JPC SYSTEMIC PATHOLOGY
Signalment (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 (WSC09-10, 6-4): Eye: There are changes in all segments of the globe. There is hypertrophy of the corneal endothelium and the anterior chamber is full of proteinaceous fluid. This iris is markedly thickened up to 2mm by many dilated, congested vessels, edema, increased amounts of fibrillar collagen (fibrosis), small amounts of fibrin and is infiltrated with large numbers of lymphocytes and plasma cells which occasionally form follicles/nodules with lesser numbers of macrophages that extend into the ciliary body. The iris is attached to the anterior lens capsule by a fibrovascular membrane(posterior fibrovascular membrane with posterior synechia). At the superficial/inner aspect of the ciliary body there is a 100um thick layer of hyaline, waxy, amorphous eosinophilic material that covers the apical aspect of the inner ciliary body epithelium (amyloid like material). Within the cytoplasm of inner non-pigmented ciliary body epithelium there are numerous linear ~ 1umX4um inclusions. There is a layer of fibrillar fibrous material extending from the surface of the ciliary body that extends to the posterior surface of the lens capsule (cyclitic membrane). The inner surface of the anterior lens capsule is covered by a thick fibrous layer (fibrous metaplasia of the lens epithelium) and lens fibers often assume a globular shape (Morgagnian globules) consistent with subcapsular cataract formation. The retina is detached and there is an eosinophilic flocculent material and few melanophages present between the retina and the mildly hypertrophic retinal pigment epithelium. Within the retina there is diffuse atrophy of the ganglion and inner nuclear layer, and the inner nuclear layer blends into the outer nuclear layer. The choroid especially at the posterior aspect is diffusely thickened, including the tapetum, with congested vessels and edema. There is pale eosinophilic fluid within the anterior chamber, posterior chamber and vitreous admixed with variable numbers of macrophages, plasma cells and small amounts of fibrin.
MORPHOLOGIC DIAGNOSIS: Eye: Uveitis, lymphoplasmacytic, chronic, diffuse, moderate, with posterior synechia, amyloid-like material, fibrovascular membranes, cataract formation and retinal detachment and atrophy.
ETIOLOGIC DIAGNOSIS: Immune mediated uveitis
CONDITION: Equine recurrent uveitis (ERU)
SYNONYMS: Equine recurrent ophthalmitis, equine periodic ophthalmia, moon blindness, iridocyclitis
- Equine recurrent uveitis (ERU), one of the most common causes of blindness in horses and mules, is characterized by episodes of gradually intensifying panuveitis followed by quiescent periods of variable length and increasing severity
- Frequent posterior synechiae, but glaucoma is rare
- 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
- Leading cause of blindness in horses and mules
- Characterized by episodes of gradually intensifying anterior uveitis followed by quiescent periods of variable length; resolution of gross lesions between attacks is less complete
- ERU is a syndrome of chronic recurrent uveitis that differs from primary uveitis; only diagnosed when clinical signs are coupled with a history of recurrent inflammation; i.e. ERU cannot be diagnosed after a single episode of inflammation
- Horses may develop ERU at any age; often begins around 4-6 years of age; more common in Appaloosas
- Unknown; likely an ocular response to lymphoid activation by a circulating antigen or native ocular antigens rather than persistence or repeated exposure to a single antigen
- The condition represents an organ specific hypersensitivity reaction to an exogenous antigen:
- Leptospira interrogans serovar Pomona –
- There is substantial evidence that this agent is causative but it is not absolute and there are conflicting reports that link causality; the cause may vary by region and there is likely more one underlying cause; leptospira organisms not detected in all cases
- Thought to play a role in the initiation of the disease but continued presence of organism not involved with recurrent disease
- High serum titer to L. interrogans are frequently found but the organism and titers may be low to negligible once disease is clinically detected
- Increased ocular immunoglobulins (IgA and IgG) specific for leptospiral lipoproteins LruA and LruB are found in horses with ERU
- interrogans serovar Pomona is the strain most frequently implicated in N. America
- kirschneri serovar Grippotyphosa is the strain most frequently implicated in Europe
- Onchocerca cervicalis occasionally implicated
- Cross reaction between leptospiral antigens and intraocular antigens, principally corneal endothelium and lens (immune mimicry) > antibody mediated complement activation > initiation of tissue damage > exposure of previously sequestered Ag (loss of immune tolerance) > delayed-type hypersensitivity to self Ag in the uveal tract
- There are circulating antibodies to various ocular proteins during active phase of disease
- The blood-ocular barrier consists of the blood-aqueous and the blood-retina barrier 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
- 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
- Autoimmunity to two major antigens reported: S-antigen and interphotoreceptor retinoid binding protein (IRBP)
- Immune response considered a Th1 response characterized by predominantly CD4+ T-cells; increased levels of IL-2 and IFN-γ, and low IL-4 in affected eyes
- Th17 response also may play a role – Based on strong immunoreactivity for
IL-6, IL-17, and IL-23 in conjunction with the fact that T lymphocytes are the predominate infiltrate
- MHC I haplotype ELA-A9 in German Warmbloods confers increased susceptibility
TYPICAL CLINICAL FINDINGS:
- May initially be unilateral; will be bilateral eventually
- Systemically ill characterized by fever, inappetance and depression
- Blepharospasm, photophobia, epiphora, miosis; depression, anorexia
- Despite frequent observation of posterior synechia glaucoma is not commonly seen; this is most likely due to increased importance of uveoscleral drainage in this species
- Drainage paths: Normally aqueous humor exits the globe through the iridocorneal angle (conventional outflow) or the uveoscleral pathway (unconventional outflow)
- The importance of uveoscleral (non-conventional) flow varies by species; the percentage of uveoscleral outflow is much less in dogs (15%) and cats (3%) than in the horse in which the routes are thought to be equally important (ie 50%)
- Three clinical syndromes: classic, insidious, posterior
- Classic ERU: most common
- Active inflammatory episodes followed by periods of minimal ocular inflammation
- Inflammation involves the iris, ciliary body, and choroid
- Concurrent involvement of cornea, anterior chamber, lens, retina, vitreous
- Results in cataracts, intraocular adhesions, phthisis bulbi, and blindness
- Insidious ERU:
- Inflammation never completely resolves; progresses to chronic signs of ERU (cataracts, adhesions, blindness)
- Commonly seen in Appaloosa and draft breed horses
- Posterior ERU:
- Inflammation predominantly within the vitreous, retina, choroids
- Bouts of inflammation, vitreal cloudiness, retinal degeneration
- Most commonly seen in warmbloods, draft breeds, European horses
TYPICAL GROSS FINDINGS:
- Hypopyon, hyphema, aqueous flare, posterior synechia, cataract formation
- Corneal edema, peripheral corneal vascularization
- Conjunctival hyperemia, chemosis
- Iridial thickening and hyperpigmentation, corpora nigra atrophy
- Retinal edema, degeneration, phthisis bulbi
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Lesions depend on stage of the disease and range from anterior uveitis, endophthalmitis with retinal scarring, or phthisis bulbi
- Infiltrate: Acutely the infiltrate is predominantly neutrophilic and within the anterior uvea but quickly becomes lymphocytes, plasma cells, and macrophages with progressive infiltration of the uveal tract (choroid, ciliary body, iris) and retina often with lymphoid follicle formation in the ciliary body and iris
- Presence of homogenous, amorphous, eosinophilic material (confirmed as amyloid) lining the ciliary body epithelium is pathognomonic for ERU
- Localized form of amyloidosis with deposition of AA amyloid
- Retinal degeneration with loss of photoreceptor segments, ganglion cell layer, and inner nuclear layer
- Exudative retinal detachment - exudate between the RPE and photoreceptor layer
- Optic nerve degeneration - secondary to retinal neuronal degeneration
- Interstitial keratitis, corneal vascularization, and persistent edema
- Posterior synechia, cataracts
- Uveal lesions regress during quiescent periods leaving residual changes (lymphoid nodules, thickened ciliary processes, corneal vascularization, chorioretinal scarring, and RPE hypertrophy/hyperplasia)
DIFFERENTIAL DIAGNOSIS: (Equine uveitis)
Three general causes of uveitis in horses: ocular, systemic, and immune-mediated
- Ocular causes: Corneal ulceration (may result in lens-induced uveitis or neurogenic reflex anterior uveitis); ocular trauma; primary neoplasia; immune-mediated (allergens); parasitic (Onchocerca cervicalis, Halicephalobus gingivalis, Toxoplasma gondii)
- Systemic causes: Bacterial +/- septicemia (Brucella, Salmonella sp., Streptococcus sp., E. coli, Rhodococcus equi), viral (equine herpesvirus-1 and -4, equine arteritis virus), toxemia
- Immune-mediated: Equine recurrent uveitis (ERU)
- Humans: Autoimmune uveitis in man is very similar to ERU in horses; human leukocyte antigen (HLA) haplotypes are strongly associated with autoimmune uveitis
- All: Nearly all species have an immune mediated component to uveitis superimposed on initial non-specific inflammation
- 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
- Idiopathic lymphocytic uveitis: Lymphocytic-plasmacytic panuveitis that tends to be more severe in the anterior uvea than in the choroid; may form lymphoid nodules
- Phacolytic uveitis: anterior uveitis that is due to leakage of denatured lens proteins through an intact lens capsule that are direct inflammatory stimulants; similar lesions as idiopathic uveitis except the inflammation is always mild in this condition
- Vogt-Koyanagi-Harada-like syndrome: Granulomatous endophthalmitis in Akitas, Siberian Huskies and Samoyeds cell-mediated immune reaction to uveal melanin
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