Uveitis is one of the most important ocular diseases in cats. Whether it involves. Causes of Feline Uveitis FOCAL POINT KEY FACTS

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1 128 Vol. 23, No. 2 February 2001 CE Article #1 (1.5 contact hours) Refereed Peer Review FOCAL POINT Feline uveitis is common, often idiopathic, and can be associated with serious systemic disease. KEY FACTS Feline uveitis is usually chronic, treatment is palliative, and sequelae are common, p Because the eye has limited responses to injury, different causes of uveitis may produce similar clinical signs, p An initial history, a physical examination, and a minimal database (complete blood cell count, serum chemistries, urinalysis) should be used to select diagnostic tests to determine the cause of uveitis, p Clinical or serologic evidence of systemic disease is found in 25% to 90% of cats with uveitis, p Causes of Feline Uveitis Colorado State University Cynthia C. Powell, DVM, MS Michael R. Lappin, DVM, PhD ABSTRACT: Uveitis describes inflammation of any portion of the uveal tract. Anterior uveitis and chorioretinitis are common in cats, but intermediate uveitis also occurs. Feline uveitis has many reported causes and has been associated with such systemic diseases as Toxoplasma gondii infection, feline infectious peritonitis, lymphoma, feline immunodeficiency virus, feline leukemia virus, and Cryptococcus neoformans infection. In addition, Bartonella organisms and feline herpesvirus have recently been associated with uveitis. Determining the cause of uveitis can be difficult. Because the eye has limited responses to injury, different causes of uveitis may produce similar clinical signs. A thorough history should be taken and a physical examination performed in all cases; if a systemic cause is suspected, a complete blood cell count, serum chemistry panel, and urinalysis should be conducted. This article reviews the available tests and recommendations for diagnosing diseases associated with feline uveitis. Uveitis is one of the most important ocular diseases in cats. Whether it involves the anterior segment, posterior segment, or both, uveitis threatens sight; it may also be the first indication of a serious or life-threatening systemic disease. Appropriate treatment of uveitis requires proper diagnosis; however, often a cause is not found. It is important for clinicians and clients to understand that uveitis is often chronic, treatment is palliative, and sequelae are common. ATOMY AND PHYSIOLOGY The uvea constitutes the vascular portion of the eye and consists of the iris, ciliary body, and choroid. The iris and ciliary body compose the anterior uveal tract, and the choroid composes the posterior uveal tract. Uveitis is any condition that involves inflammation of the uveal tract. Classification schemes for uveitis are based on location (anterior, intermediate, posterior), duration (acute, chronic, recurrent), pathology (e.g., granulomatous, suppurative), and cause (e.g., trauma, infection, neoplasia, immune mediation). The goal of treating uveitis is to stop inflammation and prevent secondary effects (e.g., synechiae, glaucoma, retinal degeneration) that contribute to vision loss. Therefore, an accurate diagnosis and understanding of the mechanisms of uveitis and its sequelae are required. Intraocular inflammation is initiated by local tissue injury (e.g., trauma, infectious agent, antigen challenge). Tissue factors and chemoattractants are released

2 Compendium February 2001 Small Animal/Exotics 129 from damaged tissue and microorganisms; vasodilation and changes in vascular permeability follow. These changes indicate disruption of the blood ocular barrier. Inflammatory mediators released by damaged tissue cells cause leukocyte activation and migration. Because the globe has no lymphatic drainage, antigens from degraded organisms are transported to the spleen or other lymphoid tissue via the venous system to activate antigen-specific T and B lymphocytes. Immunocompetent T and B lymphocytes then migrate back to the eye and reside in the uvea. 1 Factors believed to help stop the immune response include T- and B-lymphocyte production of inhibitory cytokines and eliminating the inciting antigen. 2 If the inciting antigen cannot be completely removed, as in autoimmune disease, chronic inflammation results. Proposed mechanisms contributing to the development of autoimmune uveitis include abnormal induction of tolerance to autoantigens, release of normally sequestered autoantigens because of trauma or infection, molecular mimicry (homology between pathogens and host tissue antigens), and alteration of autoantigen structure caused by tissue injury or inflammation. 1,3,4 Because the uvea contains immunocompetent lymphocytes, chronic or recurrent inflammation could also result from either specific or nonspecific activation of lymphocytes by non self-antigens. 5 CLINICAL MANIFESTATIONS The clinical appearance of uveitis varies, depending on location, duration, and severity. Ocular pain manifested by photophobia, blepharospasm, enophthalmos, elevation of the third eyelid, and/or epiphora is common in cats with acute anterior uveitis but may be absent in those with mild or chronic cases. Reddened sclera caused by injection of conjunctival and episcleral vessels and aqueous flare are hallmarks of anterior uveitis. Aqueous flare is caused by increased protein concentration in the aqueous humor and is secondary to disruption of the blood ocular barrier. Light passing through the anterior chamber is scattered in aqueous Figure 1 Keratic precipitates (black arrows) and iritis (white arrow) in a cat with anterior uveitis secondary to feline infectious peritonitis. Figure 2 Posterior synechia (arrow) causing irregular pupil shape. flare; if severe, the aqueous humor appears cloudy. Corneal edema can result from the effects of inflammation on the corneal endothelium and can be minimal to severe. As edema increases, the cornea becomes increasingly opaque and blue. Inflammatory cells in the aqueous humor may be deposited on the corneal endothelium as keratic precipitates (KPs). Normal convection currents of the aqueous humor cause KPs to be located primarily on the ventral half of the cornea. KPs vary in size; larger KPs occur more often when granulomatous inflammatory processes are associated with such diseases as feline infectious peritonitis (FIP) and toxoplasmosis (Figure 1). The iris undergoes many changes in cats with anterior uveitis. Inflammatory mediators (prostaglandins) cause miosis (excessive contraction of the pupil) by direct effect on the iris sphincter. Because very mild miosis is difficult to detect, its absence should not be used to rule out uveitis. Iritis manifested by iris vasodilation and increased iris vessel permeability often causes a subtle to pronounced change in iris color. On close examination, dilated iris vessels may be obvious (Figure 1); and the iris may appear swollen and have a thin coat of fibrin and cells, giving it a velvetlike texture. As anterior uveitis becomes more chronic, the pupil margin begins to form posterior synechiae (adhesions to the anterior lens capsule), giving the pupil an irregular shape and impairing its response to light or dilating agents (Figure 2). If posterior synechiae involve the entire pupil margin, aqueous humor cannot move from the posterior chamber to the anterior chamber. Aqueous humor then accumulates behind the iris, causing it to billow forward, a condition known as iris bombé (Figure 3). Because access to the anterior chamber is required for aqueous humor to reach the filtration angle, iris bombé is associated with increasing intraocular pressure and glaucoma. Peripheral anterior synechiae (adhesions of the peripheral iris to the cornea) can form with anterior uveitis as a result of iris bombé or secondary to iris swelling and inflammation. Inflammato- LYMPHOCYTE PRODUCTION AQUEOUS HUMOR KERATIC PRECIPITATES

3 130 Small Animal/Exotics Compendium February 2001 ry cells, iris swelling, and anterior synechiae can impair aqueous outflow and contribute to the development of secondary glaucoma. Aqueous humor formation is impaired when the ciliary body is inflamed. Thus anterior uveitis causes low intraocular pressure unless complicated by secondary glaucoma. Inflammation also causes ciliary muscle spasm, a major contributor to ocular pain. Accumulation of inflammatory cells in the peripheral anterior vitreous is known as pars planitis or intermediate uveitis. Because of its peripheral location, pars planitis is often not apparent without a dilated pupil. Posterior uveitis is inflammation of the posterior uvea or choroid. Because of the close apposition of the retina and choroid, retinal inflammation often accompanies that of the choroid, creating chorioretinitis. Changes in the ocular fundus secondary to chorioretinitis are related to the breakdown of the blood ocular barrier located at the retinal blood vessels and the retinal pigment epithelium. Increased permeability of these barriers allows components of the blood to enter the retina and subretinal space. Migration of inflammatory cells to the area of inflammation also occurs. Retinal and subretinal edema, exudation, and hemorrhage can be detected clinically. Because the retina and subretinal space overlie the tapetum, tapetal reflectivity is diminished or obscured by areas of active chorioretinitis (Figure 4). Severe chorioretinitis can lead to partial or complete retinal detachment, causing decreased vision or blindness. Inflammation of both the anterior and posterior uvea is known as endophthalmitis. Figure 3 Anterior chamber exudates (white arrow) in a cat with anterior uveitis and iris bombé. Note the curvature of the iris as it billows forward (black arrows). Figure 4 Chorioretinitis secondary to feline infectious peritonitis. Note the decrease in tapetal reflectivity (white arrow) and perivascular exudation (black arrows). DIAGNOSTIC DIFFERENTIALS The clinical presentation of uveitis is extremely variable, depending on the affected portion of the uveal tract and severity of the uveitis and whether it is acute, chronic, or recurrent. In cats with injection of the conjunctiva or sclera, a thorough intraocular examination should be performed and intraocular pressure measured. Intraocular examination should include close scrutiny of the anterior segment and pupil dilation for peripheral fundus and retinal assessment. After a diagnosis of uveitis has been made, a thorough history should be obtained, general physical examination performed, and diagnostic tests submitted to determine the cause. Causes of uveitis can be exogenous or endogenous. Exogenous uveitis is the result of an external influence on the eye (e.g., trauma, surgery). Exogenous causes of uveitis can usually be identified from the history and ocular examination. Endogenous causes of uveitis can be considerably more difficult to determine. Because intraocular inflammation attributed to different causes usually appears the same, a diagnosis can rarely be made by ocular examination alone. History and signalment can occasionally be used to help rank the diagnostic differentials. For example, uveitis caused by FIP can generally be detected in young inbred kittens. Toxoplasma gondii associated uveitis may be more common in cats that hunt. Diagnostic tests, usually including a complete blood cell count, serum biochemical panel, urinalysis, and infectious disease serologic tests, can be used to narrow the diagnostic differentials. Histopathology may occasionally be needed to make a diagnosis. Reported causes of feline uveitis have been categorized as exogenous and endogenous (see Causes of Feline Uveitis). Clinical or serologic evidence of systemic disease is detected in 25% 6 to 90% 7 of cats with uveitis; the most common diseases are T. gondii infection, FIP, feline immunodeficiency virus (FIV), lymphoma, and feline leukemia virus (FeLV). Diagnostic tests for diseases associated with feline anterior uveitis have been categorized in Table I. Toxoplasmosis Cats are most commonly infected with T. gondii by ingestion of tissue cysts in prey species. Ocular infection with T. gondii after neonatal infection has also been docu- PARS PLANITIS CHORIORETINITIS EXOGENOUS AND ENDOGENOUS CAUSES

4 Compendium February 2001 Small Animal/Exotics 131 EXOGENOUS Trauma Secondary bacterial infection Sterile inflammation Ocular surgery Secondary bacterial infection Sterile inflammation Keratitis Ulcer Infection Drug or toxin intoxication Pilocarpine Latanoprost Causes of Feline Uveitis Infection Bacterial Mycobacterium species Bartonella henselae Rickettsial Ehrlichia species Viral Feline leukemia virus Feline infectious peritonitis Feline immunodeficiency virus Parasitic Toxoplasma gondii Cuterebra species Metastrongylidae mented in cats and humans. 8 Field strains of T. gondii likely vary in ophthalmic disease inducing potential, 9 which may partially explain why relatively few T. gondii seropositive cats have ophthalmic disease. The prevalence of ocular toxoplasmosis in naturally exposed cats is unknown because confirming the diagnosis can be difficult. Serum antibodies against T. gondii have been detected in up to 78.5% of cats with anterior or posterior uveitis. No other obvious cause can be determined in many T. gondii seropositive cats with uveitis, some of which may respond to drugs with anti Toxoplasma activity. 7 When available, ocular histopathology rarely identifies the organism, 10 making it difficult to correlate positive serology with ocular infection. However, D of the organism can be detected in the aqueous humor of some cats by using the polymerase chain reaction (PCR) to confirm presence of the organism in the eye. 11 The pathogenesis of ocular toxoplasmosis is largely undetermined but is likely a combination of organism replication and immune-mediated events directed against the organism. ENDOGENOUS Mycotic Cryptococcus neoformans Blastomyces dermatitidis Histoplasma capsulatum Coccidioides immitis Candida albicans Neoplasia Primary Diffuse iris melanoma Ciliary body adenoma/ adenocarcinoma Metastatic Lymphosarcoma Others Idiopathic Immune-mediated Induced by the lens In cats with active organism replication, fever and other clinical signs are generally present. Ocular toxoplasmosis can result in anterior or posterior uveitis and can be unilateral or bilateral. 12 Clinical diagnosis of ocular toxoplasmosis should be made using history of potential exposure (hunting) combined with serum or aqueous humor testing. Serum IgG antibodies develop approximately 2 weeks after infection and may remain elevated for years, even in healthy animals. 13 The prevalence of T. gondii IgG in healthy cats is 30% to 50%, making correlation between test results from this antibody class and clinical illness difficult to determine. An increasing IgG titer (fourfold increase within 2 to 3 weeks) can indicate recent or active infection and may correlate better with disease. Serum IgM against T. gondii can be used as an indicator of recent infection because this antibody class usually is not detectable more than 9 weeks after infection. Detection of T. gondii IgM may also be superior to that of IgG for correlation with clinical illness because IgM is rarely detected in the background population of healthy cats (1.2%). 14 Detection of T. gondii antibody production in the aqueous humor can also be used to support the diagnosis of ocular toxoplasmosis. 15 This test uses an ELISA to detect antibodies to T. gondii in both serum and aqueous humor. The Goldman- Witmer coefficient (C value) should be calculated to adjust for antibody leakage from the serum. A C value greater than 1 indicates that T. gondii specific antibody is being produced in the eye. Because IgM production has been detected only in the aqueous humor of cats with uveitis, 15 detection of IgM might indicate disease caused by T. gondii infection. Systemically ill, T. gondii seropositive cats should always be treated with an anti Toxoplasma drug. Treatment with an anti Toxoplasma drug can also be justified in T. gondii seropositive cats with uveitis when other causes of uveitis have been ruled out, particularly if glucocorticoid therapy has failed. TOXOPLASMOSIS I g G ANTIBODIES I g M ANTIBODIES

5 134 Small Animal/Exotics Compendium February 2001 TABLE I Diagnostic Tests for Diseases Associated with Feline Anterior Uveitis Aqueous Vitreous Diagnosis Whole Blood Serum Humor Humor Miscellaneous Toxoplasma gondii infection FIP Feline immunodeficiency virus Feline leukemia virus/lymphoma Bartonella henselae infection Cryptococcus neoformans infection PCR, virus isolation Antigen (ELISA), PCR, virus isolation Culture, PCR IgM, IgG (ELISA) Antibody (IFA), PCR, globulin >5.1, low A:G ratio Antibody (ELISA, IFA, Western blot) Antigen (ELISA) IgG (ELISA) Antigen (latex agglutination or ELISA) IgM, IgG (ELISA), PCR PCR a PCR a Cytology Culture, PCR Cytology, culture, antigen (latex agglutination or ELISA) PCR a PCR a Cytology Cytology, culture, antigen (latex agglutination or ELISA) Effusion PCR, effusion γ-globulin 35%: consistent with FIP, effusion A:G ratio 0.81: not consistent with FIP Cytology/culture: nasal, skin exudates, cerebrospinal fluid a Diagnostic utility of PCR testing is yet to be determined. A:G ratio = albumin:globulin ratio; FIP = feline infectious peritonitis; IFA = immunofluorescent antibody; = not available; PCR = polymerase chain reaction. Feline Infectious Peritonitis Coronaviruses are common in cats and are spread when cats are exposed to coronaviruses shed in the environment by infected cats. Whether clinical disease occurs depends on the strain of coronavirus and the immune status of the host. Spontaneous mutation of nonpathogenic strains into FIP-inducing strains can occur. 16 FIP is clinically divided into effusive and noneffusive forms. 17 Ocular lesions are most often found in cats with the noneffusive (dry) form of FIP. Anterior or posterior uveitis may be present. Iritis, large KPs, clots of fibrin and blood in the anterior chamber, cuffing of the retinal vasculature, and chorioretinitis are common (Figures 1, 3, and 4). Like that of toxoplasmosis, diagnosis of FIP can be challenging. Studies have shown that 25% of outdoor cats and 80% or more of cattery-reared cats carry serum antibodies to feline coronavirus. 17 Because current tests cannot distinguish among antibodies to FIP-induced coronavirus, feline enteric coronaviruses, or other coronaviruses, 18 diagnosis is based on the combination of clinical and laboratory findings. Many cats with FIP are younger than 2 years of age, 19 and most present with other evidence of systemic disease. Ocular disease accompanied by ascites, thoracic or pericardial effusion, depression, icterus, renal failure, diarrhea, or neurologic signs is suggestive of FIP. High serum globulin levels (greater than 5.1 g/dl), low albumin:globulin ratio, and effusion total protein content greater than 3.5 g/dl are supportive as well. Although also supportive, a high coronavirus antibody titer does not correlate with disease as well as does hyperglobulinemia or a low albumin:globulin ratio. 20,21 A test that detects antibodies against the 7B protein of coronaviruses is available but does not prove FIP. PCR for detection of feline coronavirus D in effusions can aid in the diagnosis of the effusive form, 22 but positive test results using blood do not distinguish enteric coronaviruses from FIP. In addition, PCR results can be used to detect virus shedders or D in antibody-negative cats suspected of having FIP; however, as with serum antibody titers, detection of the organism does not correlate well with disease or COROVIRUSES POLYMERASE CHAIN REACTION D

6 Compendium February 2001 Small Animal/Exotics 135 herald disease development. 23 In two cats with histologically confirmed ocular FIP, PCR testing for coronavirus D on aqueous humor was negative a ; thus aqueous humor PCR testing may have minimal value. Feline Leukemia Virus/Lymphosarcoma Feline leukemia virus is a retrovirus transmitted by prolonged passive contact. Clinical disease is usually associated with myelodysplasia, lymphosarcoma (LSA) or other neoplasia, or secondary infections as immunodeficiency develops. Uveitis probably does not occur in cats with FeLV infection except by its association with the development of LSA or potentially by predisposing to secondary causes resulting from immunosuppression. The reported incidence of ocular disease among clinically apparent FeLV-positive cats is approximately 2% or less 24 ; however, LSA has been shown to be a common cause of uveitis in enucleated eyes. 10 In studies of cats with uveitis and no obvious underlying cause, FeLV serum antigen tests were positive in 0% to 12%. 6,7,10,25 Uveitis associated with LSA results from neoplastic infiltration of the uveal tract, and the clinical presentation depends on tumor distribution (Figure 5). Nodular or diffuse infiltration of the anterior or posterior uveal tract is possible and, when diffuse, appears similar to uveitis by other causes. 26 Although isolated ocular LSA is uncommon, it is not unusual for ocular disease to be the presenting clinical sign; many cats with ocular LSA may appear clinically healthy otherwise. 26 Diagnosis of ocular LSA requires identification of neoplastic lymphocytes and can sometimes be made from aqueous humor cytology, but cytologic or histopathologic detection of a tumor located elsewhere is usually necessary. The ELISA for detecting the p27 antigen in the blood is the most widely used commercial screening test for FeLV because it can be conducted in the clinic. Serum should be the medium a Lappin MR: Personal communication. Fort Collins, CO, Colorado State University, Figure 5 Inflammation of the temporal iris due to lymphosarcoma (white arrow). Figure 6 Pars planitis. Inflammatory cells can be seen within the vitreous (white arrow) between the margin of the widely dilated pupil (a) and the edge of the sclerotic lens nucleus (b). assessed because the results are more accurate than are those associated with whole blood, plasma, saliva, or tears. However, positive immunofluorescent antibody correlates better with persistent viremia than does positive ELISA. 27 Testing for FeLV is always indicated in cats with suspected ocular LSA because treatment and prognosis depend on FeLV status. 28 However, a positive FeLV test does not prove ocular disease caused by the virus because most FeLV-positive cats do not have LSA. Conversely, a negative FeLV test does not rule out LSA because 20% to 70% of cats with confirmed LSA are FeLV negative. 29 Feline Immunodeficiency Virus Feline immunodeficiency virus, a retroviral infection, is usually acquired transplacentally, during lactation, or by direct inoculation while fighting with infected cats. Thus infection is documented most often in cats with potential for exposure to infected cats. Clinical disease in FIV-infected cats is usually associated with immunodeficiency, but primary disease syndromes attributed to the virus include uveitis, enteritis, and renal disease. Histopathologic evidence of anterior uveitis is common in cats with advanced FIV infection, 30 suggesting that the virus is a primary cause of uveitis. Local production of FIV antibodies and antigens in aqueous humor was recently documented in FIV-infected cats with uveitis but not in healthy FIV-seropositive cats. 31 These results support the hypothesis that FIV infects the eyes of some cats and can result in uveitis. In naturally exposed cats, immunodeficiency associated with FIV may possibly result in uveitis from opportunistic infections. For example, T. gondii and Cryptococcus neoformans infections have been detected concurrently in FIV-seropositive cats. 32 Anterior uveitis, pars planitis, and glaucoma with or without concurrent uveitis have been clinically identified in cats infected with FIV. 33 Pars planitis appears as white, punctate infiltrates concentrated in the peripheral anterior vitreous (Figure 6). DISEASE-ASSOCIATED CONDITIONS DETECTING THE VIRUS IMMUNODEFICIENCY

7 136 Small Animal/Exotics Compendium February 2001 Serum antibodies against FIV can be detected by ELISA, Western blot immunoassay, or immunofluorescent antibody. The organism can be detected in blood by PCR or virus isolation. ELISA testing is used most often because it is available for private practice use. 34 FIV is not cleared by the immune response; therefore, positive antibody tests generally indicate current infection. Because ELISA results are occasionally false-positive, positive results should always be confirmed with Western blot immunoassay, immunofluorescent antibody, or PCR. Detecting FIV antibodies does not prove that uveitis is a result of FIV. Many FIV-seropositive cats with uveitis have serologic evidence of exposure to other pathogens associated with uveitis. 7,25 Other opportunistic infections should be excluded as diagnostic differentials before attributing uveitis to FIV. Feline Herpesvirus-1 Herpesvirus infections in humans have commonly been associated with uveitis. 35 Until recently, feline herpesvirus-1 (FHV1) was believed to cause only conjunctivitis and keratitis. 36 In one study, serum and aqueous humor were collected from healthy cats, cats with idiopathic uveitis, and cats with suspected Toxoplasma uveitis. 37 FHV1 antibodies were measured in serum and aqueous humor, and the presence of FHV1 D was evaluated in aqueous humor by PCR. Local production of FHV1 antibodies was detected frequently in cats with uveitis; C values greater than 8 were detected only in cats with idiopathic uveitis. In addition, D was detected in the aqueous humor of 11 of 73 cats with uveitis but only 1 of 22 healthy cats. These results show that FHV1 enters the eyes of cats and may be associated with uveitis. Because a majority of client-owned cats have been vaccinated or preexposed to FHV1, antibodies can be detected in the serum of most. 37 Thus serum antibody detection has no diagnostic benefit in FHV1- associated uveitis. Further data are needed before treatment recommendations can be made. Systemic Mycosis Ocular disease resulting from disseminated histoplasmosis, blastomycosis, coccidioidomycosis, cryptococcosis, and, rarely, candidiasis has been reported in cats Cryptococcosis, the most common systemic mycosis in Figure 7 Chorioretinitis (black arrows) due to Cryptococcus neoformans infection. cats, is usually associated with upper respiratory disease. Cutaneous involvement, especially of the nasal region, and neurologic signs are also common. 40,41 Although chorioretinitis alone is most common (Figure 7), intraocular manifestations of systemic mycosis also include chorioretinitis and/or anterior uveitis. Definitive diagnosis is made by demonstrating organisms in cerebrospinal fluid or vitreous or aqueous humor or by cytology of cutaneous and nasal exudates. Culture or tissue biopsy and histopathology may be necessary for diagnosis. C. neoformans antigen testing by latex agglutination and ELISA can use serum, aqueous humor, or vitreous humor and is superior to antibody testing because positive test results confirm that the organism is in the body. Even if the organism is identified on cytology, histology, or culture, serum antigen testing should be conducted to serve as a baseline for therapeutic monitoring. Detecting antibodies against Coccidioides immitis and Blastomyces dermatitidis can aid in the diagnosis. Serologic tests for Histoplasma capsulatum are unreliable. Bartonellosis Bartonella henselae and Bartonella clarridgeiae are two causes of cat-scratch disease in humans. 42 Uveal tract inflammation from B. henselae infection in humans has been reported. 43 Cats are the apparent reservoir for B. henselae, and 55% to 81% of cats test seropositive for B. henselae. Because fleas transmit the organism, the incidence is highest in areas endemic for Ctenocephalides felis. A majority of naturally infected or experimentally infected cats show no clinical evidence of disease; however, transient fever, lymphadenopathy, and neurologic signs have been reported. 44 Bartonella species were suggested as likely causes of anterior uveitis in one cat based on the production of Bartonella species antibody in aqueous humor and response to doxycycline. 45 In another study, production of Bartonella species aqueous antibody was evident in 7 of 49 cats with uveitis but 0 of 49 healthy cats 46 ; 3 of 24 cats with uveitis and 1 of 49 healthy cats had Bartonella D in aqueous humor detected by PCR. These results suggest that the organism can invade the eyes of cats and may be associated with uveitis. Until recently, culture was the most accurate means of diagnosing active Bartonella infection in cats; a PCR DETECTING ANTIBODIES SYSTEMIC DISEASE ANTIBODY PRODUCTION

8 138 Small Animal/Exotics Compendium February 2001 test is now available and may be more sensitive than is culture. 47 Because many healthy cats are seropositive as well as positive in PCR or culture of whole blood, these tests cannot be used to prove ocular bartonellosis. Further information is needed regarding diagnostic use of aqueous humor testing. Bartonella species should be considered as a diagnostic differential for cats with uveitis without other known causes, particularly if glucocorticoid therapy is ineffective and there is a history of flea infestation. If patients meet these criteria, administering a drug with anti Bartonella activity is recommended. Ehrlichiosis Ehrlichia species are gram-negative rickettsia that can infect a variety of hosts and are often tick-borne. Ehrlichia infections have been detected in some dogs with uveal-tract inflammation. 48 There are few published reports of cats with ehrlichiosis. Reported clinical signs in cats have not included uveitis but otherwise are similar to those in dogs. 49 A statistical association was made between ocular discharge and uveitis in an epidemiologic study comparing the incidence of clinical signs in cats with and without serum antibodies to Ehrlichia species. 49 Further research is required to determine the involvement of Ehrlichia infection in cats with uveitis. Tuberculosis Feline tuberculosis is most commonly caused by ingestion of uncooked meat or unpasteurized milk from cattle infected with Mycobacterium bovis. Because of eradication measures, bovine and thus feline tuberculosis are rare in the United States. 50 Chronic anterior uveitis, granulomatous chorioretinitis, ocular hemorrhage, and retinal detachment may be found in cats with tuberculosis. 51 Other clinical signs reflect the site of primary infection and are often gastrointestinal. Diagnosis is made by identifying acid-fast bacilli from tissue aspirates or biopsy specimens. Intradermal skin testing and serologic testing are unreliable in cats. Commercially available PCR tests will likely be on the market soon. 50 Intraocular Parasite Migration Intraocular parasite migration, an uncommon cause of ocular disease in cats, is usually caused by larval stages of the rabbit and rodent botfly Cuterebra 52 ; however, intraocular migration of an adult nematode has also been reported. 53 Anterior chamber involvement can cause acute anterior segment inflammation that is often poorly responsive to medical therapy. When possible, the parasite should be removed surgically, and aggressive medical management of uveitis should follow. Retinal degeneration (by an unknown mechanism) may be a sequela to anterior segment Cuterebra infection. 53,54 Posterior segment parasite migration causes minimal inflammation when confined to the subretinal space. Diagnosis is made by observing the parasite or its typical roadmaplike subretinal migration tracts. 55 Neoplasia Primary and secondary uveal tumors may present as an intraocular mass and/or uveitis and should always be considered a diagnostic differential for uveitis. Diffuse iris melanoma is the most common primary tumor and LSA the most common metastatic tumor reported in cats. Other reported tumors include primary ciliary body tumors, posttraumatic sarcoma, metastatic squamous cell carcinoma, adenocarcinoma, and hemangiosarcoma. 54 Ocular ultrasonography is used to locate mass lesions behind the iris. Cataracts Anterior uveitis can develop as the result of a rapidly developing or hypermature cataract. Diagnosis is based on the history of a cataract preceding uveitis. Lens removal combined with medical therapy for anterior uveitis is usually successful in treating lens-induced uveitis. Caution should be used in diagnosing lens-induced uveitis because feline cataracts are most often secondary to anterior uveitis. Idiopathic Uveitis In 10% to 70% of cats with uveitis, a cause cannot be identified. 6,7,10 The lymphocytic-plasmacytic infiltration of the anterior uvea found on histopathology in cases lacking a diagnosis 10 suggests that at least some may be immune mediated. Whether the immune-mediated reaction is a true autoimmune disease or is activated by other antigenic stimulation is yet to be determined in cats. Coinfection The possibility of infection by more than one agent should be considered in cats with uveitis. Coinfection is commonly found in FIV-positive cats with serologic evidence of concurrent infection with FeLV (5.5% of cases), coronaviruses (26.8% of cases), and T. gondii (57.1% of cases). 56 Cats with serologic evidence of coinfection with T. gondii and FIV are more likely to have ocular disease than are cats with FIV alone, and ocular signs may be the result of toxoplasmosis rather than infection with FIV. Routine testing for the most common infections associated with uveitis (FeLV, FIV, coronavirus, T. gondii ) is recommended in all cases of uveitis. INFECTION TESTING TREATMENT

9 Compendium February 2001 Small Animal/Exotics 139 REFERENCES 1. Pararajasegaram G: Basic principles: Mechanisms of uveitis, in Yanoff M, Duker JS, Rao (eds): Ophthalmology. Philadelphia, Mosby, 1999, pp 10/ Forrester J, Dick A, McMenamin P, et al: The Eye: Basic Sciences in Practice. Philadelphia, WB Saunders Co, 1996, pp Singh V-K, Kalra HK, Yamaki K, et al: Molecular mimicry between an uveitopathogenic site of S-antigen and viral peptides: Induction of experimental autoimmune uveitis in Lewis rats. J Immunol 144(4): , Kroemer G, Angrew JL, Gonzalo JA, et al: Interleukin-2, autotolerance and autoimmunity. Adv Immunol 50: , Lappin MR, Chavkin MJ, Munana KR, et al: Feline ocular and cerebrospinal fluid Toxoplasma gondii specific humoral immune response following specific and nonspecific immune stimulation. Vet Immunol Immunopathol 55(1 3):23 31, Davidson MG, Nasisse MP, English RV, et al: Feline anterior uveitis: A study of 53 cases. 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JAAHA 3(4): , Shelly SM, Scarlett-Kranz J, Blue JT: Protein electrophoresis on effusions from cats as a diagnostic test for feline infectious peritonitis. JAAHA 24(5): , Gunn-Moore DA, Gruffydd-Jones TJ, Harbour DA: Detection of feline coronaviruses by culture and reverse transcriptase-polymerase chain reaction of blood samples from healthy cats and cats with clinical feline infectious peritonitis. Vet Microbiol 62(3): , Gamble DA, Lovviani A, Gramegna M, et al: Development of a nested PCR assay for detection of feline infectious peritonitis virus in clinical specimens. J Clin Microbiol 35(3): , Brightman AH, Ogilvie GK, Tompkins M: Ocular disease in FeLV-positive cats: 11 cases ( ). JAVMA 198(6): , Lappin MR, Marks A, Greene CE, et al: Serologic prevalence of selected infectious diseases in cats with uveitis. JAVMA 201(7): , Corcoran KA, Peiffer RL, Koch SA: Histopathologic features of feline ocular lymphosarcoma: 49 cases ( ). Vet Comp Ophthalmol 5(1):35 41, Jacobson RH, Lopez : Comparative study of diagnostic testing for feline leukemia virus infection. JAVMA 199(10): , Vail DM, Moore AS, Ogilvie GK, et al: Feline lymphoma (145 cases): Proliferation indices, cluster of differentiation 3 immunoreactivity, and their association with prognosis in 90 cats. J Vet Intern Med 12(5): , Jarrett O: Feline leukemia virus, in Chandler EA, Gaskell CJ, Gaskell RM (eds): Feline Medicine and Therapeutics. Oxford, England, Blackwell Scientific Publications, 1994, pp Loesenbeck G, Drommer W, Heider HJ: Findings in the eyes of serologically FIV (feline immunodeficiency virus) positive cats. Dtsch Tierarztl Wochenschr 102(9): , Gomez N: PhD Dissertation. Buenos Aires, Argentina, University of Buenos Aires, Lappin MR: Opportunistic infections associated with retroviral infections in cats. Semin Vet Med Surg Small Anim 104(4): , English RV, Davidson MG, Nasisse MP, et al: Intraocular disease associated with feline immunodeficiency virus infection in cats. JAVMA 196(7): , Hopper CD, Sparkes AH, Harbour DA: Feline immunodeficiency virus, in Chandler EA, Gaskell CJ, Gaskell RM (eds): Feline Medicine and Therapeutics. Oxford, England, Blackwell Scientific Publications, 1994, pp Stiles J: The cat, in Gelatt KN (ed): Veterinary Ophthalmology. Philadelphia, Williams & Wilkins, 1999, pp Maggs DJ, Lappin MR, Nasisse MP: Detection of feline herpesvirus-specific antibodies and D in aqueous humor from cats with or without uveitis. Am J Vet Res 60(8): , Maggs DJ, Lappin MR, Reif JS, et al: Evaluation of serologic and viral detection methods for diagnosing feline herpesvirus-1 infection in cats with acute respiratory tract or chronic ocular disease. JAVMA 214(4): , Whitley RD, Hamilton HL, Weigand CM: Glaucoma and disorders of the uvea, lens, and retina in cats. 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10 140 Small Animal/Exotics Compendium February 2001 ed candidiasis in an immunosuppressed cat. JAVMA 204(10): , Medleau L, Jacobs GJ, Marks MA: Intraconazole for the treatment of cryptococcosis in cats. J Vet Intern Med 9(1): 39 42, Malik R, Wigney DI, Muir DB, et al: Cryptococcosis in cats: Clinical and mycological assessment of 29 cases and evaluation of treatment using orally administered fluconazole. J Med Vet Mycol 30(2): , Maguina C, Gotuzzo E: Bartonellosis: New and old. Infect Dis Clin North Am 14(1):1 22, Soheilian M, Markomichelakis N, Foster CS: Intermediate uveitis and retinal vasculitis as manifestations of cat scratch disease. Am J Ophthalmol 122(4): , Breitschwerdt EB, Greene CE: Bartonellosis, in Greene CE (ed): Infectious Diseases of the Dog and Cat. Philadelphia, WB Saunders Co, 1998, pp Lappin MR, Black JC: Bartonella spp. infection as a possible cause of uveitis in a cat. JAVMA 214(8): , Lappin MR, Jensen W, Kordick DL, et al: Bartonella spp. antibodies and D in aqueous humor of cats. Fel Med Surg (in review), Kordick DL, Brown TT, Shin K, et al: Clinical and pathologic evaluation of chronic Bartonella henselae or Bartonella clarridgeiae infection in cats. J Clin Microbiol 37(5): , Martin CL: Ocular infections, in Greene CE (ed): Infectious Diseases of the Dog and Cat. Philadelphia, WB Saunders Co, 1998, pp Stubbs CJ, Holland CJ, Reif JS, et al: Feline ehrlichiosis. Compend Contin Educ Pract Vet 22(4): , Greene CE, Gunn-Moore DA: Mycobacterial infections, in Greene CE (ed): Infectious Diseases of the Dog and Cat. Philadelphia, WB Saunders Co, 1998, pp Formston C: Retinal detachment and bovine tuberculosis in cats. J Small Anim Pract 35(1):5 8, Harris BP, Miller PE, Bloss JR, et al: Ophthalmomyiasis interna anterior associated with Cuterebra spp. in a cat. JAVMA 216(3): , Bussanich MN, Rootman J: Intraocular nematode in a cat. Feline Pract 13(4):20 26, Gwin RM, Merideth R, Martin CL, et al: Ophthalmomyiasis interna posterior in two cats and a dog. JAAHA 20(3): , Dubielzig RR: Ocular neoplasia in small animals. Vet Clin North Am Small Anim Pract 20(3): , O Neil SA, Lappin MR, Reif JS, et al: Clinical and epidemiological aspects of feline immunodeficiency virus and Toxoplasma gondii coinfections in cats. JAAHA 27(2): , About the Authors Drs. Powell and Lappin are affiliated with the College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins. Dr. Powell is a Diplomate of the American College of Veterinary Ophthalmology, and Dr. Lappin is a Diplomate of the American College of Veterinary Internal Medicine. ARTICLE #1 CE TEST The article you have read qualifies for 1.5 contact hours of Continuing Education Credit from the Auburn University College of Veterinary Medicine. Choose only the one best answer to each of the following questions; then mark your answers on the test form inserted in Compendium. 1. Uveitis a. directly causes an increase in intraocular pressure. b. has a similar clinical presentation regardless of location or duration. c. is associated with disruption of the blood ocular barrier. d. is rarely idiopathic. 2. Aqueous flare a. indicates hemorrhage into the anterior chamber. b. is caused by increased protein concentration in the aqueous humor attributable to changes in vascular permeability. c. is caused by the breakdown of the blood aqueous barrier in the retina. d. only occurs in cats with severe anterior uveitis. 3. In cats with anterior uveitis, the intraocular pressure a. is usually stabile and in the normal range. b. is usually decreased but may be normal or increased because of obstruction of aqueous humor outflow. c. usually increases because of increased aqueous humor production. d. usually is only important if there is severe corneal edema. 4. Studies investigating the causes of feline uveitis a. show that most systemic diseases commonly associated with uveitis can be easily confirmed as the cause. b. indicate that clinical or serologic evidence of systemic disease is found in 25% to 90% of cats with uveitis. c. have all suggested that it is rarely idiopathic. d. have shown that organisms are usually found on ocular histopathology from cats with uveitis and serology positive for T. gondii. 5. Which of the following statements regarding cats with anterior or posterior uveitis and serologic evidence of T. gondii infection is false? a. Serum antibodies to T. gondii have been detected in up to 78.5% of cats with anterior or posterior uveitis. b. Positive serology is difficult to correlate with ocular infection.

11 Compendium February 2001 Small Animal/Exotics 141 c. Disease pathogenesis is likely a combination of organism replication and immune-mediated events directed against the organism. d. Treatment with an anti Toxoplasma drug is always indicated. 6. The diagnosis of ocular toxoplasmosis a. can be made if the IgG titer is 1:1024 or less. b. is not supported by detection of IgM because levels often remain elevated for months or years. c. is difficult to make based on serology because the prevalence of T. gondii IgG in healthy cats is 30% to 50%. d. is definitive if the aqueous humor C value for IgM is less than Which of the following statements regarding the ocular manifestations of FIP is false? a. Ocular lesions occur most often in cats with the noneffusive (dry) form. b. Anterior or posterior uveitis may be present. c. KPs and chorioretinitis are usually present without evidence of other systemic disease. d. Iritis, large KPs, and clots of fibrin and blood in the anterior chamber are common. 8. The diagnosis of FIP a. is based on a high serum antibody titer to feline coronavirus. b. is most often made in cats older than 4 years of age. c. can be confirmed by a specific PCR that distinguishes it from feline enteric coronaviruses. d. is supported by high serum globulin levels or a low albumin:globulin ratio. 9. Ocular LSA a. can be ruled out in FeLV-negative cats. b. is often treated successfully by enucleation if diagnosed early. c. is generally not associated with tumors elsewhere in the body. d. can be nodular or diffuse and may have the same appearance as does anterior uveitis from other causes. 10. Which of the following statements regarding ocular disease is false? a. Ocular FIV is usually manifested as chorioretinitis. b. Pars planitis is a common ocular finding associated with FIV. c. FIV-related ocular disease may be either directly related to ocular infection by the virus or secondary to immunosuppression. d. Anterior uveitis, pars planitis, and glaucoma have been identified in cats infected with FIV.