JPC SYSTEMIC PATHOLOGY

SPECIAL SENSES SYSTEM

APRIL 2024

S-M07

 

SIGNALMENT (JPC #2921796-00): Tissue from a 7-year-old male castrated Akita

 

HISTORY: Bilateral retinal detachment and partial resolution with systemic corticosteroids; Vogt-Koyanagi-Harada-like syndrome was strongly suspected

 

HISTOPATHOLOGIC DESCRIPTION: Eye: There is diffuse, moderate to marked expansion of the iris, ciliary body, and choroid (uveal tract) up to 1 mm in diameter by abundant macrophages often containing intracytoplasmic pigment (melanin), fewer plasma cells and lymphocytes, and scattered neutrophils,   as well as increased collagen (fibrosis), many dilated and congested vessels, eosinophilic fibrillar material (fibrin), increased clear space (edema), scant hemorrhage, and scattered free melanin granules. This inflammatory infiltrate obliterates the trabecular meshwork of the iridocorneal angle, multifocally extends into the sclera, and surrounds the optic nerve. Within the anterior chamber, posterior chamber, and vitreous, there is pale eosinophilic proteinaceous fluid admixed with variable numbers of macrophages, lymphocytes, plasma cells, and scant fibrin. Fibrovascular membranes extend over the anterior and posterior surfaces of the iris (pre-iridal and post-iridal fibrovascular membranes, respectively) and over the ciliary body extending to the posterior lens capsule (cyclitic membrane). There is anterior retraction of the pupil margin into the anterior chamber (ectropion uveae). The peripheral aspect of one iris leaflet is adherent to the corneal endothelium (peripheral anterior synechia). There is diffuse retinal detachment and degeneration/atrophy of the retina characterized by: vacuolation of the nerve fiber layer (axonal degeneration); degeneration or loss of ganglion cells; multifocal atrophy of the inner and outer plexiform layers; atrophy, loss, or blending of the inner nuclear layer into the outer nuclear layer; and multifocal scant hemorrhage and/or edema. Multifocally, the retinal pigment epithelium is subtended by aggregates of melanin-laden macrophages. At the posterior aspect of the globe, the choroid contains aggregates of lymphocytes (lymphoid nodules). The peripheral cornea contains few capillaries extending toward the central cornea (vascularization), and the corneal stromal fibers exhibit multifocal areas of increased pallor and decreased organization (corneal edema). Within periocular adipose tissue and separating periocular skeletal muscle fibers there are multifocal, predominantly perivascular, infiltrates of lymphocytes, plasma cells, and fewer macrophages. 

 

MORPHOLOGIC DIAGNOSIS: Eye: Panuveitis, granulomatous, chronic, diffuse, severe, with abundant melanin-laden macrophages (pigment dispersion), fibrosis, loss of retinal pigment epithelium, retinal detachment and atrophy, fibrovascular membranes, and corneal vascularization and edema, Akita, canine.

 

ETIOLOGIC DIAGNOSIS: Immune-mediated panophthalmitis/panuveitis

 

CONDITION: Uveodermatologic syndrome; Vogt-Koyanagi-Harada-like syndrome

 

GENERAL DISCUSSION:  

• Vogt-Koyanagi-Harada (VKH)-like syndrome (uveodermatologic syndrome) is an autoimmune disease that targets uveal and dermal melanocytes  
• This syndrome is most common in young adult arctic breeds: Akitas, Siberian huskies, Chow Chow, Alaskan malamutes, and Samoyeds suggestive of an inherited basis, and is relatively frequent in areas where these breeds are popular; but is also reported in other breeds
• Ocular lesions commonly precede or are recognized prior to dermal changes and are more important because they may lead to blindness

 

PATHOGENESIS:  

• Thought to be a T-lymphocyte immune-mediated attack directed against a protein involved in production of melanin or melanocytes (uveal and epidermal), likely tyrosinase or a tyrosinase-related protein > destructive granulomatous inflammation; humoral immunity may also be involved
• In Akitas, specific dog leukocyte antigen (DLA) class II gene alleles appear to predispose to development of this disease (DLA are a part of the major histocompatibility complex)
• Breakdown of the blood-retinal barrier > exposure of retina-specific antigen > production of anti-retinal antibodies  
• Skin lesions of this syndrome are mediated by T cells and macrophages (Th1 immunity); ocular lesions more consistent with B cell and macrophage response (Th2 immunity)

 

TYPICAL CLINICAL/GROSS FINDINGS:

• The clinical syndrome of facial dermal depigmentation and severe, generally bilaterally symmetric, uveitis is distinctive, although many dogs examined for uveitis are not noted to have skin lesions
• Eyes:  
  • Severe bilateral panuveitis (may be anterior or posterior uveitis in milder cases), with secondary lesions including retinal detachment, retinitis, +/- cataracts, anterior synechiae, and glaucoma with buphthalmia; unilateral disease is rare, associated with asymmetric uveal pigmentation, with the blue eye unaffected
  • Dogs often present for acute blindness
  • In a retrospective case series, the most common ophthalmic signs in the dog include: aqueous flare, iris abnormalities, retinal detachment, and choroidal depigmentation or chorioretinal infiltrates; at initial presentation; 36% of dogs had glaucoma and 57% were bilaterally blind (Zarfoss, J Am Vet Med Assoc. 2018)
• Skin:
  • Vitiligo (depigmented white patches of skin) of the eyelids, nasal planum, lips, scrotum/vulva, anal skin, ears, and paw pads, less commonly more diffuse
  • Poliosis/leukotrichia (focally depigmented hair) of the facial area, rarely elsewhere on body 
  • Pruritus with epidermal ulceration, crusting of nasal planum, lips, scrotum, footpads

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Eye (ocular lesions precede skin lesions)
  • Inflammation: Severe destructive granulomatous endophthalmitis/panuveitis centered on melanin-containing cells (e.g. retinal pigmented epithelium (RPE), other pigmented uveal cells) with abundant dispersion of melanin
    • Inflammation is strikingly uveocentric, leaving the vitreous, aqueous, retina, and cornea relatively “quiet”
    • Inflammation is always histiocyte-rich
    • Some dogs have marked uveal thickening due to solid sheets of histiocytic inflammation, while others have no thickening and bland histiocytic infiltrate
    • Histiocytes are peppered with melanin granules (phagocytosed from the depigmented areas)
    • Inflammation can be severe in any part of the uvea, but the choroid is always affected
    • Symmetry of inflammation between both eyes is often striking
    • Clusters of histiocytes within the choroid and subtending the intact pigmented RPE are reminiscent of Dalen-Fuch’s nodules (collections of epithelioid cells between the RPE and Bruch’s membrane)
  • +/- Retinal detachment
  • Most cases are chronic and have been treated extensively so histologic lesions are rarely “textbook” and may be dominated by uveal scarring with dispersal of pigment
• Skin: Histiocytic lichenoid interface dermatitis composed of large macrophages that often contain melanin pigment (melanophages, pigmentary incontinence), plasma cells and small lymphocytes; inflammation usually occurs parallel to the epidermal surface and may extend around adnexa, and usually does not obscure the interface
  1. Absence of basal cell necrosis is a helpful feature to discriminate from other autoimmune disease (see differentials below)

 

DIFFERENTIAL DIAGNOSIS:

Ac       quired hypopigmentation:

• Insults to epidermal melanin, e.g. trauma, inflammation, radiation, endocrinopathies, infections, nutritional deficiencies, neoplasia
  • Mild injury typically results in pigmentary incontinence and epidermal hypopigmentation, but hyperpigmentation can occur possibly from release of melanocyte-stimulating factor from surviving keratinocytes; severe injury results in the death of melanocytes which do not regenerate > no repigmentation
• Vitiligo: melanocyte destruction of undetermined cause results in gradually expanding pale macules that are often symmetric or segmental (horses, cattle, dogs [primarily Belgian Tervurens], cats)
• Rubber contact: Monobenzene ether of hydroquinone (a common ingredient in rubber) inhibits melanogenesis > cutaneous depigmentation (horses, dogs)

Uveitis:

• Fungal endophthalmitis: More prevalent than VKH-like syndrome; systemic disease with visceral involvement, inflammation does not specifically target pigmented ocular tissues and lacks the distinctive skin lesions
• Autoimmune uveitis: Melanin dispersion is not a prominent feature, dermatitis is not present

Immune-mediated dermatitis:

• Systemic lupus erythematosus, epidermolysis bullosa acquisita, lupoid drug reactions: Lichenoid interface dermatitis is predominantly lymphocytic, there is prominent basal cell hydropic degeneration that may progress to cleft and bulla formation, presence of prominent basal cell apoptosis (Civatte bodies)
• Erythema multiforme: Histologically similar to the above except for keratinocyte apoptosis in all layers of the epidermis

 

COMPARATIVE PATHOLOGY:  

• Vogt-Koyanagi-Harada (VKH) syndrome is only reported in people, and VKH-like syndrome (uveodermatologic syndrome; UDS) is only reported in dogs
  1. A key distinction is that human VKH disease also commonly encompasses meningitis and/or deafness and ear pain (dysacousia) which are rare features in the canine UDS 

 

REFERENCES:   

1. Dubielzig RR, Ketring KL, McLellan GJ, Albert DM. Veterinary Ocular Pathology: a comparative review. St. Louis, MO: Saunders Elsevier; 2010:260-263.
2. Grahn B, Peiffer R, Wilcock B. Histologic Basis of Ocular Disease in Animals. Hoboken, NJ: John Wiley & Sons; 2019: 233-236.
3. Labelle P. The eye. In: Zachary JF, eds. Pathologic Basis of Veterinary Disease.  7th ed. St. Louis, MO: Mosby Inc; 2022:1428-1429.  
4. Mauldin EA, Peters-Kennedy J. Integumentary System. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:557.
5. Welle MM, Linder KE. Integumentary system. In: Zachary JF, eds. Pathologic Basis of Veterinary Disease.  7th ed. St. Louis, MO: Mosby Inc; 2022:1202, 1243.  
6. Wilcock BP, Njaa BL. Special senses. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. 6th ed. Vol 1. St. Louis, MO: Elsevier Inc; 2016:453-457 
7. Zarfoss MZ, et al. Clinical findings and outcomes for dogs with uveodermatologic syndrome. J Am Vet Med Assoc. 2018; 252(10): 1263-1271. 

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