JPC SYSTEMIC PATHOLOGY
SPECIAL SENSES
April 2021
S-M05

Signalment (JPC #C-2593-86): Tissue from an English setter.

HISTORY:  This 9-week-old female English setter dog had posterior capsular pigmentation of the lens, retinal detachment, and neovascularization; the eye was enucleated.

HISTOPATHOLOGIC DESCRIPTION:  Eye: Diffusely, the retina is disorganized, folded, and separated from the underlying hypertrophied, rounded retinal pigment epithelium (RPE; tombstoning).  Multifocally, there is loss of the normal retinal architecture, characterized by variation in thickness of the outer and inner nuclear layers, extensive loss and thinning of the outer plexiform layer, and multifocal coalescence of the outer and inner nuclear layers.  The outer nuclear layer multifocally forms rosettes composed of neuroblastic cells which surround a central clear space and contain eosinophilic fibrils (rods and cones).  Ganglion cells are multifocally clustered in areas of retinal folding. There is vacuolation in the nerve fiber layer (axonal degeneration and/or spongiosis).  There is a focal area of fibrous metaplasia on the posterior aspect of the lens admixed with scant melanin.

MORPHOLOGIC DIAGNOSIS:  Eye, retina:  Dysplasia, diffuse, severe with multifocal retinal folds - rosettes, thinning of outer plexiform layer, and retinal detachment, English setter, canine.

CONDITION:  Retinal dysplasia

GENERAL DISCUSSION:

• True retinal dysplasia refers to abnormal differentiation of the retina characterized by disorganized retinal layers and glial proliferation
• Etiology is often hereditary but can be secondary to in utero viral infection, drug administration, vitamin A deficiency, x-rays, and intrauterine trauma
• Retinal dysplasia is an inherited defect in English Springer Spaniels, Miniature Schnauzers, and collies
• Retinal dysplasia may be a response to postnatal injury in dogs, cats, and mice, in which development of the retina is not complete for about 6 weeks after birth and proceeds radially from the central retina
• The retina is mature at birth in ruminants and horses, therefore retinal dysplasia is an in utero event in these species

PATHOGENESIS:

• Primary (1 type):
  • “True” retinal dysplasia (rare, except in collies)
  • Retinal folds, retinal rosettes, patchy to diffuse blending of nuclear layers, loss of retinal cells, and glial scars
  • Due to failure of proper apposition of the two layers of the optic cup or failure of proper induction of retinal maturation by the retinal pigment epithelium (RPE)
  • Chondrodysplasia occurs concomitantly with hereditary retinal dysplasia in Labrador retrievers and Samoyeds due to mutations affecting the COL3 domain of collagen IX
  • Labrador retrievers - drd1 dwarfism with retinal dysplasia type 1 is caused by a 1-bp insertion in COL9A3 (collagen IX, α3 chain); result of a single gene with recessive effects on the skeleton and incompletely dominant effects on the eye; affects collagens II and XI
  • Samoyeds - drd2 dwarfism with retinal dysplasia type 2 is caused by a large deletion at the 5′ end of COL9A2 (collagen IX, α2 chain)
• Secondary (2 types):
  • Post necrotic retinal dysplasia (uncommon)
    • The initial ocular lesion is non suppurative panuveitis and retinitis with multifocal retinal and choroidal necrosis
    • Necrosis or inflammation of the developing retina due to viral, physical or chemical insults (postnecrotic/postinflammatory retinal dysplasia)
    • Damage occurs while retinal neurons still have proliferative capacity and attempt at regeneration results in dysplasia
    • Scars represent unsuccessful attempts at post-necrotic healing
  • Retinal folding (most common)
    • Not a true dysplasia if present in the absence of disorganized retinal layers
    • Proposed to be due to buckling and folding of the retina when the retinal growth rate exceeds the growth rate of the surrounding choroid/sclera in juvenile animals

TYPICAL CLINICAL FINDINGS:

• Unilateral or bilateral, signs variable from clinically insignificant to blindness

TYPICAL GROSS FINDINGS:

• Ophthalmoscopically, retinal folds and rosettes are vermiform streaks or round gray elevations in the non-tapetal fundus or gray, hyperreflective scars associated with pigment disturbances in the tapetal fundus
• The ophthalmological appearance of retinal dysplasia varies from breed to breed but tends to be consistent within a given breed

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Primary:
  • Retinal rosettes, nuclear layer blending, variations in thickness, and disorganization of retinal layers
  • Retinal dysplasia hallmark: rosette, composed of a central lumen surrounded by one to three layers of neuroblasts; the three-layered rosette is reportedly the most common type in naturally occurring retinal dysplasia in animals
  • Possible retinal detachment
• Secondary:
  • Postnecrotic retinal dysplasia
• Postnecrotic scarring in the retina, optic nerve, and possibly choroid
• Loss of nuclei from all retinal layers
• Disorganized retinal layers (if damage occurred when neurons still had proliferative capability)
• Possibly some residual inflammatory cells
• RPE hyperplasia, migration into injured retina, and/or metaplastic formation into fibroglial plaques
  • Retinal folding
• Retinal folds, detached from choroid/sclera
• No jumbling of retinal layers
• No scarring

COMPARATIVE PATHOLOGY:

• Cattle: bovine viral diarrhea virus (Flaviviridae; Pestivirus); viral infection of the fetus between days 79 and 150 of gestation results in retinal dysplasia; other associated lesions of BVDV are cerebellar atrophy and hydrocephalus or hydranencephaly
• Sheep: bluetongue virus (Reoviridae; Orbivirus), cerebellar atrophy
• Cats: feline panleukopenia (Parvoviridae; Parvovirus) and feline leukemia virus (Retroviridae), cerebellar atrophy
• Abyssinian breed early-onset rod-cone dysplasia: autosomal dominant, histologically similar to the disease in Irish setter dogs, and affected cats are blind by a few months of age
• Abyssinian breed late-onset retinal degeneration (affecting rods before cones): autosomal recessive, slow progression, affected cats are blind by 5-10 years of age
• Dogs: Herpesvirus and adenovirus
• Retinal dysplasia occurs in combination with other ocular defects in dobermans, Akitas, chow chows, and Australian shepherd dogs; and in collies with collie eye anomaly
• Rd (retinal degeneration) mouse: naturally occurring, early onset, autosomal inherited blindness in certain strains of mice
• Retinal dysplasia has also been described in horses, cows, pigs, deer, rats, chickens, and wild otters

REFERENCES:

1. Cantile C, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6^th Philadelphia, PA: Elsevier Saunders; 2016:281-283.
2. Craig LE, Dittmer KE, Thompson KG. Bones and joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. Vol. 1. 6th ed. Philadelphia, PA: Elsevier; 2016: 45, 82.
3. Dubielzig RR, Ketring KL, McLellan GJ, et al. eds. Veterinary Ocular Pathology: A Comparative Review. St. Louis, MO: Elsevier Saunders; 2010: 33, 39-42.
4. Gelatt KN, Plummer CE. Color Atlas of Veterinary Ophthalmology. 2^nd Ames, IA: Wiley Blackwell; 2017:219-220, 277.
5. Labelle P. The eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6^th St. Louis, MO: Elsevier; 2017: 1307-1308.
6. Wilcock BP, Njaa BL. Special senses. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6^th St. Louis, MO: Elsevier; 2016:419-420, 469-470.

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