Conference 20 - 2015 Case: 02 20160406

Signalment:

9-year-old male neutered Labrador retriever dog (Canis familiaris).Chronic glaucoma of the left eye for approximately 1 year with pain and blindness. Glaucoma is poorly controlled with medical management and history of cataract with cataract surgery in the same eye 1.5 years prior.

Gross Description:

The globe is enlarged and there is multifocal nodular to coalescing severe thickening of the sclera at the limbus and extending nearly circumferentially around the globe, measuring up to 0.7 cm in the thickest areas. There is intraocular blood and there is corneal opacity.

Histopathologic Description:

Please note that the section available for participants contains the majority of the scleral lesion, but may not contain all of the internal lesions within the globe. The globe is enlarged and severely expanding the sclera at the limbus and extending nearly circumferentially, there is a nodular to diffuse inflammatory infiltrate with extensive fibroplasia and fibrosis. The inflammation is composed of predominantly epithelioid macrophages, lymphocytes, and plasma cells, with fewer neutrophils. There are occasional discrete granulomatous foci with central altered collagen that is hyp-ereosinophilic and smudged (coll-agenolysis), surrounded by a rim of epithelioid macrophages. There is extensive collagen deposition within the inflammatory lesion, and in some areas the collagenous tissue is in a storiform-like pattern that multifocally has central similarly altered collagen that is hypereosinophilic with smudging (collagenolysis). The inflammatory lesion and collagen deposition extends from the nodular area of the limbus posteriorly to adjacent to the optic nerve, and extends outward into the adjacent extraocular skeletal muscle. Within the cornea, there is hyperplasia of the epithelium with irregular rete ridge formation, and within the stroma, there is fibrosis, neovascularization, and a mild inflammatory infiltrate, composed of lymp-hocytes, plasma cells, and neutrophils. There is a focal break in Descemets membrane (corneal stria) filled in with fibroplasia and fibrosis. Within the anterior uvea, there is iris and ciliary body atrophy, a pre-iridal fibrovascular membrane that spans across the filtration angle, and a mild to moderate perivascular accumulation of lymphocytes and plasma cells. There is blood within the anterior and posterior chambers, as well as in the vitreous. A fragment of lens is present, which includes lens capsule, and the lens fibers are fragmented, hypereosinophilic, and have occasional Morgagnian globules and bladder cells. There is a fibrovascular membrane adhered to the posterior aspect of the lens capsule. There is diffuse retinal detachment with hypertrophy of the retinal pigmented epithelium, and there is mild atrophy of the inner nuclear and ganglion cell layers of the retina. Massons trichrome: There is segmental red staining of the lesional collagen with Massons trichrome.

Morphologic Diagnosis:

Eye (left):

1. Severe granulomatous scleritis with altered collagen, consistent with necrotizing scleritis (also known as granulomatous scleritis).

2. Buphthalmia; corneal fibrosis, neovascularization, keratitis, and focal rupture of Descemets membrane (corneal stria); mild lymphoplasmacytic anterior uveitis with pre-iridal fibrovascular membrane, occlusion of filtration angle and hyphema; retinal detachment with inner retinal atrophy; and lens cataractous change.

Lab Results:

Results of complete blood count and chemistry panel are within reference interval.

Condition:

Necrotizing scleritis (aka granulomatous scleritis)

Contributor Comment:

The scleritis in this case is consistent with the disease entity known as necrotizing scleritis. The most diagnostic features are the formation of discrete granulomas within the inflammatory lesion, as well as the altered collagen appearance, which is often referred to as collagenolysis or collagen necrosis. Necrotizing scleritis is discussed in more detail below. The other intraocular lesions described in this globe, as well as the clinical glaucoma, may be secondary to the scleritis², although the granulomatous inflammation does not extend into the intraocular structures in this case. Another possible pathogenesis for the glaucoma is a lens-induced uveitis or other idiopathic or immune-mediated lymphoplasmacytic uv-eitis leading to formation of a pre-iridal fibrovascular membrane and subsequent occlusion of the filtration angle. Histologic evidence supporting the clinical diagnosis of secondary glaucoma includes the buphthalmia, iris and ciliary body atrophy, keratitis with focal rupture of Descemets membrane (corneal stria), retinal detachment with retinal pigmented epithelial hypertrophy, and inner retinal atrophy.

The majority of scleral disease in dogs is inflammatory in nature and is most often the result of secondary involvement of the sclera with either intraocular inflammation or extension from an orbital cellulitis,⁷ as with a penetrating foreign body, trauma, or in-fectious etiology.⁵ Primary scleral/episcleral inflammation can be clinically divided into unilateral versus bilateral, nodular versus diffuse, and scleral versus episcleral categories, but there is often overlap in the clinical presentation of these entities and of secondary scleritis/episcleritis.⁵ One of the most common primary inflammatory diseases of the sclera/episcera is nodular granulomatous episcleritis, while necrotizing scleritis is rare in comparison.

Nodular granulomatous episcleritis, not present in this case, is also referred to as ocular nodular fasciitis, among other names, and is a proliferative nodular inflammatory lesion at the limbus of the eye that behaves somewhat like a neoplasm in its locally infiltrative growth.⁷ The histologic lesion consists of a proliferation of histiocytes, spindle cells and lymphocytes and plasma cells. The inflammation has a diffuse gran-ulomatous pattern, but discrete gran-ulomatous foci are not present, and collagenolysis is not a feature.⁷

Necrotizing scleritis, the disease entity in the present case, is also an inflammatory and proliferative process within the sclera, and has more recently been referred to by some as granulomatous scleritis.^1,3 For the remainder of the discussion, this entity will be referred to as necrotizing scleritis, the more well-known name for the condition. In necrotizing scleritis, there is a similar composition of inflammatory cell types to that identified in cases of nodular gran-ulomatous episcleritis, including histiocytes, lymphocytes, plasma cells and spindle cells. Some lesions also have a neutrophilic component, as in the present case, or an eosinophilic component.⁶ The two main distinguishing features of necrotizing scleritis from nodular granulomatous episcleritis are the formation of discrete granulomatous foci, and the presence of altered collagen (collagenolysis).^6,7 The altered collagen is often surrounded by epithelioid macrophages to form the discrete granulomas. Altered collagen may have an abnormal tinctorial staining quality with Massons trichrome,² which is identified in the present case as segmental red-staining of the collagen rather than the usual blue. The terms collagenolysis and collagen necrosis are somewhat controversial since collagen is considered inert and therefore cannot technically become necrotic. There is also often a granulomatous vasculitis, but this is not present in every case³. In the current case, although the inflammation appears somewhat vasocentric in some areas, overt vasculitis is not identified.

In necrotizing scleritis, the inflammation and spindle cell proliferation typically begins in the anterior sclera and slowly spreads circumferentially and posteriorly with eventual progression to involvement of the uvea and retina.⁷ On gross evaluation, the sclera is severely thickened and bright white.³ Staphyloma, which is a protrusion of uveal tissue through a weakened portion of the sclera, is a possible sequela in some cases, along with disinsertion of the extraocular muscles.^4,5 Necrotizing scleritis is most commonly bilateral, but the second eye may not be affected until later in the course of the disease.^3,7 It is critical to alert clinicians to the likelihood of involvement of the contralateral eye, given the important prognostic implications for vision³. The treatment for necrotizing scleritis is aggressive life-long anti-inflammatory or immunosuppressive therapy, but complete remission is rare and medical management fails in many cases, leading to enucleation of the affected eye(s).^5,7

The pathogenesis of necrotizing scleritis is not well-understood. No etiologic agents have been identified in these cases,⁷ although necrotizing scleritis has been reported in dogs with ehrlichiosis.³ An immune-mediated pathogenesis has been suggested, particularly due to the co-mparable lesion in humans, which is an autoimmune disease process, as well as the partial response to immunosuppressive therapy in dogs.^1,2,5 Most cases reported appear to be localized to the eye, with rare reports that have evidence for other systemic immune-mediated disease, which is the case for humans with necrotizing scleritis.¹ There is some evidence for a type III and type IV hypersensitivity mechanism to the pa-thogenesis of necrotizing scleritis in dogs, but there is variability in the literature as to whether T- or B-lymphocytes predominate in the lymphocytic component of the inflammation.^1,2 Some pathologists have made the comparison between necrotizing scleritis and systemic reactive histiocytosis in dogs and consider that these entities may be related (personal communication, R. Dubielzig). This is in particular due to the vasocentric nature of the cellular infiltrate in necrotizing scleritis (personal communication, R. Dubielzig).

In conclusion, this case is a classic example of necrotizing scleritis in the eye of a dog, highlighting the characteristic histologic features of this condition including the granulomatous inflammation and the altered collagen within the lesion.

JPC Diagnosis:

1.Eye, sclera: Scleritis, granulomatous and sclerosing, focally extensive, severe with optic nerve demyelination.

2.Eye: Panuveitis, lymphoplasmacytic, chronic, diffuse, moderate with hyphema, pre and post iridial fibrovascular membranes, retinal detachment and atrophy, and hypermature cataract.

Conference Comment:

The contributor provides a comprehensive and very informative review of this entity. The conference analysis of this case included separating the ocular lesions into two separate processes as alluded to in the contributors discussion.The first process, the scleritis with formation of vague gran-ulomas, includes a tremendous fibroblastic response (fibrosis) initiated by inflammation and necrosis. The second, primarily intraocular process is quite extensive, and encompasses the corneal changes (squamous metaplasia of the corneal epithelium and a break in Descemets membrane), cataract, pre- and post-iridal fibrovascular membrane formation with drainage angle obstruction,. changes in the ciliary body and iris, intraocular hemorrhage, and retinal detachment.The moderator cautioned against over interpreting retinal degenerative changes particularly in a detached retina that has been artifactually folded and distorted.Some sections contain optic nerve in which moderate to severe degenerative changes (i.e. axonal degeneration and gitter cells) are seen.

References:

1. Day MJ, Mould JRB and Carter WJ. An immunohistochemical investigation of canine idiopathic granulomatous scleritis. Vet Ophthalmol. 2008;11:11-17.

2. Denk N, et al. A retrospective study of the clinical, histological, and immunohistochemical manifestations of 5 dogs originally diagnosed histologically as necrotizing scleritis. Vet Ophthalmol. 2012; 15:102-109.

3. Dubielzig RR. Diseases of the cornea and sclera. In: Veterinary Ocular Pathology a comparative review. Saunders Elsevier: New York, NY; 2010: 232-234.

4. Grahn BH, Cullen CL and Wolfer J. Diagnostic ophthalmology, Necrotic scleritis and uveitis. Can Vet J. 1999; 40:679-680.

5. Grahn BH and Sandmeyer LS. Canine episcleritis, nodular episclerokeratitis, scleritis, and necrotic scleritis. Vet Clin Small Anim. 2008;38:291-308.

6. Njaa BL and Wilcock BP. The ear and eye. In: Zachary and McGavin, ed. Pathologic Basis of Veterinary Disease. 5^th ed. Mosby Elsevier: St. Louis, MO; 2012:1153-1244.

7. Wilcock BP. Eye and ear. In: Maxie, MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. 5^th ed. Vol. 1. Saunders Elsevier: Philadephia, PA; 2007:459-552.