JPC SYSTEMIC PATHOLOGY
SPECIAL SENSES SYSTEM
April 2018
S-M12

Signalment (JPC #2839056):  Collie

HISTORY:  Tissue from a collie dog

HISTOPATHOLOGIC DESCRIPTION: Eye: There are diffuse dysplastic changes affecting the retina, sclera, iris/trabecular meshwork and choroid.  Multifocally, all layers of the retina are disorganized with the formation of multiple rosettes; detachment from the rounded, hypertrophied retinal pigment epithelium (“tombstoning”); an indistinct nerve fiber layer, ganglion cell layer, and outer plexiform layer; thinning of the inner plexiform and nuclear layers (retinal atrophy) or coalescence of the nuclear layers.  The choroid is diffusely and markedly thinned, composed of a thin fibrous stroma, few vessels, and lack of pigmentation (choroidal hypoplasia); there is focally extensive thinning of the tapetum adjacent to the optic disc.  There is a 10 x 15 mm retrobulbar cystic, thin-walled outpouching or defect in the sclera (ectasia), that is multifocally lined by neuroectoderm (coloboma), contains numerous inward papillary projections and extends from the optic disc to the ciliary body. Multifocally and predominately along the anterior lens, there is disruption of lens fiber architecture by numerous bladder cells, morgagnian globules (cataractous change), and reactive hyperplasia of the capsular lens epithelium, with posterior migration of the epithelial cells.  There are small amounts of eosinophilic granular to flocculant material within both the anterior and posterior segments that appear adhered to both the ciliary body and retina. There is ciliary body and iris atrophy and the iris is focally displaced rostrally and adhered to the cornea (anterior synechiae), obscuring the ciliary cleft.

MORPHOLOGIC DIAGNOSIS: 

1. Eye: Choroidal hypoplasia and hypopigmentation, diffuse, severe, with retinal detachment and atrophy, and cataractous change, Collie, canine
2. Eye, optic nerve: Scleral coloboma.

ETIOLOGY: Hereditary posterior segment anomaly (dysgenesis)

CONDITION:  Collie eye anomaly (CEA)

GENERAL DISCUSSION: 

• Collie eye anomaly (CEA) is a canine inherited bilateral ocular disorder which shows a variety of manifestations of clinical lesions
• CEA is common in Collies (smooth and rough-coated), Shetland sheepdogs, Australian shepherds, and Border collies, other herding breeds, and occasionally observed in various non-Collie breeds (Australian shepherd, beagle, dachshund, and German shepherd dog); there are four main lesions:
  • Choroidal hypoplasia
  • Coloboma; +/- sclera ectasia, posterior staphyloma
  • Retinal detachment and dysplasia
  • Intraocular (posterior segment) hemorrhage
• The earliest lesion of this anomaly is defective differentiation of primitive retinal pigment epithelium (RPE) that forms rosette-like structures near the optic disc 
• All cases demonstrate a regionally defined area of choroidal hypoplasia (most consistent finding) and segmental tapetal aplasia lateral to the optic disc; coloboma may occur in up to 34% of cases which may result in retinal detachment and hemorrhage

PATHOGENESIS:

• An inherited autosomal recessive trait; the underlying genetic mutation, is a homozygous deletion of 7799-bp in the NHEJ1 gene
• Proper development of the eye requires obliteration of the intraretinal space and apposition of the pigment layer and neural retina
• CEA results from either: 1. imperfect apposition of the pigment epithelium and neural retina or 2. defective differentiation of the pigment epithelium; since pigment epithelium plays such a critical role in development of the eye, the primary defect is presumed to be in the retinal pigment epithelium

TYPICAL CLINICAL (OPTHALMOSCOPIC) FINDINGS:

• Collie eye anomaly may be diagnosed as early as 5-10 weeks of age; after 12 weeks of age, it is hard to perform a diagnostic eye exam because the lesion can be covered up by pigment (Note: If the proper eye examination period is missed, then the condition remains unknown until symptoms become apparent)   
• Bilateral lesions, although one eye may be worse than other
• Retinal vessel tortuosity
• Focal to diffuse choroidal and tapetal hypoplasia
• Optic nerve coloboma
• Retinal folds or detachment with intraocular hemorrhage
• Enophthalmos, microphthalmos, and corneal stromal mineralization

 TYPICAL GROSS FINDINGS:

• There are four gross lesions: choroidal hypoplasia, posterior coloboma(+/- sclera ectasia), retinal detachment, vitreous/retinal hemorrhage
• Choroidal hypoplasia:
• Focally extensive to diffuse thinning and pallor (depigmentation) of the choroid usually adjacent to the optic disk at the tapetal-nontapetal junction
• Choroid and sclera will be translucent if transilluminated
• Choroidal vessels are fewer, wider, and abnormally arranged
• Normally bilateral, but often asymmetric
• Coloboma:
• Gray or pink indentations (variably sized) that are within or adjacent to the optic disk
• Retinal vasculature changes course or disappears at the edge of the coloboma
• Scleral ectasia or posterior staphyloma may occur when a large coloboma produces a bulge in the overlying sclera
• Retinal detachment:
  • Most often a sequela from coloboma; arises adjacent to the optic disk and extends out peripherally
• Subretinal, intraretinal, or preretinal, intravitreal hemorrhage
• Retinal separation with the only sites of attachment at the optic disk and ora ciliaris
• If the retina detaches from the ora ciliaris (retinal disinsertion), the folded retina will sink to the floor of the globe

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Earliest lesion is defective differentiation of primitive RPE to form rosette-like structures near the optic disc
• Choroidal hypoplasia:
• Marked diffuse thinning of the choroid (choroid hypoplasia) with decreased pigmentation and a thin or absent tapetum
• Retinal pigment epithelium is poorly pigmented and may be vacuolated
• Tortuous vasculature
• Coloboma:
  • Lamina cribosa or scleral defect with outward bulging or ectasia, often adjacent to the optic disc (but not in all cases)
• Bulging of dysplastic or atrophic neuroectoderm, continuous with the retina, into the pit in the optic nerve head; lining the coloboma or staphyloma
• Neuroectoderm may show differentiation into ganglion cells, photoreceptor rosettes, glial cells, or pigment epithelium
• In large colobomas, choroid may be lacking and sclera thinned
• Rosette-like structures near or imbedded in the optic disk
• Retinal detachment:
• Retinal folds are visible as tubes in cross section; these indicate a retina that temporarily has outgrown the space available within the optic cup and correspond to vermiform streaks in fundus seen clinically; the folds gradually disappear as the eye matures and expands in diameter
• Hemorrhage
• May be focal or diffuse
• May also see pre-iridal fibrovascular membrane formation and hemorrhage into the posterior segment

ADDITIONAL DIAGNOSTIC TESTS:

• Novel SYBR Green-based-real time PCR on blood and saliva samples (rapid genotyping technique)

DIFFERENTIAL DIAGNOSIS:

• Primary retinal dysplasia: This is linear folding of the sensory retina with formation of rosettes and in severe cases, retinal detachment; may be hereditary or associated with systemic disease

COMPARATIVE PATHOLOGY:

• Colobomas: Occur in all domestic species as a result of complete fusion of the lips of the optic fissue; most often in blue-eyed or albino animals; Charolais cattle inherit colobomas as an autosomal dominant trait with incomplete penetrance; recent report in free-ranging white-tailed deer
• Choroidal hypoplasia: Occurs in a variety of dog breeds associated with color dilution
• Other breed associated ocular abnormalities:
  • Merle ocular dysgenesis: Micropthalmia with abnormalities in the lens, sclera and retina including coloboma formation, retinal detachment and retinal dysplasia
  • Rocky Mountain horses: Microphthalmia, cornea globose, iris abnormalities, ciliary cysts, cataracts, etc.
  • Doberman Pinscher and Staffordshire bull terrier (inherited): persistent hyperplastic primary vitreous and persistent hyperplastic tunica vasculosa lentis; may also occur in other breeds

REFERENCES:

1. Chang HS, Mizukami K, Yabuki A, et al. A Novel Rapid Genotyping Technique for Collie Eye Anomaly: SYBR Green-Based Real-Time Polymerase Chain Reaction Method Applicable to Blood and Saliva Specimens on Flinders Technology Associates Filter Paper. J Vet Diagn Invest. 2010;22:708-715.
2. Clarke LL, Niedringhaus KD, Carmichael KP, Keel MK, Fenton H. Congenital ocular abnormalities in free-ranging white-tailed deer. Vet Pathol. 2018; DOI: 10.1177/0300985818759771 (epub ahead of print).
3. Dubielzig RR, Ketring KL, McLellan GJ, Albert DM. Veterinary Ocular Pathology: a comparative review. St Loius, MO: Saunders Elsevier; 2010;34-35,353,401.
4. Labelle P. The Eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St Louis, MO: Elsevier; 2012:1315.
5. Munyard KA, Sherry CR, Sherry L. A retrospective evaluation of congenital ocular defects in Australian Shepherd dogs in Australia. Vet Ophthalmol. 2007;10:19-22.
6. Wallin-Hakanson B, Wallin-Hakanson N, Hedhammar A. Collie eye anomaly in the rough collie in Sweden: genetic transmission and influence on offspring vitality. J Small Anim Pract. 2000;41:254-258.
7. Wallin-Hakanson B, Wallin-Hakanson N, Hedhammar A. Influence of selective breeding on the prevalence of chorioretinal dysplasia and coloboma in the rough collie in Sweden. J Small Anim Pract. 2000;41:56-59.
8. Wilcock BP, Njaa BL: Special senses. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:412-414.

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