JPC SYSTEMIC PATHOLOGY

SPECIAL SENSES SYSTEM

April 2024

S-M01

 

Signalment (JPC #3134618): Horse, 7-year-old castrated male paint horse

 

HISTORY: Small non-visual eye for the past year, clinically suspected chronic uveitis; other eye was normal.

 

HISTOPATHOLOGIC DESCRIPTION: Eye: All segments of the globe have histologic changes. The peripheral cornea contains few capillaries extending toward the central cornea (vascularization), with few perivascular plasma cells and lymphocytes. There is hypertrophy of the corneal endothelium. The anterior chamber contains abundant eosinophilic proteinaceous fluid. This iris is markedly thickened up to 2mm by many lymphocytes and plasma cells and fewer macrophages that extend into the ciliary body, as well as many dilated and congested vessels, increased clear space (edema), increased fibrillar collagen (fibrosis), and small amounts of fibrin. The lymphocytes variably form  perivascular aggregates (lymphoid nodules). The iris is extensively attached to the anterior lens capsule (posterior synechia) by a fibrovascular membrane (posterior iridal fibrovascular membrane). The inner non-pigmented ciliary body epithelium is covered by a 100µm thick layer of hyaline, waxy, amorphous eosinophilic material (amyloid-like material). Within the cytoplasm of the inner non-pigmented ciliary body epithelium, there are numerous linear, 1µm x 4µm, eosinophilic inclusions. A layer of fibrillar to fibrous material extends from the surface of the ciliary body to the posterior surface of the lens capsule (cyclitic membrane). Subjacent to the anterior lens capsule there is a layer of fibrosis up to 400 µm thick (fibrous metaplasia of the lens epithelium), and multifocally lens fibers often assume a globular shape (Morgagnian globules) (cataractous change). The retina is focally extensively detached; in this area the subretinal space contains eosinophilic flocculent material and few melanophages, and the retinal pigmented epithelium is mildly hypertrophic. Within the retina, there are occasional small perivascular infiltrates of few lymphocytes and plasma cells, multifocal atrophy of the ganglion and inner nuclear layers, and the inner nuclear layer multifocally blends into the outer nuclear layer (retinal atrophy). The choroid, including the tapetum, is infiltrated by low to moderate numbers of often perivascular lymphocytes and plasma cells and is thickened by congested vessels and edema. Within the anterior chamber, posterior chamber, and vitreous, there is pale eosinophilic fluid admixed with variable numbers of macrophages, lymphocytes, plasma cells, and scant fibrin. 

 

MORPHOLOGIC DIAGNOSIS: Eye: Panuveitis, lymphoplasmacytic, chronic, diffuse, moderate, with posterior synechia, amyloid-like material, fibrovascular membranes, cataractous change, retinal detachment and atrophy, and corneal vascularization, paint horse, equine.

 

ETIOLOGIC DIAGNOSIS: Immune-mediated uveitis

 

CONDITION: Equine recurrent uveitis (ERU) 

 

SYNONYMS: Equine recurrent ophthalmitis, equine periodic ophthalmia, moon blindness, iridocyclitis

 

GENERAL DISCUSSION: 

• ERU is characterized by recurring episodes of gradually intensifying anterior uveitis followed by quiescent periods of variable length; resolution of gross lesions between attacks is less complete
• Leading cause of blindness in horses and mules
• Horses may develop ERU at any age; often begins around 4-6 years of age; more common in Appaloosas
• The condition most likely represents an organ specific immune-mediated disease with hypersensitivity to an infectious agent; Leptospira interrogans serovar pomona is most commonly implicated
• A recent retrospective report of equine ocular disorders found ERU as the second and third most prevalent disease in autopsies and enucleations (Flores, J Vet Diagn Invest. 2020)

• ERU was commonly associated with glaucoma
• Infectious agents were not detected in the globes affected by ERU 
• Some cases were associated with sepsis secondary to Rhodococcus equi infection, ocular neoplasia, and anterior segment dysgenesis

 

PATHOGENESIS:

• Pathogenesis remains controversial
• Increased vascular permeability and loss of blood-aqueous barrier likely predispose animal to deposition of circulating immune complexes and subsequent type III hypersensitivity-induced inflammation 
• Leptospira interrogans serovar pomona has been implicated in the pathogenesis of equine recurrent ophthalmitis 

• L. interrogans serovar pomona is the serovar most commonly associated with severe morbidity in horses, including recurrent uveitis, abortion, and sporadic cases of renal and hepatic disease (Fagre, J Vet Diagn Invest. 2020)
• 50-70% of horses with classic clinical and histologic ERU have demonstrated leptospiral antigens or DNA within the globe; some exceptions. Similarly, horses experimentally injected subcutaneously with L. interrogans serovar pomona developed bacteremia and then ERU syndrome

• Cross reaction between leptospiral antigens and intraocular antigens, principally corneal endothelium and lens (microbial mimicry) > antibody mediated complement activation > initiation of tissue damage > exposure of previously sequestered Ag (loss of immune tolerance) > type III/IV hypersensitivity to ocular self-antigen including retinal antigens: interphotoreceptor-binding protein (IRPB), S-antigen, and cellular retinaldehyde-binding protein (CRALBP)
• Immune response is considered a Th1 response, characterized by predominantly CD4+ T-cells
• Normal ocular immunity:

• Ocular immunity is normally suppressed to prevent delayed-type hypersensitivity and excessive reaction to antigens resulting in anterior chamber-associated immune deviation; components of this ocular immune suppression include:

• Suppressor T-cells and antigen presenting cells that circulate to thymus and spleen
• Soluble immunosuppressive factors in the aqueous humor
• Antigen reactivity altering cytokines including: TGF-β2, TNF-α, vasoactive intestinal peptide, and substance P

• The blood-ocular barrier consists of the blood-aqueous and the blood-retina barriers, which maintain the eye as an immuno-privileged site

• Blood-aqueous barrier formed by:

• Tight junctions in the ciliary body and iridal capillaries 
• Phagocytic function of the ciliary epithelium 

• Blood-retinal barrier formed by:

• Tight junctions in the non-fenestrated capillary endothelium
• Tight junctions between the retinal pigment epithelial cells

 

TYPICAL CLINICAL FINDINGS:

• May initially be unilateral; will be bilateral eventually
• Acute disease: Systemic illness with fever, inappetance, and depression; lacrimation, photophobia

 

TYPICAL GROSS FINDINGS:

• In acute disease, findings are characteristic of anterior uveitis in any species: Corneal edema; serous conjunctivitis; chemosis; circumcorneal ciliary hyperemia; plasmoid aqueous and vitreous, with fibrin and leukocytes in the aqueous
• Recurrent disease often increases in severity, with incomplete resolution of gross lesions
• Common lesions during quiescent disease include: Peripheral corneal vascularization with fibrosis and edema, iris pigmentation with irregular thickening, posterior synechiae, peripapillary retinal hypereflectivity (scarring), multifocal uveal pigment on lens capsule

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Lesions depend on stage of the disease; a continuum from anterior uveitis, to endophthalmitis with retinal scarring, to phthisis bulbi

• Early disease: 

• Most often observed in the anterior uvea, especially within ciliary processes; initially neutrophilic infiltrates that rapidly progresses to lymphocytic infiltrates 
• Fibrin and leukocytes in the anterior chamber, with stromal edema, perivascular lymphocytic infiltrates in iris and ciliary body may persist and/or progress to lymphoid nodules

• Neutrophilic and/or lymphocytic pars planitis (inflammation of the flat, posterior portion of the ciliary body, i.e. pars plana) is characteristic
• Chronic lesions observed in horses following several bouts of uveitis:

• Perivascular lymphoplasmacytic infiltrates of anterior uvea, choroid, retina, optic nerve, +/- multifocal retinal separation secondary to chorioretinitis
• Cornea: Peripheral corneal vascularization with edema extending from conjunctival and limbal ciliary vessels towards central cornea
• Ciliary body: Thickening of ciliary processes (secondary to fibrous organization of stromal edema), with eosinophilic amyloid-like material within the apical cytoplasm of the nonpigmented ciliary epithelium 

• This material may appear like a hyaline membrane covering the ciliary epithelium 
• Eosinophilic linear inclusions within the nonpigmented ciliary epithelium have also been described 

• Choroid: Thick-walled vessels secondary to edema or fibrin
• Retina: Focal retinal photoreceptor loss, disorganization of layers, and gliosis consistent with peripapillary chorioretinal scarring
• Secondary changes associated with chronic ERU:

• ERU is the most common cause of cataracts in the horse
• Glaucoma-related changes; anterior and posterior synechiae, often associated with retrocorneal or preiridal fibrovascular membranes

 

ADDITIONAL DIAGNOSTICS:

• AA amyloid material within nonpigmented ciliary epithelium (Congo red with apple green birefringence and immunoreactive to AA specific antibodies)
• Masson’s trichrome: Facilitates identification of eosinophilic linear inclusions within nonpigmented epithelial cells
• Microscopic agglutination test (MAT): Considered the gold standard serologic assay to determine the L. interrogans serovar in affected horses (Fagre, J Vet Diagn Invest. 2020)
• PCR: More rapid and sensitive assay than MAT; however, use can be limited due to intermittent shedding and leptospiremia in affected horses

 

DIFFERENTIAL DIAGNOSIS: 

Three general causes of uveitis in horses: 

• Primary ocular disease: Corneal ulceration (may result in lens-induced uveitis or neurogenic reflex anterior uveitis); ocular trauma; primary neoplasia; parasitic (Onchocerca cervicalis, Halicephalobus gingivalis, Toxoplasma gondii)
• Systemic infection: Bacterial +/- septicemia (Brucella sp., Salmonella sp., Streptococcus sp., E. coli, Rhodococcus equi), viral (equine herpesvirus-1 and -4, equine arteritis virus), toxemia
• Immune-mediated: Equine recurrent uveitis, allergens 

 

COMPARATIVE PATHOLOGY:

• Nearly all species have an immune-mediated component to uveitis superimposed on initial non-specific inflammation
• Humans: Autoimmune uveitis is very similar to ERU in horses; human leukocyte antigen (HLA) haplotypes are strongly associated with autoimmune uveitis

 

Immune-mediated uveitis

• Cats: Idiopathic lymphonodular uveitis; most common cause of glaucoma in cats; large perivascular lymphocytic-plasmacytic aggregates throughout the uvea and subtle involvement of the choroid, trabecular meshwork, and ciliary body; nodules may be visible grossly; the cause is unknown but is presumed to be immune-mediated
• Dogs: 

• Idiopathic lymphocytic uveitis: Lymphocytic-plasmacytic panuveitis; tends to be more severe in the anterior uvea than the choroid; may form lymphoid nodules
• Phacolytic uveitis (S-M06): Anterior uveitis secondary to leakage of denatured lens proteins (direct inflammatory stimulants) through an intact lens; similar lesions as idiopathic uveitis, except the inflammation is typically mild in this condition
• Vogt-Koyanagi-Harada-like syndrome (S-M07): Granulomatous endophthalmitis in Akitas, Siberian huskies, and Samoyeds; cell-mediated immune reaction to uveal melanin

 

REFERENCES:

1. Fagre AC, Mayo CE, Pabilonia KL, Landolt GA. Seroprevalence of Leptospira spp, in Colorado equids and association with clinical disease. J Vet Diagn Invest. 2020; 32(5): 718-721.
2. Flores MM, Del Piero F, Habecker PL, Langohr IM. A retrospective study of 140 cases of clinically significant equine ocular disorders. J Vet Diagn Invest. 2020; 32(3): 382-388.
3. Gilger BC: Equine ophthalmology. In: Veterinary Ophthalmology, ed. Gelatt K, 5rd ed., Baltimore, MD: Lippincott Williams & Wilkins; 2013:1587-1591.
4. Labelle P. The Eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1425.
5. Snyder PW. Diseases of Immunity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:323. 
6. Wilcock BP: Special Senses. In: Jubb, Kennedy and Palmers Pathology of Domestic Animals, ed. Maxie MG, 6th ed., vol. 1, Philadelphia, PA: Elsevier-Saunders: 2016:454-456.

 

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