Introductory Philosophy

The uvea contains familiar tissues and cell types (lymphocytes, smooth muscle, and blood vessels, for example), is inflamed by familiar antigens (infectious agents, neoplasia, auto-antigens) and reacts with the 5 cardinal signs of inflammation seen elsewhere (heat, pain, swelling, etc.). This review aims to aid diagnosis and therapy of uveitis by likening it to inflammation elsewhere (because it is more similar than it is different) while highlighting differences (because these are helpful).

Clinical Signs

Active (Acute) Uveitis

Uveitis has few pathognomonic signs and these are notably more subtle in cats than they are in dogs. Therefore, uveitis in cats often goes undetected by owners and untreated by veterinarians until potentially blinding sequelae such as glaucoma, cataracts, and retinal detachment or degeneration occur. Therefore, clinicians must maintain a high index of suspicion regarding uveitis in all cats with ocular disease and even those with nonspecific signs such as lethargy, “hiding”, anorexia, or fever.

Uveitis, like inflammation elsewhere, is evident as one or a combination of the 5 cardinal signs of inflammation: heat, pain, swelling, redness, and loss of function. One just has to think about how these are best seen:

• Intraocular pain: blepharospasm or epiphora; however, cats seem more likely to show subtle and less localizing signs such as lethargy or anorexia.
• Iridal swelling requires that the eye is examined using a source of magnification (such as the Optivisor®) in association with a bright and focal light source (such as the Finoff transilluminator®) directed very obliquely across the globe. Look for a loss of the normal “texture”.
• Redness evident as scleral injection is typically evident in dogs but can be particularly subtle in many cats. The tendency to diagnose any redness of this region as conjunctivitis must be avoided. Redness of the iris usually indicates neovascularization and not congestion and is discussed below under chronic changes.
• Dysfunction: Given the diverse range of critical functions of the uvea, loss of function produces an important series of clinical signs evident as breakdown of the blood aqueous barrier (BAB), miosis, corneal edema, and hypotony. Of these BAB breakdown is pathognomonic and so the anterior chamber is worthy of special attention since the aqueous humor is equivalent to the interstitial space. In particular look for hypopyon (white blood cells), hyphema (red blood cells), and fibrin, aqueous flare (albumin and other small proteins) and keratic precipitates (white blood cells and inflammatory proteins clumped against the corneal endothelial surface).

Chronic uveitis and its sequelae are associated with scarring (fusion of one tissue to another and cicatrization), chronic dysfunction, and neovascularization evident as glaucoma (due to scarring or clogging of the iridocorneal angle), anterior or posterior synechia (adhesions between the iris and corneal endothelium or lens, respectively), phthisis (globe contracture) or retinal detachment (due to contraction of vitreous fibrin). Altered aqueous humor composition and circulation also causes a relative malnutrition of the lens (evident as cataract) and inner cornea (evident as corneal edema, vascularization, fibrosis etc.). Lens luxation may occur due to enzymatic lysis or phagocytosis of the lens zonules, secondary to cataract development, or as a sequela to buphthalmos due to secondary glaucoma. Neovascularization of the face of the iris (rubeosis iridis) is a pathognomonic sign of subacute or chronic active uveitis. It is one of the signs that is seen more easily in cats than in dogs due to the typically lighter iris color of cats.

Diagnosis

Box 1 highlights the important tests to diagnose whether uveitis is present. Confirming or eliminating all suspected etiological diagnoses is the essential next step. By conducting an excellent general physical and ophthalmic exam as well as gathering a focused history, the initial goal is to establish whether further diagnostic testing is strongly supported. I do this by categorizing the uveitis as present in a well or systemically ill patient, unilateral or bilateral; exogenous or endogenous; acute or chronic; and as involving the anterior uvea, choroid, or both.

Box 1. Essential diagnostic tests to detect evidence of uveitis

Tests should be conducted in this order: IOP = intraocular pressure; KPs = keratic precipitates; AC = anterior chamber; BAB = blood-ocular barrier.

An etiologic diagnosis should then be pursued through a diagnostic workup identical to that employed for a cat with lymphadenopathy. Consider CBC, Biochemistry, urinalysis, serology, chest and abdominal imaging, etc. as appropriate for the following agents.

Etiology

The known causes of endogenous anterior uveitis in cats are expanding but still too few to explain the majority (∼70%) of cases.

Infectious agents as a cause of uveitis

* Via immunosuppression or oncogenesis
† Chorioretinitis predominates
¥ Seroprevalence data only; no clinical evidence

Neoplasia as a Cause of Uveitis

The most common primary intraocular neoplasm is melanoma; however, this typically causes little or no uveitis. By sharp contrast, the most common metastatic ocular neoplasm—lymphoma—tends to be associated with marked breakdown of the BAB with hypopyon formation, fibrin exudation into the anterior chamber, and hyphema. One of the curious observations with this disease is that the degree of apparent pain often seems less than might be expected from the severity of other signs of intraocular inflammation. The exception to this is when secondary glaucoma occurs, which can be quite frequent due to the highly cellular and fibrinous nature of the anterior chamber exudate.

Treatment

Treatment of anterior uveitis must be tailored to the individual case based on proven or suspected cause, severity, anatomical location, chronicity, and presence of systemic or other intraocular disease. Regardless, some general therapeutic guidelines are possible.

Optimal treatment relies upon identification and removal or reduction of the causative antigen; however, this is rarely possible. Additionally, all patients with uveitis need their intraocular inflammation controlled rapidly and completely, since it is painful and produces vision-threatening sequelae. Thus, immunomodulating drugs form the mainstay of therapy for uveitis. The major decisions are therefore which immunomodulating drugs should be given, via what route and, at what dose.

Immunomodulatory Therapy

Corticosteroids are commonly used for uveitis. Their systemic use should be reserved until a definitive cause responsive to corticosteroids has been found or, failing this, until causes known to be worsened by glucocorticoids have been adequately eliminated. In particular, the systemic mycoses must be adequately eliminated as potential causes. Likewise, patients in which lymphoma is possible and which would benefit from a multidrug chemotherapeutic regimen should not be treated with systemic corticosteroids alone. By contrast, topical administration of corticosteroids may be employed safely even when an infectious or neoplastic cause might prevent systemic administration of the same drugs. Prednisolone acetate (1% or 0.125%) and dexamethasone (0.1%) will penetrate intact corneal epithelium and reach the anterior uveal tract. Hydrocortisone (as found in many combined antibiotic-corticosteroid ophthalmic preparations) does not penetrate intra-ocularly and should not be used. The frequency of application should be tailored to the severity of the uveitis; starting as frequently as q 2 hours and tapering as a clinical response is noted. When safe, corticosteroids should be administered systemically for posterior uveitis and when more significant immunomodulation is necessary, or when corneal ulceration prohibits their topical use. Typical doses of prednisolone range from 1 mg/kg q 12 hours when notable inflammation is present to 0.5 mg/kg once daily when a more moderate anti-inflammatory effect is desired. As with topical corticosteroids, dose and dose frequency of systemically administered glucocorticoids should be carefully reduced based entirely upon clinical evidence of waning disease.

Compared with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) are not immunosuppressive, and may be more expensive, sold in smaller volumes (as topical ophthalmic solutions), and sometimes unavailable in ointment form. These limitations must be borne in mind for dogs and cats with uveitis; however, they may be preferred over corticosteroids in patients with diabetes or other endocrinopathies in which corticosteroid use may not be wise. They can also be administered systemically instead of corticosteroids when systemic infectious disease is suspected or proven, or until lymphosarcoma is eliminated as a differential consideration. And they may be given in conjunction with a topical steroid. As such, they may make an excellent choice for initial control of inflammation while likely causes are being ruled in or out. The same general comments regarding dose frequency and route made for corticosteroids apply equally to NSAIDs.

Iridocycloplegic Agents

Atropine has multiple favorable actions in eyes with uveitis and form a critical component of treatment. It paralyzes the iris sphincter and ciliary body muscles causing mydriasis and cycloplegia, respectively. Pupil dilation reduces leakage of vascular elements into the aqueous humor by causing radial blood vessels within the iris stroma to “concertina” upon themselves (thus providing a physiological tamponade); decreasing iris surface area (from which inflammatory mediators and vascular components originate); reducing uveal vascular endothelial permeability; and by reducing chances and consequences of posterior synechiation. However “bunching” of the iris in the periphery does increase the chance of anterior synechia and potentially obstruction of the iridocorneal angle. Cycloplegia reduces ocular pain but also increases resistance to aqueous outflow. Therefore, pupil dilation and cycloplegia are desirable in all cases of uveitis except those where secondary glaucoma is present or likely. This is more likely in some dog breeds predisposed to primary glaucoma but can also occur in cats and non-predisposed dogs The effect of mydriasis upon IOP can be tested by a single application of the short acting drug tropicamide followed by tonometry when the pupil is fully dilated. If IOP is increased by tropicamide, atropine should not be administered. If atropine is initiated, IOP should be rechecked regularly and application discontinued if IOP increases above normal. In cats, atropine should be applied as an ophthalmic ointment rather than a solution because it is bitter and passage down the nasolacrimal duct can cause violent salivation and frothing that is harmless but disturbing to the cat and its owner.

Monitoring and Sequelae

Prompt specific treatment of uveitis with tapering of therapy based upon reduction of clinical signs may result in some sequelae but these are usually mild and should be static. If they are not, this suggests chronic or recurrent uveitis and further investigations and treatment are necessary. Classic sequelae include corneal fibrosis, cataract, or posterior synechia. None of these changes should result in pain or, unless severe, vision disturbance. By contrast, more severe, unrecognized, persistent, or recurrent uveitis frequently results in a blind and sometimes painful globe. The most common sequelae (and their prevalence in cats) include cataracts in 20–36% of eyes, lens luxation in 11–18%, glaucoma in 16–46% and enucleation in 29%. Many patients experience more than one of these sequelae. For these reasons, frequent and careful monitoring of a patient with uveitis is essential. This should be performed as for patients with immune-mediated disease elsewhere with gradual tapering of medications and re-examination at doubling intervals presuming there is improvement; more often if there is not. Re-examination and tapering of medications should be continued until there is complete resolution of every clinical sign of active uveitis. I believe that tonometry is the most sensitive test with which to monitor uveitis during treatment because subtle hypotony (sometimes only relative to the contralateral eye) can continue long after other more overt signs have normalized. Continued treatment of these patients may prevent or delay development of sight-threatening ocular complications.