Conference 11 - 2016 Case: 1 20161116

Signalment:

Eight-week-old, female, Wistar-Han rat, (Rattus norvegicus).Control rat from a 7-day exploratory toxicity study.

Gross Description:

In the right and left eyes, diffusely opaque lens noted at necropsy.

Histopathologic Description:

Eye, lens: Multifocally, there is disruption and dissolution of the lenticular fibers often replaced by variably sized, irregular vacuoles which contain spherical to irregularly-shaped globular eosinophilic aggregates (Morgagnian globules). Lens epithelial cells are multifocally swollen with abundant eosinophilic microvacuolated cytoplasm (bladder cells). At one pole, lens epithelial cells become spindyloid and are separated by fine collagen fibers (fibrous metaplasia). The iris is attached to the anterior lens capsule (posterior synechia).

Eye, retina: Diffusely, the retina is disorganized. The outer nuclear layer forms numerous rosettes which surround a central space that contain eosinophilic fibrils (rods and cones). There is thinning of the outer plexiform layer and multifocal blending of the inner and outer nuclear layers. Retinal pigment epithelium is frequently vacuolated admixed with occasional nuclear cell debris and infiltration of macrophages. There is minimal hemorrhage admixed with scattered macrophages, lymphocytes, and neutrophils within the vitreous space.

Morphologic Diagnosis:

1. Eye, lens: Cataract, diffuse, moderate to severe, with epithelial hyperplasia, posterior synechiae, and fibrous metaplasia.
2. Eye, retina: Dysplasia.
3. Eye, retina: Degeneration, multifocal, mild.

Lab Results:

None.

Condition:

Retinal dysplasia

Contributor Comment:

Cataracts are the most common lenticular disease in aged Sprague-Dawley and Wistar rats. Cataracts are subclassified by the location in the lens: nuclear cataract involving the central area of the lens; cortical cataract involving the lenticular surface; and posterior capsular cataract involving the posterior surface of the lens and often arising under the capsule.⁶ The case present herein is an example of the latter classification. Posterior capsular cataracts were described in 32% of aged Wistar rats and overrepresented in females.¹⁰The pathogenesis of cataract formation involves initial lens swelling due to loss of Na-K-dependent ATPase osmotic pumps resulting in potassium loss and sodium and calcium entry into the lens causing vacuolation and protein aggregation of the lens epithelium (bladder cell formation) with subsequent denaturation and hydrolysis of lens fibers (Morgagnian globules).⁶ Cataract is considered a major cause of visual impairment in diabetic patients. The initiating mechanism in diabetic cataract formation is the generation of polyols from glucose by the aldose reductase pathway, resulting in a similar increased osmotic stress as described in spontaneous cataract formation leading to lens fiber swelling and rupture.⁶

Retinal dysplasia is the disorderly proliferation and differentiation of the retina and is characterized by blending and folding of the retinal layers, rosette formation, most commonly the inner and outer nuclear layers, and occasionally degeneration. Retinal dysplasia is an incidental develop-mental anomaly. These retinal folds and blending of the layers have been described in Wistar rats occasionally showing micro-phthalmia and cataracts.⁶Retinal dysplasia is spontaneous or inherited and is rarely progressive.⁹ A linear form of retinal dysplasia has been reported in Sprague-Dawley rats at 7-10 weeks of age consisting of loss of the outer layers of the retina resulting in confluency of the inner nuclear layer with the choroid.⁹ The findings described in this vehicle-treated animal were considered incidental.

JPC Diagnosis:

1. Eye, lens: Cataractous change, subcapsular, diffuse, characterized by Morgagnian globules, bladder cells, and fibrous metaplasia, with posterior synechia, Wistar-Han rat, Rattus norvegicus.
2. Eye, retina: Dysplasia.

Conference Comment:

The contributor provides a superb example of the histologic changes associated with the formation of cataracts and retinal dysplasia in the rat. Cataracts result from exposure of the lens to a large variety of insults, including ultraviolet light, physical and chemical damage, increased intraocular pressure, numerous toxins, direct trauma, nutrient imbalance, and inflammation.¹⁰ Spontaneous cataracts have also been reported to occur in up to 9.8% of Sprague-Dawley rats and 32% of aged (>2 years) Wistar rats.^2,10 Despite the wide variety of possible causes, the histologic lesions associated with cataractous change are relatively stereotypic across species. The lenticular lesions present in this case include Morgagnian globules, composed of bright eosinophilic globules of denatured lens protein; bladder cells, which are large foamy nucleated cells that may represent abortive epithelial attempts at new lens fiber formation; lens epithelial hyperplasia; and posterior migration of lens epithelium followed by fibroblastic metaplasia. The latter two changes are associated with chronic cataract formation.¹⁰ Conference participants also noted the large size of the lens resulting in narrowing of the anterior chamber, which is a normal finding in the rat.³

This case also generated some spirited discussion among conference participants regarding whether the retinal changes represent a dysplastic or degenerative process. The albino Wistar rat is currently one of the most popular rats used for laboratory research and is exquisitely sensitive to phototoxicity due to the lack of melanin pigment.^3,7 Given the history of bilateral lesions, strain of the rat in this case, and relatively young age of the animal, the conference moderator posited that the cataractous change and retinal lesions could be secondary to phototoxicity. Rats housed in areas of greater light intensity, such as the outer columns and top racks, are more susceptible to developing phototoxic lesions.⁷ Additionally, light-induced retinal degenerative changes typically manifest as disorganization and loss of photoreceptor cells in the outer retina, vacuolation of pigmented retinal epithelium, and accumulation of intracytoplasmic lipofuscin pigment, all of which are present in this case.¹

Conference participants also discussed the possibility that the lesions in this case represent spontaneous and dysplastic change. Albino rodents are well known to have several kinds of spontaneous ocular lesions, including corneal dystrophy (calcium deposition), cataract, and retinal fold/dysplasia .³ To help elucidate the possible underlying cause(s) of the retinal changes, this case was studied in consultation with the Dr. Leandro Teixeira, a board certified veterinary pathologist and recognized expert with extensive experience in the area of veterinary ocular pathology. Dr. Teixeira agrees with the contributor that the retinal rosettes, retinal folds, retinal atrophy, and blending of the inner and outer layers of the retina are common dysplastic changes in the rat, and are a result of faulty retinal development rather than a degenerative change. Similar dysplastic lesions can be induced by the administration of various toxins and carcinogens, such as cytosine arabinose, cycasin, N-methyl-N-nitrosurea, and trimethylin; however, this animal is reported to be a control rat and exposure to the aforementioned compounds is unlikely. Dysplastic lesions can be unilateral or bilateral, as in this case.⁹ The lesions in the retinal pigmented epithelium, such as hypertrophy and vacuolation of pigmented epithelium and accumulation of lipofuscin, are also common mild cellular degenerative changes secondary to retinal dysplasia in the rat.

References:

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