4 Pathology of the uvea

Uveitis is commonly encountered, and a good understanding of pathophysiology of the disease will serve you well in practice. Unfortunately, like many other parts of ophthalmology, the terms related to uveitis are confusing, and I suggest you review and then keep the Glossary handy while going through this section.

The uvea represents three structures that compose the vascular supply to the eye: the iris, ciliary body, and choroid (see Figure 1.1 to refresh your memory). Inflammation of the uveal structures – especially inflammation that is on-going or recurrent – can have a wide range of impacts beyond the uvea itself.

The iris is a relatively porous tissue, and when inflamed, leukocytes, blood and/or fibrin exit vessels and rapidly transit through the iris and into the aqueous. Clinically (or grossly), this manifests as an accumulation of cells and/or protein in the anterior chamber. Hyphema is the presence of hemorrhage within the anterior chamber, while hypopyon is an accumulation of neutrophils. Aqueous flare is the clinically visualized presence of increased protein in the aqueous humour.

Corneal edema is a reasonably common clinically observed secondary effect of uveitis. It can result from damage to the corneal endothelium, or from a cytokine-mediated increase in vascular permeability in the peripheral limbic vessels.

Fibrin within the anterior chamber may coat the iris, and lead to adherence of the iris to the cornea (anterior synechia) or to the lens (posterior synechia).

A common sequela of inflammation is the development of granulation tissue, and the eye is no exception. In the eye, granulation tissue often forms as a membrane that layers pre-existing ocular structures. Unfortunately for vision, the delicate and carefully organized structures of the eye are frequently altered by these membranes of granulation tissue. The exact consequence of the membrane depends on the location in which it forms: a pre-iridal fibrovascular membrane, for example, forms on the surface of the iris and may a) grow over the iridocorneal angle, leading to glaucoma (see the section on Glaucoma for more details); or it may b) grow over the pupil, leading to complete pupillary block and iris bombe; or it may c) simply cover the iris, and following maturation and contraction, deviate the free edge of the iris forward, leading to ectropion uvea. Alternatively, a membrane developing in the posterior segment over the choroid, known as a cyclitic membrane, may lead to retinal detachment as it matures and contracts (known as tractional retinal detachment).

The lens, too, is susceptible to the secondary effects of uveitis. Cataracts may develop, possibly a result of uveal attachment to its surface (posterior synechia), or an alteration in aqueous flow, or simply by an excess of inflammatory cytokines and by-products appearing in the aqueous. More information can be found in the section on the Pathology of the lens.

There are many causes of uveitis, including a number of infectious organisms that we are not going to cover. Below are some of the more commonly encountered conditions.

4.1 Mycotic endophthalmitis

A variety of different fungal organisms can gain access to the eye. Blastomyces dermatitis is the most frequent in dogs, while Cryptococcus neoformans is the most common in cats. There is nothing particularly surprising about these agents: they present with a profound, usually pyogranulomatous endophthalmitis that one would expect following a fungal infection. Retinal detachment may result secondary to the accumulation of inflammatory exudates.

4.2 Uveodermatologic syndrome (Vogt-Koyanagi-Harada-like syndrome)

This syndrome is relatively frequently seen in dogs, particularly in arctic-type breeds (Siberian huskies, Alaskan malamutes, Akitas, etc). The root of the condition is an immune-mediated targeting of proteins involved in the production of melanin. The inflammation, which is granulomatous in nature, targets the uvea and the skin of the face, though the ocular disease is typically more severe and of more consequence.

Because the inflammation targets the production of melanin, one of the most notable clinical signs is uveal and dermal depigmentation. The granulomatous inflammation of the uvea leads to destruction of melanocytes and dispersal of melanin. Inflammation in the choroid tends to be most severe, and can lead to Retinal detachment, PIFM, and glaucoma.

4.3 Canine adenovirus

In North America, canine adenovirus is mostly of historical relevance due to widespread vaccination. In areas with poor vaccination, the ocular manifestation of adenovirus is still significant.

In unvaccinated animals – or, rarely, animals receiving a modified live virus – canine adenovirus infects the uveal and corneal endothelial cells. Damage to uveal endothelium can lead to anterior uveitis, while corneal edema (due to damage to the corneal endothelium) may develop.

4.4 Equine recurrent uveitis

Equine recurrent uveitis (ERU) is the most common cause of glaucoma, cataracts, and blindness in horses. Although the condition may start out affecting only one eye, it virtually always ends up being bilateral. As it’s name suggests, the disease presents as waxing and waning episodes of uveitis that gradually increase in frequency. The gross/clinical signs of the disease are, like many ocular diseases, a constellation of lesions that require an astute ophthalmological exam. Uveitis, of course, is one of the main features, manifesting as increased proteinaceous content in the anterior chamber (“aqueous flare”) and vitreous. Corneal edema is also frequently present. In severe cases, there may be hyphema or hypopyon. In more chronic cases, cataracts, lens luxation, retinal detachment, and glaucoma may all be observed.

Microscopically in the early course of disease, there tends to be neutrophilic inflammation of the iris and ciliary body with fibrin and proteinaceous material found within the anterior chamber. Over a fairly short period of time, the inflammation becomes predominantly lymphoplasmacytic and histiocytic. In the chronic stages, lymphoplasmacytic inflammation of the entire uvea (panuveitis) dominates, and lymphoid follicles within the iris and ciliary body are characteristic.

The pathogenesis of ERU is still under investigation and is not fully understood. The current favoured theory is that ERU represents a multifactorial immune-mediated disease. There is a body of evidence – that is not conclusive – that implicates previous exposure or infection to Leptospira interrogans serovar pomona as an initiating cause. Many cases have been associated with seropositivity for Leptospira, and experimental infection can induce the disease; however, a significant portion of cases are not associated with leptospirosis, rendering this hypothesis somewhat flawed. Instead, the modern belief is that some initiating cause – at this point, unknown – causes a uveitis that alters the normal immune privilege status of the eye. Proteins within the eye that were previously restricted may become accessible to the immune system, and become antigenic stimuli as a result; similarly, antibodies generated through exposure to exogenous sources that may cross-react with ocular antigens may now have access to ocular structures. This breakdown in ocular immune privilege is what may lead to the continuing inflammation within the eye, and regardless of the initial cause, is probably the more important aspect of the disease.

4.5 Feline lymphonodular uveitis

Feline lymphonodular uveitis, also known as feline lymphoplasmacytic uveitis, is the most common cause of uveitis in the cat, and along with Diffuse iris melanoma, is one of the top causes of feline glaucoma. The condition generally starts off unilaterally, however, the contralateral eye is to be considered at risk.

Cats with the condition may present with one or more of the following symptoms: corneal edema with neovascularization; keratitic precipitates (cellular deposits on the corneal endothelium); and/or thickened irides. Eventually, glaucoma may develop, though the mechanism through which this occurs is unknown. Microscopically, the disease is characterized (as expected) by lymphoplasmacytic inflammation of the uvea, particularly within the iris, where lymphoid nodules may develop in severe cases.

The cause of feline lymphondular uveitis is unknown, but the pathogenesis is thought to be similar to ERU.

4.6 Feline infectious peritonitis

As with other locations in the body, feline infectious peritonitis virus can causes a significant vasculitis within the vascular structures of the eye (i.e. the uvea). Pyogranulomatous inflammation, particularly of the anterior uvea, tends to predominate. Grossly, anterior uveitis, manifesting as aqueous flare, is common. Diagnosis cannot be made on histopathology alone; ancillary diagnostics (e.g. IHC) are required.

4.7 Bovine MCF-associated uveitis

Malignant catarrhal fever virus causes a vasculitis with invasion of the vascular wall by lymphocytes. It is therefore a lymphocytic uveitis. Uveitis and corneal edema are noted grossly, and, when considered with the other gross lesions of MCF, the corneal edema can be particularly useful in helping distinguish between MCF and other mucosal diseases.

4.8 Lens-induced uveitis

(Please refer to the section on the lens for more information on the lens itself).

The lens is an immunologically privileged site, and the proteins that make up the lens fibers are thus not-recognized as self. Exposure of these proteins to the immune system can therefore elicit an immune response, the severity of which depends to some degree on the amount of protein encountered.

4.8.1 Phacolytic uveitis

Phacolytic uveitis refers to a mild to moderate lymphoplasmacytic uveitis resulting from the leakage of liquefied lens protein through an intact lens capsule. Liquefaction of lens proteins occurs routinely as cataracts mature; it can be relatively safely assumed that all animals with mature cataract have at least some degree of phacolytic uveitis. This condition cannot be distinguished from other idiopathic anterior uveitis based on histopathology (see Equine recurrent uveitis and Feline lymphonodular uveitis.

4.8.2 Phacoclastic uveitis

In contrast to the relatively mild inflammatory response in a phacolytic uveitis, the inflammation in phacoclastic uveitis is severe, profound, and centered around a lens material extruded through a ruptured lens capsule. Rupture of the lens capsule is most often caused by a penetrating foreign object (e.g. a thorn, or, more frequently, the business end of a cat’s paw). The type of inflammation is somewhat variable, but in the acute stages is neutrophilic and accompanied by fibrin; in more chronic cases, fibrosis with little inflammation dominates.

Iatrogenic phacoclastic uveitis may occur during cataract surgery, if lens protein is inadvertently left behind.

In rabbits, infection with Encephalitozoon cuniculi can lead to a phacoclastic uveitis, presumably through infection derived weakening of the lens capsule. The inflammation is characteristically granulomatous.

4.9 Diffuse iris melanoma

This is an important (and contentious!) condition seen in cats. It is the most common ocular neoplasm of cats. The condition begins as patchy areas of golden brown pigmentation on the anterior surface iris, which progress slowly (over the course of years) to coalesce and gradually expand the iris. The pupil may become irregular. Expansion and invasion into adjacent structures eventually leads to Glaucoma in virtually all cases, but this eventual fate may take years to occur. Feline diffuse iris melanomas also have significant metastatic potential. Seeding of the aqueous by neoplastic cells gives them access to outflow and general circulation. The neoplasm may then grow in the lungs, liver, and/or lymph nodes. There is considerable debate regarding the literature and studies on prognosis of cats with diffuse iris melanoma. Some advocate swift enucleation following a diagnosis, arguing that this reduces opportunity for metastasis and thus complications. Others suggest that the metastatic potential is relatively low, and that systemic disease resulting from said metastases is not a guarantee, and thus recommend waiting until complications (i.e. Glaucoma) have occurred prior to enucleation.

4.10 Canine uveal melanocytoma

This is the most frequent intraocular tumour of dogs. Specifically, the anterior uvea is the most frequent site of occurrance, but they can occur in any portion of the uvea (iris, ciliary body, or choroid). Anterior uveal melanocytomas present as an expansile mass originating from the root of the iris that is usually pigmented. Prognosis based on clinical/gross appearance is challenging: a small proportion (~ 5-20%) are malignant and have true metastatic potential, but this determination is based on histopathology, and cannot be predicted without a biopsy. However, even those that are histologically benign may represent a significant problem for the globe. They frequently are locally invasive, and by infiltrating the intraocular structures, many will grow to occlude the ciliary cleft, leading to Glaucoma.