. 13.6)

•Complete closure of the ciliary cleft with indistinguishable corneoscleral trabecular meshwork

•Dispersion of pigment remains a prominent feature within the anterior chamber and filtration angle

•Loss of the posterior pigmented epithelium from the pupillary margin of the iris

•Neutrophilic inflammatory cell infiltrate is rarely seen

•Evidence of cellular proliferation remains apparent within the limbal tissues

Chronic changes (Fig. 13.7)

•Complete collapse of the ciliary cleft with indistinguishable corneoscleral trabecular meshwork

•No neutrophilic inflammation

•Pigment dispersion remains, but rarely at a significant level

The Glaucomas Chapter 13

Sequential changes in the retina following acute IOP elevation in goniodysgenesis-related glaucoma

The first 24 h (Figs 13.8, 13.9)

•Radiating sectors of edematous retina apparent grossly

•Hypereosinophilic, necrotic retinal ganglion cell profiles seen

■This change is seen rarely at later stages, in association with more chronic disease, suggesting that retinal degeneration can occur as a cyclic or ongoing process

•Outer retinal edema but no cellular necrosis or apoptosis

•Müller cell expression of glial fibrillary acidic protein (GFAP) is little changed from background

•Neutrophilic inflammatory cell infiltrate in the retinal tissue

1–5 days (Fig. 13.10)

•Radiating zones of retinal edema and degeneration still apparent grossly

•Extensive, segmental, full-thickness retinal cell apoptosis. The pattern of regionally variable severity correlates with the radiating pattern of edema and degeneration seen grossly

•Segmental full-thickness retinal degeneration and necrosis is characteristic in dogs with acute goniodysgenesis-related glaucoma, but is not a typical feature associated with glaucoma in any other species

•Marked upregulation in the expression of GFAP by Müller cells and astrocytes

•Degenerative changes often appear more advanced within the dependant, non-tapetal, retina (a phenomenon referred to as ‘tapetal sparing’)

Chronic changes (Fig. 13.11)

•Full thickness retinal atrophy with elevated expression of GFAP

•The process of apoptosis continues far beyond 5 days, and rarely, hypereosinophilic ganglion cells, interpreted as necrotic but not apoptotic, are seen even in long standing disease

•The relative sparing of the superior retina is most prominently seen in the eyes of chronically glaucomatous dogs

■Although this phenomenon is called ‘tapetal sparing’, in atapetal dogs there is still relative sparing of the superior retina

Sequential changes in the optic nerve following acute IOP elevation in goniodysgenesis-related glaucoma

The first 24 h (Fig. 13.12)

•Swelling of the optic nerve head

•Necrotic neuropil with a few phagocytic cells (gitter cells)

•This change can be hard to appreciate because the neuropil is not very cellular to begin with

•Granular neuropil remnants often protrude into the vitreous

•Neutrophils within the neuropil of the optic nerve head

2–5 days (Fig. 13.13)

•Malacia of the optic nerve head

■Gitter cells predominate

■With the phagocytosis of optic disc neuropil, the tissue becomes cavitated

•Vitreous matrix is often incorporated into the cavitated optic nerve (Schnabel’s cavernous atrophy)

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Chronic changes (Figs 13.14, 13.15)

•End-stage gliosis, atrophy and cupping of the optic nerve head

•In the progression of optic nerve cupping in dogs the distortion of the nerve head is more a matter of necrosis and collapse than a backwards thrust against the lamina cribrosa of the optic nerve.

Comparative Comments

•Primary angle-closure glaucoma in humans is a form of glaucoma in which there is an anatomic predisposition to obstruction of aqueous outflow by irido-trabecular contact as a result of a narrow angle and/or shallow anterior chamber

•An additional predisposing anatomical feature is a plateau iris

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•Other factors include hyperopic eyes, in which the sizes of the lens and the anterior chamber are disproportionate, and small eyes

•Primary angle-closure glaucoma is more common in Eskimos and East Asians, as well as in middle age and in women. There is often a family history

•Attacks of primary angle-closure glaucoma tend to occur when the pupil is in mid-dilatation. Here, greater iris contact with the anterior lens capsule increases resistance to the passage of aqueous humor through the pupil, and this increased resistance displaces the iris root anteriorly. In this situation, angle closure may occur

•On histopathologic examination of an untreated globe with narrow-angle glaucoma, the anterior chamber is seen to be

A

B C

Figure 13.7  Goniodysgenesis, chronic disease. Photomicrograph, from a dog with glaucoma for 1 week or longer, showing the completely collapsed and atrophied ciliary cleft and corneoscleral trabecular meshwork.

The Glaucomas Chapter 13

Figure 13.6  Goniodysgenesis and pigment dispersion in acute glaucoma.

(A) Low magnification photomicrograph from a dog with a 4-day history of glaucoma and goniodysgenesis showing large amounts of free pigment in the dependent aspect of the anterior chamber and complete collapse of the ciliary cleft. (B,C) Higher magnification photomicrographs showing what remains of the atrophied corneoscleral trabecular meshwork. Notice the pigment in the atrophied structure (arrows).

Comparative Comments (continued)

narrow and the angle closed. Usually a relatively large lens is evident

–Necrosis of the dilator and sphincter muscles is observed and leads to irregularities in the pupillary shape

–Segmental iris atrophy is often present, together with generalized atrophy of the iris stroma

–Small subcapsular anterior white opacities in the lens (glaukomflecken) are characteristic if there have been multiple attacks

–The corneal epithelium shows damage, and the corneal stroma may be edematous

–Because of blockage of venous return, optic disk edema and even central retinal vein occlusion may be seen

–Commonly, the prolonged contact of the iris with the trabecular meshwork has led to peripheral anterior synechiae (PAS), as well as fibrosis of the trabecular meshwork

–Often there is evidence of laser peripheral iridotomy or surgical iridectomy.

A B

C D

Canine primary open-angle glaucoma (POAG)

•Infrequently encountered in practice or submitted to diagnostic pathology services

•Heritable POAG has been extensively studied in Beagles, within a colony of affected dogs at the University of Florida

•Abnormalities in ocular vascular resistance, tonographic aqueous outflow facility (which progressively declines from several months of age) and IOP have been confirmed in affected dogs, prior to the late-stage development of angle closure and advanced glaucoma that occurs from about the third year of

life

•Of the few cases that are encountered sporadically in clinical veterinary practice, many are presented once glaucoma is advanced and, in general, histopathological findings are likely to be similar to those seen in primary goniodysgenetic glaucoma

•In Beagles, as in humans with POAG, the precise mechanism for aqueous outflow obstruction remains unclear. However, the site of increased aqueous outflow resistance in POAG appears to reside in the trabecular meshwork and its extracellular matrix. In addition to the accumulation of abnormal, enzyme resistant glycosaminoglycans in the extracellular meshwork of the TM of affected dogs, abnormal amounts of myocilin protein have been identified in eyes of affected Beagles.

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Figure 13.8  Retinal disease in acute goniodysgenesis glaucoma, fundus.

(A)Samoyed, 4 years old: the optic disc is swollen and retinal vessels are dilated. The peripapillary retina is edematous and has a large bullous detachment (arrow).

(B)The same eye as in (A), 12 days following treatment, is now a normotensive eye. The optic disc is pale. Peripapillary tapetal pigmentation and hyperreflectivity (arrow) are present. The eye was visual. (C) Cocker Spaniel, 8 years old: the peripapillary retina is edematous. The optic nerve changes are discussed in Figure 13.12. (D) This is the same eye as (C), 4 weeks later. The peripapillary retina is atrophic, resulting in tapetal hyperreflectivity. The eye was visual.

Comparative Comments

•Primary open-angle glaucoma (POAG) is by far the most common type of human glaucoma, affecting 1–2% of the population over 40 years of age. If untreated, it can lead to marked visual loss and blindness

•POAG is a chronic, slowly progressive, usually bilateral disease, characterized by an increased resistance to aqueous outflow. There is usually an increased intraocular pressure with associated injury to the retinal ganglion cell axons

•The pathogenesis of this disease is unclear. The microscopic structure of the anterior chamber angle is normal. The histopathology findings related to POAG are controversial, with the changes appearing similar to aging changes, but they appear to be more severe and occur earlier in glaucomatous eyes

•It is generally believed that the disease is multifactorial and results in an imbalance between intraocular pressure and vascular perfusion of the optic nerve head. In addition, mechanical pressure on the ganglion cell axons at the neuroretinal rim may interfere with axonal flow and result in retrograde neuronal degeneration

•Probably a subset of POAG, ‘normal tension glaucoma’ or ‘low tension glaucoma’ is a disease in which optic disk cupping, atrophy of the optic disk, and visual field loss may occur in the absence of a demonstrable elevation of intraocular pressure.

Lens luxation glaucoma (Fig. 13.16)

•Lens luxation is a risk factor for glaucoma for a variety of reasons, not all of which are understood. Complicating interpretation of lens luxation and glaucoma is the fact that lens luxation often occurs as a consequence of buphthalmos in animals with glaucoma

■Luxation of the lens into the anterior chamber may lead to pupil-block or obstruction of aqueous flow within the anterior chamber, by either the lens itself, or by anteriorly prolapsed vitreous, and the relationship to the development of glaucoma is quite obvious

■Luxation or subluxation of the lens in the posterior chamber or into the vitreous is also a risk factor for glaucoma, but the mechanism for secondary glaucoma is not as obvious

–The loss of zonular ligament tension might tend to close the ciliary cleft

–Anteriorly prolapsed vitreous may obstruct aqueous outflow

•Lens luxation occurs for a variety of reasons, that are discussed in greater detail in Chapter 10

■Trauma

■Secondary to glaucoma with enlargement of the globe (buphthalmos)

■Cataract

■Breed-related zonular ligament dysplasia

•Special features of glaucoma secondary to lens luxation:

■About half of dogs with glaucoma secondary to lens luxation do not exhibit the phenomenon of ‘tapetal sparing’.

Neovascular glaucoma (Fig. 13.17)

•A diagnosis of neovascular glaucoma implies that the iridocorneal angle is obstructed by peripheral anterior synechiae resulting from a pre-iridal fibrovascular membrane (see Ch. 9)

■Neovascular glaucoma occurs secondary to an underlying process which stimulates the formation of the neovascular membrane

–Retinal ischemia secondary to retinal detachment

–Intraocular neoplasia

–Uveitis

–Trauma.

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