JPC SYSTEMIC PATHOLOGY

SPECIAL SENSES SYSTEM

April 2024

S-M04

SLIDE A: Signalment (JPC #2165081): 1 year-old New Zealand White rabbit.

HISTORY: This rabbit had a two-week history of buphthalmos and a one day history of excessive lacrimation, corneal ulcer, and bilateral marked scleral injection.  

HISTOPATHOLOGIC DESCRIPTION: Eye: Changes within the narrowed filtration angle are characterized by a continuous iris stroma spanning the iridocorneal angle and loss of the uveoscleral trabecular meshwork within the ciliary cleft (trabecular hypoplasia) (Note: These changes are partially obscured by artifactual separation). Diffusely there is mild to marked thinning of the retina, more severely affecting the inner layers, with loss of the afferent nerve fiber layer and nearly all ganglion cells. Few remaining ganglion cells are shrunken and hyperchromatic with pyknotic nuclei (necrosis). Diffusely there is variable thinning of the inner and outer plexiform and nuclear layers with resultant accentuation of the Muller fibers (retinal atrophy). There is marked cupping of the optic nerve head which exhibits scattered spongiosis and few dilated myelin sheaths. Diffusely the fibers of the corneal substantia propria (stroma) are separated by irregular clefts, and lymphatics within the sclera are ectatic (edema). There is atrophy of the choroid, ciliary body, and iris, and the sclera is markedly thin.

MORPHOLOGIC DIAGNOSIS: Eye: Goniodysgenesis with retinal atrophy, optic nerve cupping, uveal tract atrophy, scleral thinning, and corneal edema, New Zealand White rabbit, lagomorph.

CONDITION: Primary (congenital) glaucoma; goniodysgenesis

SLIDE B: Signalment (JPC #1505464): A 7-year-old Bassett Hound.

HISTORY: This dog had a sudden onset of buphthalmia of the right eye.

HISTOPATHOLOGIC DESCRIPTION: There is goniodysgenesis characterized by a continuous iris stroma that spans the iridocorneal angle and inserts into the termination of Descemet’s membrane (imperforate pectinate ligament), increased connective tissue within the uveal trabecular meshwork, and loss of the uveoscleral drainage angle (trabecular hypoplasia). The anterior aspect of the corneal epithelium is attenuated, and the lateral aspects of the corneal epithelium are hyperplastic, up to 13 cell layers thick, with intracellular edema (hydropic degeneration), intercellular edema (spongiosis), and multifocal superficial keratinization. Multifocally, small caliber blood vessels extend from the limbus into the corneal stroma (corneal vascularization); these vessels are surrounded by moderate numbers of neutrophils (keratitis) and multifocal aggregates of brown, granular pigment (melanin). Multifocally, there is loss of regular clefting within the corneal stroma (corneal edema). Multifocally, within the anterior chamber and vitreous body, there are few to moderate numbers of neutrophils admixed with an eosinophilic proteinaceous exudate (hypopyon). The pupillary margin is everted with protrusion of the posterior iris pigment layer through the pupil (ectropion uveae). There is multifocal mild to moderate retinal atrophy, characterized by loss of the nerve fiber layer; ganglion cells are swollen, have clumped Nissl substance, and central chromatolysis (degeneration); there is loss and degeneration of the inner nuclear cell layer, and blending of the inner and outer plexiform layers; degenerative changes are more severe in the atapetal retina (tapetal sparing). The retina is multifocally detached from the multifocally hypertrophied retinal pigment epithelium (retinal detachment). There is mild cupping of the optic nerve, which contains few dilated axonal sheaths and rare spheroids. Focally, the sclera is markedly expanded by ectatic lymphatics, abundant eosinophilic homogenous fluid (edema), hemorrhage, and congested blood vessels. Multifocally, the bulbar and palpebral conjunctiva is expanded by a cellular infiltrate composed of lymphocytes, plasma cells, macrophages and neutrophils, markedly congested blood vessels, hemorrhage, and ectatic lymphatics (edema). The conjunctival epithelium is hyperplastic, with acanthosis, spongiosis, and intraepithelial neutrophilic pustules (conjunctivitis and blepharitis).

MORPHOLOGIC DIAGNOSIS:  

1. Eye: Goniodysgenesis with retinal atrophy and retinal detachment, basset hound, canine.

2. Eye: Uveitis and keratoconjunctivitis, neutrophilic, multifocal, moderate, with hemorrhage and edema.

CONDITION: Glaucoma (primary); Goniodysgenesis

GENERAL DISCUSSION:  

• Glaucomas are a group of diseases creating a clinical syndrome characterized by a prolonged increase in intraocular pressure (IOP) due to decreased aqueous humor drainage and resulting in various degenerative changes within the ocular tissues, including functionally significant injury to the optic nerve and retina and leading to ocular pain and blindness
• Glaucoma is one of the most frequent ocular conditions submitted for histologic evaluation; it is common in dogs, less common in cats, occasional in horses, and rare in other species
• Normal aqueous humor production, flow, and drainage:
  1. Aqueous humor produced by the ciliary body/ciliary processes (plasma filtration, diffusion, and active secretion by the ciliary epithelium) -> Posterior chamber (nourishes lens) -> Through pupil -> Anterior chamber (nourishes cornea)
     • Iridocorneal outflow (through the “filtration apparatus”) (“conventional pathway”): Past pectinate ligament -> Into ciliary cleft containing the uveal and corneoscleral trabecular meshwork -> (Schlemm canal (listed in some references) -> Scleral venous plexus -> Systemic circulation
       • The ciliary cleft is an area of perforated mesenchyme and is bordered externally by sclera, posteriorly by the muscles of the ciliary body, and internally by the iris stroma and anterior chamber
     • Uveoscleral outflow (“unconventional pathway”): Percolate through the iris root and ciliary body interstitium to reach the supraciliary space (between the ciliary body and sclera) or suprachoroidal space (between the choroid and sclera) to exit the globe
  2. The amount through each pathway varies by species (e.g., uveoscleral drainage is most common in horses)
  3. The ciliary cleft extends 360 degrees around the iridocorneal angle; blockage of most of it is required for the development of glaucoma
• Glaucomas are classified as primary and secondary  
  1. Primary glaucoma: Due to developmental errors in the structure and function of the iridocorneal angle and aqueous humor drainage; may be genetic; usually bilateral; almost exclusively seen in dogs; subdivided into open-angle glaucoma and closed-angle glaucoma
     • Open-angle glaucoma: No primary histologic lesions affecting the iridocorneal angle
       • Reported in dogs (e.g., Beagle dogs), cats, and horses
     • Closed-angle glaucoma: Incomplete development of the iridocorneal angle and aqueous humor draining pathway, e.g., Goniodysgenesis: generally only seen in dogs; two types account for most canine cases:
       • Pectinate ligament dysplasia (also known as imperforate pectinate ligament)
         1. Characterized by continuation of mature iris stroma across the uveal trabecular meshwork with insertion at the terminal edge of Descemet’s membrane
         2. Usually bilateral but clinically initially present in only one eye
         3. Breed-associated, thus presumed to be inherited (see Comp Path)
       • Trabecular hypoplasia: Arrested maturation of the trabecular meshwork resulting in increased dense tissue (primitive mesenchymal tissue) filling the filtration angle
         1. More severe and may lead to congenital glaucoma
       • Note: Presence of goniodysgenesis does not confirm primary glaucoma, as many dogs with developmental anomalies never develop glaucoma
  2. Secondary glaucoma: Acquired (e.g., obstruction or collapse of the iridocorneal angle); causes may include: fibrovascular proliferation, lens luxation, inflammation, or intraocular neoplasms [e.g., melanocytic neoplasms (e.g. uveal melanocytoma, diffuse iris melanoma), iridociliary epithelial tumor (iridociliary adenoma, iridociliary carcinoma), lymphoma]
     • Development of a pre-iridal fibrovascular membrane (PIFM) is the most common cause
     • Other causes include forward bowing of the iris in iris bombe, pupillary obstruction by vitreal prolapse (may occur due to anterior lens luxation), or from adhesion of an inflamed iris to the cornea

PATHOGENESIS:  

• Causes of glaucoma
  1. Blockage of the flow of aqueous humor anywhere along the outflow system can result in increased IOP -> Sustained IOP causes retinal atrophy, optic nerve cupping, and other secondary changes
  2. Uveitis can induce fibrovascular membrane formation at different locations within the eye, with preiridial (PIFM) being the most common; fibrovascular membranes, similar to granulation tissue, form due to cytokines such as VEGF, and may proliferate to cover/obstruct the iridocorneal angle (secondary “neovascular” glaucoma) or may cause adhesions (e.g., synechiae) that cause secondary glaucoma
• Effects of glaucoma
  1. Retinal atrophy (degeneration) is the most important secondary change in glaucoma because it causes blindness due to retinal ganglion cell death (and axonal damage); it occurs predominantly via apoptosis, with necrotic cell death occurring later in the disease
     • There is characteristic atrophy of the nerve fiber layer and loss of ganglion cells (“inner retinal atrophy”) with sparing of the outer nuclear layer and photoreceptors
     • Necrotic retinal ganglion cell death is due to:
       • Pressure-induced ischemic damage: Blood vessels in the retina, optic nerve, or choroid collapse due to increased pressure in the vitreous; posterior bowing of the lamina cribrosa (where the optic nerve passes through the sclera) contributes to the altered blood flow
       • Impaired anterograde and retrograde axoplasmic flow
       • Excitotoxicity: Damaged ganglion cells release excitatory compounds (especially the neurotransmitter glutamate) which may induce apoptosis in uninjured ganglion cells; glutamate may cause glial cells to release neurotoxic factors such as TNF-α, nitric oxide, and α2-macroglobulins
     • The dorsal/superior retina (overlying the tapetum lucidum) is generally LESS severely affected than the ventral retina (‘tapetal sparing” – although occurs in ateptal retinas as well); the cause remains unknown, although it may be related to the anatomy of the lamina cribrosa
  2. Corneal edema develops when aqueous pressure exceeds the ability of corneal endothelium sodium pumps to dehydrate the cornea and is more severe with pressure-induced corneal endothelial injury
  3. Lens subluxation (partial displacement) or luxation (displacement into the anterior or posterior segment due to rupture of zonular ligament) may be a cause or a consequence of glaucoma
     • Luxation causing glaucoma may occur with posterior synechia and pupillary block, by obstructing aqueous humor flow in the anterior chamber, or by displacing the vitreous
     • Glaucoma causing luxation may occur with buphthalmos -> Stretching/tearing zonular ligaments
  4. The nitric oxide (NO)–soluble guanylate cyclase (sGC)-cGMP pathway plays an important role in aqueous humor outflow and ocular blood flow (relaxes trabecular meshwork and smooth muscle) and is a potential target for glaucoma therapy (Lin, Toxicol Pathol. 2021)
  5. Cataract often forms secondary to glaucoma due to stagnation of aqueous humor and subsequent lens malnutrition

TYPICAL CLINICAL FINDINGS:

• Enlargement of the globe (buphthalmos or megaloglobus); increased IOP; cataract; failure of eyelids to cover the cornea (lagophthalmos); corneal edema, erosion, and/or ulceration; scleral injection; mydriasis; lens subluxation or luxation; anterior or posterior synechiae; impaired vision or blindness  
  1. Buphthalmos is more common in young animals and in animals with thin scleras (rats, rabbits, cats, dogs) that can stretch more readily  

TYPICAL GROSS FINDINGS:

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Cupping of the optic disk is pathognomonic when present (absence does not rule out glaucoma as it may take up to 7 days to develop); often more pronounced in cats and rabbits
  1. Secondary effects: Gliosis, axon degeneration (Wallerian degeneration)
  2. The cup sometimes is filled with fibrillar, PAS-positive material thought to represent degenerate vitreous
• Inner retinal atrophy (begins in nerve fiber and ganglion layers) with preservation of the outer nuclear layer and photoreceptors
  1. Loss of nerve fibers unmasks the normally inconspicuous Muller fibers
  2. May progress to loss of inner nuclear layer with increased duration or severity
  3. Dogs with high-pressure glaucoma may develop full-thickness retinal atrophy
  4. Retinoschisis is an uncommon form of retinal degeneration characterized by cyst-like splitting between the inner nuclear and outer plexiform layers and may occur secondary to glaucoma, inflammation, and neoplasia (Di Bernardo, J Comp Pathol. 2023)
• Buphthalmos: Thin sclera and anterior chamber anterior-posterior dimension increased
• Cornea: Keratitis with diffuse edema, neovascularization, eventual fibrosis
  1. Corneal striae (breaks in Descemet’s membrane, also known as Haab’s striae) – Most frequent in horses
  2. Failure of lids to cover enlarged globe > corneal desiccation and eventual ulceration > secondary corneal cutaneous metaplasia and/or ulceration
  3. Migration of corneal endothelium across the face of the pectinate ligament and onto the surface of the iris
• Iris and ciliary body atrophy (thinning and flattening of ciliary processes)
• Collapse of the ciliary cleft and trabecular meshwork (making evaluation for goniodysgenesis very difficult)
• Cataract (e.g., lens cortex liquefaction, Morgagnian globules, bladder cells, posterior migration of the lens epithelium, mineralization)

ADDITIONAL DIAGNOSTIC TESTS:  

• Ophthalmoscopy
• Tonometry (single measurement of IOP)
• Tonography (evaluates functional integrity of the aqueous outflow tract)
• Gonioscopy (reveals structural filtration angle abnormalities)
• Cytology: Aqueous humor aspirates may reveal inflammatory cells indicative of uveitis, if present

DIFFERENTIAL DIAGNOSIS:

COMPARATIVE PATHOLOGY:

• Dogs:
  1. Primary open-angle: The best known primary open-angle glaucoma is a heritable condition in Beagle dogs, which is used as a primary glaucoma model for human beings
  2. Primary closed-angle/goniodysgenesis due to imperforate pectinate ligament is breed-related (presumably inherited) defect in seen in Bouvier des Flandres, Basset Hounds, American Cocker Spaniels, Dandie Dinmont Terriers, Siberian Huskies, Samoyeds, Chows, and numerous other breeds
  3. Anterior uveal melanocytoma, by far the most frequent intraocular tumor in dogs, will eventually cause glaucoma due to ciliary cleft occlusion
  4. Melanocytosis:
     • Diffuse uveal melanocytosis is due to massive pigmentation of the uveal tract; histologically indistinguishable from a diffuse uveal melanocytoma, is controversially associated with glaucoma; also called “canine diffuse uveal melanosis”
     • Secondary glaucoma described due to concurrent lacrimal gland melanocytoma and ocular melanocytosis (Mitsui, J Vet Diagn Invest. 2022)
     • Oculodermal melanocytosis, also called a nevus of Ota or a dermal melanocytic hamartoma, is described in a dog with extensive ocular pigmentation + sharply demarcated ipsilateral dermal hyperpigmentation corresponding to the distribution of the ophthalmic and maxillary branches of the trigeminal nerve (Giannikaki, Vet Pathol. 2019)
• Cats:
  1. The most common causes are diffuse iridal melanomas, other neoplasms (e.g., lymphoma) and idiopathic lymphocytic-plasmacytic anterior uveitis
  2. Glaucoma may be caused by feline neovascular vitreoretinopathy (FNV), a newly described, rare, idiopathic condition of cats characterized by avascular peripheral retinae and epiretinal vascular membranes and gliosis (Beckwith-Cohen, Vet Pathol. 2019)
• Horse: 
  1. Uveoscleral outflow (“unconventional pathway”) of aqueous outflow (due to thick pectinate fibers and inconspicuous corneoscleral trabecular meshwork and scleral plexus
  2. Secondary glaucoma due to anterior uveitis or intraocular neoplasia is most commonly recognized
  3. Equine recurrent uveitis (ERU) (S-M01) is one of the most common primary equine ocular conditions; with glaucoma (and cataract) the most prevalent secondary alterations; ERU in considered by some to be one of the most common causes of glaucoma in the horse (Flores, J Vet Diagn Invest. 2020)
• Goat: Secondary glaucoma due to an invasive uveal melanoma described in an Aradi goat (El-Shafaey, J Comp Pathol. 2020)
• Rabbits: Congenital glaucoma of New Zealand White rabbits due to inherited autosomal recessive defect in the bu gene leading to goniodysgenesis characterized by underdevelopment or absence of outflow channels; usually evident by 3-5 months; results in non-painful, uni- or bilateral buphthalmia with subsequent corneal opacity; defective bu gene carriers associated with small litter sizes, poor neonatal survival due to a close linkage of the bu gene with a semilethal locus
• Avians:
  1. Glaucoma occasionally described, usually secondary to trauma, but primary glaucoma has been described
  2. Raptors with ocular trauma may develop lentoid bodies: intraretinal, lens-like structures produced by Müller cells or other components of the neuroretina subsequent to retinal trauma  
• Mustelids: Older ferrets may spontaneously develop glaucoma with buphthalmia
• Lab animal: Various methods to created inducible models for retinal ganglion cell (RGC) atrophy of Primary Open Angle Glaucoma (POAG) in humans are described in various species (such as rhesus monkey, rats, and mice) and include complete optic nerve transection, optic nerve crush, as well as inherited models such as DBA/2J,118 laser photocoagulation, microbead occlusion, and episcleral vein occlusion (Muthuswamy, Toxicol Pathol. 2021)

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